CN1889929A - Excipients in drug delivery vehicles - Google Patents

Abstract

Injectable depot gel compositions and kits that provide an excipient for modulating a release rate and stabilizing beneficial agents are provided. Methods of administering and preparing such systems are also provided. The gel compositions comprise biodegradable, bioerodible polymers and water-immiscible solvents in amounts effective to plasticize the polymers and form gels with the polymers. Suitable excipients include pH modifiers, reducing agents, and antioxidants.

Description

Excipient in the medicine delivery vehicle

The cross reference of related application

The application requires the U.S. Provisional Application No.60/519 that submitted on November 14th, 2003, the U.S. Patent application No.10/. that on November 10th, 972 and 2004 submitted to ... ... interests, quote as a reference at this.

Invention field

The present invention relates generally to continue the depot compositions and the test kit of release, they provide the lasting release of beneficiating ingredient.The present invention also relates to preparation and give described method for compositions.

Background of invention

Biodegradable polymer uses for many years in medical applications.The device example of being made up of Biodegradable polymer comprises stitching thread, surgery folder, medical nail, implant and drug delivery system.These Biodegradable polymers of great majority are based on Acetic acid, hydroxy-, bimol. cyclic ester, lactide, caprolactone and copolymer thereof.

Injectable implant adopts the solvent/plasticizer that dissolves in very much or relatively aqueous body fluid with the Biodegradable polymer preparation, to promote the rapid curing of polymer at implant site, promotes that medicine spreads from implant.When implant is placed in body neutralization when being exposed to aqueous body fluid, it is a serious problem that water adopts the polymeric implants of water-soluble solvent to divide a word with a hyphen at the end of a line rapidly to this class.Moisture picked-up rapidly often causes implant to have the uneven loose structure of size and shape.Usually, surperficial aperture presents finger sample pore structure, extends in from implant surface to implant to reach 1/3rd millimeters or more, and this class finger sample hole makes implant surface open to environment for use.It is littler that inner aperture is tending towards, and the fluid that is present in the environment for use is not accessible.Moisture picked-up feature often causes the release of beneficiating ingredient out of control rapidly, shows as the initial rapidly release of beneficiating ingredient from polymer formulations, " prominent the releasing " of the beneficiating ingredient that is equivalent to discharge from implant.Prominent release the major part that often causes beneficiating ingredient, if not whole, in the very short time, discharge for example a few hours or 1-2 days.A kind of like this effect may be unacceptable, particularly in those environment that needs control is sent, beneficiating ingredient sending in a controlled manner just, last two weeks above or reach one month or even reach 1 year, perhaps existing narrow treatment window and excessive beneficiating ingredient to discharge therein may cause in those environment of adverse consequences the curee, perhaps be necessary therein to simulate beneficiating ingredient, for example hormone etc. in curee's body abiogenous every day curve those environment in.

Therefore, when implanting this class device, point the sample hole and allow very fast aqueous body fluid picked-up to enter implant inside, the significant quantity beneficiating ingredient dissolves immediately and rapidly subsequently, and the without hindrance environment for use that diffuses into of beneficiating ingredient produces burst effect as discussed above.

In addition, moisture picked-up rapidly may cause too early polymer precipitation, so that produces hardened implant or have the implant of sclerosis crust.The inner aperture that contains beneficiating ingredient is cut off with body fluid with a lot of inner spaces and contacts, may be not in the inapparent time (" lag time ") cause the release of beneficiating ingredient significantly to reduce.From the viewpoint of the controlled, sustained release of beneficiating ingredient is provided to the curee, be unwanted this lag time.Viewed then is prominent the releasing that discharge at short notice of beneficiating ingredient soon after implantation, wherein do not have or beneficiating ingredient d/d lag time seldom, subsequently beneficiating ingredient continue to send (supposition beneficiating ingredient after prominent releasing, also have remain), exhaust until the supply of beneficiating ingredient.

Various control beneficiating ingredients are prominent to be released and regulation and control are sent and made that its method of stabilizing is existing to be described.Following patent United States Patent(USP) Nos. 6,468,961; 6,331,311; 6,130,200; 5,990,194; 5,780,044; 5,733,950; 5,656,297; 5,654,010; 4,985,404 and 4,853,218 and PCT communique WO 98/27962 it is believed that be the representative, quote as a reference at this.Although obtain certain success, but these methods are still not exclusively satisfactory with regard to the beneficiating ingredient of in a large number implanted thing effectively being sent.

The influence that the initial burst release of medicine and release rate profile can be subjected to several factors, for example the water miscibilty of the molecular weight of the ratio of polymer and solvent, polymer, solvent and the character of drug particle.But, reach required rate of release and may be subjected to the rotten inhibition of beneficiating ingredient in some cases.In addition, when polymeric matrices is caught beneficiating ingredient, beneficiating ingredient from polymeric matrix inside to be released in that polymeric matrix begins before the significantly degraded may mainly be diffusion-control, cause it may is not desirable release rate profile.

Using the problem that some Biodegradable polymers faced in drug delivery system is the degraded of polymer, causes the accumulation of for example sour by-product in delivery system.The environment that gained contains polymer degradation products may damage beneficiating ingredient, for example protein, peptide and small-molecule drug.

Another problem of using some implantable systems to face is the existence from the free radical and/or the peroxide of body fluid.The normal foreign body reaction of for example implantable drug delivery system is also caused the generation of free radical and peroxide.Therefore, free radical and peroxide may diffuse into the drug delivery system of being implanted, and are deleterious to beneficiating ingredient.

As a result, beneficiating ingredient is subjected to the influence of some factors apt to deteriorate, reduces the general validity of dosage form thus, because be not the treatment that the beneficiating ingredient all wanted can be used for the curee.

Still be starved of such drug delivery system, they can make the beneficiating ingredient stabilisation that is exposed to harmful microenvironment owing to the existence of depolymerization and/or unwanted free radical or peroxide.In addition, still need to regulate and control the release of beneficiating ingredient from drug delivery system, to reach required rate of release.

Summary of the invention

The invention provides Injectable depot gel combination and test kit, the persistent period that they go through short persistent period and prolongation discharges beneficiating ingredient.The method that gives and prepare this based composition also is provided.Compositions according to the present invention comprises gel vehicle, dissolves or is dispersed in beneficiating ingredient and the excipient in this gel vehicle.Gel vehicle comprises not miscibilty solvent of bioerosion, biocompatible polymer and water, and content is for plasticized polymer and to generate gel with polymer be effective.In some situation, form solvent with water not the miscibilty solvent use.The present composition uses excipient regulation and control release profiles and makes the beneficiating ingredient stabilisation.For example, some excipient can be offset the effect of depolymerization.Other excipient can be offset the effect from the peroxide and/or the free radical of body fluid.

Comprise the Injectable depot gel combination that continues to send beneficiating ingredient according to the embodiment of the present invention, comprise: gel vehicle, comprise not miscibilty solvent of bioerosion, biocompatible polymer and water, content is for plasticized polymer and to generate gel with it be effective; Dissolving or be dispersed in beneficiating ingredient in this gel vehicle; Regulation and control rate of release and the excipient that makes the beneficiating ingredient stabilisation; Wherein continue to send occur in about twenty four hours after the administration between about 12 months during.

Although the excipient that is fit to has a lot, example comprises pH modifier, Reducing agent and antioxidant.Embodiments of the present invention can be used the combination of single excipient or excipient.

PH modifier class excipient includes but not limited to inorganic salt, for example zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.Reducing agent class excipient can be cysteine or methionine.Antioxidant as excipient can be selected from down group: d-α tocopherol acetate, the d1-alpha tocopherol, anti-bad blood acyl cetylate, butylation hydroxyl anidole, ascorbic acid, butylatedhydroxyanisole, the butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, the gallate monooctyl ester, the gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin, ethanolamine and their combination.

About excipient, compositions of the present invention can comprise between about 0.01% and about 50%, by weight; Between about 0.05% and about 40%, by weight; Between perhaps about 0.1% and about 30%, by weight.In addition, the ratio between excipient and the beneficiating ingredient can be between about 0.1: 99.9 and about 99: 1, and preferably, this ratio is between about 1: 99 and about 60: 40.

The water of the present invention not water miscibilty of miscibilty solvent can be to be less than or equal to about 7 weight % under 25 ℃.In addition, compositions can not moisture miscibilty under 25 ℃ greater than the solvent of 7 weight %.Solvent can be selected from down group: the rudimentary aralkyl ester of the lower alkyl esters of aromatic alcohol, aryl acid, aryl acid; The lower alkyl esters of aryl ketones, aralkyl ketone, lower alkyl ketone, citric acid and their combination.Other can be used for solvent of the present invention benzylalcohol, benzoic acid benzyl ester, ethyl benzoate and glyceryl triacetate.

Some embodiments of the present invention comprise the composition solvent that is selected from down group: glyceryl triacetate, diacetin, tributyorin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl group glyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate., mineral oil, polybutene, silicone fluid, glycerol, ethylene glycol, Polyethylene Glycol, capryl alcohol, ethyl lactate, propylene glycol, Allyl carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, the N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, butanone, dimethyl formamide, dimethyl sulfoxide, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid, 1-dodecyl-aza-cycloheptane alkane-2-ketone and their combination.

Can be selected from down group according to polymer used in the present invention: polyactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(caprolactone), polyanhydride, polyamine, polyesteramide, poe, poly-two  alkane ketone, polyacetals, polyketals, Merlon, poly phosphate, polyester, the poly terephthalic acid butene esters, poly-orthocarbonic ester, polyphosphazene, succinate, poly-(malic acid), poly-(aminoacid), polyvinylpyrrolidone, Polyethylene Glycol, poly-hydroxylated cellulose, polysaccharide, chitin, chitosan, hyaluronic acid and their copolymer, terpolymer and mixture.Can use lactide acid polymer in the present invention, the copolymer (PLGA) of preferred lactic acid and glycolic comprises poly-(D, L-lactide-be total to-Acetic acid, hydroxy-, bimol. cyclic ester) and poly-(L-lactide-be total to-Acetic acid, hydroxy-, bimol. cyclic ester).In some embodiments, the weight average molecular weight of PLGA polymer is between about 3,000 to about 120,000, and the monomer ratio of lactic acid and glycolic is between about 50: 50 to about 100: 0.Also can use caprolactone polymer in the present invention.

Other embodiments of the present invention comprise between about 5 weight % and the about 90 weight %, between about 25 weight % and the about 80 weight % or the polymer between about 35 weight % and the about 75 weight %.With the proportional meter of polymer and solvent, some ratios can be between about 5: 95 and about 90: 10, and other ratios can be between about 20: 80 and 80: 20, and other ratios can be between about 30: 70 and about 75: 25.

According to the present invention, compositions can further comprise at least a following ingredients: emulsifying agent, pore former, anesthetis dissolubility adjusting control agent and penetrating agent.

About beneficiating ingredient, compositions can comprise about 0.1% to about 50%, about 0.5% to about 40% or about 1% to about 30% beneficiating ingredient, by weight.The mean diameter of beneficiating ingredient can be less than about 250 μ m, between about 5 μ m and the 250 μ m, between about 20 μ m and the about 125 μ m or between about 38 μ m and about 63 μ m.

Beneficiating ingredient can be selected from down group: protein, peptide, medicine and their combination.For example, when useful composition comprised protein, this protein can be selected from down group: human growth hormone, Intederon Alpha-2a, Interferon Alpha-2b, EPO, methionine-human growth hormone, go-the phenylalanine human growth hormone, synonym interferon and their combination.When useful composition comprised medicine, this medicine can be bupivacaine or paclitaxel.Peptide class beneficiating ingredient can comprise leuprolide or Desmopressin.

In one embodiment of the invention, provide preparation to go through about twenty four hours extremely continued to send the Injectable depot gel combination of beneficiating ingredient in about 12 months to the curee method, this method comprises: the water of mixed biologic aggressivity, biocompatible polymer and effective plasticising amount is the miscibilty solvent not, generates gel vehicle; In this gel vehicle, mix beneficiating ingredient; The excipient that in this gel vehicle, mixes the regulation and control rate of release; With make this beneficiating ingredient stabilisation, wherein the effect of depolymerization is offset in the existence of this excipient.This method can further be included in gel vehicle premixing excipient and beneficiating ingredient before the admixed excipients and beneficiating ingredient.On the other hand, this method can further comprise to gel vehicle and loads excipient and beneficiating ingredient separately.Described excipient can dissolve or be dispersed in the gel vehicle.

In other embodiments of the present invention, provide preparation to go through about twenty four hours extremely continued to send the Injectable depot gel combination of beneficiating ingredient in about 12 months to the curee method, this method comprises: the water of mixed biologic aggressivity, biocompatible polymer and effective plasticising amount is the miscibilty solvent not, generates gel vehicle; In this gel vehicle, mix beneficiating ingredient; The excipient that in this gel vehicle, mixes the regulation and control rate of release; With make this beneficiating ingredient stabilisation, wherein the existence of this excipient offset the peroxide see in the body fluid or free radical or this two.

Another embodiment of the invention comprises goes through about twenty four hours continued to discharge beneficiating ingredient to about 12 months Injectable depot method for compositions, comprise and give a kind of compositions, said composition comprises: gel vehicle, comprise bioerosion, biocompatible polymer and the effective water miscibilty solvent not of plasticising amount, generate gel vehicle; Dissolving or be dispersed in beneficiating ingredient in this gel vehicle; Regulation and control rate of release and the excipient that makes this beneficiating ingredient stabilisation.Compositions can give once.On the other hand, compositions can give repeatedly.Compositions can part or systemic delivery.In addition, compositions can be delivered to a plurality of positions on the curee.

Another embodiment of the invention comprises that continuing to send beneficiating ingredient reaches after the administration about twenty four hours to about 12 months administration test kit, this test kit comprises: gel vehicle, comprise not miscibilty solvent of bioerosion, biocompatible polymer and water, content is for this polymer of plasticising and to generate gel with it be effective; Dissolving or be dispersed in beneficiating ingredient in this gel vehicle; The excipient of regulation and control rate of release, wherein this excipient makes this beneficiating ingredient stabilisation by the effect of offsetting depolymerization; With optional one or more following ingredients: emulsifying agent; Pore former; Optional and the associating anesthetis of this beneficiating ingredient dissolubility adjusting control agent; And penetrating agent; The associating anesthetis of wherein optional at least and this dissolubility adjusting control agent keeps and separated from solvent, until anesthetis in curee's administration.

Another embodiment of the invention comprises that continuing to send beneficiating ingredient reaches after the administration about twenty four hours to about 12 months administration test kit, this test kit comprises: gel vehicle, comprise not miscibilty solvent of bioerosion, biocompatible polymer and water, content is for this polymer of plasticising and to generate gel with it be effective; Dissolving or be dispersed in beneficiating ingredient in this gel vehicle; The excipient of regulation and control rate of release, wherein this excipient makes this beneficiating ingredient stabilisation by the effect of offsetting depolymerization; With optional one or more following ingredients: emulsifying agent; Pore former; Optional and the associating anesthetis of this beneficiating ingredient dissolubility adjusting control agent; And penetrating agent; The associating anesthetis of wherein optional at least and this dissolubility adjusting control agent keeps and separated from solvent, until anesthetis in curee's administration.

See disclosing of this paper, these and other embodiments will be understanded by those of ordinary skills easily.

Brief description of drawings

After reading following detailed description and accompanying drawing as described below, above-mentioned and other objects of the present invention, feature and advantage are with easier to understand.

Fig. 1 sets forth from the interior release profiles of the body of depot formulations of the present invention (preparation 1-2) gained bupivacaine alkali.

Fig. 2 sets forth from the interior release profiles of the body of depot formulations of the present invention (preparation 3-5) gained bupivacaine hydrochloride.

Fig. 3 sets forth from the interior release profiles of the body of depot formulations of the present invention (preparation 6-8) gained hGH.

Describe in detail

Have been found that in some system, in the presence of excipient, can make beneficiating ingredient stabilisation and their release of regulation and control of Injectable depot composition.

Composition of the present invention uses excipient to offset effect and the regulation and control release profiles of depolymerization. Although the excipient that is fit to has a lot, but example comprises pH modifier and antioxidant, for example reducing agent and free radical scavenger.

PH modifier includes but not limited to inorganic and organic salt, comprises zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium monohydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium monohydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, trbasic zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination. Reducing agent includes but not limited to cysteine or methionine. Antioxidant includes but not limited to d-α tocopherol acetate, d1-alpha tocopherol, Vitamin C acyl palmitate, butylation hydroxyl anidole, ascorbic acid, butylated hydroxy anisole (BHA), butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, gallate monooctyl ester, gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin and monoethanolamine.

The present invention for composition comprise those that mix excipient; inorganic salts for example; for example magnesium carbonate or zinc carbonate; their local pH in can (1) balance depot formulations; avoid the impact of low pH after the depolymerization with the protection beneficiating ingredient, and (2) regulate and control release rate profile by dynamic creation microcellular structure in polymer. Because the alkalescent of more selected inorganic salts, can balance by the local acid pH in the bank microenvironment due to the depolymerization. Therefore can protect beneficiating ingredient, especially protein, peptide and medicine are avoided the adverse effect of low pH. In addition, do not plan to accept opinion and limit, think that the white space that former cause salt occupies is with the dynamic creation microcellular structure when the particle of excipient, for example inorganic salts leaves polymeric matrices because dissolving in water. The size of aperture and density may be subject to the control of raw material and loading level. Thereby required release profiles can be programmable.

And then a lot of small-molecule drugs exist with multi-form, and this depends on the pH of the environment that medicine exposes. For example, small-molecule drug can possess positive charge under low pH, possess negative electrical charge under higher pH, does not have electric charge under middle pH. Therefore, by changing local pH, can easily determine hydrophilic-hydrophobic matter and the solubility of medicine in matrix of medicine. Thereby, can regulate and control the initial burst of beneficiating ingredient from bank and discharge and release rate profile. The release rate profile of known activity composition from bank can highly depend on the hydrophilic-hydrophobic matter of medicine. Because the hydrophilic-hydrophobic matter of medicine can easily depend on its chemical species and depend under many circumstances local pH, method of the present invention may not need to add any other preparation raw material with the solubility of regulating medicine in the drug particle preparation, thereby makes pharmaceutical preparation simpler.

And then a lot of small-molecule drugs contain when peroxide or free radical exist the functional group to the oxidation sensitivity, for example amine, hydroxyl. When oxidized, medicine may be lost the active of them and/or cause some unwanted side effects. By mixing antioxidant; such as but not limited to reducing agent or free radical scavenger; can protect the integrality of medicine to avoid the two attack of peroxide or free radical or this; they diffuse into gel vehicle from body fluid, perhaps produced by the normal foreign body reaction to implant. In addition, not planning to accept opinion limits, think that the white space that former cause excipient occupies is with the dynamic creation microcellular structure when the dispersant liquid drop of the particle of excipient, for example solid reductant, antioxidant and free radical scavenger or excipient, for example solid reductant, antioxidant and free radical scavenger leaves polymeric matrices because of diffusion. The size of aperture and density may be subject to the control of raw material and loading level. Thereby required release profiles can be programmable.

Bioactive ingredients, when peroxide or free radical exist, be responsive to oxidation generally such as protein, peptide, monoclonal antibody etc. When oxidized, bioactive ingredients may be lost the active of them and/or cause some unwanted side effect, for example immune responses. By mixing reducing agent, antioxidant or free radical scavenger; can protect the integrality of composition to avoid the attack of peroxide and/or free radical; they diffuse into gel vehicle from body fluid, perhaps produced by the normal foreign body reaction to implant. In addition, not planning to accept opinion limits, think that the white space that former cause excipient occupies is with the dynamic creation microcellular structure when the dispersant liquid drop of the particle of excipient, for example solid reductant, antioxidant and free radical scavenger or excipient, for example solid reductant, antioxidant and free radical scavenger leaves polymeric matrices because of diffusion. The size of aperture and density may be subject to the control of raw material and loading level. Thereby required release profiles can be programmable.

Composition according to the present invention mixes excipient, for example antioxidant, reducing agent and/or free radical scavenger, they are the target free radical and the peroxide that diffuse into gel vehicle or produced by the normal foreign body reaction to implant from body fluid for example.

Mix excipient in the gel vehicle and for example can carry out like this, during the drug particle formulated, in drug particle, directly mix or the premixed excipient. On the other hand, can in gel vehicle, load separately excipient and medicine. Excipient can dissolve or be dispersed in the gel vehicle as the beneficiating ingredient.

Definition

Describing and claimed when of the present invention, will be according to following definition use following term.

Singulative " one ", " a kind of " and " being somebody's turn to do " comprise plural indicant, and context has except the clear and definite instruction in addition. Thereby for example, the appellation of " a kind of solvent " is comprised single solvent and the mixture of two or more different solvents, the appellation of " a kind of anesthetic " is comprised single anesthetic and two or more different narcotic combinations, etc.

Appellation to " effect of depolymerization " represents to decompose those accessory substances that produce by Biodegradable polymer without limitation. This class accessory substance can comprise sour accessory substance, and for example lactic acid and glycolic are for example when using PLGA. In addition, accessory substances such as oxide, peroxide and free radical also may exist. Therefore, the appellation of " counteracting degradation effect " is meaned prevent accessory substance infringement beneficiating ingredient. For example, comprising the excipient of salt can the neutralizing acid accessory substance. The excipient that comprises reducing agent suppresses peroxide, and is same, and polyphenoils prevents oxide degraded beneficiating ingredient.

To the appellation of " peroxide or free radical or this two " represent without limitation to be present in the body fluid, those peroxide and/or free radical that may be harmful to beneficiating ingredient. For example, the normal foreign body reaction of for example implant generated free radical and the peroxide that may enter implant and degraded beneficiating ingredient. Other peroxide and free radical are the results of normal body function, and be also still harmful to beneficiating ingredient.

Term " excipient " represents in the preparation except beneficiating ingredient or for any useful composition the raw material that generates gel vehicle. Can be used for regulating and control rate of release and make the excipient of beneficiating ingredient stabilisation comprise pH modifier, reducing agent, antioxidant and free radical scavenger.

Area under term " AUC " the expression curee in vivoassay curve obtained is measured the PC of beneficiating ingredient the curee from composition Implantation Time time " t " after implant, and the time is mapped. Time t will be equivalent to beneficiating ingredient to curee's Delivery time section.

Term " prominent release index " represents that about the particular composition that is used for the beneficiating ingredient systemic delivery following (i) is divided by (ii) gained quotient: (i) implant very first time section is calculated behind the curee AUC divided by the hourage (t of very first time section according to composition₁); (ii) AUC that calculates according to the Delivery time of beneficiating ingredient is divided by the hourage (t of total Delivery time₂). For example, prominent 24 hours the time to release index be following (i) divided by (ii) gained quotient: (i) implant AUC that the front twenty four hours behind the curee calculates divided by numeral 24 according to composition; (ii) AUC that calculates according to the Delivery time of beneficiating ingredient is divided by the hourage of total Delivery time.

Wording " dissolving or dispersion " plans to contain the means that all set up beneficiating ingredient and/or the existence of excipient in gel combination, comprises dissolving, dispersion, suspension etc.

Term " whole body " about beneficiating ingredient to the curee send or administration means in the blood plasma of beneficiating ingredient the curee, be detectable in biology on the significant level.

Term " part " about beneficiating ingredient to the curee send or administration means that beneficiating ingredient is delivered to curee's localization position, but in curee's blood plasma, in biology, be not detectable on the significant level.

Term " gel vehicle " is illustrated under the existence that does not have beneficiating ingredient the compositions that mixture generated by polymer and solvent.

Term " short-term " or " short persistent period " are used interchangeably, the time period that beneficiating ingredient discharges from bank gel combination of the present invention takes place in expression, generally will be equal to or less than for two weeks, preferred about 24 hours to about 2 weeks, preferred about 10 days or shorter, preferred about 7 days or shorter, more preferably from about 3 days to about 7 days.

The time period that beneficiating ingredient discharges from implant of the present invention takes place in term " for a long time " or " persistent period of prolongation " expression, generally will be an about week or longer, preferred about 30 days or longer, more preferably 1 year.

Term " initial burst " represents that about particular composition of the present invention following (i) is divided by (ii) gained quotient: (i) weight that beneficiating ingredient discharges in the predetermined initial time section after implantation from compositions; (ii) remain the beneficiating ingredient total amount of from the compositions of being implanted, sending.Self-evident, initial burst can be different because of the shape and the surface area of implant.Therefore, percentage ratio relevant with initial burst described herein and the prominent index of releasing are intended for use the compositions of testing in the mode of assign group compound from standard syringe.

Term " dissolubility adjusting control agent " is represented a kind of like this composition about beneficiating ingredient, and it will change the dissolubility of beneficiating ingredient with respect to polymer solvent or water, is different from the beneficiating ingredient dissolubility in the presence of this adjusting control agent not.Adjusting control agent can improve or reduce the dissolubility of beneficiating ingredient in solvent or water.But, be under the situation of high water soluble at beneficiating ingredient, the dissolubility adjusting control agent generally will be the composition that reduces the dissolubility of beneficiating ingredient in water.The effect of beneficiating ingredient dissolubility adjusting control agent may from dissolubility adjusting control agent and solvent or with the interaction of beneficiating ingredient itself, for example generate coordination compound, perhaps this two.For this purpose, when dissolubility adjusting control agent and beneficiating ingredient " association ", all these classes interact or nucleus formation all might take place.Can with mixed dissolution degree adjusting control agent and beneficiating ingredient before viscogel combines, perhaps can before adding beneficiating ingredient, join in the viscogel, depend on the circumstances.

Term " curee " and " patient " represent animal or human's class about the administration of the present composition.

Since all solvents at least all will be on certain very limited degree on the molecular level water soluble (just with water can mix), term used herein " can not mix " mean by weight 7% following, preferred 5% or following solvent be water soluble or can mix with water.For purpose disclosed herein, under being considered to be in 25 ℃, the solubility values of solvent in water measure.Because the generally acknowledged solubility values of being reported may always not carried out under the same conditions, this paper may not be absolute as limitting with the dissolubility that water can mix or water-soluble percentage by weight is quoted, and is the part of a kind of scope or the upper limit.For example, if the upper solubility limit of solvent in water is cited as " 7 weight % " in this article, and do not provide further the restriction of solvent, reported so that water solubility was that the solvents " glyceryl triacetate " of the every 100ml water of 7.17 grams are regarded as being included in 7% the limit.Water solubility limit used herein does not comprise that less than 7 weight % solvent glyceryl triacetate or water solubility are equal to or greater than the solvent of glyceryl triacetate.

Term " bioerosion " expression is decomposed on the spot gradually, dissolving, hydrolysis and/or erosive material.Generally speaking, " bioerosion " polymer herein is the hydrolyzable and main hydrolysis polymer of bioerosion on the spot that passes through.

Polymer of the present invention, solvent and other compositions must be " biocompatibility "; Just they must not cause stimulation, inflammation or necrosis to environment for use.Environment for use is a fluid environment, can comprise in human or animal's subcutaneous, the intramuscular, blood vessel in (high/low flow), myocardium inside and outside film, the tumor or part in the brain, wound location, joint space or body cavity closely.

The hydrocarbyl group that term used herein " alkyl " expression is saturated, usually only must not contain 1 to about 30 carbon atoms, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, octyl group, decyl etc., and cycloalkyl, for example cyclopenta, cyclohexyl etc.Generally speaking, but still be not inevitably, alkyl herein contains 1 to about 12 carbon atoms.The alkyl of 1 to 6 carbon atom of term " low alkyl group " expression, preferred 1 to 4 carbon atom.The alkyl that " alkyl of replacement " expression is replaced by one or more substituent groups, term " contain heteroatomic alkyl " and " assorted alkyl " represents that wherein at least one carbon atom is by the displaced alkyl of hetero atom.If not other indication is arranged, term " alkyl " and " low alkyl group " comprise straight chain, side chain, ring-type, do not replace, replace and/or contain heteroatomic alkyl or low alkyl group.

Term used herein " aryl " unless otherwise specified, the expression aromatic substituent, contain single aromatic ring or a plurality ofly condense together, covalently bound or be connected in the aromatic ring of public group, for example methylene or ethylidene part.Preferred aryl groups contains an aromatic ring or two aromatic rings that condense or connect, for example phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamines, benzophenone etc., and most preferred aryl is monocyclic.The aryl moiety that " aryl of replacement " expression is replaced by one or more substituent groups, term " contain heteroatomic aryl " and " heteroaryl " represents that wherein at least one carbon atom is by the displaced aryl of hetero atom.Unless indication is arranged in addition, term " aryl " comprises the aryl of heteroaryl, replacement and the heteroaryl of replacement.

The alkyl that term " aralkyl " expression is replaced by aryl, wherein alkyl and aryl are as defined above.The alkyl that term " heteroarylalkyl " expression is replaced by heteroaryl.Unless indication is arranged in addition, term " aralkyl " comprises the aralkyl and the unsubstituted aralkyl of heteroarylalkyl and replacement.Generally speaking, the low alkyl group of the term of this paper " aralkyl " expression aryl-replacement, the low alkyl group of preferred phenyl-replacement, for example benzyl, phenethyl, 1-phenyl propyl, 2-phenyl propyl etc.

I. Injectable depot compositions

Opposite with former polymer class Injectable depot, bank of the present invention uses a kind of excipient, and it regulates and control rate of release, and makes the beneficiating ingredient stabilisation by the effect of offsetting depolymerization.Can before injecting bank, generate the Injectable depot compositions that is used for sending for a long time beneficiating ingredient, be viscogel to the curee.The viscogel carrier disperses beneficiating ingredient, so that suitable delivery curves to be provided, comprises that along with beneficiating ingredient discharges, the initial burst of beneficiating ingredient is lower from bank.

Usually, from the standard subcutaneous injections device that is filled with beneficiating ingredient-viscogel compositions in advance, inject viscogel, generate bank.When being injected, skin and subcutaneous tissue often preferably utilize the syringe needle (minimum diameter) of minimum dimension to inject, to reduce curee's discomfort.Needing can be by 16guage and higher needle injection gel, preferred 20gauge and higher, more preferably 22gauge and higher, and then more preferably 24gauge and higher.With regard to the high viscosity gel, just viscosity is about 200 pool or bigger gels, and the injection force of distribution gel may be very high from the syringe of syringe needle in the 20-30gauge scope, so that very difficult or quite impossible when manual the injection.Meanwhile, the high viscosity of gel is to keep the integrity of bank required after the injection and between allotment period, also helping the required suspension feature of beneficiating ingredient in gel.

Bank gel combination described herein shows the viscosity that has reduced when being subjected to shearing force.The degree that reduces is the function of the polydispersity of the molecular weight of the shear rate of gel when being subjected to shearing force, polymer and polymeric matrix on the part degree.When removing shearing force, the viscosity recovery of bank gel combination to be subjected to before the shearing force viscosity or near.Therefore, the bank gel combination can be subjected to shearing force when injection from syringe, and this can temporarily reduce the viscosity during the injection process.When finishing injection process, remove shearing force, gel reverts to very near former state.

Excipient

Just as discussed above, can be used for regulating and control rate of release and make the excipient of beneficiating ingredient stabilisation comprise in the preparation or be used to generate any useful composition the raw material of gel vehicle except that beneficiating ingredient.Can be used for regulating and control rate of release and make the excipient of beneficiating ingredient stabilisation for example comprise pH modifier, Reducing agent, antioxidant and free radical scavenger.

PH modifier includes but not limited to inorganic and organic salt, comprises zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.Reducing agent includes but not limited to cysteine or methionine.Antioxidant includes but not limited to d-α tocopherol acetate, the d1-alpha tocopherol, anti-bad blood acyl cetylate, butylation hydroxyl anidole, ascorbic acid, butylatedhydroxyanisole, the butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, the gallate monooctyl ester, the gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin and ethanolamine.

Bioerosion, biocompatible polymer

The polymer that can be used for the inventive method and compositions is bioerosion, that is to say their hydrolysis gradually in the aqueous fluids of patient body, dissolving, physical erosion or otherwise disintegrate.Generally speaking, polymer is as the result of hydrolysis or physical erosion and bioerosion takes place, but main normally hydrolysis of bioerosion process.

This base polymer includes but not limited to polyactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(caprolactone), polyanhydride, polyamine, polyurethane, polyesteramide, poe, poly-two  alkane ketone, polyacetals, polyketals, Merlon, poly phosphate, polyoxaester, poly-orthocarbonic ester, polyphosphazene, succinate, poly-(malic acid), poly-(aminoacid), polyvinylpyrrolidone, Polyethylene Glycol, poly-hydroxylated cellulose, chitin, chitosan, hyaluronic acid and their copolymer, terpolymer and mixture.

At present preferred polymer is a polyactide, lactide acid polymer just, it may be only based on lactic acid, perhaps may be based on the copolymer of lactic acid and glycolic, and can comprise a small amount of other comonomers, the favourable outcome that can substantial effect can not reach according to the present invention.Term used herein " lactic acid " comprises isomer L-lactic acid, D-lactic acid, DL-lactic acid and lactide, and term " glycolic " comprises Acetic acid, hydroxy-, bimol. cyclic ester.Most preferably poly-(lactide-co-glycolide) copolymer generally is called as " PLGA ".The lactic acid of polymer/glycolic monomer ratio can be from about 100: 0 to about 15: 85, and preferred about 75: 25 to about 30: 70, more preferably from about 60: 40 to about 40: 60, the lactic acid of the copolymer that is particularly useful/glycolic monomer ratio was about 50: 50.

As U.S. Patent No. 5,242, shown in 910, polymer can be according to U.S. Patent No. 4,443, and 340 instruction is prepared.Select as an alternative, lactide acid polymer can be directly prepares from the mixture of lactic acid or lactic acid and glycolic (contain or do not have further comonomer), according to U.S. Patent No. 5,310, and 865 described instructions.The content of all these patents is all quoted at this as a reference.The lactide acid polymer that is fit to is commercially available.For example, molecular weight is 8,000,10,000,30,000 and 100,000 50:50 lactic acid: ethanol copolymer can be from Boehringer Ingelheim (Petersburg, VA), MedisorbTechnologies International L.P. (Cincinatti, OH) and BirminghamPolymers, Inc. (Birmingham, AL) obtain, as described below.

The polymer that is fit to includes but not limited to gather (D, L-lactide-be total to-Acetic acid, hydroxy-, bimol. cyclic ester) (PLGA), 50: 50 DL-PLG, intrinsic viscosity 0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham, AL), 50: 50 Resomer  RG502 (PLGA RG 502), poly-(D, L-lactide) Resomer  L104, PLA-L104, code no.33007, and Poly (D, the L-lactide-altogether-and Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG502, code no.0000366, poly-(D, the L-lactide-altogether-and Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG502H, PLGA-502H, code no.260187, poly-(D, the L-lactide-altogether-and Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG503, PLGA-503, code no.0080765, poly-(D, the L-lactide-altogether-and Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG755, PLGA-755, code no.95037, poly-L-lactide MW 2,000 (Resomer  L 206, Resomer  L 207, Resomer  L 209, Resomer  L 214); Poly-D, L-lactide (Resomer  R 104, Resomer  R 202, Resomer  R 203, Resomer  R 206, Resomer  R 207, Resomer  R 208); Poly-L-lactide-altogether-D, L-lactide 90: 10 (Resomer  LR 209); Poly-D-L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 75: 25 (Resomer  RG 752, Resomer  RG 756); Poly-D, the L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 85: 15 (Resomer  RG 858); Poly-L-lactide-altogether-carbonic acid trimethylene ester 70: 30 (Resomer  LT 706); Poly-two  alkane ketone (Resomer  X 210) (BoehringerIngelheim Chemicals, Inc., Petersburg, VA); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 100: 0 (MEDISORB  Polymer 100 DL High, MEDISORB  Polymer 100DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 85/15 (MEDISORB  Polymer 8515DL High, MEDISORB  Polymer 8515 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 75/25 (MEDISORB  Polymer 7525 DL High, MEDISORB  Polymer 7525 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 65/35 (MEDI SORB  Polymer 6535 DL, High, MEDISORB  Polymer 6535 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 54/46 (MEDISORB  Polymer 5050 DL High, MEDISORB  Polymer 5050 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 54/46 (MEDISORB  Polymer 5050 DL 2A (3), MEDISORB  Polymer 5050 DL 3A (3), MEDISORB  Polymer 5050 DL4A (3)) (Medisorb Teclmologies International L.P., Cincinnati, OH); Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 50: 50; Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 65: 35; Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 75: 25; Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 85: 15; Poly-DL-lactide; Poly-L-lactide; Poly-Acetic acid, hydroxy-, bimol. cyclic ester; Poly-epsilon-caprolactone; Poly-DL-lactide-altogether-caprolactone 25: 75; With poly-DL-lactide-altogether-caprolactone 75: 25 (Birmingham Polymers, Inc., Bi rmingham, AL).

Biocompatibility, the content of bioerosion polymer in gel combination account for about 5 to about 90% of viscogel weight, preferred about 25 to about 80%, usually about 35 to about 75%, and viscogel comprises the biocompatible polymer of combined amount and at the solvent of 25 ℃ of following water miscibilties less than 7wt.%.

To add solvent to polymer by following amount, so that implantable or injectable viscogel to be provided.

Solvent

Injectable depot compositions of the present invention can also contain at the solvent of 25 ℃ of following water miscibilties less than 7wt.% except bioerosion polymer, excipient and beneficiating ingredient.Solvent must be a biocompatibility, should generate gel, preferred viscogel with polymer, and the picked-up of restriction moisture enters implant.The solvent that is fit to will limit the picked-up of implant to moisture basically, and as mentioned above, can with water not miscibilty be feature, just water solubility or miscibilty are 7 weight % at the most.Preferably, the water solubility of aromatic alcohol is 5wt.% or following, more preferably 3wt.% or following, and then more preferably 1wt.% or following.Most preferably, the water solubility of aromatic alcohol is equal to or less than 0.5 weight %.In preferred embodiment, solvent is selected from ester, aromatic ketone and their mixture of aromatic alcohol, aromatic acid.

The water miscibilty can following measuring: (1-5g) places the transparent vessel that tares with water, and about 25 ℃ of control temperature is weighed, and drips candidate's solvent.Make solution rotating, be separated with observation.As if when reaching saturation point, this depends on the observation that is separated, and solution is placed spent the night, reexamined in second day.If it is saturated that solution remains, this depends on the observation that is separated, and measures the percentage ratio (w/w) of the solvent that is added so.Otherwise add more solvent, repeat this process.The gross weight of the solvent that is added is measured dissolubility or miscibilty divided by the final weight of solvent/water mixture.When using solvent mixture, before being added to the water premixing they.

Except water not the miscibilty solvent, compositions can also comprise one or more other miscibilty solvents (" composition solvent "), as long as the other solvent of this class is not a low-grade alkane alcohol arbitrarily.And composition solvent that can mix compatible with basic solvent can have higher water miscibilty, and the gained mixture still can show moisture is absorbed the remarkable restriction that enters implant.This class mixture will be called as " composition solvent mixture ".Useful composition solvent mixture can show the water solubility greater than basic solvent itself, usually 0.1 weight % until and comprise between the 50 weight %, preferably until and comprise 30 weight %, most preferably until and comprise 10 weight %, can not influence the moisture picked-up inhibitory action that shows by implant of the present invention nocuously.

Can be used on the composition solvent of forming in the solvent mixture is those solvents that can mix with basic solvent or solvent mixture, includes but not limited to glyceryl triacetate, diacetin, tributyorin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl group glyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate., mineral oil, polybutene, silicone fluid, glycerol, ethylene glycol, Polyethylene Glycol, capryl alcohol, ethyl lactate, propylene glycol, Allyl carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, the N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, butanone, dimethyl formamide, dimethyl sulfoxide, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid, 1-dodecyl-aza-cycloheptane alkane-2-ketone and their mixture.

Solvent or solvent mixture can dissolve polymers, generate viscogel, can keep the dissolving of beneficiating ingredient particle before discharging or disperse, and separate with environment for use.Compositions of the present invention provides has the low prominent exponential implant of releasing.The moisture picked-up is subjected to solvent or forms the control of solvent mixture, and its solubilising or plasticized polymer enter implant but limit the moisture picked-up basically.

The content of solvent or solvent mixture account for usually viscogel weight about 95 to about 5%, preferred about 75 to about 15%, most preferably from about 65% to about 20%.In especially preferred embodiment, solvent is selected from aromatic alcohol, benzoic low alkyl group and aralkyl ester.At present, most preferred solvent is mixture, BB and the alcoholic acid mixture of benzoic acid benzyl ester (BB), benzylalcohol (BA), ethyl benzoate (EB), BB and BA and the mixture of BB and EB.

The ratio of polymer and solvent comprises between about 5: 95 and about 90: 10, preferably between about 20: 80 and about 80: 20, more preferably between about 30: 70 and about 75: 25.

Beneficiating ingredient

Beneficiating ingredient can be physiology or pharmacological active substance arbitrarily, alternatively with pharmaceutically acceptable carrier and the combination of composition in addition, for example antioxidant, stabilizing agent, penetration enhancers etc., they can influence the favourable outcome that can be reached by the present invention basically sharply.Beneficiating ingredient can be any such composition, their known human or animal bodies that is delivered to, and preferential water soluble rather than polymer-dissolubility solvent.These compositions comprise ingredient, medicine, vitamin, nutrient etc.In satisfying the component type of this requirement, comprise low molecular weight compound, protein, peptide, genetic stocks, nutrient, vitamin, food additive, sexual organ's antibacterial, fertility inhibitor and fertility promoter.

Can comprise by the ingredient that the present invention sends and act on following medicine: peripheral nervous, adrenoreceptor, cholinoceptor, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, joint part, neural effector junction, endocrine and hormone system, immune system, reproductive system, skeletal system, autacoid system, nutrition and Excretory system, histamine system and central nervous system.The composition that is fit to for example can be selected from protein, enzyme, hormone, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, steroid, analgesic, local anesthetic, antibiotic, chemotherapeutics, immunosuppressant, antiinflammatory (comprising anti-inflammatory corticosteroid), antiproliferative, antimitotic agent, angiogenic agent, major tranquilizer, central nervous system (CNS) agent, anticoagulant, the fibrin distintegrant, somatomedin, antibody, medicament for the eyes, metabolite with these kinds, analog (comprising analog synthetic and that replace), derivant (comprising covalent conjugates) with manner known in the art and other macromolecular aggregation conjugate/fusions and nothing to do with chemical part, fragment, and purification, separate, reorganization and chemosynthesis version.

Can include but not limited to Bupivacaine by the exemplary drugs that the present composition is sent; Buprenorphine; The ethionic acid prochlorperazine; Ferrous sulfate; Aminocaproic acid; Mecamylamine hydrochloride; Procaine amide hydrochloride; Amphetamine sulfate; Besoxyephedrine hydrochloride; Hydrochloric acid benzamphetamine; Isoprenaline sulfate; Phenmetrazine hydrochloride; Bethanechol Chloride; Methacholine Chloride; Pilocarpine hydrochloride; Atropine sulfate; The bromine hyoscine; Isopropamide Iodide; Tridihexethyl chloride; DB2; Methylphenidate hydrochloride; The cholic acid theophylline; Cefalexin hydrochloride; Difenidol; Meclozine hydrochloride; The maleic acid prochlorperazine; Phenoxybenzamine; Thiethylperazine dimaleate; Anisindione; Diphenadione; Cardilate; Digoxin; Diisopropyl fluorophosphate; Acetazolamide; Methazolamide; Bendroflumethiazide; Chloropromaide; Tolazamide; Chlormadinone; Phenaglycodol; Allopurinol; Aluminium aspirin; Methotrexate (MTX); The different  azoles of sulfacetamide; Erythromycin; Hydrocortisone; The acetic acid hydrocortisone; The acetic acid cortisone; Dexamethasone and derivative thereof (for example betamethasone); Fluoxyprednisolone; Methyltestosterone; Testosterone; The 17-S-estradiol; Ethinylestradiol; Ethinylestradiol 3-methyl ether; Prednisolone; Acetic acid 17 Alpha-hydroxy progesterone; 19-removes first-progesterone; Norgestrel; Norethindrone; The alkynes nordinone; Norethiederone; Progesterone; Norgesterone; Norethynodrel; Aspirin; Indocin; Naproxen; Fenoprofen; Sulindac; Indoprofen; Monobel; ISDN; Propranolol; Timolol; Atenolol; Alprenolol; Cimetidine; Clonidine; Imipramine; Levodopa; Chlorpromazine; Ethyldopa; Dihydroxyphenylalanine; Theophylline; Calcium gluconae; Ketoprofen; Brufen; Cefalexin; Erythromycin; Haloperole; The U.S. acid of assistant; Ferrous lactate; Vincamine; Diazepam; Phenoxybenzamine; Ground that sulphur ; Milrinone; Mandol; Quanbenz; Hydrochioro; Ranitidine; Flurbiprofen; Fenufen; Fluprofen; Tolmetin; Alclofenac; Mefenamic acid; Flufenamic acid; Difuinal; Nimodipine; Nitrendipine; Nisoldipine; Nicardipine; Felodipine; Lidoflazine; Tiapamil; Gallopamil; Amlodipine; Mioflazine; Lisinopril; Enalapril; Enalaprilat; Captopril; Ramipril; Famotidine; Nizatidine; Ulcerlmin; Etintidine; Tetratolol; Minoxidil; Chlorine nitrogen ; Diazepam; Amitriptyline; Imipramine; Paliperidone; Resperidone; Octreotide; Alendronic acid; α-4, β-7 receptor antagonist leukosite and infliximab (Remicade).

The further example of beneficiating ingredient is protein and peptide, they include but not limited to bone morphogenetic protein, insulin, colchicine, glucagon, thyrotropin, parathyroid gland and pituitary hormone, calcitonin, feritin, prolactin antagonist, thyroliberin, parent's thyroxin, follicle-stimulating hormone, chorionic gonadotropin, gonadotropin-releasing hormone, bovine growth hormone, pig growth hormone, oxytocin, vassopressin, GRF, somatostatin, lypressin, Pancreozymin, lutropin, LHRH, LHRH agonist and antagonist, leuprolide, interferon (Intederon Alpha-2a for example, Interferon Alpha-2b and synonym interferon), interleukin, growth hormone (for example human growth hormone and derivant thereof, methionine-human growth hormone and remove-the phenylalanine human growth hormone parathyroid hormone for example, bovine growth hormone and pig growth hormone), fertility inhibitor (for example prostaglandin), fertility promoter, somatomedin (epidermal growth factor (EGF) for example, platelet derived growth factor (PDGF), fibroblast growth factor (FGF), transforminggrowthfactor-(TGF-α), transforming growth factor-beta (TGGF-β), erythropoietin (EPO), insulin like growth factor-1 (IGF-I), insulin like growth factor-1 I (IGGF-II), il-1, interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-β (TNF-β), interferon-' alpha ' (INF-α), interferon-beta (INF-β), interferon-(INF-γ), interferon-ω (INF-ω), colony stimulating factor (CGF), the vascular cell growth factor (VEGF), thrombopoietin (TPO), stroma cell derivative factor (SDF), placental growth factor (PlGF), hepatocyte growth factor (HGF), granulocyte macrophage colony stimulating factor (GM-CSF), the neuroglia close neural factor (GDNF) of deriving, granulocyte colony-stimulating factor (G-CSF), parent's ciliary nerves factor (CNTF), skeletal growth factor, transforming growth factor), bone morphogenetic protein (BMP), thrombin, human pancreas's releasing factor, the pharmaceutically acceptable salt of the analog of these chemical compounds and derivant and these chemical compounds or their analog or derivant.

The present invention also can be used for chemotherapeutics, is used for the topical application of these compositions, to avoid or to reduce systemic side effects.The gel of the present invention that contains chemotherapeutics can enter tumor tissues by direct injection, be used for chemotherapeutics go through a period of time continue send.In some cases, particularly after the excision of tumor, gel can directly be implanted in the gained cavity, perhaps can be used as coating and is applied to the residue tissue.Under the situation of implanted gel after the operation, might adopt gel, because they needn't pass the syringe needle of minor diameter with viscosity higher.Can for example comprise translation of inhibition oncogene or carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecine, etoposide, cytokine, ribozyme, interferon, oligonucleotide and the oligonucleotide sequence of transcribing, above-mentioned functional deriv and known chemotherapeutics according to the representative chemotherapeutics that practice of the present invention is sent, for example U.S. Patent No. 5,651,986 described those.The application be particularly useful for the water solublity chemotherapeutics continue send the soluble derivative of cisplatin and carboplatin and paclitaxel for example.Those features that the present invention minimizes burst effect are particularly conducive to the administration of all kinds water solublity beneficiating ingredient, but particularly useful clinically and effectively but may have those chemical compounds of adverse side effect.

On the degree of above not mentioning, also can use above-mentioned U.S. Patent No. 5,242,910 described beneficiating ingredients.A kind of definite advantage of the present invention is raw material, for example protein that is difficult to microencapsulation or is processed into microsphere, with the lysozyme is example, with the cDNA and the DNA that are incorporated in virus and the non-virus carrier, can be incorporated in the compositions of the present invention, can not degrade because of being exposed to the high temperature and the degeneration solvent that often are present in other process technologies.

Beneficiating ingredient preferably is incorporated into from the viscogel of polymer and solvent generation, is the form of particle, and mean diameter is generally less than 250 microns, about 5 to about 250 microns, and preferred about 20 to about 125 microns often is 38 to 68 microns.

For in the suspension or the dispersion that from the viscogel of polymer and solvent generation, generate the beneficiating ingredient particle, can under environmental condition, utilize the low shear of any conventional, for example the two planetary-type mixers of Ross.In such a way, can realize effective distribution of beneficiating ingredient, non-degradable basically beneficiating ingredient.

Beneficiating ingredient dissolving or the amount in the compositions of being dispersed in account for usually polymeric blends, solvent and beneficiating ingredient gross weight 0.1% to about 50%, preferred about 1% to about 30%, more preferably from about 2% to about 20%, often 2 to 10%.According to the content of beneficiating ingredient in the compositions, can obtain different release profiles and the prominent index of releasing.More specifically, with regard to given polymer and solvent, the amount by regulating these components and the amount of beneficiating ingredient can obtain to depend on the release profiles that depolymerization spreads from compositions more than beneficiating ingredient, and vice versa.In this, under lower beneficiating ingredient LOADING RATES, the general release profiles that obtains the reflection depolymerization, wherein rate of release increased along with the time.Under higher LOADING RATES, the general acquisition spread the release profiles that is caused by beneficiating ingredient, and wherein rate of release reduced along with the time.Under middle LOADING RATES, obtain the release profiles of combination, so that if necessary, can reach the rate of release of substantial constant.For prominent releasing minimized, the LOADING RATES of beneficiating ingredient be whole gel combinations, just polymer, solvent and beneficiating ingredient weight 30% or below be preferred, LOADING RATES be 20% or below be preferred.

By regulating the rate of release and the LOADING RATES of beneficiating ingredient, the treatment effectiveness that provides beneficiating ingredient to go through the lasting delivery phase of expection is sent.Preferably, beneficiating ingredient will exist with such concentration in polymer gel, and they are more than the water saturation concentration of beneficiating ingredient, with the medicine storage that provides beneficiating ingredient therefrom to distribute.Although the rate of release of beneficiating ingredient depends on particular environment, the beneficiating ingredient that will give for example, but rate of release can be that about 0.1 microgram/sky is to about 10 mg/day, preferred about 1 microgram/sky is to about 5 mg/day, more preferably from about 10 microgram/skies last about 24 hours to about 360 days, preferred 24 hours to about 180 days to about 1 mg/day, more preferably 24 hours to about 120 days, often 3 days to about 90 days.And then, by regulating the amount of the bank gel of being injected, can regulate the dosage of beneficiating ingredient.In shorter time, send if desired, can send bigger amount.Generally speaking, if bigger prominent releasing can be tolerated, so higher rate of release is possible.Be used as in the situation of " leaving over " bank the more high dose that normally gives in the time of might being provided at the injection implant in the situation that gel combination is implanted by performing the operation or when treating the operation of morbid state or another kind of disease at the same time.And then, by regulating the volume of gel of being implanted or the injectable gel of being injected, can control the dosage of beneficiating ingredient.Preferably, this system discharges 40 weight % or the following beneficiating ingredient that is present in the viscogel in preceding 24 hours after implanting the curee.More preferably, after implantation, will discharge 30 weight % or following beneficiating ingredient in preceding 24 hours, the compositions of being implanted prominent release index be 12 or below, preferred 8 or below.

Optional other components

In gel combination, can there be other components, need or for compositions provides useful properties, for example Polyethylene Glycol, hygroscopic agent, stabilizing agent, pore former, thixotropic agent and other as long as have.When compositions is included in the aqueous environments solvable or unsettled peptide or protein, may need in compositions, comprise the dissolubility adjusting control agent by height, for example can be stabilizing agent.Various adjusting control agents are described in United States Patent(USP) Nos. 5,654, and in 010 and 5,656,297, its disclosure is quoted at this as a reference.For example under the situation of hGH, preferably include a certain amount of divalent metal salt, preferred zinc.Can cooperate with beneficiating ingredient or associate provides this class adjusting control agent and the stabilizing agent example of stabilisation or regulation and control release effects to comprise metal cation, preferred bivalence, in compositions, exist: magnesium carbonate, zinc carbonate, calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc sulfate, zinc chloride, magnesium chloride, magnesium oxide, magnesium hydroxide, other antacids etc. with following form.The amount of used this constituents will depend on the attribute of the coordination compound that generates between beneficiating ingredient and this composition, if any, and the perhaps attribute of association.The mol ratio of dissolubility adjusting control agent or stabilizing agent and beneficiating ingredient can adopt about 100: 1 to 1: 1 usually, preferred 10: 1 to 1: 1.

Pore former comprises biocompatible materials, and they dissolve when contacting with body fluid, disperse or degrade, and produces hole or passage in polymeric matrix.Usually, can use organic and inorganic material as pore former by convention, they have water-soluble sugar (for example sucrose, glucose), water soluble salt (for example sodium chloride, sodium phosphate, potassium chloride and sodium carbonate), water-soluble solvent (for example N-N-methyl-2-2-pyrrolidone N-and Polyethylene Glycol) and water-soluble polymer (for example carboxymethyl cellulose, hydroxypropyl cellulose etc.).The content of this class material can account for polymer weight about 0.1% to about 100%, but usually will be less than 50% of polymer weight, more generally less than 10-20%.

Thixotropic agent comprises gives the composition of polymer gel with thixotropic nature, for example low-grade alkane alcohol (for example ethanol, isopropyl alcohol) etc.Self-evident, thixotropic agent of the present invention can not constitute simple diluent or polymer solvent, only reduces viscosity by each concentration of component that reduces compositions.The use of conventional diluent can reduce viscosity, but also can cause above-mentioned burst effect when injection process dilute compositions.On the contrary, Injectable depot compositions of the present invention can be avoided burst effect through preparation by selecting thixotropic agent, so that in case injection enters the space, thixotropic agent only has inappreciable influence to the releasing properties of primal system.Preferably, this system discharges 40 weight % or the following beneficiating ingredient that is present in the viscogel in preceding 24 hours after implanting the curee.More preferably, after implantation, will discharge 30 weight % or following beneficiating ingredient in preceding 24 hours, the compositions of being implanted prominent release index be 12 or below, preferred 8 or below.

II. use and administration

The means of administration of implant is not limited to injection, but this mode of sending may often be preferred.If implant will be as leaving over the product administration, it can adapt to the body cavity that exists after operation is finished, and perhaps flowable gel can be brushed or is spread upon on remnant tissue or the bone.This class is used and can allow to load the beneficiating ingredient that is higher than usually the concentration that exists with Injectable composition in gel.

In order further to understand various aspects of the present invention, obtain the described result of aforementioned figures according to the following example.

Embodiment

Be the some embodiment that implement the specific embodiment of the present invention below.These embodiment only for explanation, do not plan to limit the scope of the invention by any way.

Embodiment 1

Bank preparing gel thing

Be prepared as follows the gel vehicle that is used in the Injectable depot compositions.Glass container is placed on the Mettler PJ3000 top carrying balance.Being weighed into poly-(D, L-lactide-co-glycolide) to glass container (PLGA), is 50: 50 DL-PLG, intrinsic viscosity is 0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham, AL) and 50: 50 Resomer  RG502 (PLGA RG502).Tare to the glass container that contains polymer, add corresponding solvent.The percentage ratio of various polymer/solvent combination is described in table 1 below.Polymer/solvent mixture is stirred under 250 ± 50rpm (Stanfen Germany) about 5-10 minute, obtains containing the viscous paste sample material of polymer particle for IKA electricity agitator, IKH-Werke GmbH and Co..To contain the seal of vessel of polymer/solvent mixture, and place the temperature control calorstat of balance to 37 ℃ to reach 1 to 4 day, the intermittent stirring, this depends on the ratio of solvent and polymer type and solvent and polymer.When presenting the amber homogeneous solution of clarification, from calorstat, take out polymer/solvent mixture.Then, mixture is placed baking oven (65 ℃) reach 30 minutes.Notice that taking out back PLGA from baking oven is dissolved in the mixture.

Utilize following solvent or solvent mixture and following polymers to prepare other bank gel vehicle: benzoic acid benzyl ester (BB), benzylalcohol (BA), ethyl benzoate (EB), BB/BA, BB/ ethanol, BB/EB; Poly-(D, L-lactide) Resomer  L104, PLA-L104, code no.33007, poly-(D, the L-lactide-altogether-and Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG502, code no.0000366, poly-(D, the L-lactide-altogether-and Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG502H, PLGA-502H, code no.260187, poly-(D, the L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50 Resomer  RG503, PLGA-503, code no.0080765, poly-(D, the L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester) 50: 50Resomer  RG 755, PLGA-755, code no.95037, poly-L-lactide MW 2,000 (Resomer  L206, Resomer  L 207, Resomer  L 209, Resomer  L214); Poly-D, L-lactide (Resomer  R 104, Resomer  R 202, Resomer  R203, Resomer  R 206, Resomer  R 207, Resomer  R 208); Poly-L-lactide-altogether-D, L-lactide 90:10 (Resomer  LR 209); Poly-D-L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 75: 25 (Resomer  RG 752, Resomer  RG 756); Poly-D, the L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 85: 15 (Resomer  RG 858); Poly-L-lactide-altogether-carbonic acid trimethylene ester 70: 30 (Resomer  LT 706); Poly-two  alkane ketone (Resomer  X 210) (Boehringer Ingelheim Chemicals, Inc., Petersburg, VA); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 100: 0 (MEDISORB  Polymer 100 DL High, MEDISORB  Polymer 100 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 85/15 (MEDISORB  Polymer8515 DL High, MEDISORB  Polymer 8515 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 75/25 (MEDISORB  Polymer 7525 DL High, MEDISORB  Polymer 7525DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 65/35 (MEDISORB  Polymer 6535 DL High, MEDISORB  Polymer 6535 DL Low); DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 54/46 (MEDISORB  Polymer 5050 DL High, MEDISORB  Polymer 5050 DL Low); With DL-lactide/Acetic acid, hydroxy-, bimol. cyclic ester 54/46 (MEDISORB  Polymer 5050 DL 2A (3), MEDISORB  Polymer 5050 DL 3A (3), MEDISORB  Polymer 5050 DL4A (3)) (Medisorb Technologies International L.P., Cincinnati, OH); With poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 50: 50; Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 65: 35; Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 75: 25; Poly-D, L-lactide-altogether-Acetic acid, hydroxy-, bimol. cyclic ester 85: 15; Poly-DL-lactide; Poly-L-lactide; Poly-Acetic acid, hydroxy-, bimol. cyclic ester; Poly-epsilon-caprolactone; Poly-DL-lactide-altogether-caprolactone 25: 75; With poly-DL-lactide-altogether-caprolactone 75: 25 (BirminghamPolymers, Inc., Birmingham, AL).

Embodiment 2

Bupivacaine alkali prepared product

(Sigma-Aldrich Corporation, St.Louis MO) are dissolved in deionization (D I) water, and concentration is 40mg/ml (saturated) with bupivacaine hydrochloride.To the sodium hydroxide (1N solution) of this solution adding amount of calculation, regulate the pH to 10 of final mixture, to be settled out BP alkali.The sedimentary product of institute is filtered, further use DI water washing at least three times.With the sedimentary product of institute in about 40 ℃ of vacuum dry 24 hours.

Embodiment 3

Bupivacaine particle preparation thing

(Sigma-Aldrich Corporation, St.Louis MO) or according to the bupivacaine alkali and the hydrochlorate of embodiment 2 preparation prepare the bupivacaine drug particle to following use bupivacaine hydrochloride.Grinding bupivacaine, utilize 3 then " stainless steel sift sieves.Typical scope comprises 25 μ m to 38 μ m, 38 μ m to 63 μ m and 63 μ m to 125 μ m.

Embodiment 4

HGH/Zn coordination compound prepared product

Utilize to concentrate/dialysis selection diafiltration instrument, (BresaGenCorporation, Adelaide Australia) are concentrated into 10mg/ml with hGH aqueous solution (5mg/ml).To further in 5mM TRIS buffer, be concentrated into the 40mg/ml solution of hGH through TRIS (pH 7.6) washing of the hGH solution of diafiltration with 5 times of volumes.Add the solution of 27.2mM zinc (from zinc acetate) in 5mM TRIS buffer of equal portions, obtain final mixture, zinc: the mol ratio of hGH is 15: 1.Make this mixture cooperate about 1 hour down at 4 ℃.This coordination compound is precooled to-70 ℃ then, utilizes the lyophilizing of Durastop μ P lyophil apparatus according to the following lyophilization cycle.

Freeze cycle	Reduce to-30 ℃ by 2.5 ℃/min, keep 30min
		Reduce to-30 ℃ by 2.5 ℃/min, keep 30min
	Arid cycle		Rise to 10 ℃ by 0.5 ℃/min, keep 960min
Rise to 20 ℃ by 0.5 ℃/min, keep 480min
		Rise to 25 ℃ by 0.5 ℃/min, keep 300min
Rise to 30 ℃ by 0.5 ℃/min, keep 300min
		Rise to 5 ℃ by 0.5 ℃/min, keep 5000min

Embodiment 5

The particle of hGH/Zn coordination compound prepared product

Prepare the different particles of hGH/Zn coordination compound from embodiment 4 prepared lyophilizing hGH/Zn coordination compounds, not compacting or through compacting: 1) utilize the Waring blender to grind, not compacting through freeze dried hGH/Zn coordination compound.Collect the particle between 120 orders (125 μ m) and 400 orders (38 μ m).2) will be transferred to the circular compacting of 13mm punch die through freeze dried hGH/Zn coordination compound, compacting is 5 minutes under 5 tons of pressure, forms granule.Utilize Waring blender abrasive grains.Collect the particle between 120 orders (125 μ m) and 400 orders (38 μ m).

Embodiment 6

Zinc carbonate particle preparation thing

Utilize 3 " stainless steel sift, sieve by 38 μ m, keep 15 μ m, preparation zinc carbonate zinc hydroxide hydrate (ZnCO ₃2Zn (OH) ₂XH ₂O) (Aldrich, Milwaukee, WI, particle USA), size is 15-38 μ m.

Embodiment 7

Medicine loads

The particle of as above preparation is joined in the gel vehicle, and consumption is 10-30 weight %, and manual fusion is moistening fully until dry powder.Utilize Caframo mechanical agitator to mix the light yellow particle/gel mixture of abundant fusion emulsus then by routine with square-most advanced and sophisticated metal spoon.The gained preparation is as described in the table 1,2 and 3.

Table 1

Preparation	PLGA RG 502 a (wt％)	Benzoic acid benzyl ester (wt%)	Bupivacaine alkali (wt%)	ZnCO 3(wt％)
					1	45	45	10	0
2	43.5	43.5	10	3

^aPLGA RG 502，MW＝16,000

Table 2

Preparation	LMW PLGA a (wt％)	Benzylalcohol (wt%)	Bupivacaine HCl (wt%)	ZnCO 3(wt％)
					3	67.5	22.5	10	0
4	65.2	21.8	10	3
					5	63.0	21	10	6

^aLow-molecular-weight (LMW, MW=10,000) PLGA with carboxyl terminal

Embodiment 8

The common loading of bupivacaine and zinc carbonate

The zinc carbonate particle that embodiment 3 drug prepared particles and embodiment 6 is prepared is by the predetermined ratio premixing, and the particles mixture with medicine and zinc carbonate in process as described in embodiment 7 joins in the gel vehicle.The gained preparation is as described in table 1 and 2.

Embodiment 9

The common loading of hGH/Zn coordination compound particle and zinc carbonate

The hGH/Zn coordination compound particle that embodiment 5 is prepared and embodiment 6 prepared zinc carbonate particles join separately in the gel vehicle by predetermined ratio, mix the particle of hGH/Zn coordination compound and zinc carbonate in process as described in embodiment 7 in gel vehicle.The gained preparation is as described in Table 3.

Table 3

Preparation	PLGA RG502 a (wt％)	Benzoic acid benzyl ester (wt%)	HGH/Zn coordination compound (wt%)	ZnCO 3(wt％)
					6	45.0	45.0	10 b	0
7	45.0	45.0	10 c	0
					8	43.5	43.5	10 c	3

^aPLGA RG 502，MW＝16,000；

^bCompacting does not in advance prepare hGH/Zn coordination compound particle;

^cThrough the hGH/Zn of compacting preparation in advance coordination compound particle.

Embodiment 10

Research in the bupivacaine body

Follow open scheme and carry out research (4 or 5 every group) in the rat body, to be determined at the bupivacaine blood plasma level of bupivacaine after via implant system whole body of the present invention administration.Bank gel bupivacaine preparation is loaded in the 0.5cc disposable syringe of customization.To syringe disposable 18gauge syringe needle is installed, is utilized circulation to bathe and be heated to 37 ℃.Bank gel bupivacaine preparation is expelled in the rat,, utilizes LC/MS to analyze bupivacaine by fixed time (1 hour, 4 hours and the 1st, 2,5,7,9,14,21 and 28 day) blood drawing at interval.

Fig. 1 sets forth release profiles in the representative bupivacaine alkali rat body that obtains with depot formulations (about 1 month) from various long-term systems, comprise of the present invention those.There is not ZnCO ₃The common depot formulations (preparation 1) that loads shows biphase release profiles, that is to say in the phase I (＜1-2 week), rate of release reduces (control of mainly being spread) along with the time, and in the latter half (1-2 is after week), discharging becomes steadily or along with the time increases (because depolymerization and diffusion).ZnCO is arranged ₃The common depot formulations (preparation 2) that loads does not show typical biphase release profiles, discharges the back release profiles more steadily (near there not being ZnCO in initial burst ₃Preparation 1), replace of short duration release duration.This discovery clearly proves, adds ZnCO to depot formulations ₃Can become release rate profile near the zero order release rate curve from typical two facies patterns, and the regulation and control release duration.

Surprising is by ZnCO is arranged ₃The shown rate of release of the common depot formulations (preparation 2) that loads is faster than there not being ZnCO ₃The common preparation (preparation 1) that loads.Usually, in alkaline environment (pH＞7.0), the expection bupivacaine keeps its alkali form, discharges because its hydrophobicity will show slowly.But shown in preparation 2, in the presence of weakly alkaline, ZnCO for example ₃(pKa＞7), rate of release are not faster than there being weak base, to by be in the hydrophilic state that bupivacaine showed was similar.

Fig. 2 sets forth release profiles in the representative hydrochloric acid bupivacaine rat body that obtains with depot formulations (2 weeks at the most) from various short-term system, comprise of the present invention those.There is not ZnCO ₃The release that common depot formulations (preparation 3) the performance medicine that loads reduces in time shows the release profiles that is mainly DIFFUSION CONTROLLED.But, ZnCO is arranged ₃The common depot formulations (preparation 4 and 5) that loads with do not have ZnCO ₃The common preparation (preparation 3) that loads is compared prominent releases that performance reduced and release profiles (near zero level) more stably, shows to depot formulations adding ZnCO ₃Also can change the release rate profile of short-term bank.

Embodiment 11

Research in the hGH body

Follow open scheme and carry out research in the rat body, to be determined at the hGH serum levels of hGH after via implant system whole body of the present invention administration.Bank gel hGH preparation is loaded in the 0.5cc disposable syringe of customization.To syringe disposable 18gauge 1 is installed " syringe needle, utilize circulation to bathe and be heated to 37 ℃.Bank gel hGH preparation is expelled in the immunosuppressant rat, collected blood serum sample in back 1 hour, 4 hours, the 1st, 2,4,7,10,14,21 and 28 day in injection.Before analysis, all blood serum sample is stored under 4 ℃.Utilize the complete hGH content of radioimmunoassay (RIA) analytic sample.When research finishes, make rat euthanasia, carry out rough clinical observation, fetch bank, carry out integrity and observe.

Fig. 3 sets forth release profiles in representative human growth hormone (hGH) the rat body that obtains from various depot compositions, comprise of the present invention those.ZnCO is arranged ₃The common depot formulations (preparation 8) that loads with do not have ZnCO ₃The common preparation (preparation 6 and 7) that loads is compared and is tending towards having release rate profile and shorter release duration more stably, as the bupivacaine among Fig. 1.This further shows as described herein to depot formulations adding ZnCO ₃Also can change protein release rate profile and regulation and control release duration.

Embodiment 12

The particle preparation thing of Reducing agent

Utilizing 3 " stainless steel sift sieves by 38 μ m, keeps 15 μ m, preparation Reducing agent methionine (Sigma, St.Louis, MO, particle USA), size is 15-38 μ m.

Embodiment 13

In bank, load hGH and methionine and body build-in test

To the Reducing agent methionine of gel vehicle adding embodiment 12, consumption is 0.1-20 weight %, and manual fusion is moistening fully until dry powder.Utilize Caframo mechanical agitator to mix the light yellow particle/gel mixture of abundant fusion emulsus then by routine with square-most advanced and sophisticated metal spoon.Load therapeutic agent to gel vehicle, for example protein resembles hGH, perhaps micromolecule, for example bupivacaine.The ratio of methionine and therapeutic agent is between about 0.1: 99.9 to about 70: 30.Carry out the body build-in test, to generate release rate profile.

Embodiment 14

The particle preparation thing of antioxidant

Utilizing 3 " stainless steel sift sieves by 38 μ m, keeps 15 μ m, preparation antioxidant vitamin E acid succinate (Sigma, St.Louis, MO, particle USA), size is 15-38 μ m.

Embodiment 15

Medicine loads and the body build-in test

To the antioxidant vitamin E of gel vehicle adding embodiment 14, consumption is 0.1-20 weight %, and manual fusion is moistening fully until dry powder.Utilize Caframo mechanical agitator to mix the light yellow particle/gel mixture of abundant fusion emulsus then by routine with square-most advanced and sophisticated metal spoon.When the content of vitamin E is very low (between about 0.1 to about 5 weight %), it is dissolved in the gel vehicle.Load therapeutic agent to gel vehicle, for example protein resembles hGH, perhaps micromolecule, for example bupivacaine.The ratio of vitamin E and therapeutic agent is between about 0.1: 99.9 to about 70: 30.Carry out the body build-in test, to generate release rate profile.

Claims (72)

1, continue to send the Injectable depot gel combination of beneficiating ingredient, comprise:

Gel vehicle comprises not miscibilty solvent of bioerosion, biocompatible polymer and water, and content is for this polymer of plasticising and to generate gel with it be effective;

Dissolving or be dispersed in beneficiating ingredient in this gel vehicle; With

The excipient of regulation and control rate of release, wherein this excipient makes this beneficiating ingredient stabilisation by the effect of offsetting depolymerization;

Wherein between about twenty four hours after the administration was to about 12 months, continue to send.

2, the compositions of claim 1, wherein this excipient is offset the effect of depolymerization, comprises pH modifier.

3, the compositions of claim 2, wherein this pH modifier is selected from down group: inorganic salt, organic salt and their combination.

4, the compositions of claim 3, wherein this pH modifier is selected from down group: zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.

5, the compositions of claim 1, wherein this excipient is offset the two effect of peroxide or free radical or this, comprises antioxidant.

6, the compositions of claim 5, wherein this antioxidant comprises Reducing agent, and it comprises cysteine or methionine.

7, the compositions of claim 5, wherein this antioxidant comprises free radical scavenger.

8, the compositions of claim 5, wherein this antioxidant is selected from down group: d-α tocopherol acetate, dl-alpha tocopherol, anti-bad blood acyl cetylate, butylation hydroxyl anidole, ascorbic acid, butylatedhydroxyanisole, butylation hydroxyquinone, BHA, Hydroxycoumarin, Yoshinox BHT, cephalm, ethyl gallate, propyl gallate, gallate monooctyl ester, gallate lauryl, nipasol, trihydroxy butyl rophenone, xylenol, DI-tert-butylphenol compounds, vitamin E, lecithin, ethanolamine and their combination.

9, the compositions of claim 1 comprises the excipient of about 0.01 weight % to about 50 weight %.

10, the compositions of claim 9 comprises the excipient of about 0.05 weight % to about 40 weight %.

11, the compositions of claim 10 comprises the excipient of about 0.1 weight % to about 30 weight %.

12, the compositions of claim 1, wherein the ratio between this excipient and this beneficiating ingredient is between about 0.1: 99.9 and about 99: 1.

13, the compositions of claim 12, wherein this ratio is between about 1: 99 and about 60: 40.

14, the compositions of claim 1, wherein the water miscibilty of this solvent is less than or equal to about 7 weight % under 25 ℃.

15, the compositions of claim 1, wherein the not moisture miscibilty of said composition under 25 ℃ greater than the solvent of 7 weight %.

16, the compositions of claim 1, wherein this solvent is selected from down group: the rudimentary aralkyl ester of the lower alkyl esters of aromatic alcohol, aryl acid, aryl acid; The lower alkyl esters of aryl ketones, aralkyl ketone, lower alkyl ketone, citric acid and their combination.

17, the compositions of claim 1, wherein this solvent comprises benzylalcohol.

18, the compositions of claim 1, wherein this solvent comprises benzoic acid benzyl ester.

19, the compositions of claim 1, wherein this solvent comprises ethyl benzoate.

20, the compositions of claim 1, wherein this solvent comprises glyceryl triacetate.

21, the compositions of claim 1, wherein this solvent comprises the composition solvent that is selected from down group: glyceryl triacetate, diacetin, tributyorin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl group glyceride, triethyl phosphate, diethyl phthalate, diethyl tartrate., mineral oil, polybutene, silicone fluid, glycerol, ethylene glycol, Polyethylene Glycol, capryl alcohol, ethyl lactate, propylene glycol, Allyl carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, the N-N-methyl-2-2-pyrrolidone N-, 2-Pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, butanone, dimethyl formamide, dimethyl sulfoxide, oxolane, caprolactam, decyl methyl sulfoxide, oleic acid, 1-dodecyl-aza-cycloheptane alkane-2-ketone and their combination.

22, the compositions of claim 1, wherein this polymer comprises lactide acid polymer.

23, the compositions of claim 22, wherein this polymer comprises the copolymer (PLGA) of lactic acid and glycolic.

24, the compositions of claim 23, wherein the weight average molecular weight of this polymer is between about 3,000 to about 120,000, and the lactic acid of this copolymer and the monomer ratio of glycolic are between about 50: 50 to about 100: 0.

25, the compositions of claim 23, wherein this polymer comprises poly-(D, L-lactide-co-glycolide).

26, the compositions of claim 23, wherein this polymer comprises poly-(L-lactide-co-glycolide).

27, the compositions of claim 1, wherein this polymer comprises caprolactone polymer.

28, the compositions of claim 1, wherein this polymer is selected from down group: polyactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(caprolactone), polyanhydride, polyamine, polyesteramide, poe, poly-two  alkane ketone, polyacetals, polyketals, Merlon, poly phosphate, polyester, poly terephthalic acid butene esters, poly-orthocarbonic ester, polyphosphazene, succinate, poly-(malic acid), poly-(aminoacid), polyvinylpyrrolidone, Polyethylene Glycol, poly-hydroxylated cellulose, polysaccharide, chitin, chitosan, hyaluronic acid and their copolymer, terpolymer and mixture.

29, the compositions of claim 1 comprises the polymer of about 5 weight % to about 90 weight %.

30, the compositions of claim 29 comprises the polymer of about 25 weight % to about 80 weight %.

31, the compositions of claim 30 comprises the polymer of about 35 weight % to about 75 weight %.

32, the compositions of claim 1, wherein said composition comprises the beneficiating ingredient of about 0.1 weight % to about 50 weight %.

33, the compositions of claim 32, wherein said composition comprises the beneficiating ingredient of about 0.5 weight % to about 40 weight %.

34, the compositions of claim 33, wherein said composition comprises the beneficiating ingredient of about 1 weight % to about 30 weight %.

35, the compositions of claim 1, wherein the ratio of this polymer and this solvent is between about 5: 95 and about 90: 10.

36, the compositions of claim 35, wherein the ratio of this polymer and this solvent is between about 20: 80 and about 80: 20.

37, the compositions of claim 36, wherein the ratio of this polymer and this solvent is between about 30: 70 and about 75: 25.

38, the compositions of claim 1 further comprises at least a following ingredients: emulsifying agent, pore former, anesthetis dissolubility adjusting control agent and penetrating agent.

39, the compositions of claim 1, wherein this beneficiating ingredient comprises the particle of mean diameter less than about 250 μ m.

40, the compositions of claim 39, wherein this mean diameter is between about 5 μ m and 250 μ m.

41, the compositions of claim 40, wherein this mean diameter is between about 20 μ m and 125 μ m.

42, the compositions of claim 41, wherein this mean diameter is between about 38 μ m and 63 μ m.

43, the compositions of claim 1, wherein this beneficiating ingredient is selected from down group: protein, peptide, medicine and their combination.

44, the compositions of claim 43, wherein this beneficiating ingredient comprises the protein that is selected from down group: human growth hormone, Intederon Alpha-2a, Interferon Alpha-2b, EPO, methionine-human growth hormone, go-the phenylalanine human growth hormone, synonym interferon and their combination.

45, the compositions of claim 43, wherein this beneficiating ingredient comprises medicine, and it comprises bupivacaine or paclitaxel.

46, the compositions of claim 43, wherein this beneficiating ingredient comprises peptide, and it comprises leuprolide or Desmopressin.

47, the method that about twenty four hours extremely continued to send the Injectable depot gel combination of beneficiating ingredient to the curee in about 12 months is gone through in preparation, comprises:

The water of mixed biologic aggressivity, biocompatible polymer and effective plasticising amount is the miscibilty solvent not, generates gel vehicle;

Dissolving or dispersion beneficiating ingredient in this gel vehicle;

The excipient that in this gel vehicle, mixes the regulation and control rate of release; With

Make this beneficiating ingredient stabilisation,

Wherein the effect of depolymerization is offset in the existence of this excipient.

48, the method for claim 47 further is included in gel vehicle premixing excipient and beneficiating ingredient before the admixed excipients and beneficiating ingredient.

49, the method for claim 47 further comprises to gel vehicle and loads excipient and beneficiating ingredient separately.

50, the method for claim 47, wherein this excipient is dissolving or is dispersed in this gel vehicle.

51, the method for claim 47, wherein this excipient is offset the effect of depolymerization, comprises pH modifier.

52, the method for claim 51, wherein this pH modifier is selected from down group: inorganic salt, organic salt and their combination.

53, the method for claim 52, wherein this pH modifier is selected from down group: zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, maleic acid magnesium, magnesium oleate, magnesium oxalate, zinc acetate, phosphoric acid hydrogen zinc, zinc phosphate, zinc lactate, MALEIC ACID, ZINC SALT, zinc oleate, zinc oxalate and their combination.

54, the method for claim 47 further comprises the excipient to about 50 weight % to the about 0.01 weight % of composition loaded.

55, the method for claim 47 further comprises excipient and the beneficiating ingredient of loading ratio between about 0.1: 99.9 and about 99: 1.

56, the method for claim 55, wherein this ratio is between about 1: 99 and about 60: 40.

57, the method for claim 47, wherein the water miscibilty of this solvent is less than or equal to about 7 weight % under 25 ℃.

58, the method for claim 47, wherein the not moisture miscibilty of said composition under 25 ℃ greater than the solvent of 7 weight %.

59, the method for claim 47, wherein this polymer comprises lactide acid polymer.

60, the method for claim 59, wherein this polymer comprises the copolymer (PLGA) of lactic acid and glycolic.

61, the method for claim 60, wherein the weight average molecular weight of this polymer is between about 3,000 to about 120,000, and the lactic acid of this copolymer and the monomer ratio of glycolic are between about 100: 0 to about 15: 85.

62, the method for claim 60, wherein this polymer comprises poly-(D, L-lactide-co-glycolide).

63, the method for claim 60, wherein this polymer comprises poly-(L-lactide-co-glycolide).

64, the method for claim 47 further comprises the polymer to about 90 weight % to the about 5 weight % of composition loaded.

65, the method for claim 47 further comprises the beneficiating ingredient to about 50 weight % to the about 0.1 weight % of composition loaded.

66, go through about twenty four hours continued to discharge beneficiating ingredient to about 12 months Injectable depot method for compositions, comprise:

Give a kind of compositions, said composition comprises: gel vehicle, comprise bioerosion, biocompatible polymer and the effective water miscibilty solvent not of plasticising amount, and generate gel vehicle; Dissolving or be dispersed in beneficiating ingredient in this gel vehicle; By offsetting this depolymerization effect regulation and control rate of release and the excipient that makes this beneficiating ingredient stabilisation.

67, the method for claim 66 further comprises and gives said composition once.

68, the method for claim 66 further comprises the local delivery said composition.

69, the method for claim 66 further comprises the systemic delivery said composition.

70, the method for claim 66 further comprises and sends said composition to a plurality of positions.

71, the method for claim 66 further comprises and gives said composition repeatedly.

72, continue to send beneficiating ingredient and reach that about twenty four hours is to about 12 months administration test kit after the administration, this test kit comprises:

Gel vehicle comprises not miscibilty solvent of bioerosion, biocompatible polymer and water, and content is for this polymer of plasticising and to generate gel with it be effective;

Dissolving or be dispersed in beneficiating ingredient in this gel vehicle;

Regulation and control rate of release and the excipient that makes this beneficiating ingredient stabilisation; With

Optional one or more following ingredients: emulsifying agent; Pore former; Optional and the associating anesthetis of this beneficiating ingredient dissolubility adjusting control agent; And penetrating agent;

The associating anesthetis of wherein optional at least and this dissolubility adjusting control agent keeps and separated from solvent, until anesthetis in curee's administration.

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