CN104857573A - Drug releasing coating for medical device - Google Patents

Abstract

The invention relates to a medical device for delivering a therapeutic agent to tissue. The medical device is provided with a coating that covers outer surface of the medical device. The coating contains the therapeutic agent, an antioxygen agent and an additive. In certain specific embodiments, the additive has a hydrophilic portion and a drug affinity portion, and at least one portion among a hydrophobic portion, a portion with the affinity to the therapeutic agent through a hydrogen bond and a portion with the affinity to the therapeutic agent through a van der waals interaction can serve as the drug affinity portion. In certain specific embodiments, the additive is a liquid. In other specific embodiments, at least one substance among surface active agents and compounds can serve as the additive, and the compounds have one or more hydroxyls, amino groups, carbonyls, carboxyls, acids, amides or ester groups.

Description

For the release coating of armarium

This divisional application is 201080066594.6 based on application number, and the applying date is on March 25th, 2010, and denomination of invention is the divisional application of the original Chinese patent application of " the release coating for armarium ".

The cross reference of related application

The application is the application No.12/121 submitted on May 16th, 2008, the part continuation application of 986, it is the application No.11/942 submitted on November 19th, 2007, the part continuation application of 452, require with the U.S. Provisional Application No.60/860 that on November 20th, 2006 submits to, 084, the U.S. Provisional Application No.60/880 that on January 17th, 2007 submits to, 742, the U.S. Provisional Application No.60/897 that on January 25th, 2007 submits to, 427, the U.S. Provisional Application No.60/903 that on February 26th, 2007 submits to, 529, the U.S. Provisional Application No.60/904 that on March 2nd, 2007 submits to, 473, the U.S. Provisional Application No.60/926 that on April 30th, 2007 submits to, 850, the U.S. Provisional Application No.60/981 that on October 19th, 2007 submits to, the U.S. Provisional Application No.60/981 that on October 19th, 380 and 2007 submits to, 384 is the rights and interests of priority, all these disclosures at this by reference to being merged in.

Invention field

The specific embodiment of the present invention relates to the armarium of coating, particularly relates to the foley's tube of coating, and they for rapid delivery therapeutic agent to the application of particular organization or body cavity disease therapy, particularly reduce the narrow of body cavity and late luminal is lost.The specific embodiment of the present invention also relates to the method for the method of producing these armarium, the coating be provided on these armarium, the solution preparing those coatings and treatment body cavity such as vascular system, comprise particularly arterial pulse system, such as, use the armarium that these apply.

Background of invention

Become more and more general by treating various medical conditions in introducing armarium to the vascular system or other chamber (such as esophagus, trachea, colon, biliary tract or urethra) of human or animal patient.Such as, the armarium being used for the treatment of angiopathy comprises support, conduit, foley's tube, seal wire, intubate etc.Very successful when although these armarium occur at first, its benefit suffers damage due to the appearance of complication usually, and such as advanced thrombus is formed or palindromia, such as, narrow (restenosis) after this kind for the treatment of.

Such as, restenosis relates to a kind of physiological reaction of the blood vessel injury that angioplasty causes.As time goes on, the damage of Endothelial denodation and smooth muscle cell causes thrombosis deposition, leukocyte and macrophages infiltration, smooth muscle cell proliferation/transfer, fibrosis and extrtacellular matrix deposition.Inflammation plays very important effect in the final result contacting early stage blood vessel injury and inner membrance growth and chamber damage.In the tremulous pulse of balloon injured, leukocyte set is only limitted to Neutrophil and infiltrates, and in tremulous pulse after support, is long-term macrophage accumulation after early stage leukocyte set.Widely using of coronary stent changes the reaction of blood vessel to damage, due to the chronic stimulation from implantation foreign body, cause stronger and long-term inflammatory conditions, and in the situation of bracket for eluting medicament (DES), from insufficient biocompatibility of polymer coating.

In the past few years, many topical drug delivery systems have been developed to treat and/or prevent balloon angioplasty or the postoperative restenosis of stenter to implant.Example comprises localized drug delivery conduit, sends foley's tube and polymeric medicine drug delivery medical device.Consider that numerous disease affects specific localized site or organ in body, it is favourable for preferentially only treating affected region.Which avoid the high systemic drug level that can cause adverse side effect, and therapeutic agent is concentrated on the regional area of their needs.By only disease therapy tissue, required medicine total amount significantly can be reduced.In addition, localized drug delivery can allow to use some effective therapeutic agent, and it is too large or nonspecific and not used for whole body that they are considered to toxicity in the past.

An example of local delivery system is bracket for eluting medicament (DES).This support polymer-coated that impregnated of medicine.When support is inserted in blood vessel, depolymerization slow releasing medicine.It is reported, within the time of several weeks to the several months, slow releasing medicine is one of major advantage using DES.But, although slow releasing may be favourable when using foreign body such as support, but, it is the source of chronic stimulation and inflammation, if foreign body is not implanted, on the contrary, it, when treating the inflammation after suppressing acute injury and cell proliferation, can be conducive to rapid delivery medicine to vascular tissue.Therefore, DES or any design are used for the sizable shortcoming of other implantable medical equipment of slow releasing pharmaceutical, are that medicine can not be discharged into rapidly in blood vessel.

In addition, although it is the technology of a kind of effective minimizing and prevention of restenosis that bracket for eluting medicament shows at first, their effect and safety is recently queried.The life-threatening complication of this technology, advanced thrombus are formed and become subject matter.The heavy damage that bracket for eluting medicament causes tremulous pulse to heal, be characterised in that and lack complete endothelialization again and fibrin persistence compared with bare mental stents (BMS), it is considered to the thrombotic basic reason of DES in late period.The problem proposed also has, and because polymer used is not fully biocompatible, the polymeric matrix that support embedded in anti-proliferative drugs may aggravates inflammation and thrombosis.These polymer systems are designed to be conducive to long latency release medicine within the time of a couple of days, several months or several years, instead of discharge within the time of several seconds or several minutes.The polymeric medicine coating of these armarium can not release polymers, itself or even still retain in a device after medicine is released.Even if employ biodegradable polymer, but polymer and medicine can not discharge at one time.The specific embodiment of the invention be intended that rapid delivery of pharmaceuticals, it is impossible in these polymer systems.Therefore, in armarium coating, combined treatment agent and polymer have obvious shortcoming.

Another important restriction of DES is that water-insoluble drug can not be uniformly distributed in the polymeric matrix of coating.In addition, medicine and polymer concentrate on the framework of support, instead of in space between framework.The uneven distribution of medicine can cause medicine to discharge unevenly to vascular wall tissue.This can cause the regional organization's damage and thrombosis that exposed drug, and the region hypertrophy of insufficient therapy and restenosis.Therefore, there is the uniformity needing improvement medicine to send to target tissue, this can be improved the dissolubility of medicine in armarium coating and carry out by the compatibility increasing carrier in medicine and coating, such as polymeric matrix, thus eliminate or reduce the size of medicine crystal granule in polymeric matrix or other coating, to reach the uniform drug distribution of medication coat on armarium.

Another important restriction of DES only can be loaded into limited amount activating agent to the relatively little surface area of support.

Based on non-stent local delivery system such as foley's tube treat and prevention of restenosis time be also effective.Sacculus activating agent applies, and when vasodilation, sacculus is pressed against active agent delivery in blood vessel wall.Therefore, when using foley's tube, for being rapidly favourable for release the medicine absorbed by vascular tissue in the coating.When using foley's tube, then take away in body because it expands within the very short time, therefore any component that can suppress release fast in coating, such as lipid or polymer or encapsulated particles are all necessarily disadvantageous.

The foley's tube delivery of hydrophilic medicine such as heparin that applies with polyalcohol hydrogel of report.But polyalcohol hydrogel coating can not send water-insoluble drug (such as paclitaxel and rapamycin) effectively, because they can not mix with hydrogel coating.In addition, when discharging medicine, the crosslinked hydrogel polymer after drug release can be retained on sacculus.Carry out coated spheres ductus bursae with diodone Iopromide and paclitaxel, and obtain some successes on treatment restenosis.It is reported, contrast agent improves the adhesion of paclitaxel to balloon surface.But diodone has several shortcoming be widely known by the people.When for diagnotor, they may have the complication rate of 5-30%.These materials and trouble tachycardia, ventricular arrhythmia, hypotension, heart block, sinus arrest, sinus tachycardia are relevant with fibrillar risk.Diodone also may bring out renal failure, therefore, makes and much makes great efforts to be removed from vascular system by these contrast agent after diagnotor.

In addition, the second time public health that U.S. food and drug administration (FDA) have issued in 2006 about the serious later stage untoward reaction of contrast agent is seeked advice from, and known has kidney source sexual system fibrosis or renal fibrosis dermatosis.Consider the range of endovascular delivery contrast agent about adverse events, need to improve armarium, its coating itself does not need to give extra contrast agent in order to send required therapeutic agent to patient.

X-ray diodone is large-scale hydrophilic global molecular.Their feature is extracellular distribution and glomerular filtration fast and renal excretion.Due to the polar hydrophilic molecule that they are large, the cell that bilayer lipid membrane enters vascular system therefore can not be striden across.So they the best can not load hydrophobic drug such as paclitaxel and enter cell effectively, and it is reported that paclitaxel is only had 5-20% by the percentage ratio that vascular tissue absorbs after these equipment of use.In addition, the compatibility or the miscibility of paclitaxel and Iopromide are bad, and the integrity of coating and lack of homogeneity.Granule easily comes off from coating, and loses in processing procedure.These defects have a negative impact to the quantity of target tissue and uniformity to drug delivery.So need the coating improved, this coating can not only avoid unnecessary contrast agent administration, can also keep integrity in processing procedure, and can more effectively and more uniformly delivering drugs, and promote the absorption of tissue to medicine.

Or, report and mix with oil or lipid or be encapsulated in the hydrophobic therapeutic agent coated spheres ductus bursae in granule such as liposome or polymer.All these drug delivery formulations have obvious shortcoming.Unlike hydrophilic contrast agent, oil and the good mixing of lipid and water-insoluble drug such as paclitaxel or rapamycin, but relatively unstable for its particle diameter of oil of solubilising therapeutic agent, to have diameter be hundreds of nanometer to the wide particle size distribution of several microns.

The Drug loading capacity of classical micellar is very low.Another shortcoming based on the Liposomal formulation of oil is the absorption rate and the lipolytic degree that rely on medicine.Lipidolysis based on the triglyceride of oil is very difficult and depend on many factors, and triglyceride must be digested and discharge medicine, to be absorbed by pathological tissues.Very low to the hydrophobic drug amount of tissue by these substance delivery, because liposome and micelle can not discharge hydrophobic drug effectively, taken away by liposome and micelle before hydrophobic drug is absorbed by tissue.So oil and lipid can not promote quickly and efficiently to organize ingestion of drugs within the very of short duration equipment use time, and report is not had to show that the coating of these types is effective.In these formulations, the ratio of medicine and lipid is generally 0.2-0.3, because medicine is encapsulated in granule, micelle or liposome, therefore needs the lipid concentration apparently higher than medicine.These technology comprise first formation drug/lipid granule, then with the grain coating armarium of preparation.Have several sections of reports to show, medicine is from the scope discharging a couple of days to several weeks or several months now of these oil/lipid preparations.The situation that this performance occurs in the scope of several seconds to several minutes for drug release is undesirable.Therefore, in order to be used for this situation, the technology of oil/lipid preparation needs significantly to improve.

The medicine be encapsulated in polymer beads may need the time more grown from coating diffusion (scope of report is that the several months is to the several years), and will have more difficulty during rapid osmotic target tissue.When being used for encapsulating water-insoluble drug, the microsphere formed by polymeric material such as polyester can not discharge medicine, until polymeric material degrades.Therefore, these polymer microballoons can be used to slow releasing pharmaceutical in long time, but can not also promote tissue picked-up by rapid delivery of pharmaceuticals.

The combination of medicine and armarium is a complicated technical field.It relates to common formulation challenges, those of such as oral or drug for injection, and keeps drug adhesion on armarium until its arrives target site and subsequently medicine is delivered to the additional challenge of target tissue with desirable emission and absorption kinetics.The medication coat of armarium also must have performance and make equipment they can not ftracture when expanding and shrink, such as foley's tube or support.In addition, coating must can not damage functional performance, the compliance of such as burst pressure and sacculus or from-or the radial strength of sacculus-expanding stent.The thickness of coating also minimally, because thick coating can increase the profile of armarium, thus must cause poor tracing property and sending property.These coatings are generally hardly containing the liquid chemical substance being commonly used to stable medicine.Therefore, with ball or inject effective preparation and may not work for the coating of armarium.Discharge from equipment if medicine is too easy, may lose in its equipment delivery process before being used by target site, or it may dash forward in the initial period of inflation and releases from equipment, thus be depressed into contact with the target tissue of body lumen wall before be flushed away.If drug adhesion ground is too strong, equipment may at release medicine and by the tissue resorption of target tissue before be removed.

Therefore, still the high specific coating needing exploitation for armarium is had, its can to carry out in medical procedure or afterwards by direct to therapeutic agent, medicine or bioactive materials rapid delivery to position tissue region, thus treatment or prevention blood vessel and non-vascular disease, such as restenosis.Equipment should be able to discharge therapeutic agent in effective and efficient mode at required target position immediately, and wherein therapeutic agent answers rapid osmotic target tissue to carry out disease therapy, such as, alleviate narrow and prevention of restenosis and body cavity late luminal and lose.

In addition, often kind of therapeutic agent has different structures and characteristics, therefore needs different preparations to reach desirable coating performance and best treatment benefit.Therapeutic agent has different reactions from different pharmaceutical carriers, and the reaction between medicine and additive can make therapeutic agent invalid or produce potential toxic decomposition products.Due in the high surface area of medication coat armarium and sterilization process to the exposure of heat, humidity and the state of oxidation, this is complicated further.If medicine is to wet sensitive sense or easily hydrolysis or oxidation, these are problem especially.Paclitaxel can be hydrolyzed, and it can react with many chemical functional groups.Rapamycin and derivant thereof are easily hydrolyzed and are oxidized.Therefore; the object of some detailed description of the invention of the present invention is to provide the coating for armarium; comprise additive and therapeutic agent; it can not cause agent undergoes degradation maybe can protect the not oxidized and hydrolysis in sterilizing and equipment storage process before use of therapeutic agent such as rapamycin and derivant thereof, still by the drug delivery of therapeutic dose and can penetrate into target tissue simultaneously.The specific embodiment of the present invention relates to compositions, and the oxidation of therapeutic agent such as rapamycin and derivant thereof and/or hydrolysis is reduced to the production method of minimum coating medical equipment for the preparation of with processing.The coating of the specific embodiment of the invention comprises therapeutic agent and at least one additive, and the degraded of medicine is reduced to minimum based on the special performance of often kind of therapeutic agent with the combinations of substances in coating by it, and provides medication coat armarium safely and effectively.

Summary of the invention

The present invention finds, with such as comprising therapeutic agent and have the outer surface, particularly foley's tube of layer coating medical equipment of additive or the support of hydrophilic parts and the affine part of medicine simultaneously, very useful when relevant with the coating problem of the above-mentioned discussion of solution.Part that medicine is affine is hydrophobic parts and/or has affinity by hydrogen bond and/or Van der Waals interaction to therapeutic agent.Surprisingly, the present inventor finds at least one additive comprising hydrophilic parts and the affine part of medicine according to the specific embodiment of the invention, on armarium, effective drug delivery coating is formed with after therapeutic combination, and do not need to use oil and lipid, thus the dependency avoided lipidolysis and traditional other shortcoming based on the coating agent of oil.In addition, quick medicament eluting and medicine is facilitated to the superior permeability of disease sites tissue according to the additive of the specific embodiment of the invention.Therefore, provide according to the coating of the specific embodiment of the invention absorption rate and/or degree that hydrophobic therapeutic agent improves in vascular system or other body cavity illing tissue.In the specific embodiment of the present invention, coating apparatus within the very short service time being less than 2 minutes by therapeutic agent delivery to tissue, and decrease and narrowly to lose with the late luminal of body cavity.

In a detailed description of the invention, the present invention relates to the armarium of therapeutic agent delivery to tissue, this equipment comprises the layer being covered in armarium outer surface.Equipment comprises foley's tube, tube for transfusion is far-end perforation medication infusion pipe such as, perforation sacculus, two sacculus at interval, porous sacculus, with sepage sacculus (weeping balloon), Cutting balloon conduit (cutting ballooncatheter), integrating sphere ductus bursae (ascoring balloon catheter), laser catheter, atherectomy device (atherectomy device), speckle ablation catheter (debulking catheter), support, filter, stent graft, overlay film frame (coveredstent), paster, one in line and valve.In addition, this tissue comprises tissue a kind of in coronary arterial vasculature, peripheral vasculature, brain vascular system, esophagus, respiratory tract, hole (sinus), trachea, colon, biliary tract, urethra, prostate and nicergoline road.

In a detailed description of the invention of armarium, the coating covering armarium surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 80 to 750.

In a detailed description of the invention of armarium, the coating covering armarium surface comprises therapeutic agent, antioxidant and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, there is one or more hydroxyl, amino, carbonyl, carboxyl, acid, the compound of amide or ester group is selected from amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester, amide, ether, anhydride, hydroxy-ketone, hydroxy ester, phosphoric acid sugar (sugar phosphate), Sulfated saccharides (sugar sulfate), ether, ethohexadiol (ethyl glycol), aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, solubility polyvidone, the soluble polyvinylpyrrilidone that molecular weight is less than 4000, Kollidon 12 PF, Kollidon 17 PF, carbamide, biuret, acetamide, lactamide, amino acid amide, acetaminophen, uric acid, polyureas, urethanes, urea derivative, nicotiamide, N-methylacetamide, N,N-dimethylacetamide, sulphacetamide, versetamide, lauric acid diethyl amide (lauric diethanolamide), lauric myristic diglycollic amide (lauric myristic diethanolamide), N, N-two (2-hydroxyethyl stearmide), coconut oleoyl amine MEA, coconut oleoyl amine DEA, arginine, two (2-ethylhexyl) ester of phthalic acid, phthalic acid two-just own ester, diethyl phthalate, two (2-ethylhexyl) ester of adipic acid, dimethyl adipate, dioctyl adipate, dibutyl sebacate, dibutyl maleate, triethyl citrate, acetyl triethyl citrate, trioctyl lemon acid, THC, bytyry THC, trimethyl citrate, acetic acid and anhydride, benzoic acid and anhydride, diethylene-triamine pentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, anhydride diethylene glycol, glutaric anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, aspartic acid, nicotinic acid, 2-Pyrrolidone-5-carboxylic acid, aleuritic acid, lac acid, and the molecule of their replacement.

In a detailed description of the invention of armarium, the coating covering armarium surface comprises therapeutic agent, antioxidant and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750.In another embodiment, the coating covering armarium surface is made up of therapeutic agent, antioxidant and additive substantially.

In a detailed description of the invention, antioxidant is oligomeric or polymeric proanthocyanidins, polyphenol, polyphosphate, poly methylene imine (polyazomethine), high-sulfate agar oligomer, Chitosan Oligosacchaides, multifunctional low polythiaether has hindered phenolic, hindered amine, p-phenylenediamine (PPD), trimethyl dihydro-quinolone, and alkylated diphenylamine, hindered phenol, the tert-butyl group, arylamine, phosphite ester, azanol, benzofuranone, p-phenylenediamine (PPD), diphenylamines, the dibasic p-phenylenediamine of N, N', Yoshinox BHT (" BHT "), butylated hydroxyanisol (" BHA "), L-AA salt (vitamin C), vitamin E, draft Herba Rosmarini Officinalis, Salvia japonica Thunb. (sage) extract, glutathion, resveratrol, ethoxyquin, rosmanol (rosmanol), different rosmanol (isorosmanol), diterpene phenol (rosmaridiphenol), propyl gallate, gallic acid, caffeic acid, P-coumaric acid, P-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrogenation zingiberone (dehydrozingerone), chlorogenic acid, ellagic acid, propyl p-hydroxybenzoate, sinapic acid, daidzin, glycitin (glycitin), genistin, daidzein, Glycitein, genistein, osajin, tert-butyl hydroquinone, two (stearyl) pentaerythritol diphosphites, three (2,4-, bis--tert-butyl-phenyl) phosphite ester, dilauryl thiodipropionate, two (2,4-, bis--tert-butyl-phenyl) pentaerythritol diphosphites, octadecyl-3,5, two-tertiary butyl-4-hydroxy cinnamate, four-methylene-3-(3', 5'-bis--tert-butyl-hydroxy phenyl) propionate methane 2,5-, bis--tert-butyl hydroquinone, ionol, 1,2,3,-thrihydroxy-benzene, retinol, octadecyl-3-(3,5-, bis--tert-butyl-hydroxy phenyl) propionic ester, glutathion, thioctic acid, melatonin, tocopherol, tocotrienol, sulfur alcohol, beta-carotene, tretinoin, kryptoxanthin, 2,6-, bis--tert-butyl phenol, propyl gallate, catechin, catechin and gallate, Quercetin, and at least one in derivant.

In another detailed description of the invention of armarium, the coating of coating medical device outer surface comprises therapeutic agent, antioxidant and additive, wherein additive is selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polysorbas20, tween 21, polysorbate40, polysorbate60, Tween61, Tween 80, sorbimacrogol oleate100, polysorbate85, polyethylene glycol (PEG) oleate, polyglycol distearate, PEG-1512-hydroxy stearic acid ester (solutol HS 15), Cremophor EL & ELP, Cremophor RH40, the block copolymer of polyester-Polyethylene Glycol, PLLA-PEG, PEG-PLLA-PEG, PEG-PPG, PEG-PPG-PEG, polyethyleneglycol-graft copolymer, Soluplus, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer, polyethylene glycol glycerol laurate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, lanolin alcohol polyethers (Laneth)-5, lanolin alcohol polyethers-10, lanolin alcohol polyethers-15, lanolin alcohol polyethers-20, lanolin alcohol polyethers-25, lanolin alcohol polyethers-40, laureth (Laureth)-5, laureth-10, laureth-15, laureth-20, laureth-25, laureth-40, oleth (Oleth)-2, oleth-5, oleth-10, oleth-12, oleth-16, oleth-20, with oleth-25, stereth (Steareth)-2, stereth-7, stereth-8, stereth-10, stereth-16, stereth-20, stereth-25, stereth-80, ceteth (Ceteth)-5, ceteth-10, ceteth-15, ceteth-20, ceteth-25, ceteth-30, ceteth-40, PEG-3 oleyl ether (volpo 3) and PEG-4 lauryl ether (Brij 30), sodium lauryl sulfate salt (sodium lauryl sulfate), laurilsulfate sodium (sodiumdodecyl sulfate), lauryl ether sulfates sodium (sodium lauryl ether sulfate), cetearyl alcohol sodium sulfate (sodium cetostearyl sulfate), sodium cetyl stearyl sulfate salt (sodium cetearyl sulfate), sodium tetradecyl sulfate (sodium tetradecylsulfate), sulfated castor oil, Cholesterol sulfate sodium (sodium cholesterylsulfate), sodium tetradecyl sulfate (sodium tetradecyl sulfate), myristyl alcohol sulfuric ester sodium salt (sodium myristyl sulfate), capryl alcohol sulfuric ester sodium salt (sodiumoctyl sulfate), the alkyl sulfate of mid-chain branched or non-branching, docusate sodium, 2-Sulfosuccinic acid ethylhexyl sodium (dioctyl sodium sulfosuccinate), lauryl alcohol sulfoacetic acid ester sodium salt (sodium lauryl sulfoacetate), sodium alkyl benzene sulfonate, dodecylbenzene sodium sulfonate, octoxinol, nonoxynolum (monoxynol), tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-methyl glucose amide, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-methyl glucose amide, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-methyl glucose amide, pelargonyl group-β-D-glucosinolate (n-noyl-β-D-glucopyranoside), caprylyl-N-methyl glucose amide, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone sodium carboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin (cycothiamine), pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphoric acid, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen (firbinogens), lipase, benzalkonium chloride, benzethonium chloride, dodecyl bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone (mannoic lactone), ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, solubility polyvidone, the soluble polyvinylpyrrilidone that molecular weight is less than 4000, Kollidon 12PF, Kollidon 17PF, carbamide, biuret, acetamide, lactamide, amino acid amide, acetaminophen, uric acid, polyureas, urethanes, urea derivative, nicotiamide, N-methylacetamide, N,N-dimethylacetamide, sulphacetamide, versetamide, lauric acid diethyl amide, lauric myristic diglycollic amide, N, N-two (2-hydroxyethyl stearmide), coconut oleoyl amine MEA, coconut oleoyl amine DEA, arginine and derivant thereof, and combination.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and one or more additives, wherein often kind of additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, and the one wherein in one or more additives is liquid additive.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and at least one additive, wherein at least one additive-package is containing the first additive and Second addition, wherein often kind of additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, and wherein the hydrophilic of the first additive is greater than Second addition.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and at least one additive, wherein at least one additive-package is containing the first additive and Second addition, wherein often kind of additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, and wherein the HLB of the first additive is higher than Second addition.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and at least one additive, wherein at least one additive-package is containing the first additive and Second addition, wherein often kind of additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, and wherein the Log P of the first additive will lower than Second addition.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and at least one additive, and wherein at least one additive-package has the compound of at least one ester group containing at least one.The example with the compound of ester group is the product of organic acid and alcohol.The compound with ester group is typically used as the plasticizer of polymeric material.The example with the compound of at least one ester group comprises: sebacate, adipate ester, glutarate and phthalic acid ester.The example of these compounds has phthalic acid two (2-ethylhexyl) ester, phthalic acid two-just own ester, diethyl phthalate, adipic acid two (2-ethylhexyl) ester, dimethyl adipate, dioctyl adipate, dibutyl sebacate, dibutyl maleate, triethyl citrate, acetyl triethyl citrate, trioctyl lemon acid, THC, bytyry THC and trimethyl citrate.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and at least one additive, and wherein at least one additive-package has the compound of at least one amide groups containing at least one.In some detailed description of the invention, the compound with at least one amide groups is very important for coating agent.The example with the compound of at least one amide groups has urea.Other example with the compound of at least one amide groups comprises: biuret, acetamide, lactamide, amino acid amide, acetaminophen, uric acid, polyureas, urethanes, urea derivative, nicotiamide, N-methylacetamide, N, N-dimethyl acetylamide, sulphacetamide, versetamide, lauric acid diethyl amide, lauric myristic diglycollic amide, N, N-two (2-hydroxyethyl stearmide), coconut oleoyl amine MEA, coconut oleoyl amine DEA, arginine, and other organic acid amide and derivant thereof.Some compounds with at least one amide groups also have one or more hydroxyl, amino, carbonyl, carboxyl, acid or ester group.

A kind of compound with at least one amide groups is the low-molecular-weight polyvidone of solubility.Some examples of polyvidone comprise Kollidon 12 PF, Kollidon 17 PF, Kollidon 17, Kollidon 25 and Kollidon 30.Kollidon product comprises the various molecular weight of solvable and soluble level and polyvinylpyrrolidone, the vinyl pyrrolidone/vinyl acetate copolymer of particle diameter, and the blend of polyvinyl acetate and polyvinylpyrrolidine.These series of products are named as Povidone, Crospovidone and Copovidone.Low-molecular-weight and Povidone and Copovidone of solubility is the important additives in the specific embodiment of the invention, such as Kollidon 12PF, Kollidon 17 PF and Kollidon 17.Solid polyvidone can keep the integrity of coating on armarium.Low-molecular-weight polyvidone can be absorbed and be penetrated into pathological tissues.The preferred molecular weight ranges of polyvidone is less than 54,000, is less than 11,000, is less than 7,000 and be less than 4,000.Polyvidone can make water-insoluble therapeutic agent solubilising.Due to their character (solid-state, low-molecular-weight and tissue resorption/permeability), Povidones and Copovidones is specially adapted to the specific embodiment of the present invention.In the specific embodiment of the present invention, polyvidone can use with other additive combination.In a detailed description of the invention, polyvidone and non-ionic surface active agent (such as PEG-15 12-hydroxy stearic acid ester (Solutol HS 15), polysorbas20, Tween 80, CremophorRH40, Cremophor EL & ELP) can be mixed with coating for armarium such as foley's tube with paclitaxel or rapamycin or its analog.

In a detailed description of the invention, the coating covering armarium outer surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is at least one in surfactant and compound, and wherein compound has the hydroxyl of more than four.In a detailed description of the invention, compound has the hydroxyl of more than four and fusing point is 120 DEG C or lower, and compound is alcohol or ester.

In a detailed description of the invention, the layer covering armarium outer surface is made up of therapeutic agent and additive substantially.In a detailed description of the invention, the layer covering armarium outer surface does not comprise the contrast agent of iodine covalent bonding.In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, compound is selected from the molecule of amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester, anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin and their replacement.In another embodiment, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.

In another embodiment, the coating covering armarium surface comprises therapeutic agent and additive, and wherein additive is surfactant.In another embodiment, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether, amide and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan, sugared fatty ester, Polyethylene Glycol sugar ester, and derivant.

In another embodiment, additive is the compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from the molecule of amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester, amide, ether, anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin and their replacement.

In another embodiment, additive be have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group molecular weight be less than 5,000-10,000 compound, is preferably less than 1000-5, and 000, be more preferably less than 750-1,000, or be most preferably less than 750.The molecular weight of additive is preferably less than the medicine be delivered.Micromolecule can spread rapidly, and they easily discharge from the balloon surface of sending being loaded with medicine.When medicine be attached to organize time, their rapid diffusion leave medicine.But the molecular weight of additive can not be too low; Molecular weight is undesirable lower than the additive of 80, because they easily evaporate and are not stable composition in the coating.Such as, if additive has low-molecular-weight but can not volatilize, pasty state or solid, and can not evaporate or react easily, so the molecular weight of additive can lower than 80, lower than 50 or lower than 20.In another embodiment, additive is surfactant and the combination of compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In another embodiment, additive is amino alcohol and organic acid combination; Said composition is very favourable, the unstability produced because it can stop the reactivity of acid or amine and medicine such as paclitaxel.In another embodiment, additive is hydroxy-ketone, hydroxy-lactone, hydroxy acid, hydroxy ester or hydroxy amide.In another embodiment, additive is its gluconolactone or ribose acid lactone.In another embodiment, additive is selected from meglumine/lactic acid, meglumine/gentisic acid, meglumine/acetic acid, lactobionic acid, polysorbas20/sorbitol, polysorbas20/lactobionic acid, polysorbas20/sugar or sugar derivatives, and N-caprylyl N-METHYL-ALPHA-L-GLUCOSAMINE.In another embodiment, additive is vitamin or derivatives thereof.In another embodiment, additive is aminoacid or derivatives thereof.In another embodiment, additive is protein or derivatives thereof.In another embodiment, additive is albumin.In another embodiment, additive is solvable and solvable in organic solvent in aqueous solvent.In another embodiment, additive is organic acid or its anhydride.In another embodiment, additive is selected from sorbitanoleate and sorbitan fatty acid ester.

In another embodiment, cover the coating on armarium surface and comprise therapeutic agent and additive, wherein additive is water miscible, and wherein additive to be molecular weight be 20 to 750 compound.

In a detailed description of the invention, the layer covering armarium outer surface does not comprise oil, lipid or polymer.In another embodiment, the layer covering armarium outer surface does not comprise oil.In another embodiment, the layer covering armarium outer surface does not comprise polymer.In another embodiment, the layer covering armarium outer surface does not comprise pure hydrophobic additive.In a detailed description of the invention, additive is not therapeutic agent.In another embodiment, additive is not salicylic acid or its salt.

In another embodiment, the coating covering armarium surface comprises therapeutic agent and additive, and wherein additive-package is containing hydrophilic parts and the affine part of medicine, and its Chinese medicine is affine, and part is hydrophobic parts, have the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, and wherein additive is selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol lauric acid branch, polysorbas20, polysorbate40, polysorbate60, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone carboxylic acid salt, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), and derivant and combination.

In a detailed description of the invention, therapeutic agent is paclitaxel and analog, rapamycin and analog thereof, β-lapachol and analog, biological vitamin D and analog thereof, and the one in the mixture of these therapeutic agents.In another embodiment, therapeutic agent and the coupling of the second therapeutic agent, wherein therapeutic agent is the one in paclitaxel, rapamycin and analog thereof, and wherein the second therapeutic agent is the one in β-lapachol, bioactive vitamin D and analog thereof.

In a detailed description of the invention, the armarium including the layer covering armarium outer surface comprises the adhesion layer between armarium outer surface and this layer further.In another embodiment, this equipment comprises the top layer be covered on this layer of surface further, is delivered to loss in organizational process in vivo for reducing medicine.In another embodiment, the top layer that the surface being covered in the layer on armarium outer surface covers comprises additive, its hydrophilic is less than the additive be covered in armarium outer surface layer, and wherein the additive of top layer is selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polysorbas20, polysorbate40, polysorbate60, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol laurate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone carboxylic acid salt, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination.

In another embodiment, armarium comprises dimethyl sulfoxine layer further, and wherein dimethylsulfoxide solvent layer covers on top layer.

In a detailed description of the invention of armarium, equipment can discharge therapeutic agent and additive, and in about 0.1 to 2 minute by therapeutic agent delivery to tissue.In a detailed description of the invention, the concentration of therapeutic agent in layer is 1 to 20 μ g/mm ².In a detailed description of the invention, the concentration of therapeutic agent in layer is 2 to 10 μ g/mm ².In a detailed description of the invention, therapeutic agent is water-insoluble.

In one embodiment, additive facilitates the release of therapeutic agent from sacculus.In another embodiment, additive facilitates therapeutic agent infiltration in the tissue and absorption.In another embodiment, water and the dissolve with ethanol degree of additive are at least 1mg/ml, and therapeutic agent is water-insoluble.

In another detailed description of the invention of armarium, the layer covering armarium outer surface comprises therapeutic agent and at least two kinds of additives, wherein often kind of additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, and wherein often kind of additive is solvable and insoluble in water in polar organic solvent.In the one side of this detailed description of the invention, polar organic solvent is selected from methanol, ethanol, isopropyl alcohol, acetone, dimethyl formamide, oxolane, methyl ethyl ketone, dimethyl sulfoxine, acetonitrile, ethyl acetate, acetic acid and chloroform, and the mixture of these polar organic solvents and water.This detailed description of the invention another in, the top layer that the surface that equipment comprises the layer be covered on armarium outer surface further covers, is delivered to loss in target tissue process in vivo for reducing medicine.

In another detailed description of the invention of armarium, the layer being covered in armarium outer surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive reduces crystal size and the amounts of particles of therapeutic agent, and wherein additive is water miscible and therapeutic agent is water-insoluble.

In another detailed description of the invention of armarium, the layer being covered in armarium outer surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive has the aliphatic chain of acid, ester, ether or alcohol, wherein aliphatic chain can directly be inserted in the lipid membrane structure of tissue, and wherein therapeutic agent is water-insoluble.

In another detailed description of the invention of armarium, the layer being covered in armarium outer surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, wherein additive may penetrate into tissue and rearranges its lipid membrane structure, and wherein therapeutic agent is water-insoluble and is not closed in micelle or is encapsulated in polymer beads.

In another detailed description of the invention of armarium, the layer being covered in armarium outer surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, wherein additive has acid, ester, the aliphatic chain of ether or alcohol, wherein aliphatic chain can directly be inserted in the lipid membrane structure of tissue, wherein additive has one or more interaction by hydrogen bond and/or Van der Waals has the functional group of affinity to medicine (functional group comprises hydroxyl, ester group, amide, carboxylic acid, primary, the second month in a season and tertiary amine, carbonyl, anhydride, oxide and amino alcohol), wherein therapeutic agent is water-insoluble and is not closed in micelle or is encapsulated in polymer beads, and wherein this layer does not comprise polymer, and this layer does not comprise the contrast agent of iodine covalent bonding.

In another embodiment, the present invention relates to for delivering therapeutic agents to the bracket coating organized, this bracket coating comprises the layer being covered in rack surface.In the one side of this detailed description of the invention, the layer being covered in rack surface comprises therapeutic agent, additive and polymeric matrix, wherein therapeutic agent is with Granular composite but be not in the polymer matrix encapsulated, wherein additive-package is containing hydrophilic parts and the affine part of medicine, and its Chinese medicine is affine is hydrophobic parts, have the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals.In the one side of this detailed description of the invention, additive improves the compatibility of therapeutic agent and polymeric matrix, additive reduces particle diameter and improves therapeutic agent distributing homogeneity in the polymer matrix, and additive facilitates the quick release of medicine from polymeric matrix.

In another embodiment, the present invention relates to a kind of armarium coating extremely organized for delivering drugs prepared by mixture.In the one side of this detailed description of the invention, coating is prepared by the mixture comprising in it organic facies and containing water-soluble additive aqueous phase having disperseed drug particles.In the one side of this detailed description of the invention, water-soluble additives is selected from Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, polypeptide, water soluble surfactant active, water soluble vitamins and protein.In the another aspect of this detailed description of the invention, the preparation of mixture is included in shear conditions and optional homogenizing under pressure.

In another embodiment, the present invention relates to for delivering therapeutic agents to the foley's tube of blood vessel, this conduit comprises the coating being covered in sacculus outer surface.In a detailed description of the invention of foley's tube, coating comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, and wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750.

In another detailed description of the invention of foley's tube, coating comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is at least one in surfactant and compound, and wherein compound has the hydroxyl of more than four.In the one side of this detailed description of the invention, the melting point compound with more than four hydroxyls is 120 DEG C or lower, and compound is alcohol or ester.

In a detailed description of the invention of foley's tube, the coating being covered in armarium outer surface is made up of therapeutic agent and additive substantially.In another embodiment, the layer being covered in armarium outer surface does not comprise the contrast agent of iodine covalent bonding.

In a detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan fatty acid ester, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, and the molecule of their replacement.

In a detailed description of the invention of foley's tube, the coating being covered in sacculus outer surface does not comprise pure hydrophobic additive.In another embodiment, the coating being covered in balloon surface does not comprise iodinated contrast media.In another embodiment, additive is not therapeutic agent.In another embodiment, additive is not salicylic acid or its salt.In another embodiment, the coating being covered in balloon surface does not comprise oil, lipid or polymer.In another embodiment, the coating being covered in balloon surface does not comprise oil.In the another aspect of this detailed description of the invention, this coating does not comprise polymer.

In a detailed description of the invention of foley's tube, the additive-package in coating is containing therapeutic agent and be selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polysorbas20, polysorbate40, polysorbate60, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol laurate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone carboxylic acid salt, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and the additive of derivant and combination.

In a detailed description of the invention, therapeutic agent is paclitaxel and analog, rapamycin and analog thereof, β-lapachol and analog, biological vitamin D and analog thereof, and the one in the mixture of these therapeutic agents.In another embodiment, therapeutic agent and the coupling of the second therapeutic agent, wherein therapeutic agent is the one in paclitaxel, rapamycin and analog thereof, and wherein the second therapeutic agent is the one in β-lapachol, bioactive vitamin D and analog thereof.In a detailed description of the invention, therapeutic agent is water-insoluble.

In a detailed description of the invention, additive is solvable in organic solvent and water.In another embodiment, additive facilitates therapeutic agent in the infiltration of vascular tissue and absorption.In another embodiment, therapeutic agent is water-insoluble.In another embodiment, additive has water and the dissolve with ethanol degree of at least 1mg/ml, and therapeutic agent is water-insoluble.

In a detailed description of the invention of foley's tube, conduit comprises the adhesion layer between sacculus outer surface and coating further.In another embodiment, conduit comprises the top layer be covered in coating further, and wherein top layer decreases therapeutic agent and is delivered to loss in vascular process in vivo.The additive that top layer comprises is selected from which additive according to the specific embodiment of the invention as herein described.Top layer is delivered in vivo in the process of the body cavity target site being used for the treatment of intervention and will slowly dissolves.When the armarium of the specific embodiment of the invention be depressed into contact with lumen organization time, this top layer is by the loss reduced in delivery process and increase the medicine that can be used for tissue.In a detailed description of the invention, in top layer, the hydrophilic of additive is less than the additive in coating.In another embodiment, conduit comprises dimethylsulfoxide solvent layer further, and wherein dimethylsulfoxide solvent layer is covered in the surface of coating.

In a detailed description of the invention, foley's tube can discharge therapeutic agent and additive, and about 0.1 to 2 minute inland river therapeutic agent delivery to blood vessel.

In a detailed description of the invention of foley's tube, therapeutic agent concentration is in the coating 1 to 20 μ g/mm ².In another embodiment, therapeutic agent concentration is in the coating 2 to 10 μ g/mm ².

In further detailed description of the invention, the present invention relates to the foley's tube of delivering therapeutic agents to blood vessel.In the one side of this detailed description of the invention, conduit comprise there is chamber and front end elongation film, be connected to and elongate film front end and can the dilatation balloon that is communicated with of fluid and the coating that is coated on sacculus outer surface with chamber.In the one side of this detailed description of the invention, the coating being covered in balloon surface comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750, and wherein conduit can discharge therapeutic agent and additive being less than in about 2 minutes, and by therapeutic agent delivery to vascular tissue.In the one side of this detailed description of the invention, described layer is not containing iodinated contrast media.

In a detailed description of the invention, foley's tube comprises the dimethylsulfoxide solvent layer of seal coat further, and wherein dimethyl sulfoxine layer enhances therapeutic agent and penetrates into endovascular ability.In another embodiment, foley's tube comprises the adhesion layer between sacculus outer surface and coating further.In another embodiment, foley's tube comprises the top layer of seal coat further, and wherein top layer can maintain coating at the integrity being delivered through blood vessel arrival treatment intervention target site.

In a detailed description of the invention, therapeutic agent concentration is in the coating 2.5 to 6 μ g/mm ².In a detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan fatty acid ester, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, and the molecule of their replacement.In a detailed description of the invention, compound has the hydroxyl of more than four and fusing point is 120 DEG C or following, and compound is alcohol or ester.

In a detailed description of the invention of foley's tube, additive is selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol laurate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, polysorbas20, polysorbate40, polysorbate60, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone sodium carboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination.

In further detailed description of the invention, the present invention relates to a kind of pharmaceutical composition, it comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750.In the one side of this detailed description of the invention, pharmaceutical composition does not comprise contrast agent or the polymer of iodine covalent bonding, and wherein therapeutic agent is not encapsulated in micelle or granule.

In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, and the molecule of their replacement.In a detailed description of the invention, compound has the hydroxyl of more than four and fusing point is 120 DEG C or following, and compound is alcohol or ester.In a detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan fatty acid ester, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.

In a detailed description of the invention of pharmaceutical composition, additive is selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol laurate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polysorbas20, polysorbate40, polysorbate60, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone sodium carboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination.

In further detailed description of the invention, the present invention relates to a kind of Therapeutic Method being used for the treatment of pathological changes body cavity or chamber after operation or intervention program, comprise by injection or be sprayed at operative site delivering drugs compositions with conduit, wherein pharmaceutical composition comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750.In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, additive is water miscible, and wherein compositions does not comprise the contrast agent of iodine covalent bonding.

In a detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan fatty acid ester, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, and the molecule of their replacement.

In further detailed description of the invention, the present invention relates to the pharmaceutical composition of Therapeutic cancer, comprise ovary, mammary gland, lung, esophagus, head and neck area, bladder, prostate, brain, liver, colon and lymphadenomatous cancer, wherein compositions comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein therapeutic agent is not closed in micelle or is encapsulated in polymer beads, and wherein compositions does not comprise the contrast agent of iodine covalent bonding.In the one side of this detailed description of the invention, therapeutic agent is selected from paclitaxel and analog thereof and rapamycin and analog thereof.

In further detailed description of the invention, the present invention relates to the solution for coating medical equipment.In the one side of this detailed description of the invention, solution comprises organic solvent, therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750.In another embodiment, the contrast agent of iodine covalent bonding, oil, lipid or polymer is not comprised for the solution of coating medical equipment.

In a detailed description of the invention, compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, and the molecule of their replacement.In a detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan fatty acid ester, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.In a detailed description of the invention, therapeutic agent is paclitaxel or rapamycin or its analog or derivant.

In another embodiment, the additive in coating solution is selected from different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol laurate, polysorbas20, polysorbate60, Tween 80, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, polidocanol, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone sodium carboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, ripple connects albumen, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, bromination trimethyl ammonium, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination.

In further detailed description of the invention, the present invention relates to for delivering therapeutic agents to the armarium organized, this equipment comprises the ground floor being applied to armarium outer surface and the second layer covering ground floor.In the one side of this detailed description of the invention, ground floor comprises therapeutic agent, the second layer comprises additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, and part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent.In the one side of this detailed description of the invention, ground floor comprises additive further, and wherein additive is water miscible, and this layer does not comprise iodinated contrast media.In the another aspect of this detailed description of the invention, the second layer comprises therapeutic agent further.In this detailed description of the invention is further, ground floor comprises additive further and the second layer comprises therapeutic agent further.

In further detailed description of the invention, the present invention relates to two layers of coatings, comprise the ground floor containing therapeutic agent and the top layer containing additive.In the one side of this detailed description of the invention, top layer can cover ground floor.In the one side of this detailed description of the invention, additive-package simultaneously in ground floor and top layer is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750.In the one side of this detailed description of the invention, ground floor does not comprise the contrast agent of iodine bonding.In the another aspect of this detailed description of the invention, top layer comprises therapeutic agent further.

In further detailed description of the invention, the present invention relates to the method for the preparation of armarium.In the one side of this detailed description of the invention, the method comprises: (a) preparation comprises organic solvent, the coating solution of therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 80 to 750, b coating solution is applied on armarium by (), (c) dry coating solution, form coating.In the one side of this detailed description of the invention, coating does not comprise the contrast agent of iodine bonding.In the one side of this detailed description of the invention, coating solution is applied by being impregnated in coating solution by the partial outer face of armarium.In the another aspect of this detailed description of the invention, coating solution passes through the partial outer face of armarium coating solution spray applications.In the another aspect of this detailed description of the invention, repeat step (b) and step (c), until the therapeutic agent for the treatment of effective dose in coating to be deposited to the surface of armarium.In the another aspect of this detailed description of the invention, the gross thickness of coating is about 0.1 to 200 micron.In the another aspect of this detailed description of the invention, the method comprises further and to be applied to by dimethyl sulfoxine layer on dry coating that step (c) obtains.

In further detailed description of the invention, the present invention relates to the method for the preparation of drug coated balloon catheter.In the one side of this detailed description of the invention, the method comprises: (a) preparation comprises organic solvent, the coating solution of therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is at least one in surfactant and compound, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750, b coating is applied on foley's tube by (), and (c) tightens and folding foley's tube, and dry coating solution is to increase the uniformity of medication coat.

In further detailed description of the invention, the present invention relates to the method being used for the treatment of blood vessel.In the one side of this detailed description of the invention, the method comprises: be inserted in blood vessel by the armarium comprising coating, its floating coat comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750, and discharged therapeutic agent and additive in 2 minutes or less, and by therapeutic agent delivery to vascular tissue.In the one side of this detailed description of the invention, coating does not comprise the contrast agent of iodine bonding.

In further detailed description of the invention, the present invention relates to and be used for the treatment of body internal channel full cut-off plug or narrow method.In the one side of this detailed description of the invention, the method comprises: remove speckle from body internal channel, the armarium comprising coating is inserted into body internal channel, its floating coat comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 80 to 750, and discharged therapeutic agent and additive in 2 minutes or less, and by therapeutic agent delivery to body internal channel tissue.

In further detailed description of the invention, the present invention relates to the method being used for the treatment of in-vivo tissue, comprise: the armarium comprising coating is contacted with in-vivo tissue, its floating coat comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, its Chinese medicine is affine, and part is hydrophobic parts, there is the part of affinity by hydrogen bond to therapeutic agent and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750, and discharged therapeutic agent and additive in 2 minutes or less, and by therapeutic agent delivery to tissue.In a detailed description of the invention, coating does not comprise iodine covalency contrast agent.In the one side of this detailed description of the invention, described tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.

In further detailed description of the invention, the present invention relates to the preparation method of foley's tube.In the one side of this detailed description of the invention, the method comprises: preparation is containing the solution of organic solvent, therapeutic agent and additive, wherein additive-package is containing hydrophilic and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent, wherein additive is water miscible, wherein additive is at least one in surfactant and compound, and wherein compound has the molecular weight of 20 to 750; Described solution is applied to foley's tube; And evaporating solvent.In a detailed description of the invention, solution is not containing iodinated contrast media.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, and wherein additive is polyethylene glycol fatty ester, polyethylene glycol fatty acid ether and Pegylation fatty alcohol.In the one side of this detailed description of the invention, this additive is selected from PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, Polyethylene Glycol-9 oleate, Polyethylene Glycol-10 laurate, Polyethylene Glycol-10 oleate, Polyethylene Glycol-12 laurate, Polyethylene Glycol-12 oleate, Polyethylene Glycol-15 oleate, Polyethylene Glycol-20 laurate, Polyethylene Glycol-20 oleate, Polyethylene Glycol-20 dilaurate, Polyethylene Glycol-20 dioleate, Polyethylene Glycol-20 distearate, Polyethylene Glycol-32 dilaurate and Polyethylene Glycol-32 dioleate.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, and wherein additive is the one in glycerol and polyglycereol fatty ester and polyethylene glycol glycerol fatty ester.In the one side of this detailed description of the invention, additive is selected from polyglycerol acrylate, polyglycereol-2 dioleate, Natrulon H-10 trioleate, polyglycerol stearate, polyglyceryl laurate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglyceryl linoleate, Natrulon H-10 laurate, Natrulon H-10 oleate, the list of Natrulon H-10, dioleate, Natrulon H-10 stearate, Natrulon H-10 laurate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Natrulon H-10 linoleate, polyglycereol-6 stearate, polyglycereol-6 laurate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, polyglycereol-6 linoleate, polyglycereol ricinoleate ester, Polyethylene Glycol-20 glyceryl laurate ester, Polyethylene Glycol-30 glyceryl laurate, Polyethylene Glycol-40 glyceryl laurate, Polyethylene Glycol-20 glyceryl oleate and Polyethylene Glycol-30 olein.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, and wherein additive is the one in sorbitan fatty acid ester and Polyethylene Glycol sorbitan.In the one side of this detailed description of the invention, additive is selected from sorbitan monolaurate, span 40, dehydrated sorbitol mono-fatty acid ester, sorbitan monostearate, Polyethylene Glycol-20 sorbitan monolaurate, Polyethylene Glycol-20 span 40, Polyethylene Glycol-20 dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol-20 sorbitan monostearate.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, and wherein additive is the compound comprising phenolic groups.In the one side of this detailed description of the invention, additive is selected from different nonyl benzene oxygen poly epihydric alcohol, octoxinol, nonoxynolum, tyloxapol, octoxynol 9 and Nonoxynol-9.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, and wherein additive is selected from sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, D-glucoascorbic acid and salt thereof, trometamol, glycosamine, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid and glycosamine.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, wherein additive are ionic surfactants.In the one side of this detailed description of the invention, additive is selected from benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, Dodecyl trimethyl ammonium chloride, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, edrophonium chloride, domiphen bromide, the dialkyl of sodium sulfosuccinate, 2-Sulfosuccinic acid ethylhexyl sodium, sodium cholate and sodium taurocholate.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, wherein additive are vitamin or vitamin derivative.In the one side of this detailed description of the invention, additive is selected from acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid and salt thereof, pyridoxal 5-phosphate, nicotiamide ascorbic acid, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, vitamin U, ergosterol, 1-α-hydroxycholecalciferol, vitamin D2, vitamin D3, alpha-carotene, beta-carotene, gamma carotene, vitamin A, fursultiamine, methylol riboflavin, octotiamine, prosultiamine, riboflavin, styrene thiamine, dihydroxyvitamin K1, menadiol diacetate esters, menadiol dibutyl ester, menadiol dithionate, menadiol, vitamin K1, phylloquinone oxide, Menaquinone K6 and vitamin K--S (II).In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to the armarium comprising the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, wherein additive are aminoacid, amino acid salts or amino acid derivativges.In the one side of this detailed description of the invention, additive is selected from alanine, arginine, agedoite, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine and derivant thereof.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to for delivering therapeutic agents to the armarium organized, this equipment comprises the layer being covered in armarium outer surface, and described layer comprises therapeutic agent and additive, and wherein additive is peptide, oligopeptide or protein.In the one side of this detailed description of the invention, additive is selected from albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, Fibrinogen and lipase.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In further detailed description of the invention, the present invention relates to for delivering therapeutic agents to the armarium organized, this equipment comprises the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, wherein additive comprises compositions or the mixture of surfactant and compound, and wherein compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In the one side of this detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.In the another aspect of this detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound have 20 to 750 molecular weight.In the another aspect of this detailed description of the invention, compound is selected from the molecule of amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester, anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin and their replacement.In the another aspect of this detailed description of the invention, there is one or more hydroxyl, amino, carbonyl, carboxyl, acid, the compound of amide or ester group is selected from acetic acid and anhydride, phthalic acid and anhydride, diethylene-triamine pentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, diglycolic acid and anhydride, 1,3-propanedicarboxylic acid and anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid aspartic acid, niacin, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconolactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sorbitol, sorbitol, phosphoric acid sugar, Glucopyranose. phosphoric acid, Sulfated saccharides, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, xylitol, cellosolvo, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine, acetic acid, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of above-mentioned any organic acid and amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, the salt of two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), the oligomer of PEG, two (propylene glycol), three (propylene glycol), four (propylene glycol), with five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant combines with it.In the another aspect of this detailed description of the invention, tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate and nicergoline road.In the another aspect of this detailed description of the invention, equipment comprises the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter, atherectomy device, speckle ablation catheter, support, filter, stent graft, overlay film frame, paster, line and valve.

In another embodiment, the present invention relates to for mammal administration pharmaceutical preparation, comprise the combination of paclitaxel or rapamycin or derivatives thereof and surfactant and compound, wherein compound has one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.In a detailed description of the invention, surfactant is selected from ion, nonionic, aliphatic series and aromatic surfactants, polyethylene glycol fatty ester, Polyethylene Glycol ω-3 fatty ester, ether and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan, sugared fatty ester, Polyethylene Glycol sugar ester and derivant thereof.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound molecular weight be 20 to 750.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from the molecule of amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sugar, glucose, sucrose, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin and their replacement.In a detailed description of the invention, there is one or more hydroxyl, amino, carbonyl, carboxyl, acid, the compound of amide or ester group is selected from L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconolactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, acetaminophen, ibuprofen, tretinoin, lysine acetic acid, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, ribose acid lactone, meglumine/lactic acid, meglumine/gentisic acid, meglumine/acetic acid, sorbitol, xylitol, cellosolvo, sugar, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, the salt of any organic acid and amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, the salt of two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), the oligomer of PEG, two (propylene glycol), three (propylene glycol), four (propylene glycol), with five (propylene glycol), the oligomer of poly-(propylene glycol), the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant combines with it.

In another embodiment, the present invention relates to for mammal administration pharmaceutical preparation, comprise paclitaxel or rapamycin or derivatives thereof and there is the compound of one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group, wherein have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound molecular weight be 20 to 750.In a detailed description of the invention, have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from amino alcohol and organic acid combination, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, phosphoric acid sugar, Sulfated saccharides, catechin, catechin and gallate.In the one side of this detailed description of the invention, amino alcohol is selected from trometamol, triethanolamine, diethanolamine, meglumine, glycosamine, glycosamine, lysine and derivant thereof; And organic acid is selected from glucoheptonic acid, gluconic acid, glutamic acid, benzoic acid, hydroxy benzoic acid, gentisic acid, lactobionic acid, vanillic acid, dlactic acid, acetic acid and derivant thereof.

In another embodiment, the present invention relates to the pharmaceutical preparation to mammal administration, comprise: paclitaxel or rapamycin or derivatives thereof; With amino alcohol and organic acid combination, wherein amino alcohol is selected from trometamol, triethanolamine, diethanolamine, meglumine, glycosamine, glycosamine, lysine and derivant thereof; And organic acid is selected from glucoheptonic acid, gluconic acid, glutamic acid, benzoic acid, hydroxy benzoic acid, gentisic acid, lactobionic acid, vanillic acid, dlactic acid, acetic acid and derivant thereof.

In another embodiment, the present invention relates to for delivering therapeutic agents to the armarium organized, this equipment comprises the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, and wherein additive is selected from hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone and lactobionic acid.

In another embodiment, the present invention relates to for delivering therapeutic agents to the armarium organized, this equipment comprises the layer being covered in armarium outer surface, described layer comprises therapeutic agent and additive, wherein therapeutic agent is paclitaxel and analog thereof or rapamycin and analog thereof, and additive is selected from sorbitol, diethylene glycol, 2,2'-ethylenedioxybis(ethanol)., tetraethylene glycol (TEG), the oligomer of Polyethylene Glycol, the oligomer of polypropylene glycol, the block copolymer oligomer of Polyethylene Glycol and polypropylene glycol, xylitol, cellosolvo, sugar, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, polysorbas20, polysorbate40, polysorbate60 and derivant thereof, the weight ratio of its Chinese medicine and additive is 0.5 to 3, wherein therapeutic agent and additive are released simultaneously.

Many detailed description of the invention of the present invention are to treatment angiopathy and reduce narrow and late luminal and lose particularly useful, or for the equipment manufacturing this object be useful.

It should be understood that general description above and detailed description are below all only exemplary with illustrative, not restricted to the present invention as claimed in claim.

Accompanying drawing is sketched

Fig. 1 is the axonometric chart of an exemplary embodiments according to foley's tube of the present invention.

Fig. 2 A-2C is the sectional view of the different detailed description of the invention of fore-end of Fig. 1 foley's tube, shows exemplary coating along A-A line.

The detailed description of exemplary embodiments

The specific embodiment of the present invention relates to the armarium with quick release coating, comprises particularly foley's tube and support, and prepares the method for this coating apparatus.Do not need to postpone or discharge for a long time according to the therapeutic agent of the specific embodiment of the invention, on the contrary, preferred therapeutic agents and additive discharge within the very short time provides contacting of therapeutic agent and tissue.An object of the specific embodiment of the invention helps target tissue to absorb quickly and efficiently medicine in the of short duration process being placed in target site of equipment.

As shown in Figure 1, in a detailed description of the invention, armarium is foley's tube.Foley's tube can be any appropriate catheter for required purposes, comprises the conventional balloon catheter that those skilled in the art is known.Such as, foley's tube 10 elongate flexible elements 14 that can comprise the expansion inflating balloon 12 being positioned at conduit 10 far-end, the Handleset 16 being positioned at conduit 10 near-end and extend between the proximal and distal ends.Handleset 16 can connect and/or receive one or more suitable armarium, such as, expand medium source (such as air, normal saline or contrast agent).Flexible member 14 can be the pipe that suitable biocompatible material is made, and has one or more chamber in it.Have at least a chamber to be configured to receive expansion medium and this medium is passed into sacculus 12 and be used for its expansion.Foley's tube can be exchange rapidly or transmitting catheter, and available any suitable biocompatible materials is made.

In a detailed description of the invention, the invention provides a kind of armarium extremely organized for delivering therapeutic agents.This equipment comprises the layer being applied to armarium such as foley's tube or rack outer surface.Described layer comprises therapeutic agent and additive.Such as, as shown in the detailed description of the invention that Fig. 2 A describes, sacculus 12 layer 20 comprising therapeutic agent and additive applies.In some embodiments, described layer is made up of therapeutic agent and additive substantially, and namely described layer only comprises therapeutic agent and additive, and not containing other important composition any.In some embodiments, this equipment optionally comprises adhesion layer.Such as, as shown in the detailed description of the invention that Fig. 2 B describes, sacculus 12 adhesion layer 22 applies.The adhesion layer layer 24 comprising therapeutic agent and additive applies.Adhesion layer is the sealing coat be positioned at below medication coat, which promotes the adhesiveness of medication coat to armarium outer surface, and protects the integrity of coating.Such as, if medicine is different with the adhesiveness of additive to armarium, adhesion layer can prevent the difference of component from losing, thus keeps being delivered to the ratio that target site is used for the treatment of medicine in intervention procedure and additive.In addition, adhesion layer can be used to help coating ingredients to discharge fast from equipment surface when the contact tissue of equipment surface and target site.In other detailed description of the invention, equipment can comprise top layer.Top layer can reduce the loss of medicine layer before contacting with target tissue, such as, be delivered to treatment at sacculus 12 and get involved in the process at position, or is depressed into the first moment directly contacting front sacculus 12 with target tissue and expand in coating 20.

In a detailed description of the invention, the concentration and density being applied at least one therapeutic agent on armarium surface is about 1 to 20 μ g/mm ², or preferred about 2 to 6 μ g/mm ².The weight ratio of therapeutic agent and additive is about 0.5 to 100, such as about 0.1 to 5,0.5 to 3, further such as about 0.8 to 1.2.If the ratio of therapeutic agent and additive (weight) is too low, medicine can too early release, if this ratio is too high, when when target site uses medicine can not eluting enough soon or be absorbed by tissue.

In another embodiment, described layer comprises therapeutic agent and additive, wherein therapeutic agent is paclitaxel and analog thereof or rapamycin and analog thereof, and additive is selected from sorbitol, diethylene glycol, 2,2'-ethylenedioxybis(ethanol)., tetraethylene glycol (TEG), xylitol, cellosolvo, sugar, galactose, glucose, mannose, xylose, sucrose, lactose, maltose, polysorbas20, polysorbate40, polysorbate60 and derivant thereof, wherein the weight ratio of therapeutic agent and additive is 0.5 to 3.If the ratio of medicine and additive is lower than 0.5, medicine can too early release, if ratio is greater than 3, when when target site uses medicine can not eluting enough soon or be absorbed by tissue.In other detailed description of the invention, described layer can comprise therapeutic agent and more than one additive.Such as, a kind of additive can be used to the adhesiveness improving sacculus, and another kind of additive or multiple additives are better than promoting drug release or the picked-up of tissue to medicine.

Current drug stent coating has medicine and polymer support.Medicine is dispersed in polymeric matrix, is sometimes granule.In the situation of lasting polymer, medicine passing release in time.Lasting polymer and support are stayed in human body forever.In the situation of biodegradable polymer, such as PLLA, medicine release in 1-3 month, and polymer is degraded in about 1 year or longer time.Medicine is as pure drug release.Pure drug particles adds the risk of tissue toxicity.But, the additive of the specific embodiment of the invention when combining with polymer support and for bracket coating, by this risk of reduction.In the specific embodiment of the present invention, the medicine in polymeric stent coatings and additive are different, but are discharged into tissue together at one time.This will reduce medicine to the risk of tissue toxicity.

In other detailed description of the invention, described layer can comprise at least one therapeutic agent, at least one additive and at least one polymer support, for coating medical equipment such as support or sacculus.The additive being used for combining with polymer support in bracket coating can be at least one additive according to the specific embodiment of the invention discussed in this article.Additive in said layer improves the compatibility of medicine and polymer support.It reduces or eliminates the size of medicine crystal granule in coating polymer matrix.In coating, uniform drug distribution is by more uniformly delivering drugs into target tissue and improving clinical prognosis.

In another embodiment, what this equipment comprised for armarium such as particularly foley's tube outer surface is two-layer.Ground floor comprises therapeutic agent.Ground floor optionally comprises a kind of additive or multiple additives.The second layer comprises a kind of additive or multiple additives.The second layer optionally comprises at least one therapeutic agent.When all containing therapeutic agent for first and second layers, in the second layer, the content of therapeutic agent is lower than the content of therapeutic agent in ground floor.In a detailed description of the invention, the second layer covers ground floor.In this arrangement, the second layer can prevent armarium to be placed in drug loss in body internal channel process, and such as foley's tube runs through tortuous anatomy and arrives tissue site in vascular system.

In another embodiment, what this equipment comprised for armarium such as particularly foley's tube outer surface is two-layer.Ground floor comprises therapeutic agent.Ground floor optionally comprises a kind of additive or multiple additives.The second layer comprises a kind of additive or multiple additives.The second layer optionally comprises at least one therapeutic agent.When all containing therapeutic agent for first and second layers, in ground floor, the content of therapeutic agent is lower than the content of therapeutic agent in the second layer.In a detailed description of the invention, the second layer covers ground floor.This layout is useful for such as adhering in too tight situation at therapeutic agent to balloon surface, makes it when target site expands from the quick eluting of sacculus.In this arrangement, when equipment is when treating the target site got involved and expanding, ground floor most of medicine of helping in the second layer discharges fast from equipment surface.

In other detailed description of the invention, medicine-additive layer employs the therapeutic agent of two or more coupling.

In further detailed description of the invention, the equipment with two layers of coatings optionally comprises adhesion layer.Adhesion layer is not containing therapeutic agent.Such as, as shown in the detailed description of the invention that Fig. 2 C describes, sacculus 12 adhesion layer 22 applies.Comprise therapeutic agent and cover adhesion layer 22 with the ground floor 26 of choose any one kind of them additive or multiple additives.The second layer 28 comprising additive and optional therapeutic agent covers ground floor 26.Adhesion layer improves the adhesiveness of ground floor and armarium outer surface, and protects the integrity of ground floor.Such as, if the medicine in ground floor is different with a kind of additive or the adhesion strength of multiple additives to armarium, so adhesion layer can prevent the difference of component from losing, and maintains first and second layers being delivered to target site and be used for the treatment of medicine-additive in intervention procedure and additive-additives ratio.In addition, adhesion layer can be used to help coating quick eluting from armarium, and at target site and contact tissue.In a detailed description of the invention, ground floor, the second layer and adhesion layer are separately containing additive.

Optionally, it may be favourable for carrying out post processing with dimethyl sulfoxine (DMSO) or other solvent, because DMSO can strengthen medicine further to the infiltration of tissue and absorption.DMSO replaces water from the head base of lipid and the protein domain of target cell membrane double-layer of lipoid, thus indirectly makes lipid conformation loosen, and accelerates absorption and the infiltration of medicine.

In further detailed description of the invention, the present invention relates to and be used for the treatment of operation or interventional therapy (PTCA, PTA, stent endoprosthesis, the excision of pathological tissues such as cancer and alleviation or treat narrow) pharmaceutical composition in future trouble sick body chamber or chamber, wherein pharmaceutical composition comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts and/or has affinity by hydrogen bond and/or Van der Waals interaction to therapeutic agent, and wherein therapeutic agent is not closed in micelle or is encapsulated in polymer particles intragranular.

In another embodiment, be the method for a kind of prevention operation or interventional therapy (such as PTCA, PTA, support insert, narrow or subtract the excision of tumor speckle, rotary-cut art or laser therapy) infectious-related complication or recurrent disease (such as cancer or restenosis), pharmaceutical composition is by coating medical equipment (such as medicine-coated balloon) or by spraying, by injecting or be delivered locally to by deposition or close to getting involved position.Such as, pharmaceutical composition is delivered to the chamber because cancerous tissue excision causes, to reduce risk of recurrence by spraying, injection, sacculus or other deposition process.As another example, a kind of method for delivering drugs compositions comprises and is inserted in blood vessel by armarium (such as introduce conduit or drug infusion catheter), blood vessel get involved (such as PTCA, PTA or support insert) afterwards injection of medicine compositions carry out prevention of restenosis.Wherein pharmaceutical composition comprises therapeutic agent and additive, wherein additive-package is containing hydrophilic parts and the affine part of medicine, part that its Chinese medicine is affine is hydrophobic parts and/or has affinity by hydrogen bond and/or Van der Waals interaction to therapeutic agent, and wherein therapeutic agent is not closed in micelle or is encapsulated in polymer particles intragranular.

Many detailed description of the invention of the present invention are for treatment angiopathy and lose particularly useful for reducing narrow and late luminal, or manufacture in the equipment being used for above-mentioned purpose or the method for the treatment of above-mentioned disease useful.

additive

Additive in the specific embodiment of the invention has two parts.A part is hydrophilic, and another part affine part that is medicine.Part that medicine is affine is hydrophobic parts and/or has affinity by hydrogen bond and/or Van der Waals interaction to therapeutic agent.The affine part of medicine of additive can in conjunction with lipophilic drugs, such as rapamycin or paclitaxel.Hydrophilic parts accelerates and spreads and add the infiltration of medicine to tissue.It is by preventing hydrophobic drug from assembling each other or gathering on equipment, increase the dissolubility of medicine in intercellular space, and/or accelerate the double-layer of lipoid that agent permeates therethrough polar head-group enters target tissue cell membrane, contribute to medicine when armarium is placed in target site from fast transfer armarium.Additive in the specific embodiment of the invention has two parts, they discharge with the picked-up of target tissue (by accelerating contacting of medicine and tissue from equipment surface fast with helping put procedure Chinese medicine together, medicine has high-affinity), prevent equipment to be positioned over target site prodrug simultaneously and discharge too early from equipment surface.

In the specific embodiment of the present invention, when after armarium and contact tissue, therapeutic agent is fast released and is easy to be absorbed.Such as, some detailed description of the invention of present device comprises drug coated balloon catheter, lipotropy anti-proliferative drugs (such as paclitaxel or rapamycin), by of short duration, the direct pressure contact of high drug level in balloon angioplasty process, is delivered to vascular tissue by it.Lipophilic drugs is preferably trapped in the target tissue of site of delivery, and it is at this Inhibiting proliferation and restenosis, but allows endothelialization.In these detailed description of the invention, coating agent of the present invention not only helps medicine discharge fast from balloon surface and deliver drugs into target tissue in put procedure, but also prevent from being spread apart from equipment by medicine during tortuous arteriotomy arriving before target site, and prevent from medication coat to be depressed into directly contacting with blood vessel wall surface the front starting stage in inflated from equipment quick-fried from.

According to the additive of some detailed description of the invention, there is the affine part of medicine and hydrophilic parts.Part that medicine is affine is hydrophobic parts and/or has affinity by hydrogen bond and/or Van der Waals interaction to therapeutic agent.Part that medicine is affine can comprise aliphatic series and fragrant organic hydrocarbon compound, such as benzene, toluene and alkane etc.These parts are water-insoluble.They can in conjunction with two kinds of hydrophobic drugs, and they share the lipid of structural similarity and cell membrane accordingly.They do not have the iodine of covalent bonding.Part that medicine is affine can comprise can with medicine and the functional group himself forming hydrogen bond.Hydrophilic parts can comprise the molecule etc. of hydroxyl, amido, amide groups, carbonyl, carboxylic acid and anhydride, ether, ethohexadiol, Polyethylene Glycol, ascorbic acid, aminoacid, amino alcohol, glucose, sucrose, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic salt and their replacement.Such as, one or more hydroxyls, carbonyl, acid, amide or amine groups may be favourable, because they can replace the hydrone of hydrogen bonded in polar head-group and surface of cell membrane albumen easily, and can be used to this barrier that removes between hydrophobic drug and Cell membrane lipids.These part water soluble and polar solvents.These additives are not oil, lipid or polymer.Therapeutic agent is not closed in micelle or is encapsulated in polymer particles intragranular.The additive of the specific embodiment of the invention has can bound drug and contribute to again it at the composition placed and enter from fast transfer armarium in target tissue process.

Additive in the specific embodiment of the invention is surfactant and the compound with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group.Surfactant comprises ion-type, nonionic, aliphatic series and aromatic surfactants.Have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound be selected from the molecule of amino alcohol, hydroxy carboxylic acid and anhydride, ether, ethohexadiol, aminoacid, peptide, protein, sugar, glucose, sucrose, sorbitol, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin and their replacement.

As known in the art, term " hydrophilic " and " hydrophobicity " are relative terms.In order to serve as the additive in exemplifying detailed description of the invention, compound comprises polarity or charged hydrophilic part and non-polar hydrophobic (lipotropy) part.

Drug characterization compound hydrophilic is commonly used to and hydrophobic solvent parameter is partition coefficient P in pharmaceutical chemistry, namely unionized compound two kinds of not mutual solvents mixture biphase in concentration ratio, normally pungent alcohol and water, makes P=([solute] capryl alcohol/[solute] water).The compound hydrophobicity with higher log Ps is stronger, and the compound hydrophilic with lower log Ps is stronger.Li Pingsiji rule shows, has the medical compounds easier permeable membrane usually of log P<5.For some detailed description of the invention of the present invention, the log P of preferable additives is less than the log P (such as, the log P of paclitaxel is 7.4) being formulated medicine.Log P difference larger between medicine and additive contributes to being separated of medicine.Such as, if the log P of additive is far below the log P of medicine, so additive can accelerate medicine release from equipment surface in aqueous environments, otherwise medicine possibility tight adhesion, thus quickening medicine gets involved sending of position process of short duration being placed in.In some detailed description of the invention of the present invention, the log P of additive is negative.In other detailed description of the invention, the log P of additive is less than the log P of medicine.Although the octanol-water partition coefficient P of compound or log P for measurement relative hydropathy and hydrophobicity useful, it is only the rough guide determining can be used for appropriate addn in the specific embodiment of the invention.

The coating of the specific embodiment of the invention comprises therapeutic agent and at least one additive, and as far as possible it reduce its degraded based on the peculiar property of often kind of therapeutic agent in the coating in conjunction with this material, thus provides one medication coat armarium safely and effectively.Chemical reaction can not be there is in the additive in the specific embodiment of the invention with the functional group of therapeutic activity agent.Often kind of therapeutic activity agent has chemical constitution and the character of its uniqueness, and from different additive pharmaceutical carriers, different reactions occurs, and the reaction between medicine and additive can make therapeutic agent invalid or produce the catabolite of genotoxic potential.The selection of additive should make it not containing the functional group that can react with the functional group of therapeutic activity agent.Otherwise this reaction between medicine and additive can make therapeutic agent invalid or produce potential toxic decomposition products.In order to reduce the degraded of therapeutic agent and make medication coat Safety in Medical Equipment effective as far as possible, mate very important to therapeutic agent and selected additive.Paclitaxel and many functional groups can react, such as acid, water, oxygen and amine.Rapamycin and derivant thereof are easily hydrolyzed or are oxidized.The high surface area of coating medical equipment makes the optimization of active agent stability in coating even more important.Medication coat armarium is exposed to high heat, wet and oxidizing condition in disinfecting process, and they before use often storage add long-time.Additive in the specific embodiment of the invention should be carefully chosen, and is being exposed to the degraded in harsh conditions and long term storage to reduce therapeutic agent as far as possible.Some drugs, such as rapamycin and derivant thereof to oxygen and wet sensitive sense, easily oxidized and hydrolysis.The present inventor finds, antioxidant is the additive that protection medicine such as rapamycin is not oxidized and be hydrolyzed.The specific embodiment of the present invention provides the coating for armarium, and it comprises additive and activating agent, and wherein additive can not cause the degraded of activating agent, or protects additive non-degradable by antioxidant additive.

The specific embodiment of the present invention also relates to the method for the production of (comprising the method for application composition, preparation and fabrication) coating medical equipment, its by sensitivity treatment agent such as rapamycin and derivant thereof because the degraded of oxygen and/or hydrolysis reduces to minimum.The processing of coating medical equipment, packaging and storage are particularly important for medicine stability, and in the specific embodiment of the present invention, reduce oxygen in packaging and wetly further therapeutic agent oxidation in time and hydrolysis in long storage periods are reduced to minimum.In order to the degraded of therapeutic agent is reduced to minimum, some detailed description of the invention provides the method for processing and pack coating medical equipment.

The appropriate addn that can be used for the specific embodiment of the invention includes but not limited to organic and inorganic drug excipient, natural prodcuts and derivant (such as sugar, vitamin, aminoacid, peptide, protein and fatty acid) thereof, low-molecular-weight oligomer, surfactant (anionic, cationic, nonionic and ion-type), and composition thereof.The additive used in the present invention listed in detail below only provides for exemplary purpose, and not for representing all.Other additive objects used in the present invention many.

surfactant

Surfactant can be any surfactant being applicable to pharmaceutical composition.This surfactant can be anionic, cationic, amphoteric ion type or nonionic.The mixture of surfactant also within the scope of the invention, as the combination of surfactant and other additive.Surfactant has one or more aliphatic chain usually, such as, directly can insert the fatty acid that cell membrane lipid bilayer forms a lipid conformation part, and other composition of surfactant makes lipid conformation loosen and strengthen infiltration and the absorption of medicine.Contrast agent Iopromide does not have these character.

Be usually used to characterization of surfaces activating agent relative hydropathy and hydrophobic solvent parameter is hydrophilic-lipophilic balance (" HLB " value).Have stronger compared with the surfactant hydrophobic of low hlb, and dissolubility in oil is larger, and has stronger compared with the surfactant hydrophilic of high hlb, and dissolubility is in aqueous higher.Use HLB extremely as rough guidance, hydrophilic surfactant active is considered to those compounds that HLB value is greater than about 10 usually, and the general inapplicable anion of HLB scope, cation or amphoteric compound.Equally, hydrophobic surfactant is the compound that HLB value is less than about 10.In some detailed description of the invention of the present invention, higher HLB value is preferred, because the hydrophilic increased contributes to the release of hydrophobic drug from equipment surface.In a detailed description of the invention, the HLB of surfactant additive is higher than 10.In another embodiment, the HLB of additive is higher than 14.Such as, or when being used to prevent equipment to be positioned over the loss of target site prodrug, the surfactant with lower HLB is preferred, contains extremely hydrophilic additive in the top layer covering medicine layer.In some detailed description of the invention, the HLB value scope of surfactant additive is 0.0-40.

It is to be understood that the HLB value of surfactant is only rough guidance, be commonly used to realize industry preparation, such as medicine and cosmetic emulsion.For many important surfactants, comprise several polyethoxylated surfactant, report that its HLB value can differ up to about 8HLB unit, this depends on the empirical method (Schott being chosen to measure HLB value, J.Pharm.Sciences, 79 (1), 87-88 (1990)).These intrinsic difficulties kept in mind, and use HLB value as guidance, as described herein, that can determine to be applicable to the specific embodiment of the invention has Suitable hydrophilic or hydrophobic surfactant.

polyethylene Glycol-fatty acid and Polyethylene Glycol-fatty-acid monoester and diester

Although Polyethylene Glycol (PEG) itself can not be used as surfactant, various Polyethylene Glycol-fatty acid ester has useful surfactant properties.In Polyethylene Glycol-fatty-acid monoester, the ester of lauric acid, oleic acid and stearic acid, myristoleic acid, palmitoleic acid, linoleic acid, linolenic acid, eicosapentaenoic acid, sinapic acid, castor oil acid and docosahexenoic acid is the most useful in the specific embodiment of the present invention.Preferred hydrophilic surfactant active comprises PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate.PEG-15 12-hydroxy stearic acid ester (Solutol HS 15) is the nonionic surfactant for injection solution.Solutol HS 15 is preferred additives in some detailed description of the invention of the present invention, because it is at room temperature white paste, and become liquid at about 30 DEG C, this temperature is higher than room temperature but lower than body temperature.The scope of HLB value is 4-20.

Additive (such as Solutol HS 15) at room temperature in the pasty state, solid or crystalline state, but become liquid at body temperature.It is very difficult that some can make to manufacture homogeneous coating medical equipment at the additive that room temperature is liquid.At room temperature, some liquid additive can hinder solvent to evaporate, or can not be retained in the surface of armarium in the process to equipment coating processing, the balloon portion of such as foley's tube.In some detailed description of the invention of the present invention, pasty state and solid additive are preferred, because they can be retained on armarium with homogeneous coating local, and can in drying at room temperature.In some embodiments, when the solid cladding on armarium is when being placed in human body process and being exposed to higher physiological temp about 37 DEG C, liquid can be become.In these detailed description of the invention, liquid coating is very easy to discharge from the surface of armarium, and is easily delivered to pathological tissues.In some detailed description of the invention of the present invention, the additive in physiological conditions with the change of temperature-induced state is extremely important, especially in some drugs coating ball ductus bursae.In some detailed description of the invention, solid additive and liquid additive united are used in medication coat of the present invention.Thisly combine the integrity improving armarium coating.In some detailed description of the invention of the present invention, at least one solid additive is used to medication coat.

Polyethylene glycol fatty acid diester is also applicable to the surfactant of compositions in the specific embodiment of the invention.Most preferred hydrophilic surfactant active comprises PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate.HLB value scope is 5-15.

Usually, the mixture also detailed description of the invention used in the present invention of surfactant, comprises the mixture of two or more commercial surfactant and the mixture of surfactant and other a kind of additive or multiple additives.Several Polyethylene Glycol-fatty acid ester is as the mixture commercial distribution of monoesters or diester.

fatty acid macrogolglycerides

Preferred hydrophilic surfactant active has PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate and PEG-30 olein.

alcohol-oil transesterification products

There is hydrophobicity or hydrophilic surfactant in a large number in various degree and react obtained by alcohol or polyhydric alcohol and various natural and/or hydrogenated oil and fat.The most frequently used, the oil of use is Oleum Ricini or castor oil hydrogenated, or edible vegetable oil, such as Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, palm-kernel oil, almond oil or almond oil.Preferred alcohol comprises glycerol, propylene glycol, ethylene glycol, Polyethylene Glycol, sorbitol and tetramethylolmethane.In these alcohol-grease exchange surface activating agent, preferred hydrophilic surfactant active is PEG-35 Oleum Ricini, Polyethylene Glycol-glycerol ricinoleate (Incrocas-35 and Cremophor EL & ELP), PEG-40 castor oil hydrogenated oil (Cremophor RH40), PEG-15 castor oil hydrogenated (Solutol HS 15), PEG-25 trioleate (TAGAT.RTM.TO), PEG-60 Corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm-kernel oil (Crovol PK70), PEG-50 Oleum Ricini (Emalex C-50), PEG-50 castor oil hydrogenated (Emalex HC-50), PEG-8 caprylic/capric glyceride (Labrasol) and PEG-6 caprylic/capric glyceride (Softigen767).The preferred hydrophobic surfactant of this apoplexy due to endogenous wind comprises PEG-5 castor oil hydrogenated, PEG-7 castor oil hydrogenated, PEG-9 castor oil hydrogenated, PEG-6 Semen Maydis oil (Labrafil.RTM M 2125CS), PEG-6 almond oil (Labrafil.RTM, M1966CS), PEG-6 Semen Armeniacae Amarum grease (Labrafil.RTM M 1944 CS), PEG-6 olive oil (Labrafil.RTM, M1980 CS), PEG-6 Oleum Arachidis hypogaeae semen (Labrafil.RTM, M1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil.RTM M 2130BS), PEG-6 palm-kernel oil (Labrafil.RTM M 2130 CS), PEG-6 glycerol trioleate (Labrafil.RTM.b M2735 CS), PEG-8 Semen Maydis oil (Labrafil.RTM WL2609 BS), PEG-20 Corn glycerides (Crovol M40) and PEG-20 Semen Armeniacae Amarum glyceride (Crovol A40).

polyglycerol fatty acid

Polyglycereol fatty ester is also the surfactant being applicable to the specific embodiment of the invention.In polyglycereol fatty ester, preferred hydrophobic surfactant comprises polyglycerol acrylate (PlurolOleique), polyglycereol-2 dioleate (nikkol DGDO), Natrulon H-10 trioleate, polyglycerol stearate, polyglyceryl laurate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate and polyglycereol linoleic acid.Preferred hydrophilic surfactant active comprises Natrulon H-10 laurate (nikkol Decaglyn 1-L), Natrulon H-10 oleate (nikkol Decaglyn 1-O), with the list of Natrulon H-10, dioleate (Caprol.RTM.PEG 860), Natrulon H-10 stearate, Natrulon H-10 laurate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Natrulon H-10 linoleate, polyglycereol-6 stearate, polyglycereol-6 laurate, polyglycereol-6 myristinate, polyglycereol-6 cetylate and polyglycereol-6 linoleate.Poly-castor oil acid polyglycerin ester (Polymuls) is also preferred surfactant.

propylene glycol fatty ester

The ester of propylene glycol and fatty acid is the surfactant being applicable to the specific embodiment of the invention.In this type of surfactant, preferred hydrophobic surfactant comprises PGML (Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propylene glycol mono-oleate (myverol P-O6), propylene/dicaprate (Captex.RTM.200) and propylene glycol distearyl acid (Captex.RTM.800).

sterol and sterol derivative

Sterol and sterol derivative are the surfactants being applicable to the specific embodiment of the invention.Preferred derivant comprises polyethyleneglycol derivative.The preferred surfactant of this apoplexy due to endogenous wind is PEG-24 cholesterol ethers (Solulan C-24).

polyethylene Glycol sorbitan fatty acid ester

Various Polyethylene Glycol-sorbitan fatty acid ester all can be used, and is suitable as the surfactant of the specific embodiment of the invention.In Polyethylene Glycol-sorbitan fatty acid ester, preferred surfactant comprises PEG-20 sorbitan monolaurate (polysorbas20), PEG-4 sorbitan monolaurate (tween 21), PEG-20 span 40 (polysorbate40), PEG-20 sorbitan monostearate (polysorbate60), PEG-4 sorbitan monostearate (Tween61), PEG-20 dehydrated sorbitol mono-fatty acid ester (Tween 80), PEG-4 dehydrated sorbitol mono-fatty acid ester (sorbimacrogol oleate100), PEG-20 sorbitan trioleate (polysorbate85).Laurel alcohol ester is preferred, because they have short lipid chain compared with oleate, adds the absorption of medicine.

polyethylene glycol alkyl ether

The ether of Polyethylene Glycol and alkylol is applicable to the surfactant of the specific embodiment of the invention.Preferred ether comprises lanolin alcohol polyethers (lanolin alcohol polyethers-5, lanolin alcohol polyethers-10, lanolin alcohol polyethers-15, lanolin alcohol polyethers-20, lanolin alcohol polyethers-25 and lanolin alcohol polyethers-40), laureth (laureth-5, laureth-10, laureth-15, laureth-20, laureth-25 and laureth-40), oleth (oleth-2, oleth-5, oleth-10, oleth-12, oleth-16, oleth-20 and oleth-25), stereth (stereth-2, stereth-7, stereth-8, stereth-10, stereth-16, stereth-20, stereth-25 and stereth-80), ceteth (ceteth-5, ceteth-10, ceteth-15, ceteth-20, ceteth-25, ceteth-30 and ceteth-40), PEG-3 oleyl ether (volpo3) and PEG-4 lauryl ether (Brij 30).

carbohydrates and their derivative

Sugar derivatives is applicable to the surfactant of the specific embodiment of the invention.Such preferred surfactant comprises sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside.

polyalkylene glycol alkyl phenol

Several Polyethylene Glycol-alkyl phenol surfactant is available, such as PEG-10-100 nonyl phenol and PEG-15-100 octylphenol ether, tyloxapol, octoxinol, nonoxynolum, and is applicable to the specific embodiment of the present invention.

pULLRONIC F68 (POE-POP) block copolymer

POE-POP block copolymer is a unique base polymer surfactant.The unique texture of this surfactant, namely has hydrophilic POE and the hydrophobicity POP part of clear and definite ratio and position, provides the multiple surfactant being applicable to the specific embodiment of the invention.These surfactants provide with extensive stock name, comprise Synperonic PE series (ICI); Pluronic.RTM. series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare and Plurodac.The common name of these polymer is " poloxamer " (CAS 9003-11-6).These polymer have formula:

HO (C ₂h ₄o) _a(C ₃h ₆o) _b(C ₂h ₄o) _ah, wherein " a " and " b " represents the number of polyoxyethylene and polyoxypropylene units respectively.

Such preferred hydrophilic surfactant active comprises poloxamer 108,188,217,238,288,338 and 407.Such preferred hydrophobic surfactant comprises Pluronic/Lutrol F 44,182,183,212,331 and 335.

polyester-polyethyleneglycol block copolymer

Polyethylene glycol-ester block copolymer is the polymeric surfactant of a class uniqueness.Namely the unique texture of this surfactant has hydrophilic polyglycol (PEG) and the hydrophobic polyester part of clear and definite ratio and position, provides the various surfactant being applicable to the specific embodiment of the invention.Polyester in this block polymer comprises poly-(L-lactide) (PLLA), poly-(DL-lactide) (PDLLA), PDLA (PDLA), polycaprolactone (PCL), polyesteramide (PEA), polyhydroxyalkanoatefrom, poly butyric ester (PHB), poly butyric ester-altogether-hydroxyl valerate (PHBV), poly butyric ester-altogether-hydroxycaproic ester (PHBHx), polyamino acid, PGA or polyglycolic acid (PGA), PGA and copolymer (poly-(lactic-co-glycolic acid) and lactic acid, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-caprolactone) and 6-caprolactone and poly-(Acetic acid, hydroxy-, bimol. cyclic ester-altogether-trimethylene carbonate) and trimethylene carbonate), and copolyesters.Example has PLA-b-PEG, PLLA-b-PEG, PLA-co-PGA-b-PEG, PCL-co-PLLA-b-PEG, PCL-co-PLLA-b-PEG, PEG-b-PLLA-b-PEG, PLLA-b-PEG-b-PLLA, PEG-b-PCL-b-PEG and other two, three and segmented copolymer.Hydrophilic block can be other hydrophilic or water-soluble polymer, such as polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide and polyacrylic acid.

polyethyleneglycol-graft copolymer

An example of graft copolymer is Soluplus (BASF, German).Soluplus is Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer.This copolymer is the solubilizing agent with amphipathic chemical constitution, the insoluble drug in its energy solubilising aqueous medium, such as paclitaxel, rapamycin and derivant thereof.The molecular weight ranges of this copolymer is 90,000-140000g/mol.

There is the polymer of amphipathic chemical constitution, copolymer, block copolymer and graft copolymer and be used as additive in the present invention.The polymer with amphipathic chemical constitution has block or graft copolymer.In the different repeat units of copolymer, there is multiple fragment (at least two fragments).In some embodiments, in copolymer, the hydrophilic of a fragment is better than another fragment.Equally, in copolymer, the hydrophobicity of a fragment is better than another fragment.Such as, in Soluplus (BASF, German), the hydrophilic of Polyethylene Glycol fragment is better than Vinylcaprolactam homopolymer-polyvinyl acetate fragment.In polyethylene glycol-ester block copolymer, the hydrophobicity of polyester fragment is better than Polyethylene Glycol fragment.In PEG-PLLA, the hydrophilic of PEG is better than PLLA.In PEG-b-PCL-b-PEG, the hydrophobicity of PCL is better than PEG.Hydrophilic fractions is not limited to Polyethylene Glycol.Other water-soluble polymer, such as soluble polyvinylpyrrilidone and polyvinyl alcohol can form the hydrophilic fractions in amphipathic structural polymer.In the present invention copolymer can with other additive use in conjunction.

sorbitan fatty acid ester

The sorbitan ester of fatty acid is applicable to the surfactant of the specific embodiment of the invention.In these esters, preferred hydrophobic surfactant comprises sorbitan monolaurate (arlacel 20), span 40 (span 40) and dehydrated sorbitol mono-fatty acid ester (sorbester p17), sorbitan monostearate.

Span 40 is ascorbic amphipathic derivatives (having Vitamin C activity), can play two kinds of important functions in solubilising system.The first, it has effective polar group that can regulate microenvironment.These polar groups are identical groups, and it makes vitamin C (ascorbic acid) self become one of the strongest organic solid compound of available water solublity: ascorbic acid is solvable about 30wt/wt% (closely the dissolubility of such as sodium chloride) in water.And the second, part ascorbyl palmitate can be converted into the better salt of water solublity when pH increases, such as vitamin-c palmitate sodium.

ionic surfactant

Ionic surfactant comprises cationic, anionic and amphoteric surfactant, is applicable to the hydrophilic surfactant active of the specific embodiment of the invention.

Anionic surfactant is with those of negative charge in hydrophilic parts.The anion surfactant being used as the primary categories of additive in the specific embodiment of the invention is containing those of carboxylate radical, sulfate radical and sulfonate ion.The cation being preferred for the specific embodiment of the invention has sodium, calcium, magnesium and zinc.Straight chain is saturated or undersaturated C8-C18 aliphatic group typically.The anion surfactant with carboxylic acid ion comprises aluminium stearate, sodium stearate, calcium stearate, magnesium stearate, zinc stearate, enuatrol, zinc oleate and potassium oleate, sodium stearyl fumarate, sodium lauroyl sarcosine and myristoyl-N-methylaminoacetic acid sodium.The anion surfactant with sulfate groups comprises sodium lauryl sulfate, sodium lauryl sulphate, single-, two-and triethanolamine lauryl base sodium sulfate, sodium laureth sulfate, sodium cetyl stearyl sulfate salt, spermaceti sodium sulfate, sodium tetradecyl sulfate, sulfated castor oil, cholesterol sodium sulfate, sodium tetradecyl sulfate, myristyl alcohol sulfuric ester sodium salt), capryl alcohol sulfuric ester sodium salt, the alkyl sulfate of other mid-chain branched or non-branching and ammonium lauryl sulfate.The anion surfactant with sulfonate group comprises docusate sodium, 2-Sulfosuccinic acid ethylhexyl sodium, lauryl alcohol sulfoacetic acid ester sodium salt, sodium alkyl benzene sulfonate, dodecylbenzene sodium sulfonate, diisobutyl sodium sulfosuccinate, diamyl sodium sulfosuccinate, two (2-ethylhexyl) sulfosuccinate and two (1-methyl amyl) sodium sulfonate.

Cationic surfactant the most frequently used in the specific embodiment of the invention is that to have general formula be R ₁, R ₂, R ₃, R ₄n ⁺x ^-quaternary ammonium compound, wherein X ^-be generally chloride or bromide ion, and R represents the alkyl containing C8-18 atom.The surfactant of these types due to its bactericidal property pharmaceutically very important.The dominant cation surfactant used in medicine of the present invention and armarium preparation is quaternary ammonium salt.Surfactant comprises cetrimonium bromide, cetyl trimethyl ammonium bromide, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetyltrimethylammonium chloride, chlorination is stearic, lauralkonium chloride, tetrachloro dodecyl ammonium, chlorination myristyl picoline and picoline chloride.These surfactants can react with some therapeutic agents in preparation or coating.If surfactant can not react with therapeutic agent, so they are preferred.

Amphion or amphiphilic surfactant comprise empgen BB, cocamido propyl betaine, coconut oleoyl amine both sexes base glycinate etc.

Preferred ionic surface active agent comprises sodium lauryl sulfate, sodium lauryl sulphate, sodium laureth sulfate, cetearyl alcohol sodium sulfate, sodium cetyl stearyl sulfate salt, sodium tetradecyl sulfate, sulfated castor oil, Cholesterol sulfate sodium, sodium tetradecyl sulfate, myristyl alcohol sulfuric ester sodium salt, capryl alcohol sulfuric ester sodium salt, the alkyl sulfate of other mid-chain branched or non-branching, docusate sodium, 2-Sulfosuccinic acid ethylhexyl sodium, lauryl alcohol sulfoacetic acid ester sodium salt, sodium alkyl benzene sulfonate, dodecylbenzene sodium sulfonate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, Dodecyl trimethyl ammonium chloride, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, edrophonium chloride, domiphen bromide, the dialkyl of sodium sulfosuccinate, 2-Sulfosuccinic acid ethylhexyl sodium, sodium cholate and sodium taurocholate.These quaternary ammonium salts are preferred additives.They all can dissolve in organic solvent (such as ethanol, acetone and toluene) and water.This is particularly useful in armarium coating, because it can simplify preparation and coating processing, and has good adhesion property.Water-insoluble drug is dissolved in organic solvent usually.The usual scope of HLB value of these surfactants is 20-40, and such as the HLB value of sodium lauryl sulphate (SDS) is 38-40.

Surfactants more described herein are highly stable when heating.They can survive in ethylene oxide sterilizing process.They do not react with medicine such as paclitaxel or rapamycin in sterilization process.Carboxyl, ester, amide group are preferred, because their unlikely and drug reactiones, and amine and acid groups often react with paclitaxel or rapamycin in sterilization process.In addition, surfactant additive improves integrity and the quality of coating, and granule can not be come off in processing procedure.When surfactant described herein and paclitaxel are prepared, experimentally it can protect medicine can not discharge too early in equipment delivery process, also to contribute within target site very of short duration standing time of 0.2 to 2 minute release and eluting paclitaxel fast simultaneously.The unexpected height of the experimentally absorption of target site tissue to medicine.

there is the change of one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound

Have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group compound comprise amino alcohol and organic acid combination, amino alcohol, hydroxy carboxylic acid, ester and anhydride, hydroxy-ketone, hydroxy-lactone, hydroxy ester, phosphoric acid sugar, Sulfated saccharides, ether, ethohexadiol, aminoacid, peptide, protein, sorbitan, glycerol, polyhydric alcohol, phosphate, sulfate, organic acid, ester, salt, vitamin, and the molecule of their replacement.In some detailed description of the invention, molecular weight lower than 5,000-10,000 have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group hydrophilic compounds be preferred.In other detailed description of the invention, molecular weight lower than 1000-5,000 have one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester group additive be preferred, or more preferably lower than 750-1,000, or most preferably lower than 750.In these detailed description of the invention, the molecular weight of additive is preferably lower than the molecular weight being delivered medicine.In addition, the molecular weight of additive preferably higher than 80 because molecular weight lower than 80 molecule be very easy to evaporation and can not be retained in the coating of armarium.If additive is volatile or at room temperature for liquid, in order to can not loss additive in the solvent evaporation process of processing in coating, its molecular weight be very important more than 80.But in some detailed description of the invention, additive is nonvolatile, the such as solid additive of alcohol, ester, amide, acid, amine and derivant thereof, the molecular weight of additive can lower than 80, lower than 60, and lower than 20, because this additive is not easy to evaporate from coating.Solid additive can be crystal, semi-crystal and amorphous.Micromolecule can spread rapidly.They can discharge self from sending sacculus easily, accelerate the release of medicine, and they can be left away from drug diffusion when medicine is attached to bodily cavity tissue.In some detailed description of the invention, the hydroxyl of more than four is preferred, such as, in the situation of high molecular additive.Solid tumor is slow.If the molecular weight of additive or compound is high, if such as molecular weight is greater than 800, is greater than 1000, is greater than 1200, be greater than 1500 or be greater than 2000, macromole can be very slow from the eluting of medical equipment surface, and medicine can not be discharged in 2 minutes.If these macromole contain the hydroxyl of more than four, their hydrophilicity increases, and it is necessary that this is that relatively large molecule discharges rapidly medicine.The hydrophilic increased helps from sacculus eluting coatings, accelerates the release of medicine, and enhancing or help medicine move the polar head-group by water barrier and double-layer of lipoid, and penetrates into tissue.Hydroxyl is preferred hydrophilic radical, because it may react with water-insoluble drug such as paclitaxel or rapamycin very much.In some embodiments, the melting point compound with more than four hydroxyls is 120 DEG C or lower.In some embodiments, the compound with more than four hydroxyls has three adjacent hydroxyls, its side all at molecule in spatial configuration.Such as, sorbitol and xylitol have three adjacent hydroxyls, and its spatial configuration is all in the side of molecule, and galactitol is not.This differentia influence physical property of isomer, such as fusing point.The spatial configuration of three adjacent hydroxyl groups can strengthen the combination of medicine.This will make the Compatibility improvement of water-insoluble drug and hydrophilic additive, and facilitates tissue to the picked-up of medicine and absorption.

The compound with amide group is very important in the coating agent of some detailed description of the invention of the present invention.Carbamide is a kind of compound with amide group.Other comprise biuret, acetamide, lactamide, amino acid amide, acetaminophen, uric acid, polyureas, urethanes, urea derivative, nicotiamide, N-methylacetamide, N, N-dimethyl acetylamide, sulphacetamide, versetamide, lauric acid diethyl amide, lauric myristic diglycollic amide, N, N-two (2-hydroxyethyl stearmide), coconut oleoyl amine MEA, coconut oleoyl amine DEA, arginine, and other organic acid amide and derivant thereof.Some compounds with amide groups also have one or more hydroxyl, amino, carbonyl, carboxyl, acid or ester group.

One of compound with amide group is the low-molecular-weight polyvidone of solubility.This polyvidone comprises Kollidon 12 PF, Kollidon 17 PF, Kollidon 17, Kollidon 25 and Kollidon 30.Kollidon product is by the soluble rank of various molecular weight and particle diameter and soluble level polyvinylpyrrolidone, vinyl pyrrolidone/vinyl acetate copolymer, and the mixture composition of polyvinyl acetate and polyvinylpyrrolidone.These series of products are named as Povidone, Crospovidone and Copovidone.Low-molecular-weight and Povidone and Copovidone of solubility is the additive be even more important in the present invention.Such as, Kollidon 12 PF, Kollidon 17 PF and Kollidon 17 is extremely important.Solid polyvidone can maintain the integrity of coating on armarium.Low-molecular-weight polyvidone can be absorbed or be penetrated in pathological tissues.The preferred molecular weight ranges of polyvidone is lower than 54000, lower than 11000, lower than 7000, lower than 4000.They can solubilizing water-insoluble therapeutic agent.Due to solid, low-molecular-weight and tissue resorption/permeate these character, Povidone and Copovidone is particularly useful for the present invention.Povidone in the present invention can with other additive use in conjunction.In a detailed description of the invention, Povidone and non-ionic surface active agent (such as PEG-15 12-hydroxy stearic acid ester (Solutol HS 15), polysorbas20, Tween 80, Cremophor RH40, Cremophor EL & ELP) can be mixed with coating for armarium, such as foley's tube with paclitaxel or rapamycin or its analog.

There is the compound of ester group for the coating agent particular importance in some detailed description of the invention.The product of organic acid and alcohol is the compound with ester group.The compound with ester group is often used as the plasticizer of polymeric material.Various ester compounds comprises sebacate, adipate ester, glutarate and phthalic acid ester.The example of these compounds has two (2-ethylhexyl) ester of phthalic acid, phthalic acid two-just own ester, diethyl phthalate, adipic acid two (2-ethylhexyl) ester, dimethyl adipate, dioctyl adipate, dibutyl sebacate, dibutyl maleate, triethyl citrate, acetyl triethyl citrate, trioctyl lemon acid, THC, bytyry THC and trimethyl citrate.

The compound with one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester group more as herein described is highly stable when heating.They can survive in ethylene oxide sterilizing process, and can not react with water-insoluble drug paclitaxel or rapamycin in sterilization process.On the other hand, L-AA and salt thereof and diethanolamine are not necessarily survived in this kind of sterilization process, and their can react with paclitaxel.Therefore, for the sterilizing methods that L-AA is preferably different with diethanolamine.Hydroxyl, ester and amide group are preferred because they unlikely and therapeutic agent such as paclitaxel or rapamycin react.Sometimes, experimentally say, amine and acid groups can react with paclitaxel, and such as benzoic acid, gentisic acid, diethanolamine and ascorbic acid are unstable in ethylene oxide sterilizing, heating and ageing process, and can react with paclitaxel.When compound as herein described and paclitaxel are prepared, in order to prevent the equipment delivery process Chinese medicine premature loss before being placed into target site, Topcoating is favourable, because hydrophilic micromolecule sometimes too easily discharges medicine.When being placed in target site, medicine elutes from sacculus rapidly at this by compound.Surprisingly, when coating comprises these additives, even if some drugs is delivered in target site process can loses at equipment, but only placing in an experiment organized the unexpected height of the absorption of medicine after 0.2-2 minute, such as, containing additive hydroxy-lactone, as ribose acid lactone and gluconolactone.

Antioxidant

Antioxidant is the molecule that can delay or prevent other molecular oxidation.Oxidation reaction can produce free radical, and it starts chain reaction and can cause the degraded of sensitivity treatment agent such as rapamycin and derivant thereof.Antioxidant is by removing free radical thus stopping these chain reactions, and they are by being oxidized the oxidation self carrying out inhibit activities agent further simultaneously.In some detailed description of the invention, antioxidant is used as additive to stop or delays the oxidation of therapeutic agent in armarium coating.Antioxidant is a type free base scavenger.In some detailed description of the invention of the present invention, antioxidant be used alone or with other additive conbined usage, can prevent activating agent sterilizing or use before storage process in degrade.

Some representative example that can be used for the antioxidant of the inventive method include but not limited to oligomeric or polymeric proanthocyanidins, polyphenol, polyphosphate, poly methylene imine, high-sulfate agar oligomer, the Chitosan Oligosacchaides obtained is hydrolyzed by part chitosan, there is the multifunctional low polythiaether of hindered phenolic, hindered amine, such as but not limited to p-phenylenediamine, trimethyl dihydro-quinolone and alkylated diphenylamine, there is the substituted phenol compound (hindered phenol) of one or more large functional group as the tert-butyl group, arylamine, phosphite ester, azanol and benzofuranone.In addition, the aromatic amine such as dibasic p-phenylenediamine of p-phenylenediamine (PPD), diphenylamines and N, N' can be used as free radical scavenger.Other example includes but not limited to butylated hydroxyanisol (" BHT "), butylated hydroxyanisol (" BHA "), L-AA salt (vitamin C), vitamin E, draft Herba Rosmarini Officinalis, sage extract, glutathion, resveratrol, ethoxyquin, rosmanol, different rosmanol, diterpene phenol, propyl gallic acid, gallic acid, caffeic acid, P-coumaric acid, P-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrogenation zingiberone, chlorogenic acid, ellagic acid, propyl p-hydroxybenzoate, sinapic acid, daidzin, glycitin, genistin, daidzein, Glycitein, genistein, isoflavone and tetrabutyl oxybenzene quinone.The example of some phosphite esters comprises two (octadecyl) pentaerythritol diphosphites, three (2,4-bis--tert-butyl-phenyl) phosphite ester, dilauryl thiodipropionate and two (2,4-, bis--tert-butyl-phenyl) pentaerythritol diphosphites.Some examples are not limited to hindered phenol, comprise octadecyl-3,5, two-tertiary butyl-4-hydroxy cinnamate, four-methylene-3-(3', 5'-bis--tert-butyl-hydroxy phenyl) propionate methane 2,5-bis--tert-butyl hydroquinone, ionol, 1,2,3,-thrihydroxy-benzene, retinol and octadecyl-3-(3,5-, bis--tert-butyl-hydroxy phenyl) propionic ester.Antioxidant can comprise glutathion, thioctic acid, melatonin, tocopherol, tocotrienol, mercaptan, beta-carotene, tretinoin, kryptoxanthin, 2,6-bis--tert-butyl phenols, propyl gallic acid ester, catechin, catechin and gallate and Quercetin.Preferred antioxidant is Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).

fatsoluble vitamin and salt thereof

Other various forms many and the provitamin form of vitamin A. D. E and K are considered to fatsoluble vitamin, in addition, many other vitamin and vitamin source or analog be also fat-soluble, and there is polar group and relative high octanol-water partition coefficient.Obviously, the general categories of this compound has history and the high Benefit Risk ratio of safe handling, makes the additive that they can be used in the specific embodiment of the invention.

The example in following fatsoluble vitamin derivant and/or source also can be used as additive: alpha-tocopherol, betatocopherol, Gamma-Tocopherol, Delta-Tocopherol, tocopherol acetas, ergosterol, 1-α-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene, beta-carotene, gamma carotene, vitamin A, fursultiamine, methylol riboflavin, octotiamine, prosulthiamine, riboflavin, styrene thiamine, dihydrovitamin K1, menadiol diacetate, menadiol disulfate, menadiol, vitamin K1, phylloquinone oxide, Menaquinone K6 and vitamin K--S (II).Folic acid is also the type, although formula is water miscible at physiological ph for it, it can be prepared with the form of free acid.Other fatsoluble vitamin derivant that can be used for the specific embodiment of the invention obtains easily via known chemical reaction hydrophilic molecule.

water soluble vitamins and amphipathic derivatives thereof

Have in the vitamin that vitamin B, C, U, pantothenic acid, folic acid are relevant to menadione with some/vitaminogenic various forms and be manyly considered to water soluble vitamins.These also can with hydrophobic group or multivalent ion conjugation or complexation, form the amphipathic form with relatively high octanol-water partition coefficient and polar group.Equally, this compounds can have hypotoxicity and high benefit Hazard ratio, makes the additive that they can be used as in the specific embodiment of the invention.The salt of these materials also can be used as additive of the present invention.The example of water soluble vitamins and derivant includes but not limited to acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. 5-phosphate ester, nicotiamide ascorbic acid, riboflavin, riboflavin phosphate thiamine, folic acid, menadiol diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, K6 vitamin, K6 vitamin and vitamin U.In addition, as above, under wide pH scope comprises physiological pH, folic acid is water miscible as salt.

The compound having amino or other basic group reacts carry out modification easily via there is simple Acid-Base with the acid containing hydrophobic group such as fatty acid (particularly lauric acid, oleic acid, myristic acid, Palmic acid, stearic acid or 2 ethyl hexanoic acid), aminoacid, benzoic acid, salicylic acid or acid fatsoluble vitamin (such as riboflavin) that dissolubility is low.By the such as hydroxyl reaction of other group on this kind of acid and vitamin is formed key such as ester bond etc., other compound can be obtained.Water soluble vitamin derivative containing acidic-group can be reacted by the reactant such as stearylamine or riboflavin containing hydrophobic group and generate, such as, obtain the compound that can be used for the specific embodiment of the invention.Cetylate chain obtains ascorbyl palmitate with ascorbic connection.

aminoacid and salt thereof

Propylhomoserin, arginine, aspartic acid, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine and derivant thereof are that other can be used for the additive of the specific embodiment of the invention.

The salt form of some amino acid whose zwitterionic form and/or unit price or multivalent ion has polar group, relatively high octanol-water partition coefficient, detailed description of the invention used in the present invention." aminoacid that dissolubility is low " that uses in the context of the disclosure of invention refers to the aminoacid of the dissolubility in non-buffered water lower than about 4% (40mg/ml).These materials comprise cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine.

Also aminoacid dimer, glycoconjugate and derivant thereof can be used.By simple reaction well known in the art, hydrophilic molecule can be connected on hydrophobic amino acid, or hydrophobic molecule is connected on hydrophilic amino acid, obtain the additional additive that can be used for the specific embodiment of the invention.

Catecholamine matter, such as dopamine, levodopa, carbidopa and DOPA also can be used as additive.

oligopeptide, peptide and protein

Oligopeptide and peptide can be used as additive, because hydrophobicity and hydrophilic amino acid are easy to be connected, and can test amino acid whose various sequence to promote that medicine is to the infiltration of tissue to greatest extent.

Protein also can be used as the additive of the specific embodiment of the invention.Such as, serum albumin is particularly preferred additive, because it is water miscible and carrys out bound drug containing significant hydrophobic parts: paclitaxel has 89%-98% and protein binding after to human vein's infusion, and rapamycin has 92% and protein binding, main (97%) is and albumin bound.In addition, after adding BSA, the dissolubility of paclitaxel in PBS adds 20 times.Albumin is present in serum so that high concentration is natural, is therefore very safe for inside of human body vascular applications.

Other useful protein includes but not limited to other albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, Fibrinogen, lipase etc.

organic acid and ester, amide and anhydride

Example has acetic acid and anhydride, benzoic acid and anhydride, diethylene-triamine pentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, anhydride diethylene glycol, glutaric anhydride, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid aspartic acid, nicotinic acid, 2-Pyrrolidone-5-carboxylic acid, aleuritic acid, lac acid and 2-Pyrrolidone.Aleuritic acid and lac acid can form the resin being called as Lac.The release coating of foley's tube is can be used as after the combination of paclitaxel, aleuritic acid and lac acid.

These esters and anhydride dissolve in organic solvent, such as ethanol, acetone, butanone, ethyl acetate.Water-insoluble drug dissolves in the organic solvent containing these esters, amide and anhydride, is then easy to be coated on armarium, and is hydrolyzed under high ph conditions.The anhydride of hydrolysis or ester are acid or alcohol, and they are water miscible and from equipment, effectively can bring medicine in blood vessel wall.

other has the chemical combination of one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester group thing

The amino alcohol be positioned on ring-type and linear aliphatic and aromatic group, alcohol, amine, acid, amide and hydroxy acid is comprised according to the additive of detailed description of the invention.Example has L-AA and salt thereof, D-glucoascorbic acid and salt thereof, trometamol, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactose, sorbitol, sorbitol, phosphoric acid sugar, Glucopyranose. phosphoric acid, Sulfated saccharides, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, xylitol, cellosolvo, sugar, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of above-mentioned any organic acid and amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol) and five (propylene glycol), poly-(propylene glycol) oligomer, the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination.

The compositions of additive also can be used for the present invention.

A detailed description of the invention comprises compositions or the mixture of two kinds of additives, such as, comprises the first additive of surfactant and comprises the second additive of the compound with one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester group.

The compositions of surfactant and little water soluble molecules or mixture (having one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester group) have many advantages.In some cases, the preparation comprising two kinds of additives and water-insoluble drug mixture is better than the mixture comprising separately arbitrary additive.Hydrophobic drug will be worse than the combination of their Surfactants to extremely water-soluble micromolecular combination.They are often separated from little water soluble molecules, can cause not reaching optimized coating uniformity and integrity.The Log P of water-insoluble drug is higher than surfactant and little water soluble molecules.But the Log P of surfactant is higher than the Log P of the compound with one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester group usually.Surfactant has relatively high Log P (being usually greater than 0), and water soluble molecules has low Log P (being usually less than 0).Some surfactants when being used as additive in the specific embodiment of the present invention, and it is very strong to the adhesion on water-insoluble drug and armarium surface, and the medicine when target site can not be discharged fast from medical equipment surface.On the other hand, some soluble small moleculars (having one or more hydroxyl, amine, carbonyl, carboxyl, amide or the ester group) adhesion to armarium is very weak, make to get involved in the process at position coating ball ductus bursae being delivered to targeting, to arrive before target site just by drug release to such as serum.Surprisingly the present inventor finds, in some cases, by the concentration ratio of hydrophilic small molecules and surfactant in adjustment preparation, the stability of coating in delivery process and the quick medicament when expanding and the chamber wall being depressed into treatment intervention target site is organized discharge and are better than the preparation comprising separately arbitrary additive.In addition, due to the existence of surfactant, the intersolubility between water-insoluble drug and high water soluble molecule and the compatibility is improved.Surfactant also passes through it to medicine and micromolecular good adhesion, improves uniformity and the integrity of coating.The long-chain hydrophobic part tightly bound drug of surfactant, the hydrophilic parts of surfactant is in conjunction with soluble small molecular simultaneously.

Surfactant in mixture or compositions comprises all surface activating agent for the specific embodiment of the invention as herein described.Surfactant in mixture is optional from Polyethylene Glycol fatty ester, Polyethylene Glycol ω-3 fatty ester and alcohol, glycerin fatty ester, sorbitan fatty acid ester, polyethylene glycol glycerol fatty ester, Polyethylene Glycol sorbitan fatty acid ester, sugar fatty ester, Polyethylene Glycol sugar ester, polysorbas20, polysorbate40, polysorbate60, to different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polyethylene glycol (PEG) oleate, polyglycol distearate, polyethylene glycol glycerol laurate, Polyethylene Glycol olein, Polyethylene Glycol tristerin, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 lauric acid, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oleyl ether, Polyethylene Glycol lauroyl ether, polysorbas20, polysorbate40, polysorbate60, Tween 80, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside and derivant thereof.

The compound with one or more hydroxyl, amine, carbonyl, carboxyl or ester group in mixture or compositions comprises all compounds with one or more hydroxyl, amine, carbonyl, carboxyl or ester group for the specific embodiment of the invention as herein described.In a specific embodiment of the present invention, the compound in mixture with one or more hydroxyl, amine, carbonyl, carboxyl or ester group has a hydroxyl at least.In some detailed description of the invention, preferably there is the hydroxyl of more than four, such as, in the situation of high molecular additive.In some embodiments, the fusing point with the compound of one or more hydroxyl, amine, carbonyl, carboxyl or ester group is 120 DEG C or lower.Solid tumor is slow.If the molecular weight of additive or compound is high, if such as molecular weight is more than 800, more than 1000, more than 1200, more than 1500 or more than 2000; Macromole from the eluting of medical equipment surface slowly, so that can not discharge medicine within 2 minutes.If these macromole comprise the hydroxyl of more than four, their hydrophilicity increases, and this is necessary for relatively large molecule rapid delivery of pharmaceuticals.The hydrophilic increased contributes to the release eluting coating from sacculus, accelerate medicine, and strengthens or help medicine to move polar head-group by water barrier and double-layer of lipoid thus infiltrating tissues.Hydroxyl is preferred hydrophilic parts because it unlikely and water-insoluble drug such as paclitaxel or rapamycin react.

There is in mixture one or more hydroxyl, amine, carbonyl, carboxyl, the compound of amide or ester moiety is selected from L-AA and salt thereof, D-glucoascorbic acid and salt thereof, triethanolamine, trometamol, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate salt, gentisic acid, lactobionic acid, lactose, sorbitol, sorbitol, phosphoric acid sugar, Glucopyranose. phosphoric acid, Sulfated saccharides, sinapic acid, Rhizoma et radix valerianae xylitol, acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, xylitol, cellosolvo, sugar, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of above-mentioned any organic acid and amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol), with five (propylene glycol), poly-(propylene glycol) oligomer, the block copolymer of Polyethylene Glycol and polypropylene glycol, with derivant and combination thereof.

The mixture of surfactant and soluble small molecular or compositions impart two kinds of additive advantages.Water-insoluble drug often has the poor compatibility with the compound of high water soluble, and surfactant facilitates the compatibility.Surfactant further improves the quality of coating, uniformity and integrity, and granule can not split away off from sacculus in processing procedure.Surfactant decreases the drug loss be delivered in target site process.Water soluble compound enhances medicine from the release of sacculus and medicine absorption in the tissue.Experimentally say, compositions effectively can stop the release of medicine in delivery process surprisingly, and reaches high levels of drugs at tissue in placement after very of short duration 0.2-2 minute.In addition, in zooscopy, it effectively reduces stricture of artery and late luminal loss.

The mixture of some surfactants and soluble small molecular or compositions are highly stable when heating.They can survive in ethylene oxide sterilizing process, and can not react with water-insoluble drug paclitaxel or rapamycin in sterilization process.Hydroxyl, ester, amide group are preferred because they unlikely and therapeutic agent such as paclitaxel or rapamycin react.Sometimes, amine and acid groups can react with paclitaxel, and ethylene oxide sterilizing, heating and aging time unstable.When mixture as herein described or compositions and paclitaxel are prepared, in order to protect medicine layer and prevent the medicine premature loss in equipment, the coating at top is favourable.

liquid additive

Often solid additive is used in medication coat armarium.A kind of diodone Iopromide and paclitaxel are used for coated spheres ductus bursae.The coating of these types is not containing liquid chemical.This coating is paclitaxel solid and the aggregation of Iopromide solid on foley's tube surface.This coating lacks adhesion to armarium, and coating granule can come off in process and interventional procedure.Water-insoluble drug is chemical solid often, such as paclitaxel, rapamycin and analog thereof.In the specific embodiment of the present invention, liquid additive can be used for armarium coating to improve the integrity of coating.Preferably containing the liquid additive that can improve solid drugs and/or other solid additive compatibility.Preferably containing the liquid additive that can form solid cladding solution instead of two or more solid particle polymers.When other additive and medicine are solids, preferably containing at least one liquid additive.

The liquid additive used in the specific embodiment of the invention is not solvent.Such as the solvent of ethanol, methanol, dimethyl sulfoxine and acetone will be evaporated after coating is dried.In other words, after coating drying, solvent can not retain in the coating.On the contrary, the liquid additive in the specific embodiment of the invention will retain in the coating after coating is dried.Liquid additive is liquid or semiliquid under room temperature and an atmospheric pressure.Liquid additive at room temperature can form gel.Liquid additive comprises hydrophilic parts and the affine part of medicine, and part that its Chinese medicine is affine is hydrophobic parts, has the part of affinity and to be interacted at least one had therapeutic agent in the part of affinity by Van der Waals by hydrogen bond to therapeutic agent.Liquid additive is not oil.

Nonionic surfactant is liquid additive often.The example of liquid additive wraps the polyethylene glycol fatty acid stating and mention and ester, the ester exchange offspring of Polyethylene Glycol oil, polyglycerol fatty acid and ester, propylene glycol fatty ester, Polyethylene Glycol sorbitan fatty acid ester and polyethylene glycol alkyl ether.Some examples of liquid additive have Tween 80, sorbimacrogol oleate100, polysorbas20, polysorbate40, polysorbate60, Solutol HS 15, Cremophor RH40 and Cremophor EL & ELP.

more than one additive

In a detailed description of the invention, cover the additive that the layer of armarium outer surface or coating comprise more than one, such as two kinds, three kinds or four kinds of additives.In a kind of detailed description of the invention, coating comprises at least one additive, and described at least one additive-package is containing the first additive and Second addition, and the hydrophilic of the first additive is greater than Second addition.In another embodiment, coating comprises at least one additive, and described at least one additive-package is containing the first additive and Second addition, and the first additive has the structure different from Second addition.In another embodiment, coating comprises at least one additive, and described at least one additive-package is containing the first additive and Second addition, and the HLB value of the first additive is higher than Second addition.In another embodiment, coating comprises at least one additive, and described at least one additive-package is containing the first additive and Second addition, and the LogP value of the first additive is lower than Second addition.Such as, the hydrophilic of sorbitol (Log P-4.67) is greater than polysorbas20 (Log P about 3.0).The hydrophilic of polyethylene glycol fatty ester is greater than fatty acid.The hydrophilic of butylated hydroxyanisol (BHA) (Log P 1.31) is greater than butylated hydroxyanisol (BHT) (Log P 5.32).

In another embodiment, the surfactant that the layer of armarium outer surface or coating comprise more than one is covered, such as two kinds, three kinds or four kinds of surfactants.In a detailed description of the invention, coating comprises at least one surfactant, and described at least one surfactant comprises first surface activating agent and second surface activating agent, and the hydrophilic of first surface activating agent is greater than second surface activating agent.In another embodiment, coating comprises at least one surfactant, and described at least one surfactant comprises first surface activating agent and second surface activating agent, and the HLB value of first surface activating agent is higher than second surface activating agent.Such as, the hydrophilic of Tween 80 (HLB 15) is greater than polysorbas20 (HLB 16.7).The hydrophilic of Tween 80 (HLB 15) is greater than sorbimacrogol oleate100 (HLB 10).The hydrophilic of Pluronic F68 (HLB 29) is greater than Solutol HS 15 (HLB 15.2).The hydrophilic of sodium lauryl sulphate (HBL 40) is greater than docusate sodium (HLB 10).The hydrophilic of Tween 80 (HBL 15) is greater than CreamophorEL (HBL 13).

Preferred additive comprises different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 laurate, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, octoxinol, nonoxynolum, alevaire, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine (aminoacid), cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid and salt thereof, pyridoxal 5-phosphate salt, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U (vitamin), albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, α-2-macroglobulin, fibronectin, vitronectin, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, Dodecyl trimethyl ammonium chloride, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA and salt thereof, D-glucoascorbic acid and salt thereof, tromethane, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconolactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate salt, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycol), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol), with five (propylene glycol), poly-(propylene glycol) oligomer, the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination (have one or more hydroxyl, amino, carbonyl, carboxyl, the compound of amide or ester moiety).Some in these additives simultaneously can be water-soluble and be dissolved in organic solvent.They have good adhesion property and adhere to the surface of polyamide armarium, such as foley's tube.Therefore, they can be used for the adhesion layer of the specific embodiment of the invention, top layer and/or medicine layer.Aromatic series and aliphatic group add the dissolubility of water-insoluble drug in coating solution, and the polar group of alcohol and acid accelerates the infiltration of medicine to tissue.

Amino alcohol and organic acid compositions or mixture or amide reaction product is comprised according to other preferable additives of the specific embodiment of the invention.Example has lysine/glutamic acid, lysine acetate, lactobionic acid/meglumine, lactobionic acid/trometamol, lactobionic acid/diethanolamine, lactic acid/meglumine, lactic acid/trometamol, lactic acid/diethanolamine, gentisic acid/meglumine, gentisic acid/trometamol, gentisic acid/diethanolamine, vanillic acid/meglumine, vanillic acid/trometamol, vanillic acid/diethanolamine, benzoic acid/meglumine, benzoic acid/trometamol, benzoic acid/diethanolamine, acetic acid/meglumine, acetic acid/trometamol and acetic acid/diethanolamine.

Other preferable additives according to the specific embodiment of the invention comprises hydroxy-ketone, hydroxy-lactone, hydroxy acid, hydroxy ester and hydroxy amide.Example has gluconolactone, D-glucoheptonic acid-Isosorbide-5-Nitrae-lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, three hydroxybutyric acid lactones, ribose acid lactone, glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lactic acid, acetaminophen, vanillic acid, sinapic acid, hydroxy benzoic acid, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and derivant thereof.

Other preferable additives that can be used for the specific embodiment of the invention comprises riboflavin, riboflavine phosphate, vitamin D3, folic acid (FA), vitamin B12, diethylene-triamine pentaacetic acid dianhydride, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic acid and anhydride, anhydride diethylene glycol, glutaric anhydride, L-AA, thiamine, nicotiamide, nicotinic acid, 2-Pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine.

From structure, these additives enjoy structural similarity, and compatible with water-insoluble drug (such as paclitaxel and class handkerchief mycin).They often contain double bond (such as C=C, C=N, C=O) in aromatic series or aliphatic structure.These additives are also containing amine, alcohol, ester, amide, anhydride, carboxylic acid and/or hydroxyl.They can be interacted by Van der Waals with medicine and form hydrogen bond.They also can be used for the top layer of coating.Compound containing one or more hydroxyl, carbonyl or amido such as can be used as additive especially, because they contribute to the release of medicine from equipment surface, and be easy to the water of replacing cell membrane polar head-group and surface protein side, thus the permeability of this barrier for hydrophobic drug can be removed.They accelerate hydrophobic drug and leave the lipid layer moving into cell membrane and tissue, because it has very high affinity from sacculus.They can also deliver or accelerate medicine and leave in the stronger aqueous environments of immigration from sacculus, such as intercellular space, as because of balloon angioplasty or the impaired vascular tissue of stent-expansion.Such as polyglycereol fatty ester, the acid ascorbyl ester of fatty acid, the additive of the sugar ester of fatty acid, alcohol, ether has aliphatic chain, and it can be incorporated into the lipid conformation of target tissue film, by drug carrier to lipid layer.There is in some aminoacid, vitamin and organic acid structure aromatic series C=N group and amino, hydroxyl and carboxyl moieties.They have can in conjunction with hydrophobic drug such as paclitaxel or rapamycin or the structure division with hydrophobic drug complexation, and they also have the barrier by removing between hydrophobic drug and Cell membrane lipids structure and contribute to the structure division of tissue infiltration.

Such as, different nonyl phenyl poly epihydric alcohol (Olin-10G and Surfactant-10G), polyethylene glycol glycerol monoleate, sorbitan monolaurate (arlacel 20), span 40 (span 40), dehydrated sorbitol mono-fatty acid ester (sorbester p17), sorbitan monostearate, Natrulon H-10 oleate, Natrulon H-10 laurate, Natrulon H-10 cetylate and Natrulon H-10 stearate all have the hydroxyl of more than four in its hydrophilic parts.These hydroxyls have extraordinary affinity to blood vessel wall, can replace the hydrogen bond on hydrone.Meanwhile, they have the long-chain of fatty acid, alcohol, ether and ester, can be incorporated into the part forming lipid conformation in the lipid conformation of cell membrane with hydrophobic drug complexation.This distortion of target cell lipid film or loosening hydrophobic drug of can accelerating further are to the infiltration organized.

As for another example, L-AA, thiamine, maleic acid, nicotiamide and 2-Pyrrolidone-5-carboxylic acid all have very high water and dissolve with ethanol degree, and low-molecular-weight and small size.They also have the structural constituent comprising aromatic series C=N, amino, hydroxyl and carboxyl.These structures and have the extraordinary compatibility between paclitaxel and rapamycin, and the dissolubility of these water-insoluble drugs in water can be increased and promote the absorption of tissue to them.But they are often poor to the absorption on armarium surface.Therefore, they are preferably used for medicine layer and top layer with other additive combination, and at this, they can be used to the absorption promoting medicine.Vitamin D2 and D3 particularly useful because they self have anti-restenosis effect and reduce thrombosis, particularly when applying with paclitaxel plus.

In a specific embodiment of the present invention, additive is solvable in aqueous solvent, and dissolves in organic solvent.Lack enough hydrophilic parts and exemplary extremely hydrophobic compound insoluble in aqueous solvent has such as dyestuff tonyred, it is not be used as additive in these detailed description of the invention.Tonyred also has genotoxicity.

In a detailed description of the invention, the concentration and density being applied at least one therapeutic agent on armarium surface is about 1 to 20 μ g/mm ², or be more preferably about 2 to 6 μ g/mm ².In a detailed description of the invention, the concentration and density being applied at least one additive on armarium surface is about 1 to 20 μ g/mm ².The weight ratio of specific embodiment of the invention floating coat inner additive and medicine is about 20 to 0.05, preferably about 10 to 0.5, or more preferably about 5 to 0.8.

The visual usable condition of the relative quantity of therapeutic agent and additive in coating and different.Such as, if the optimised quantity of additive can be depending on selected particular therapeutic agent and additive, surface modifier critical micelle concentration its form the octanol-water partition coefficient (P) of micelle, the hydrophilic-hydrophobic-equilibrium valve (HLB) of surfactant or additive, the fusing point of additive, additive and/or the water solubility of therapeutic agent, the surface tension etc. of surface modifier aqueous solution.

The amount that additive exists in the Exemplary coating compositions of the specific embodiment of the invention makes with after aqueous solution dilution, and carrier forms the aqueous dispersion or emulsion or solution clarified, contains hydrophobic therapeutic agent in aqueous or organic solution.When the relative quantity of surfactant is excessive, dispersions obtained is obviously " muddiness ".

The light transmittance of aqueous dispersion can use standard quantitative technology to carry out turbidity assessment and measure.The conventional method measuring turbidity uses a such as ultraviolet-uisible spectrophotometer, measures the amount of the light transmitted by solution under setted wavelength.Use the method, the corresponding high-transmission rate of light transmittance, because more muddy solution will disperse more incident illumination, will cause lower transmittivity measurement results.

Measuring the another kind of method of light transmittance and the carrier diffusion coefficient by aqueous boundary region, is the granular size that quantitative assay forms dispersion.These are measured available commercially available Particle Size Analyzer and carry out.

Other consideration is by the selection of the concrete ratio of further clear and definite different additive.These consider the biological acceptable degree comprising additive and provide the hydrophobic therapeutic agent of optimal dosage.

therapeutic agent

The medicine or the bioactive substance that can be used for the specific embodiment of the invention can be arbitrary therapeutic agent or material.Medicine can have different physical states, such as molecular distribution, crystal form or bunch conjunction form.The exemplary drugs being specially adapted to the specific embodiment of the invention has lipophilic water-fast medicine substantially, such as paclitaxel, rapamycin, daunorubicin, amycin, lapachol, vitamin D2 and D3 and sum analogous to general Dedekind sum thereof.These medicines are specially adapted to the coating on foley's tube, in order to treat vasculature tissue.

The other medicines that can be used for the specific embodiment of the invention include but not limited to glucocorticoid (such as dexamethasone, betamethasone), hirudin, angiopeptin, aspirin, somatomedin, antisense drug, cancer therapy drug, antiproliferative, oligonucleotide and are more typically anti-platelet agents, anticoagulant, antimitotic agent, antioxidant, antimetabolite, anti-chemoattractant and antiinflammatory.

That also can be used for the specific embodiment of the invention is polynucleotide, antisense, RNAi or siRNA of such as inflammation-inhibiting and/or smooth muscle cell or fibroblast proliferation.

Antiplatelet drug can comprise the medicine of such as aspirin and dipyridamole.Aspirin is divided into analgesia, antipyretic, antiinflammatory and antiplatelet drug.Dipyridamole is the medicine similar to aspirin, is that it has antiplatelet feature.Dipyridamole is also divided into coronary vasodilator.The anticoagulant that can be used for the specific embodiment of the invention can comprise the medicine of such as heparin, protamine, hirudin and Ticks anticoagulant protein.Antioxidant can comprise probucol.Antiproliferative can comprise the medicine of such as amlodipine and doxazosin.Can be used for the medicine that the antimitotic agent of the specific embodiment of the invention and antimetabolite comprise such as methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, amycin and Mitomycin.Antibacterial for the specific embodiment of the invention comprises penicillin, cefoxitin, benzylpencilline, tobramycin and gentamycin.Suitable antioxidant for the specific embodiment of the invention comprises probucol.In addition, gene or nucleic acid or its part can be used as therapeutic agent in the specific embodiment of the present invention.In addition, collagen protein synthesis inhibitor such as tranilast can be used as therapeutic agent in the specific embodiment of the present invention.

Comprise various porphyrin compound for photodynamic therapy or radiotherapeutic photosensitizer, such as porfimer sodium (porfimer), such as, also can be used as the medicine in the specific embodiment of the invention.

Medicine for the specific embodiment of the invention also comprises everolimus, somatostatin, tacrolimus, Roxithromycin, all how, mycin, ascosin, bar bifilomycin, erythromycin, midecamycin, josamycin, ConA, clarithromycin, triacetyloleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, Rosuvastatin, atorvastatin, pravastatin, Pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxyl cyclophosphamide, chlormethine, L-Sarcolysinum, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiophene is for group, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5'-dihydric phosphate, cladribine, mercaptopurine, thioguanine, cytosine arabinoside, fluorouracil, gemcitabine, capecitabine, Docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxyurea, miltefosine, pentostatin, aldesleukin, retinoic acid, asparaginase, pegaspargase, Anastrozole, exemestane, letrozole, formestane, aminoglutethimide, amycin, azithromycin, spiramycin, cepharanthine, inhibitors of smooth muscle cell proliferation-2w, Epothilones A and B, mitoxantrone, azathioprine, Bai Ruikuaer (mycophenolatmofetil), c-myc-antisense, b-myc-antisense, belulinic acid Betulinic acid, camptothecine, lapachol, β-lapachol, podophyllotoxin, betulin, Podophyllinic acid 2-ethyl hydrazides, molgramostim (rhuGM-CSF), Interferon Alfa-2b, lenograstim (r-HuG-CSF), filgrastim, Polyethylene Glycol, dacarbazine, basiliximab, Zenapax, select element (cytokine antagonist), CETP inhibitor, cadherines, basic element of cell division inhibitor, cox 2 inhibitor, NFkB, angiopeptin, ciprofloxacin, camptothecine, fluorescence embryonin (fluroblastin), suppress the monoclonal antibody of smooth muscle cell proliferation, basic fibroblast growth factor antagonist, probucol, prostaglandin, 1, 11-dimethoxy canthinone (1, 11-dimethoxycanthin-6-one), 1-hydroxyl-11-methoxyl group canthinone (1-hydroxy-11-methoxycanthin-6-one), Rhizoma Scopoliae Japonicae, Colchicine, NO donor such as pentaerythritol tetranitrate and syndnoeimines, S-nitrosoderivatives, tamoxifen, D-82041 DEISENHOFEN, beta estradiol, alpha-estradiol, estriol, estrone, ethinylestradiol, fostestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, can be used for kamebakaurin and other terpenoids of Therapeutic cancer, verapamil, tyrosine kinase inhibitor (tyrphostines), Ciclosporin A, 6-Alpha-hydroxy-paclitaxel, Tetraol, other macrocyclic oligoesters of taxotere and carbon suboxide (MCS) and derivant thereof, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoyl-phenoxy acetic acid, lignocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, Arechin (Polfa), penicillamine, oxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, cupreol, ademetionine, Myrtecaine, polidocanol, capsaicin, levomenthol, benzocaine, Sodium Aescinate, ellipticine, D-24851 (Calbiochem), colchicine, CA-E, indanocine, nocodazole, S100 albumen, bacitracin, Vitronectic receptor antagonist, azelastine, the guanidine cyclase stimulators of metalloproteases-1 and-2 tissue depressants, free nucleic acid, be incorporated into the nucleic acid in virus disseminating body, DNA and RNA fragment, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotide, VEGF inhibitor, IGF-1, from the agents of antibiotic group as cefadroxil, cefazolin sodium, Cefaclor, cefotaxime, tobramycin, gentamycin, penicillin is dicloxacillin such as, oxazacillin, sulfonamides, metronidazole, antithrombotic agents is argatroban such as, aspirin, abciximab, the antithrombase of synthesis, bivalirudin, coumarin, Enoxaparin, desulfurization and N-be acetylizad heparin again, tissue plasminogen activator, GpIIb/IIIa membrane receptor, Xa factor inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, larval carps, prourokinase, streptokinase, warfarin, urokinase, vasodilation is dipyridamole such as, rocornal, sodium nitroprusside, PDGF antagonist such as triazolo pyrimidine and seramin, ACE inhibitor is captopril such as, cilazapril, lisinopril, enalapril, losartan, thiol protease inhibitor, prostacyclin, vapiprost, interferon-ALPHA, β and γ, histamine antagonist, serotonin blocker, apoptosis inhibitor, apoptosis regulators is p65NF-kB or Bcl-xL antisense oligonucleotide such as, halofuginone hydrobromide, nifedipine, tranilast, molsidomine, tea leaf polyphenols, L-Epicatechin gallate, catechin, boswellic acid and derivant thereof, leflunomide, Antril (Synergen), Embrel, sulfasalazine, etoposide, dicloxacillin, tetracycline, omcilon, Mitomycin, procainamide, tretinoin, quinidine, disopyramide, flecainide, Propafenone, sotalol, amiodarone, the steroid such as Herba Bryophylli Pinnati toxin A that natural and synthesis obtains, Inonqqus obliquus alcohol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal material (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, Phenylbutazone, and other antiviral agent such as acyclovir, ganciclovir and zidovudine, antifungal is clotrimazole such as, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, Terbinafine, antigen biological agent such as chloroquine, mefloquine, quinine, in addition natural terpenoids such as hippocaesculin, barringtogenol C-C21-angelate, 14-dehydrogenation creeping bentgrass element, Agroskerin, creeping bentgrass element, 17-hydroxyl creeping bentgrass element, the very careless lactone of fish, 4, 7-oxygen ring anisomelic acid, baccharinoids B1, B2, B3 and B7, Bulbus Fritillariae Uninbracteatae, bruceanol A, B and C, guassin glycoside C, brucealin N and P, the smooth grass in different deoxidation ground, spend Elephantopus scaber L. lactone A and B in vain, Hedychium coronarium Koenig element A, B, C and D, ursolic acid, suaveolic acid A (hyptat ic acid A), room, pool terpene, isoiridogermanal, Maytenus diversifolius (Hemsl.) Hou alcohol, effusantin A, Amethystoidin A A and B, length copies sharp plain B, sculponeatin C, kamebaunin, leukamenin A and B, 13, 18-dehydrogenation-6 α-isoamylene acyl group oxo Ka Pali element, taxamairin A and B, regenilol, triptolide, other cymarin, apocymarin, Aristolochic Acid, mopterin, hydroxyl mopterin, Anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, root is containing three-bristle cudrania tree isoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadien-3, 20-dione, ginkgol, bilobol, ginkgoic acid, autumnolide, indicin, indicin-N-oxide, lasiocarpine, Inonqqus obliquus alcohol, glucosides 1a, podophyllotoxin, justicidin A and B, larreatin, malloterin, Firmiana platanifolia (Linn. f.) Marsili chromane alcohol, isobutyl group Firmiana platanifolia (Linn. f.) Marsili chromane alcohol, maquiroside A, plain A before ground, maytansine, lycoridicin, lycoricidine, pancratistatin, liriodendrin, double small parthenolide alkali, oxoushinsunine, aristolo-lactam-AII, double small parthenolide alkali, glucoperiplocymarin A, ghalakinoside, ursolic acid, deoxidation psorospermin, psychorubin, ricin A, Sanguinarine, the graceful dance Semen Tritici aestivi of acid, methyl sorbifolin, sphatheliachromen, stizophyllin, mansonine, strebloside, akagerine, dihydro Wu Sangbala alkali, hydroxyl usambarine, strychnopentamine, strychnophylline, usambarine, Wu Sangbala alkali, Rhizoma Coptidis, liriodendrin, oxoushinsunine, daphnoretin, lariciresinol, methoxyl group lariciresinol, Flos Caryophylli, umbelliferone, afromoson, acetyl Wei Si meter Ya ketone B, desacetylvismione A, and general shuttle oxadiazon A and B.

The specific embodiment of the present invention also can make pharmaceutical composition.Some compositions has Overlay, because they have different mechanism, and such as paclitaxel and rapamycin, paclitaxel and activated vitamin D, paclitaxel and lapachol, rapamycin and activated vitamin D, rapamycin and lapachol.Due to its Overlay, the dosage of medicine also can reduce.These compositionss can reduce the drug-induced complication because using high dose.

adhesion layer

Adhesion layer covers the optional layer of medication coat, which improves medication coat to the adhesiveness of armarium outer surface and protect the integrity of coating.If medicine is different with the adsorptivity of additive to armarium, so adhesion layer can prevent the difference of medicine layer component from losing (in delivery process) or eluting (at target site), to maintain medicine-additive consistent in medicine layer or drug-drug ratio, and by therapeutic agent delivery to the target site got involved.In addition, adhesion layer can be used to the release helping coating ingredients, otherwise coating is being organized in the of short duration process contacted can adhere to too tight to the equipment for eluting with target site.Such as, combine closely in the situation of armarium in certain drug, component stronger for hydrophilic is encapsulated in adhesion layer to reduce the affinity of medicine to armarium.

As above, adhesion layer comprises polymer or additive or both mixture.Be used for forming the polymer of adhesion layer be biocompatible and can avoid stimulating systemic those.Some examples of polymer being used for being formed adhesion layer are polymer of Biostatic, such as urethanes, polysiloxanes and polyester.Be used for being formed other polymer of adhesion layer to comprise and can dissolve on armarium and the polymer be polymerized.

Some examples for adhesion layer in the specific embodiment of the invention comprise polyolefin, polyisobutylene, the copolymer of ethylene ' alpha '-olefin, acrylic polymer and copolymer, polrvinyl chloride, polyvinyl methyl ether, polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketone, polystyrene, polyvinyl acetate, ethylene methyl methacrylate copolymer, acrylonitritrile-styrene resin, ABS resin, nylon 12 and block copolymer thereof, polycaprolactone, polyformaldehyde, polyethers, epoxy resin, urethanes, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellophane, celluloid, cellulose propionate, cellulose ether, carboxymethyl cellulose, chitin, polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxide copolymer, Polyethylene Glycol, polypropylene glycol, polyvinyl alcohol and composition thereof and block copolymer.

Because armarium will carry out mechanically actuated, namely expand and shrink, the example that can be used for the polymer of adhesion layer comprises elastomer polymer, such as polysiloxanes (polysiloxanes of such as polysiloxanes and replacement), urethanes, thermoplastic elastomer (TPE), ethylene vinyl acetate copolymer, polyolefin elastomer and EPDM rubber.Due to the elastic property of these polymer, when using these polymer, when equipment holding capacity or stress, coating can adhere to armarium surface better.

Adhesion layer also can comprise one or more foregoing additives or other composition, to maintain the integrity of coating and the adhesiveness to equipment, and help medicine and the adhesiveness of additive component in delivery process and be placed in the quick eluting that treatment gets involved position process.

top layer

In order to protect the integrity of medicine layer further, optional top layer can be used and to be entered loss in the delivery process of target site or the loss before coating directly contacts with target tissue in the preliminary expansion process of equipment by tortuous anatomy to prevent medicine.Top layer can in body cavity slow releasing, protect medicine layer simultaneously.If top layer comprises the stronger high molecular additive of hydrophobicity, its slower by corrosion.Surfactant is the example of the stronger structure of hydrophobicity with long aliphatic chain, such as polysorbas20 and polyglycerol acrylate.The additive of high molecular comprises poly(ethylene oxide), Polyethylene Glycol and polyvinylpyrrolidone.Hydrophobic drug self can serve as top layer component.Such as, paclitaxel or rapamycin are hydrophobic.They can be used in top layer.On the other hand, top layer can not corrosion obtain too slow, otherwise in fact it delayed medicine and inserting the release in target site process.Other additive for Topcoating comprises the additive with medicine or coating strong effect, such as, to different nonyl benzene oxygen poly epihydric alcohol, polyethylene glycol laurate, polysorbas20, polysorbate40, polysorbate60, polyethylene glycol (PEG) oleate, Polyethylene Glycol stearic acid, polyethylene glycol glycerol laurate, Polyethylene Glycol olein, polyethylene glycol glycerol stearate, polyglyceryl laurate, polyglycerol acrylate, polyglyceryl myristate, POGE-A POGE-B POGE-C Polyglycerin palmitate, polyglycereol-6 lauric acid, polyglycereol-6 oleate, polyglycereol-6 myristinate, polyglycereol-6 cetylate, Natrulon H-10 laurate, Natrulon H-10 oleate, Natrulon H-10 myristinate, Natrulon H-10 cetylate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol sorbitan monolaurate, Polyethylene Glycol dehydrated sorbitol mono-fatty acid ester, Polyethylene Glycol sorbitan stearate, Polyethylene Glycol oil ether, Polyethylene Glycol lauroyl ether, octoxinol, nonoxynolum, tyloxapol, sucrose palmitic acid ester, sucrose monolaurate, capryl-N-METHYL-ALPHA-L-GLUCOSAMINE, positive decyl-β-D-pyranglucoside, positive decyl-β-D-pyrans maltoside, dodecyl-β-D-pyranglucoside, dodecyl-β-D-Maltose glycosides, heptanoyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, n-heptyl-β-D-pyranglucoside, n-heptyl-β-D-thioglycoside, n-hexyl-β-D-pyranglucoside, pelargonyl group-N-METHYL-ALPHA-L-GLUCOSAMINE, pelargonyl group-β-D-pyranglucoside, caprylyl-N-METHYL-ALPHA-L-GLUCOSAMINE, n-octyl-β-D-pyranglucoside, octyl group-β-D-thioglucopyranoside, cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, agedoite, aspartic acid, glutamic acid and methionine, acetic anhydride, benzoyl oxide, ascorbic acid, 2-Pyrrolidone-5-carboxylic acid, pyrrolidone sodium carboxylate, ethylenediaminetetraacetic acid dianhydride, maleic acid and anhydride, succinic anhydrides, anhydride diethylene glycol, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine, commetamin, pantothenylol, nicotiamide, nicotinic acid, pyridoxal 5-phosphate, nicotiamide ascorbic acid, riboflavin thiamine, riboflavin phosphate, thiamine, folic acid, Methylnaphthohydroqudiphosphate diphosphate, menadione Sodium Bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6 and vitamin U, albumin, immunoglobulin, casein, hemoglobin, lysozyme, immunoglobulin, a-2-macroglobulin, fibronectin, vitronectin, Fibrinogen, lipase, benzalkonium chloride, benzethonium chloride, Dodecyl trimethyl ammonium chloride, sodium lauryl sulphate, dialkyl methylbenzyl ammonium chloride, with the dialkyl of sodium sulfosuccinate, L-AA acid and salt thereof, D-glucoascorbic acid and salt thereof, trometamol, triethanolamine, diethanolamine, meglumine, glycosamine, amine alcohol, glucoheptonic acid, gluconic acid, hydroxy-ketone, hydroxy-lactone, gluconic acid lactone, glucoheptose acid lactone, the sad lactone of glucose, gulonolactone, mannonic acid lactone, ribose acid lactone, lactobionic acid, glycosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxy benzoic acid, 4-HBA propyl ester, lysine acetate salt, gentisic acid, lactobionic acid, lactose, sinapic acid, vanillic acid, vanillin, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, tretinoin, lysine acetate, gentisic acid, catechin, catechin and gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, the salt of any organic acid and organic amine, poly epihydric alcohol, glycerol, poly-glycerine, galactitol, two (ethylene glycol), three (ethylene glycols), four (ethylene glycol), five (ethylene glycol), PEG oligomer, two (propylene glycol), three (propylene glycol), four (propylene glycol), with five (propylene glycol), poly-(propylene glycol) oligomer, the block copolymer of Polyethylene Glycol and polypropylene glycol, and derivant and combination.

solvent

Solvent for the preparation of coating can comprise such as one or more combination in any following: (a) water, (b) alkane, as hexane, octane, cyclohexane extraction and heptane, (c) arsol, as benzene, toluene and dimethylbenzene, (d) alcohol, as ethanol, propanol, and isopropyl alcohol, diethylamide, ethylene glycol monoethyl ether, Trascutol and benzyl alcohol, (e) ether, as diox, dimethyl ether and oxolane, (f) ester/acetas, as ethyl acetate and isobutyl acetate, (g) ketone, as acetone, acetonitrile, metacetone and methyl ethyl ketone, (h) mixture of water and organic solvent, such as water/ethanol, water/acetone, water/methanol, water/oxolane.In Topcoating, preferred solvent is acetone.

Organic solvent, such as short chain alcohol, diox, oxolane, dimethyl formamide, acetonitrile, dimethyl sulfoxine etc. are particularly useful and be preferred in the specific embodiment of the invention, because these organic solvents generally can destroy colloidal polyurea collective, and make all components in coating solution molten altogether.

Therapeutic agent and a kind of additive or multiple additives dispersible in, be dissolved in or mix with solvent in other forms.Medicine and additive percentage by weight in a solvent can be the scope of 0.1-80% weight, preferred 2-20% weight.

Another detailed description of the invention of the present invention relates to a kind of method preparing armarium, particularly such as foley's tube or support.First, preparation comprises coating solution or the suspension of at least one solvent, at least one therapeutic agent and at least one additive.In at least one detailed description of the invention, coating solution or suspension only comprise this three kinds of components.The content of therapeutic agent in coating solution is the 0.5-50% weight based on total solution weight.The content of additive in coating solution can be based on the 1-45% weight of total solution weight, 1-40% weight or 1-15% weight.The amount of solvent for use depends on coating procedure and viscosity.It can affect the uniformity of medicine-additive coating, but can be evaporated.

In other detailed description of the invention, two or more solvents, two or more therapeutic agents and/or two or more additives in coating solution, can be used.

In other detailed description of the invention, in coating solution such as bracket coating, therapeutic agent, additive and polymeric material can be used.In the coating, therapeutic agent is not encapsulated in polymer particles intragranular.

Various technology can be used when coating solution being applied to armarium, such as, cast, spin, spray, flood the combination of (infiltration), ink jet printing, electrostatic technique and these processes.The selection of application technology depends primarily on viscosity and the surface tension of solution.In the specific embodiment of the present invention, dipping and spraying are preferred, because it more easily controls the uniformity of coating layer thickness and is administered to the concentration of therapeutic agent of armarium.No matter whether by spray or by flood or by the combined administration coating of other method or various method, in order to control uniformity and be applied to the therapeutant of armarium and the quantity of additive, usually will often be deposited on armarium with multiple step of applying.

Each application layer has the thickness of about 0.1 micron to 15 microns.Be administered to the layer on armarium add up to about 2 to 50 scope.The gross thickness of coating is about 2 to 200 microns.

As discussed above, spraying and dipping are the paint-on techniques being specially adapted to the specific embodiment of the invention.In spray technique, the coating solution in the preparation specific embodiment of the invention or suspension, then transferred in application apparatus and used coating solution to foley's tube.

Spendable application apparatus is the paint can be connected on air-brush, such as Badger Model150, and it is by actuator pressurised air source (nitrogen, 0-160psi).When using this application apparatus, once brush the hose connection downstream to actuator compressed air source, just apply air.Pressure is adjusted to about 15-25psi, and checks nozzle situation by squeezing trigger.

Before spraying, the two ends of the sacculus relaxed two elastic keepers and alligator clamp are fixed on the securing means, and the distance adjusted between clip makes sacculus keep venting, fold, or inflate or partial inflation, deployed condition.Then, rotor be energized and rotary speed is adjusted to desirable coating speed, being approximately 40rpm.

Rotated on approximate horizontal face by sacculus, adjustable spraying nozzle makes nozzle be about 1-4 inch to the distance of sacculus.First, substantially horizontally coating solution is sprayed along sacculus brush from balloon distal to proximal direction, then proximally arrive far-end and rotate the speed sweeping motion carrying out a spray cycles with about three sacculus.With coating solution to sacculus repeated spray, then dry, until the drug deposition of effective dose is on sacculus.

In a specific embodiment of the present invention, sacculus is inflation or partial inflation, and coating solution is applied on inflating balloon, such as, by spraying, then before it is dried by Deflation and folding.Drying can be carried out under vacuo.

It is to be understood that the description of this application device, fixture and spray technique is only exemplary.Other suitable spraying any or other technology can be used for armarium coating, the particularly sacculus of coated spheres ductus bursae or stent delivery system or support.

After armarium is with coating solution spraying, coating sacculus is carried out drying, and the solvent wherein in coating solution is evaporated.This makes sacculus to create the coating matrix containing therapeutic agent.An example of dry technology coating sacculus is placed in about 20 DEG C or nearly 24 hours of higher baking oven.Other appropriate method of dry coating solution any can be used.Time and temperature can change with special additive and therapeutic agent.

optional post processing

In some detailed description of the invention of the present invention, the layer of drug containing-additive is deposited on after on equipment, by dipping or spraying or other method by dimethyl sulfoxine (DMSO) or other solvent application in the machined surface of coating.The easy dissolved substance of DMSO and be easy to permeable membrane, and can tissue resorption be improved.

It is contemplated that, the armarium of the specific embodiment of the invention can be used for blocking and the obturation for the treatment of any body passage, comprise especially vascular system, comprise coronary artery, periphery and brain vascular system, gastrointestinal tract, comprise esophagus, stomach, small intestinal and colon, lung airways, comprise trachea-bronchial epithelial cell, bronchioles, hole, biliary tract, urinary tract, prostate and nicergoline road.They are specially adapted to such as foley's tube or stent in the treatment vasculature tissue.

Another detailed description of the invention of the present invention relates to a kind of method for the treatment of blood vessel.The method comprises and being inserted in blood vessel by the armarium comprising coating.Coating comprises therapeutic agent and additive.In this specific embodiment, armarium can be configured to have at least one expandable part.Some examples of this equipment comprise two sacculus at foley's tube, perfusion balloon catheter conduit, transfusion catheter such as far-end perforation medication infusion conduit, perforation sacculus, interval, porous sacculus and sepage sacculus, Cutting balloon conduit, integrating sphere ductus bursae, self-expanding and balloon expandable stent, inlet tube, seal wire, embolization protective device and various imaging device.

As mentioned above, be coating ball ductus bursae to the example of the useful especially armarium of the present invention.Foley's tube has hollow pipe that is long, narrow, that leave epitome, flat sacculus usually.In the specific embodiment of the present invention, sacculus is applied by drug solution.Then, handle sacculus enter blocking, inaccessible position by cardiovascular system or need other tissue of therapeutic agent.Once enter suitable position, sacculus is inflated and contacts with the wall of blood vessel and/or blocking or obturation.An object of the specific embodiment of the invention is rapid delivery medicine and promotes the absorption of target tissue.It is favourable for medicine being effectively delivered to tissue in time of short duration as far as possible after equipment is placed in target site.Medication coat is depressed into lesion vessels contact tissue after such as about 0.1 to 30 minute or preferably about 0.1 to 10 minute or more preferably from about 0.2 to 2 minute or most preferably from about in inflated time of 0.1 to 1 minute, therapeutic agent is released in this tissue such as blood vessel wall.

Consider that the specific embodiment of the invention by the drug delivery for the treatment of effective dose to such as arterial wall, can be exempted the demand of support, avoid the complication that fracture is relevant with thrombosis in some cases.

If still need placing rack, the specific embodiment of the invention particularly preferred application is medicine-coated balloon support such as bare mental stents (BMS) being rolled up such as detailed description of the invention description herein.When will prop up inflated be placed on pathological changes vasculature site time, the medicine of effective dose is delivered to arterial wall, prevents or reduce the order of severity or other complication of restenosis.Alternately, support and sacculus can by together with apply, or then can roll up sacculus by drug delivery medical device.

Further, foley's tube can be used for separately treating vascular tissue/disease, or treats vascular system with other method coupling, such as photodynamic therapy or rotary-cut art.Rotary-cut art removes the Therapeutic Method of speckle.Specifically, rotary-cut art eliminates speckle from periphery and coronary artery.For the direct Atherectomy devices that the armarium of periphery or coronary artery rotary-cut art can be in laser catheter or turnery or end of conduit.Conduit to be inserted in body and to advance through tremulous pulse and enters narrow zone.After rotary-cut art removes part speckle, the balloon angioplasty using specific embodiment of the invention floating coat sacculus can be carried out.In addition, can support be carried out subsequently, or as described above while expansion coating sacculus.Photodynamic therapy makes to use up or emittance kills the Therapeutic Method of patient body intracellular targets.By the specific embodiment of the present invention, the photosensitive drug of photoactivation can be delivered to the specific region of tissue.Light or radiation source optionally activate medicine targetedly, produce cell-cytotoxic reaction and receive the antiproliferative effect for the treatment of.

Containing in some detailed description of the invention of medicine coating and layer according to of the present invention, coating or layer do not comprise polymer, oil or lipid.Further, in addition, therapeutic agent is not encapsulated in polymer beads, micelle or liposome.As above, this kind of preparation has obvious shortcoming, and can suppress the high efficiency of expection, the quick release of reagent and retardance permeability, particularly under the environment of vascular system pathological tissues.

Although illustrate herein and describe various detailed description of the invention, but should will be appreciated that, by above-mentioned instruction, it covers improvement of the present invention and modification, and fall in the authority of claims, and can not depart from marrow of the present invention and desired extent.

Except operation embodiment, or except as otherwise noted, in description and claims, in presentation layer, all numerals of the quantity, reaction condition etc. of component are interpreted as under any circumstance all adjusting by term " about ".Therefore, unless otherwise contrary explanation, the digital parameters used in this specification and the appended claims is approximation, and it can change according to character needed for the acquisition of disclosure of invention wish.

preparation

The armarium of the specific embodiment of the invention and coating can obtain according to various method.Such as, coating solution is by dispersion, dissolving or otherwise mix all the components preparation, such as, the while of therapeutic agent, additive and solvent together with.In addition, coating solution can add the preparation of each component successively based on dissolubility or other parameter any.Such as, coating solution, by first adding therapeutic agent in solvent, then adds additive preparation.Alternately, first can add additive in solvent, and then add therapeutic agent.If solvent can not abundant dissolved substance, preferably first in solvent, adding additive, is then medicine, because additive will increase medicine dissolubility in a solvent.

Embodiment

Following embodiment includes the detailed description of the invention of armarium within the scope of the present invention and coating.Although the following example is considered to example of the present invention, these embodiments should not be understood as limitation of the present invention.

Embodiment A

The preparation (if necessary, adding a small amount of water being enough to dissolve all solutes being no more than 10% volume) of coating solution:

Preparation 1.1-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) Yoshinox BHT (BHT), 15-90mg Tween 80,30-90mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and the mixing of 1-3ml ethanol.

Preparation 1.2-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) butylated hydroxyanisol (BHA), 15-90mg Tween 80,30-90mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and the mixing of 1-3ml ethanol.

Preparation 1.3-, by 30-90mg rapamycin, does not add BHT or BHA, 15-90mg Tween 80,30-90mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and the mixing of 1-3ml ethanol.

Preparation 1.4-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 15-90mg Solutol HS 15,5-30mg sodium lauryl sulphate and 1-3ml ethanol mix.

Preparation 1.5-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 15-90mg Oleth 20,15-90mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and 1-3ml ethanol mix.

Preparation 1.6-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 15-90mg Polyethylene Glycol-b-PLA (PEG-b-PLA), 30-120mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and the mixing of 1-3ml ethanol.

Preparation 1.7-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 15-90mg sorbimacrogol oleate100,30-90mg Oleth 20 and 1-3ml ethanol mix.

Preparation 1.8-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHA, 45-225mg Polyethylene Glycol-b-PLA (PEG-b-PLA) and 1-3ml ethanol mix.

Preparation 1.9-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHA, 30-180mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and 1-3ml ethanol mix.

Preparation 1.10-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHA, 15-45mg Oleth 10,15-45mg Oleth 20 and 1-3ml ethanol mix.

Preparation 1.11-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 15-90mg Solutol HS 15,15-90mg docusate sodium (2-Sulfosuccinic acid ethylhexyl sodium) and 1-3ml ethanol mix.

Preparation 1.12-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BTA or BHT, 15-90mg Solutol HS 15,15-90mg Polyethylene Glycol-b-PLA (PEG-b-PLA) and the mixing of 1-3ml ethanol.

Preparation 1.13-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHA, 3-135mg Solutol HS 15 and 1-3ml ethanol mix.

Preparation 1.14-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 3-135mg Solutol HS 15,3-90mg sorbimacrogol oleate100 and 1-3ml ethanol mix.

Preparation 1.15-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 3-135mg Solutol HS 15,3-90mg soluble polyvinylpyrrilidone (Povidone or Kollidon 12PF) and the mixing of 1-3ml ethanol.

Preparation 1.16-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg soluble polyvinylpyrrilidone (Povidone or Kollidon 12PF) and 1-3ml ethanol mix.

Preparation 1.17-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg Cremophor EL (PEG-35 Oleum Ricini or polyethylene glycol glycerol ricinoleate ester) and 1-3ml ethanol mix.

Preparation 1.18-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 3-135mg Cremophor EL (PEG-35 Oleum Ricini or polyethylene glycol glycerol ricinoleate ester), 3-90mg sorbimacrogol oleate100 and the mixing of 1-3ml ethanol.

Preparation 1.19-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg Soluplus (Polyvinylcaprolactame-polyvinyl acetate-polyethyleneglycol-graft copolymer) and 1-3ml ethanol mix.

Preparation 1.20-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg Solutol HS 15,3-90mg sorbitol and 1-3ml ethanol mix.

Preparation 1.21-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg soluble polyvinylpyrrilidone (Povidone or Kollidon 12PF), 3-90mg polysorbas20 (polysorbate20) and the mixing of 1-3ml ethanol.

Preparation 1.22-is by 30-90mg rapamycin, and 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg polysorbas20 (polysorbate20), 3-90mg sorbimacrogol oleate100 (polysorbate 81) and 1-3ml ethanol mix.

Preparation 1.23-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg soluble polyvinylpyrrilidone (Povidone or Kollidon 12PF), 3-90mg polysorbas20 (polysorbate20), 3-90mg sorbimacrogol oleate100 (polysorbate 81) and the mixing of 1-3ml ethanol

Preparation 1.24-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg soluble polyvinylpyrrilidone (Povidone or Kollidon 12PF), 3-90mg Solutol HS 15,3-90mg sorbimacrogol oleate100 (polysorbate 81) and the mixing of 1-3ml ethanol.

Preparation 1.25-is by 30-90mg rapamycin, 1-2% (weight based on rapamycin) BHA or BHT, 3-90mg soluble polyvinylpyrrilidone (Povidone or Kollidon 12PF), 3-90mg Cremophor EL (PEG-35 Oleum Ricini or polyethylene glycol glycerol ricinoleate ester), 3-90mg lecithin and the mixing of 1-3ml ethanol.

Embodiment B

By 5 PTCA foley's tubes (diameter is 3mm and length is 20mm) with U.S. Patent Application Publication No. 2010-0055294-A1 describe method coating, its entirety at this by reference to being merged in.Under 1-3 atmospheric pressure, PTCA foley's tube is inflated.By inflation after sacculus be loaded into, spraying embodiment A preparation (1.1-1.3) or be impregnated in the preparation (1.1-1.3) of embodiment A.Then, sacculus is dry, medicine carrying, spraying or dipping again, until obtain the sacculus (3 micrograms/millimeter) with q.s medicine.Coating sacculus is folded, then repacks and sterilizing, for analytical test.For the preparation 1.1 containing BHT, the rapamycin content of recovery is 79%; For the preparation 1.2 containing BHA, reclaim 100%; For the preparation 1.3 not containing BHT or BHA, reclaim 14%-50%.Antioxidant (BHT or BHA) prevent rapamycin not oxidized or degraded.

Embodiment C

By 6 PTCA foley's tubes (diameter be 3.5 and 3.0mm and length is 20mm) inflate under 1-3 atmospheric pressure.Sacculus after inflation is loaded into the preparation 1.1-1.25 in embodiment A.Sacculus obtains the medicine (3-4 microgram/square millimeter) of q.s.Inflating balloon is folded, then dry.Then, coating is folded sacculus repacks, sterilizing, and optionally vacuum drying, for animal experiment.

step: coating PTCA foley's tube is inserted into the target site (LAD, LCX and RCA) in the coronary artery vascular of the pig of 25-45 pound weight.By inflated to about 12 atmospheric pressure.Overstretching ratio (ratio of balloon diameter and pipe diameter) is about 1.15-1.40.In the gas replenishment process of 30-60 second, medicine is delivered to target tissue.Then, foley's tube exitted and reclaim in animal body.Target vessel is obtained after 0.25-24 hour in this operation.By tissue extraction and HPLC, the left drug analyzed the medicament contg in target tissue and be retained in sacculus.

In these zooscopies of part, support is twisted on drug coated balloon catheter before placement.In growing animal test, before and after all interventions, within 28-35 days, carry out angiography afterwards with operation (above-mentioned).Measure lumen diameter and calculate late luminal and lose.Late luminal lose refer to through one section follow the trail of the time of now examining (after normally getting involved, several weeks are to the several months, be in this embodiment such as after angioplasty and placing rack several weeks to the several months) difference between the minimum cavity diameter that measures immediately after the minimum cavity diameter that measures and intervention.Restenosis is quantitative by diameter stenosis, and it is that after operation, difference between mean lumen diameter is now examined and recorded immediately to tracking again divided by the mean lumen diameter recorded immediately after operation.The animal test results report of preparation 1.1-1.25 is as follows.All data are averages of five or six experimental data points.

With the support of uncoated sacculus process 18mm.Then, coating ball ductus bursae is inserted into the coronary arterial vasculature target site (LAD, LCX and RCA) of the pig of 25-45 pound weight.On 3.5mm coating ball ductus bursae, the medicament contg of preparation 1.1 is about 3-4 μ g/mm ².After carrying out aforesaid operations, medicine residual on sacculus is 21 μ g, or 4% of the total drug loading of sacculus.In the tissue obtained for 15-30 minute after the activation, medicament contg is 40.2 μ g, or 7.6% of total dose of initial loading sacculus.Draw ratio in this operation is 1.2-1.4.Late luminal after 28-35 days is lost for 0.76mm (standard deviation is 0.22).

With the support of uncoated sacculus process 18mm.Then, coating ball ductus bursae is inserted into the coronary arterial vasculature target site (LAD, LCX and RCA) of the pig of 25-45 pound weight.On 3.5mm coating ball ductus bursae, the medicament contg of preparation 1.4 is 3.0-4.0 μ g/mm ².After carrying out aforesaid operations, medicine residual on sacculus is 5.0 μ g, or 1% of the total drug loading of sacculus.In the tissue obtained for 15-30 minute after the activation, medicament contg is 6.3 μ g, or the 1-3.0% of total drug loading.Late luminal after 28-35 days is lost for 0.76mm (standard deviation is 0.28).

On 3.5mm foley's tube, the medicament contg of uncoated sacculus (stick) is 0.0 μ g/mm ².With uncoated sacculus process 18mm support.After carrying out aforesaid operations, the left drug on sacculus is 0.0 μ g, or has 0% total drug loading.In the tissue obtained for 15-30 minute after the activation, medicament contg is 0.0 μ g, or 0.0% of total drug loading.Late luminal after 28-35 days is lost for 1.14mm (standard deviation is 0.28).

On 3.5mm foley's tube, the medicament contg of preparation 1.5 is 2.88 μ g/mm ².After carrying out aforesaid operations, the left drug on sacculus is 6.29 μ g, or 1.0% of total drug loading.In the tissue obtained for 15-30 minute after the activation, medicament contg is 16 μ g, or 8.9% of total drug loading.In the tissue obtained for 28 days after the activation, medicament contg is 7.7ng/mg tissue.Late luminal after 28-35 days is lost for 0.9mm (standard deviation is 0.18).

On 3.5mm foley's tube, the medicament contg of preparation 1.6 is 3.31 μ g/mm ².After carrying out aforesaid operations, the left drug on sacculus is 37.0 μ g, or 6.0% of total drug loading.In the tissue obtained for 15-30 minute after the activation, medicament contg is 51.8 μ g, or 9.0% of total drug loading.In the tissue obtained for 28 days after the activation, medicament contg is 6.15ng/mg tissue.Late luminal after 28-35 days is lost for 0.90mm (standard deviation is 0.07).

On 3.5mm foley's tube, the medicament contg of preparation 1.7 is 3.03 μ g/mm ².After carrying out aforesaid operations, the left drug on sacculus is 4.41 μ g, or 0.8% of total drug loading.In the tissue obtained for 15-30 minute after the activation, medicament contg is 11.3 μ g, or 1.9% of total drug loading.

On 3.5mm foley's tube, the medicament contg of preparation 1.8 is 3-4 μ g/mm ².After carrying out aforesaid operations, the left drug on sacculus is 95.0 μ g, or 13.0% of total drug loading.In the tissue obtained for 28 days after the activation, medicament contg is 0.7ng/mg tissue.Late luminal after 28-35 days is lost for 1.11mm (standard deviation is 0.24).

On 3.5mm foley's tube, the medicament contg of preparation 1.9 is 3-4 μ g/mm ².After carrying out aforesaid operations, the left drug on sacculus is 57.0 μ g, or 6.4% of total drug loading.In the tissue obtained for 28 days after the activation, medicament contg is 35.2ng/mg tissue.

On 3.5mm foley's tube, the medicament contg of preparation 1.10 is 3-4 μ g/mm ².After carrying out aforesaid operations, the left drug on sacculus is 13.0 μ g, or 2.5% of total drug loading.In the tissue obtained for 28 days after the activation, medicament contg is 10.75ng/mg tissue.Late luminal after 28-35 days is lost for 0.73mm (standard deviation is 0.09).

Embodiment 1

The preparation of coating solution

Preparation 1-is by 50-150mg (0.06-0.18mmole) paclitaxel, and 2-6ml acetone (or ethanol), 25-100mg ascorbyl palmitate, 25-100mg L-AA and 0.5ml ethanol mix.

Preparation 2-is by 50-150mg (0.05-0.16mmole) rapamycin, and 2-6ml acetone (or ethanol), 50-200mg Natrulon H-10 oleate and 0.5ml ethanol mix.

Preparation 3-is by 50-150mg (0.06-0.18mmole) paclitaxel, and 2-6ml acetone (or ethanol), 50-200mg octoxynol 9 and 0.5ml ethanol mix.

Preparation 4-is by 50-150mg (0.05-0.16mmole) rapamycin, and 2-6ml acetone (or ethanol), 50-200mg is to different nonyl benzene oxygen poly epihydric alcohol and the mixing of 0.5ml ethanol.

Preparation 5-is by 50-150mg (0.06-0.18mmole) paclitaxel, and 2-6ml acetone (or ethanol), 50-200mg tyloxapol and 0.5ml ethanol mix.

Preparation 6-containing the 2-6ml acetone (or ethanol) of 50-150mg (0.05-0.16mmole) rapamycin, and will contain 1ml water or the ethanol of 50-150mg L-AA, or both mixing.

Preparation 7-is by 50-150mg (0.06-0.18mmole) paclitaxel, and 2-6ml acetone (or ethanol), containing 1ml water or the ethanol mixing of 50-150mg nicotiamide.

Preparation 8-by 50-150mg (0.05-0.16mmole) rapamycin, 2-6ml acetone (or ethanol), and containing the 1ml water of 50-200mg nicotinic acid or ethanol mixing.

Preparation 9-is by 50-150mg (0.06-0.18mmole) paclitaxel, and 2-6ml ethanol (or acetone), containing 1ml water and the 0.5ml mixing of 150mg thiamine hydrochloride.

Preparation 10-by 50-150mg (0.05-0.16mmole) rapamycin, 2-6ml acetone or alcohol and containing the 1ml water of 150mg 2-Pyrrolidone-5-carboxylic acid or ethanol mixing.

Preparation 11-is by 50-150mg (0.06-0.18mmole) paclitaxel, and 2-6ml acetone (or ethanol), 75mg is to different nonyl benzene oxygen poly epihydric alcohol, and containing 1ml water or the ethanol of 75mg nicotiamide, and 0.5ml ethanol mixes.

Preparation 12-is by 50-150mg (0.05-0.16mmole) rapamycin, and 2-6ml acetone (or ethanol), 75mg octoxynol 9, containing 1ml water or the ethanol of 75mg thiamine hydrochloride, and 0.5ml ethanol mixes.

Preparation 13-by 50-150mg (0.06-0.18mmole) paclitaxel, 2-6ml acetone (or ethanol), 75mg to different nonyl benzene oxygen poly epihydric alcohol, containing the 1ml water of 75mg 2-Pyrrolidone-5-carboxylic acid or ethanol and the mixing of 0.5ml ethanol.

Preparation 14-by 50-150mg (0.06-0.18mmole) paclitaxel, 2-6ml acetone (or ethanol), 75mg to different nonyl benzene oxygen poly epihydric alcohol, containing the 1ml water of 75mg nicotinic acid or ethanol and the mixing of 0.5ml ethanol.

Preparation 15 by 50-150mg (0.06-0.18mmole) paclitaxel, 2-6ml acetone (or ethanol), 75mg to different nonyl benzene oxygen poly epihydric alcohol, containing the 1ml water of 75mg L-AA or ethanol and the mixing of 0.5ml ethanol.

50-150mg (0.06-0.18mmole) paclitaxel is dissolved in 5-10ml dichloromethane by preparation 16.30ml human serum albumin solution (5%w/v) is added in solution.Then, emulsion was formed by homogenizing at low speed for solution 5 minutes.Then by emulsion with the power of 40kHz 50-90% at 0 to 5 DEG C ultrasonic 1 to 5 minute.

50-150mg (0.05-0.16mmole) rapamycin is dissolved in 5-10ml dichloromethane and 10-30mg in different nonyl benzene oxygen poly epihydric alcohol by preparation 17-.30ml human serum albumin solution (5%w/v) is added in solution.Then, emulsion was formed by homogenizing at low speed for solution 5 minutes.Then by emulsion with the power of 40kHz 50-90% at 0 to 5 DEG C ultrasonic 1 to 5 minute.

Preparation 18-by 50-100mg (0.06-0.12mmmole) paclitaxel, 1-1.6ml acetone, 1-1.6ml ethanol, 0.4-1.0ml water, and 50-200mg gluconic acid lactone mixing.

Preparation 19-by 35-70mg (0.042-0.084mmmole) paclitaxel, 0.5-1.0ml acetone, 0.5-1.0ml ethanol, 35-70mg polysorbas20, and 35-70mg N-caprylyl N-methylglucamine mixing.

Preparation 20-by 35-70mg (0.042-0.084mmmole) paclitaxel, 0.4-1.0ml acetone, 0.4-1.0ml ethanol, 0.2-0.4ml water, 35-70mg polysorbas20, and 35-70mg sorbitol mixing.

Preparation 21-by 40-80mg (0.048-0.096mmmole) paclitaxel, 0.5-1.0ml acetone, 0.5-1.0ml ethanol, 40-80mg meglumine, and 32-64mg gentisic acid (with meglumine equimolar ratio) mixes.

Preparation 22-by 35-70mg (0.042-0.084mmmole) paclitaxel, 0.4-0.8ml acetone, 0.4-0.8ml ethanol, 0.25-0.50ml water, 35-70mg lactobionic acid, and 10-20mg diethanolamine (with lactobionic acid equimolar ratio) mixes.

Preparation 23-by 35-70mg (0.042-0.084mmmole) paclitaxel, 0.5-1.0ml acetone, 0.5-1.0ml ethanol, and 70-140mg N-caprylyl N-methylglucamine mixing.

Preparation 24-is by 35-70mg (0.042-0.084mmmole) paclitaxel, and 0.4-0.8ml acetone, 0.4-0.8ml ethanol, 0.2-0.4ml water, 35-70mg meglumine and 18-36mg lactic acid (with meglumine equimolar ratio) mix.

Preparation 25-is by 50-100mg (0.06-0.12mmole) paclitaxel, and 0.8-1.6ml acetone, 0.8-1.6ml ethanol, 0.4-1.0ml water, 50-100mg gentisic acid and 30-60mg diethanolamine (with gentisic acid equimolar ratio) mix.

Preparation 26-comparative solution-by 50mg (0.06mmole) paclitaxel, 1ml ethanol, 0.2ml acetone and 0.042ml Ultravist 370 mix.

Preparation 27-comparative solution-by 40mg (0.048mmole) paclitaxel, 0.5ml ethanol and the mixing of 0.5ml acetone.

Preparation 28-by 35-70mg (0.042-0.084mmmole) paclitaxel, 0.5-1.0ml acetone, 0.5-1.0ml ethanol, 35-70mg Triton X-100, and 35-70mg N-heptanoyl group N-methylglucamine mixing.

Embodiment 2

5 PTCA foley's tubes (diameter is 3mm and length is 20mm) are folded into three wings under vacuo.Use the preparation of embodiment 1 (1-17) to folding sacculus spraying or dipping in a vacuum.Then, will fold sacculus dry, spraying or dipping, dry again, and again spray or dipping, until obtain the sacculus (3 micrograms/square millimeter) having q.s medicine.Then, coating is folded sacculus to repack and sterilizing, for animal experiment.

Embodiment 3

5 PTCA foley's tubes (diameter is 3mm and length is 20mm) are folded into three wings under vacuo.Use the preparation of embodiment 1 (1-5) to folding sacculus spraying or dipping in a vacuum.Then, will fold sacculus dry, spraying or dipping, dry again, and again spray or dipping, until obtain the sacculus (3 micrograms/square millimeter) having q.s medicine.Then, coating is folded sacculus to repack and sterilizing, for animal experiment.

Embodiment 4

5 PTCA foley's tubes rolled up with naked metal coronary stent (diameter is 3mm and length is 20mm) preparation (1-5) of embodiment 1 is sprayed or dipping.Then, stent delivery system is dry, again use preparation (6-10) to spray or dipping, dry, and again spray or dipping, until obtain the support and the sacculus (3 micrograms/square millimeter) that there are q.s medicine.Then, to the sterilizing of coating folding rack delivery system, for animal experiment.

Embodiment 5

Drug coated balloon catheter and uncoated foley's tube (in contrast) are inserted in the coronary artery of pig.By balloon overstretch (1:1.2), then the sacculus of inflation is fixed on blood vessel 60 seconds to discharge medicine and additive, then venting reclaiming from pig.After 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, angiography is carried out to animal.The in-house dose of animal artery that is condemned to death is measured after 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.

Embodiment 6

The preparation (1-17) of 5 radicular arteries intravascular stents (diameter is 3mm and length is 18mm) by embodiment 1 is sprayed or immersion coating.Then, support is dry, spraying or dipping again, and after drying, until obtain the support (3 micrograms/square millimeter) having q.s medicine.Then, overlay film frame is twisted on PTCA foley's tube (diameter is 3mm and length is 20mm).Then, to the overlay film frame sterilizing having foley's tube, for animal experiment.

Embodiment 7

Medicine overlay film frame and uncoated support (in contrast) are inserted in the coronary artery of pig, then by balloon overstretch (1:1.2).Stenter to implant discharged medicine and additive, then Deflation is reclaimed from pig.5 minutes, 30 minutes, 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, angiography is carried out to animal.The in-house dose of animal artery that is condemned to death is measured 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.

Embodiment 8

Sprayed or dipping by 5 PTCA foley's tubes preparation (1-17) of embodiment 1, dry, spraying or dipping, and after drying, until acquisition has the sacculus (3 micrograms/square millimeter) of q.s medicine.Naked metal coronary stent (diameter is 3mm and length is 20mm) is twisted on each coating sacculus.Then, by the coating sacculus packaging also sterilizing of being rolled up by naked metal coronary stent, for animal experiment.

Embodiment 9

5 PTCA foley's tubes preparation (1-5) of embodiment 1 is sprayed or dipping, dry, and again spray with preparation (6-10) or flood.Then, also again spray dry for sacculus or dipping, until obtain the sacculus (3 micrograms/square millimeter) having q.s medicine.Naked metal coronary stent (diameter is 3mm and length is 20mm) is twisted on each coating sacculus.Then, by the coating sacculus packaging also sterilizing of being rolled up by naked metal coronary stent, for animal experiment

Embodiment 10

Medicine-coated balloon in embodiment 8 and 9-inflatable bare mental stents and blank sacculus-inflatable bare mental stents (in contrast) are inserted in the coronary artery of pig, and by balloon overstretch (1:1.2).By stenter to implant, and sacculus is fixed inflation and discharge medicine and additive in 60 seconds, then Deflation is reclaimed from pig.Then, after 5 minutes, 30 minutes, 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, angiography is carried out to animal.The in-house dose of animal artery that is condemned to death is measured 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months

Embodiment 11

By 150mg (0.18mmole) paclitaxel, 5ml acetone (or ethyl acetate or methyl ethyl ketone), 150mg acetic anhydride or maleic anhydride or diglycolic acid anhydride and 0.5ml alcohol mixture, then stir until obtain solution.By 5 PTCA foley's tube solution sprays or dipping, dry, and again spray or dipping, until obtain the sacculus (3 micrograms/square millimeter) having q.s medicine.Then, coating sacculus is processed under high pH (scope is pH 8-11.5) condition carry out hydrolyzed acid anhydride.This confirms by infrared spectrometry.Like this, the hydrophilic of coating is improved.Then, the sterilizing of coating sacculus is used for animal experiment.

Embodiment 12

Drug coated balloon catheter and uncoated foley's tube (in contrast) are inserted into the pulmonary airways of pig through bronchoscope.By inflation, and inflating balloon is expanded be fixed in chamber 60 seconds and discharge medicine and additive.Deflation is reclaimed from pig.Then, after 3 days, 31 days, 3 months, 6 months, 9 months and 12 months, bronchoscopy is carried out to animal, and get quantitative for pathology and ingestion of drugs of tissue sample.

Embodiment 13

Uncoated stent delivery catheter is inserted in the lumen of vessels of pig.Dilating sacculus, placing rack also reclaims the sacculus of exitting.At the pharmaceutical preparation 1-15 (about 5-15mg medicine/pig) of stent implantation site injection embodiment 1 (10-100ml).Then, medicine is absorbed at damaged tissues.Then, check animal and get tissue sample for pathology.

Embodiment 14

Pathological tissues (breast carcinoma or prostate or atherosclerosis or narrow) is excised from human body by operation.Then, the pharmaceutical preparation 1-15 (10-100ml) of embodiment 1 is expelled to because operation gets involved on the operation intracavity or operation chamber produced (about 5-20mg medicine).Localized drug delivery comprises injects by minute hand, inlet tube, intervention sheath, medication infusion pipe and other medicines delivery tube.Then, medicine is absorbed by tissue at target site.

Embodiment 15

By 6 PTCA foley's tubes (diameter be 3.5 and 3.0mm and length is 20mm) inflate under 1-3 atmospheric pressure.Inflating balloon is loaded into the preparation 18-28 of embodiment 1.Obtain the sacculus (3 micrograms/square millimeter) with q.s medicine.Foldable inflating sacculus, then dry.Then, coating is folded sacculus to repack and sterilizing, for animal experiment

Coating PTCA foley's tube is inserted into the coronary arterial vasculature target site (LAD, LCX and RCA) of the pig of 25-45 pound weight.By inflated to about 12 atmospheric pressure.Overstretching ratio (ratio of balloon diameter and pipe diameter) is about 1.15-1.20.In the gas replenishment process of 30-60 second, medicine is delivered to target tissue.Then, foley's tube exitted and reclaim in animal body.Target vessel is obtained after 0.25-24 hour in this operation.By tissue extraction and HPLC, the left drug analyzed the medicament contg in target tissue and be retained in sacculus.

In these zooscopies of part, support is twisted on drug coated balloon catheter before placement.In growing animal test, before and after all interventions and after operation, within 28-35 days, carry out angiography.Measure lumen diameter and calculate late luminal and lose.Late luminal lose refer to through one section follow the trail of the time of now examining (after normally getting involved, several weeks are to the several months, be in this embodiment such as after angioplasty and placing rack several weeks to the several months) difference between the minimum cavity diameter that measures immediately after the minimum cavity diameter that measures and intervention.Restenosis is quantitative by diameter stenosis, and it is that after operation, tracking now examines difference between the mean lumen diameter recorded immediately again divided by the mean lumen diameter recorded immediately after operation.The animal test results report of preparation 18-28 is as follows.All data are averages of five or six experimental data points.

On 3.5mm foley's tube, the medicament contg of preparation 18 is 3.26 μ g/mm ².After described operation, medicine residual on sacculus is 15.92 μ g, or on sacculus total drug loading 2.3%.In the tissue that described operation obtained after 15-30 minute, medicament contg is 64.79 μ g, or 9.2% of the initial total drug loading of sacculus.When 18mm support is placed by coating sacculus, medicine residual on sacculus is 31.96 μ g, or 4.5% of drug loading, and in the tissue that described operation obtained after 15-30 minute, medicament contg is 96.49 μ g, or 13.7% of drug loading.Draw ratio in this operation is 1.3.Late luminal after 28-35 days is lost for 0.10mm (standard deviation is 0.2).Diameter stenosis is 3.3%.

On 3.5mm foley's tube, the medicament contg of preparation 19 is 3.08 μ g/mm ².After described operation, medicine residual on sacculus is 80.58 μ g, or is 11.4% of total drug loading.In the tissue that described operation obtained after 15-30 minute, medicament contg is 42.23 μ g, or 6.0% of drug loading.Late luminal after 28-35 days is lost for 0.30mm (standard deviation is 0.23).Diameter stenosis is 5.4%.

On 3.5mm foley's tube, the medicament contg of preparation 20 is 3.61 μ g/mm ².After described operation, medicine residual on sacculus is 174.24 μ g, or is 24.7% of total drug loading.In the tissue that described operation obtained after 15-30 minute, medicament contg is 83.83 μ g, or 11.9% of drug loading.When with 18mm stentplacement curling in advance, medicine residual on sacculus is 114.53 μ g, or 16.1% of total drug loading, and in the tissue that operation obtained after 15-30 minute, medicament contg is 147.95 μ g, or 18.1% of total drug loading.Draw ratio in this operation is 1.3.Late luminal after 28-35 days is lost for 0.10mm (standard deviation is 0.1).Diameter stenosis is 3.4%.

On 3.5mm foley's tube, the medicament contg of preparation 21 is 4.71 μ g/mm ².After described operation, medicine residual on sacculus is 44.39 μ g, or is 6.3% of total drug loading.In the tissue that described operation obtained after 15-30 minute, medicament contg is 77.87 μ g, or 11.0% of drug loading.Late luminal after 28-35 days is lost for 0.23mm (standard deviation is 0.44).Diameter stenosis is 7.3%.

On 3.5mm foley's tube, the medicament contg of preparation 22 is 3.85 μ g/mm ².After described operation, medicine residual on sacculus is 24.59 μ g, or is 3.5% of total drug loading.In the tissue that described operation obtained after 15-30 minute, medicament contg is 37.97 μ g, or 5.4% of drug loading.Late luminal after 28-35 days is lost for 0.33mm (standard deviation is 0.14).Diameter stenosis is 6.7%.

On 3.5mm foley's tube, the medicament contg of preparation 23 is 3.75 μ g/mm ².After described operation, medicine residual on sacculus is 0.82 μ g, or is 0.1% of total drug loading.In the tissue that described operation obtained after 60 minutes, medicament contg is 45.23 μ g, or 5.5% of drug loading.Late luminal after 28-35 days is lost for 0.49mm (standard deviation is 0.26).Diameter stenosis is 11.3%.

On 3.5mm foley's tube, the medicament contg of preparation 24 is 3.35 μ g/mm ².After described operation, medicine residual on sacculus is 62.07 μ g, or is 7.5% of total drug loading.In the tissue that described operation obtained after 60 minutes, medicament contg is 40.55 μ g, or 4.9% of drug loading.Late luminal after 28-35 days is lost for 0.47mm (standard deviation is 0.33).Diameter stenosis is 9.9%.

On 3.5mm foley's tube, the medicament contg of preparation 25 is 3.41 μ g/mm ².After described operation, medicine residual on sacculus is 50.0 μ g, or is 6.0% of total drug loading.In the tissue that described operation obtained after 60 minutes, medicament contg is 26.72 μ g, or 3.2% of drug loading.Late luminal after 28-35 days is lost for 0.36mm (standard deviation is 0.41).Diameter stenosis is 9.3%.

On 3.5mm foley's tube, the medicament contg of preparation 28 is 3.10 μ g/mm ².After described operation, medicine residual on sacculus is 1.9% of total drug loading.In the tissue that described operation obtained after 2 hours, medicament contg is 34.17 μ g, or 5.0% of drug loading.In the tissue that described operation obtained after 24 hours, medicament contg is 28.92 μ g, or 4.2% of drug loading.

On 3.5mm foley's tube, the medicament contg of control formulation (uncoated sacculus) is 0.0 μ g/mm ².After described operation, medicine residual on sacculus is 0% of total drug loading.In the tissue that described operation obtained after 15 minutes, medicament contg is 0 μ g.In the tissue that described operation obtained after 24 hours, medicament contg is 0 μ g.Late luminal after 28-35 days is lost for 0.67mm (standard deviation is 0.27).Diameter stenosis is 20.8%.Repeat in experiment at second, draw ratio is 1.3.It is 1.1 (standard deviation is 0.1) that late luminal is lost.Diameter stenosis is 37.5%.

On 3.5mm foley's tube, the medicament contg of Comparative formulation 26 is 3.21 μ g/mm ².After described operation, medicine residual on sacculus is 13.52 μ g, or 1.9% of total drug loading.In-house medicament contg is 28.32 μ g, or 4.0% of total drug loading.When sacculus is with 18mm stentplacement curling in advance, medicine residual on sacculus is 26.45 μ g, or 3.7% of total drug loading.In-house medicament contg is 113.79 μ g, or 16.1% of drug loading.Late luminal after 28-35 days is lost for 0.27mm (standard deviation is 0.15).Diameter stenosis is 7.1%.

On 3.5mm foley's tube, the medicament contg of preparation 27 (additive-free) is 4.22 μ g/mm ².After described operation, medicine residual on sacculus is 321.97 μ g, or 45.6% of total drug loading.In-house medicament contg is 12.83 μ g, or 1.8% of total drug loading.

Surprisingly, after placing the sacculus with preparation 18-25 and 28 coating according to the specific embodiment of the invention of the present invention, by the drug level of porcine coronary tissue resorption higher than the sacculus applied by Comparative formulation 26 send, and higher than those of preparation 27 independent drug coat.The late luminal that followed by for 28-35 days is lost and is less than contrast (uncoated sacculus).

Embodiment 16

By 6 PTCA foley's tubes (diameter be 3.5 and 3.0mm and length is 20mm) inflate under 1-3 atmospheric pressure.Inflating balloon is loaded into the preparation 18-25 and 28 of embodiment 1.Q.s (3 μ g/mm are obtained in balloon surface ²) medicine.Inflating balloon is dry.Then, top layer is loaded to medicine-coated balloon.The Topcoating preparation being dissolved in acetone or alcohol is selected from gentisic acid, methyl parabens, acetic acid, polysorbas20, vanillin and aspirin.Coating is folded sacculus drying, then repack and sterilizing, for animal experiment.

Devise floating experiment to test in the process inserted foley's tube and be transported to target site before inflation and have lost how many medicines.Contrast foley's tube preparation 18 applies.Also prepare the Topcoating conduit that Topcoating is propyl p-hydroxybenzoate.For Topcoating conduit, foley's tube preparation 18 applies, and then dry, in preparation 18 coating, coating is containing the acetone of 25-50mg propyl p-hydroxybenzoate (about 50% weight paclitaxel).Each contrast and Topcoating foley's tube are inserted in the tremulous pulse of pig.Time floating in pig arterial vasculature is 1 minute.Medicine, additive and Topcoating are released.Then, conduit is reclaimed.Medicine HPLC residual on foley's tube analyzes.On contrast foley's tube, residual medicine is 53% of total drug loading.The residual drug content of Topcoating foley's tube is 88%.Be transported to the condition at treatment intervention position at simulator under, Topcoating decreases the loss of medicine in vascular system.Carry out the animal experiment identical with embodiment 15, first apply sacculus with preparation 18, and cover the first coating with propyl p-hydroxybenzoate as Topcoating.Medicament contg on 3.5mm foley's tube is 3.39 μ g/mm ².After described operation, medicine residual on sacculus is 64.5 μ g, or 8.6% of total drug loading.In-house medicament contg is 28.42 μ g, or 4% of total drug loading.

Embodiment 17

To 6 PTCA sacculus assemblies (diameter be 3.5 and 3.0mm and length is 20mm) be loaded into the preparation 18 that embodiment 1 provides.Medicine (the 3 μ g/mm of q.s are obtained in balloon surface ²).Dry sacculus.

Then, for the preparation of the preparation of Topcoating.The preparation of Topcoating is the acetone being selected from the additive of polysorbas20, Tween 80, polypropylene glycol-425 (PPG-425) and polypropylene glycol-1000 (PPG-1000) containing paclitaxel and one.The balloon surface of contrast conduit is only loaded into preparation 18.In preparation 18 coating that other balloon surface applies, be coated with the acetone containing 25-50mg Topcoating preparation (about 50% weight paclitaxel).Dry coating sacculus, tests for vitro drug release.

Devise release experiment to carry out testing drug have lost how many in inflated process.Each coating sacculus is inflated 2 minutes in 12 atmospheric 1%BSA solution at 37 DEG C.Medicine, additive and Topcoating are released.Medicine HPLC residual on foley's tube analyzes.On contrast foley's tube, residual medicament contg is 34% of total drug loading.Comprise the foley's tube of the Topcoating containing polysorbas20, Tween 80, polypropylene glycol-425 (PPG-425) or polypropylene glycol-1000 (PPG-1000), its left drug content is respectively 47%, 56%, 71% and 81%.Therefore, Topcoating decreases the loss of medicine in the in vitro tests of sacculus assembly gas replenishment process.

Claims (15)

1. the armarium extremely organized for delivering therapeutic agents, described armarium comprises the coating being covered in armarium outer surface, wherein, described coating comprises therapeutic agent and at least one additive, described therapeutic agent is the water-insoluble drug being selected from paclitaxel, rapamycin, daunorubicin, amycin, β-lapachol, bioactive vitamin D and combination thereof, and described at least one additive comprises at least one compound with at least one amide group.

2. armarium according to claim 1, wherein said at least one additive is selected from urea, biuret, acetamide, lactamide, amino acid amide, acetaminophen, uric acid, polyureas, urethanes, urea derivative, nicotiamide, N-methylacetamide, N,N-dimethylacetamide, sulphacetamide, versetamide, lauric acid diethyl amide, lauric myristic diglycollic amide, N, N-two (2-hydroxyethyl stearmide), coconut oleoyl amine MEA, coconut oleoyl amine DEA.

3. armarium according to claim 1, wherein said armarium is the one in foley's tube, perfusion balloon catheter conduit, transfusion catheter, Cutting balloon conduit, integrating sphere ductus bursae, laser catheter or stent graft.

4. armarium according to claim 1, wherein said at least one additive is selected from urea, biuret, uric acid, polyureas, urethanes and urea derivative.

5. armarium according to claim 1, wherein said at least one additive comprises urea.

6. armarium according to claim 5, wherein said armarium is foley's tube.

7. armarium according to claim 1, wherein said therapeutic agent comprises paclitaxel, and described at least one additive comprises urea.

8. armarium according to claim 1, wherein said armarium is foley's tube, and described therapeutic agent comprises paclitaxel, and described at least one additive comprises urea.

9. armarium according to claim 1, wherein said armarium is stent graft, and described therapeutic agent comprises paclitaxel, and described at least one additive comprises urea.

10. armarium according to claim 1, wherein said at least one additive can not react with therapeutic agent in the sterilization process of armarium.

11. armarium according to claim 1, wherein said at least one additive can not react with therapeutic agent in the ethylene oxide sterilizing process of armarium.

12. armarium according to claim 1, wherein said therapeutic agent concentration is in the coating 1 to 20 μ g/mm ².

13. armarium according to claim 1, wherein said tissue comprises the tissue of coronary vasculature, peripheral vasculature, brain vascular system, esophagus, air flue, hole, trachea, colon, biliary tract, urinary tract, one of prostate or nicergoline road.

14. armarium according to claim 1, wherein said equipment comprises the top layer on the surface of the coating be covered on armarium outer surface further, is transported to loss in organizational process in vivo for reducing therapeutic agent.

15. armarium according to claim 14, wherein top layer is selected from gentisic acid, methyl parabens, acetic acid, PEG-20 dehydrated sorbitol mono-fatty acid ester, vanillin and aspirin.