CN100435853C

CN100435853C - Inherently radiopaque polymeric products for embolotherapy

Info

Publication number: CN100435853C
Application number: CNB2004800272693A
Authority: CN
Inventors: D·K·布兰多姆; E·施米德; J·策尔廷格; J·B·科恩; D·博利卡尔
Original assignee: Rutgers State University of New Jersey
Current assignee: Rutgers State University of New Jersey
Priority date: 2003-09-25
Filing date: 2004-09-27
Publication date: 2008-11-26
Anticipated expiration: 2024-09-27
Also published as: CN1856329A

Abstract

Preferred embodiments relate to compositions of inherently radiopaque, biocompatible, bioresorbable polymeric particles and methods of using them for embolizing a body lumen.

Description

The inherent radiopaque polymerizate that is used for embolotherapy

Relevant application

According to U.S.C. the 35th chapter the 119th (e) bar, the application requires the priority of U.S. Provisional Application that number 60/601,677 and 2003 year JIUYUE of the U.S. Provisional Application submitted on August 13rd, 2004 submitted on the 25th number 60/505,951.Two parts of disclosed contents of application all are attached to herein by reference.

Invention field

The preferred embodiments of the invention relate to inherent radiopaque, biocompatible, can biological re-absorbed polymer particles and with the method for their thromboembolism body cavitys.

Background

Embolotherapy device and reagent comprise metal plug circle, gel foam, biogum, oils and fats, alcohol or microgranule polymerization suppository, be used for control over bleeding for example, prevention before operation technique or operating process lose blood, limit or block blood confession to tumor and vascular malformation, for example be used for hysteromyoma, tumor (being chemoembolization), hemorrhage (for example accompanying hemorrhage wound) and arteriovenous malformotion, fistula and aneurysm.The most frequently used is embolic coils and microgranule.

The metal strand that conventional embolic coils is normally curled is limited in the linear structure when carrying by vessel catheter.They are pre-formed geometric " curling " state, and they revert to this state after going out delivery conduit.Though variation (for example seeing U.S. Patent number 6,358,228 and 6,117,157) on many different designs and the program is arranged with quoit; But, design metal bolt stopper ring all is in order to utilize reaction first, promptly because the blood clot that the reaction of the hemodynamics of physical blockage causes in the blood flow, and some situation is for addition reaction, the blood clot that to be body cause the biologically of coil method is wherein by in quoit or form the therapeutic purposes that clot reaches blocking blood flow on every side.

Though the metal bolt stopper ring possesses some favourable physical mechanical characteristics, for example inherent radiopacity and shape memory (reverting to preformed rolled state after promptly launching), but use the metal bolt stopper ring also to follow many shortcomings, especially comprise chronic tissue injury, hamartoplasia, vascular occlusion and forever be bonded in the tissue that launches the position.

Nonmetallic selection comprises liquid and microgranule suppository.But these also have significant disadvantages.Liquid embolizing agent is divided into sedimentary and active system usually.In the previous case, polymer carrying in the dispersive acceptable solvent biologically by blood vessel, is made polymer precipitate (for example seeing U.S. Patent number 5,851,508) in position by solvation.Such medicament may precipitate fast inadequately, thereby not solidified (viscosity) polymer embolus is divided a word with a hyphen at the end of a line and the tissue of the unexpected thromboembolism of thromboembolism.In arteriovenous malformotion, this point is even more important, and wherein material enters Venous system easily and causes tangible pulmonary infarction.Another shortcoming is the use of carrying the solvent (for example dimethyl sulfoxide) of precipitation polymers.

Active suppository mainly is various cyanoacrylate chemical systems.The example of the system of FDA approval is Cordis The cyanoacrylate embolus.Here, liquid monomer and/or low polybutylcyanoacrylate mixture are introduced vascular site, wherein start polymerization by utilizable water in the blood by conduit.Unfortunately, if when discharging the time of staying oversize, the cyanoacrylate goo may make catheter tip and tissue bond lead to grave consequences.Second problem is can comprise formaldehyde by biological re-absorbed catabolite, a kind of cytotoxic chemical thing from these materials.

Microgranule treatment embolus is made up of the microgranule of different sizes, geometry and component.Schwarz etc., J.Biomater., 25 (21), 5209-15 (2004) discloses the hydroxyl of synthesized degradable-ethyl propylene acid esters (HEA) microsphere and by zoopery, but does not make its commercialization as yet.The microgranule that is used for clinical practice is suspended in radiopaque contrast solution usually and discharges by vessel catheter through injector to inject.3 kinds of the most frequently used microgranule suppositories are at present

(Pharmacia﹠amp; The absorbable gelatin corpuscle of Upjohn), polyvinyl alcohol (PVA) foam and three acrylic gelatine microspheres (Biosphere Medical's

).Different with quoit, these emboluses are not inherent radiopaque.In fact, place to develop and to depend on when thromboembolism is operated inference fluoroscopic flow analysis.In a single day actual microgranule enters body does not just have direct method to make its development.And for PVA and EMBOSPHERE, material may all residue in patient's body all one's life, increases the danger of biological repulsive interaction.For GELFOA M, may there be tissue rejection effect to this animal derived agent.

For example, the microgranule suppository can be used for restriction or the confession of blocking-up blood, for example treats tumor and vascular malformation, for example treats hysteromyoma, cancerous tumour (being chemoembolization), hemorrhage (for example accompanying hemorrhage wound) and arteriovenous malformotion, fistula and aneurysm.When routine is used, generally include and discharge by guide catheter.

Biocompatible, can have temporary transient potential advantage by biological re-absorbed microgranule suppository.Along with time effective removing of microgranule foreign body in the past makes organized renewing to its naturalness.

Radiopaque microgranule suppository has the potential special benefits of can be when embolotherapy being operated or developing afterwards.When operation, microgranule develops and makes the doctor can accurately it be released into target vessel or tissue.That is to say that the doctor can guarantee that microgranule can not rest on unexpected position.This control level will greatly increase the safety and the effectiveness of embolotherapy.In case implant radiopaque microgranule, can be with the program limit of following the tracks of in non-interventional method, for example simple X ray photography.For example for traceable its size of tumor, because as time passes, assembling will appear in radiopaque thromboembolism part when mass/volume reduces.

Should be noted that and have biocompatible embolus microgranule in the market.In fact, with

Form can obtain can biological re-absorbed biocompatible suppository.But should be noted that because this material animal derived, so there is potential repulsive interaction.And, for this application

Do not approve by FDA.

Having attempted producing more can biocompatible degradable thromboembolism microgranule.Investigational radiopaque suppository and their potential effect have been prepared equally, by zoopery.All must add outside agent for example iodinated contrast media or metal or its salt (for example tungsten, barium sulfate etc.) or in all cases by can not biological re-absorbed compositions halogenation making it have inherent radiopacity.

But up to now, do not imagine or attempt biocompatible, can be used for embolotherapy by biological re-absorbed, inherent radiopaque microgranule.Therefore, biocompatible for exploitation, can biological re-absorbed, inherent radiopaque microgranule be used for the important of embolotherapy and need be met yet, it also allows the repetitive therapy to same area, prevents or alleviate the above-mentioned shortcoming of the microgranule suppository of existing or imagination simultaneously.

Therefore,, radiopaque suppository important can be biological re-absorbed for exploitation need not be met yet, the polymeric material that wherein is used to prepare these reagent has the metallic character (for example radiopacity) of needs, prevents simultaneously or alleviates the above-mentioned shortcoming of using quoit or one of liquid and microgranule embolus to follow.

Summary of the invention

According to the open embolotherapy product of the preferred embodiments of the invention.The embolotherapy product comprises microparticle formulation, its contain biocompatible, can biological re-absorbed polymer and optionally comprise its stereoisomer, wherein this polymer contains the halogen atom of sufficient amount, so that the embolotherapy product has inherent radiopaque.In some preferred embodiments, polymer comprises homopolymer, heteropolymer, or its mixture.

In a preferred embodiment of embolotherapy product, polymer contains the unit that one or more formula I describe:

Wherein X=I or Br; Y1 and Y2 can be independently=0,1,2,3 or 4;

Wherein f 0 and less than 1 between; G (comprises 0 and 1) between 0 and 1; And f+g (comprises 0 and 1) between 0 and 1;

Wherein A be following each:

R wherein ₁Independently for H or contain 0 to 5 and be selected from the heteroatomic of O and N from 1 alkyl to about 18 carbon atoms;

R wherein ₃Be saturated or undersaturated, replacement or unsubstituted alkyl, aryl or alkaryl, they contain about at the most 18 carbon atoms and 0 to 8 hetero atom that is selected from O and N;

Wherein B is aliphatic linearity or ramose glycol or poly-(aklylene glycol) unit; And

Wherein R and R ₂Can be independently selected from:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a; R wherein ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n; Wherein a and n (comprise 0 and 8) independently between 0 and 8; J ₁And J ₂Be Br or I independently; And for R ₂, Q contains free carboxylic acid groups, and for R, Q is selected from hydrogen and carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

In variation to the present embodiment of formula I, R and R ₂Can be selected from:

Each R wherein ₂In R ₁Be selected from the heteroatomic of O and N for containing 0 to 5 independently from 1 alkyl to about 18 carbon atoms, and the R among each R ₁Be H;

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently; And

Wherein Z is O or S independently.

In another preferred embodiment of embolotherapy product, polymer can contain the unit that one or more formula II describe:

Wherein the X of each polymer unit is Br or I independently, and Y (comprises 1 and 4) and R between 1 and 4 ₄Be 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most.

In the variation of formula II polymer, all X groups can be ortho-orientation and Y can be 1 or 2.In another kind changes, R ₄Be alkyl.

In another kind changes, R ₄Structure be:

The R of each unit wherein ₉Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most; And R ₅And R ₆Be selected from hydrogen independently of one another and have 18 carbon atoms and 0 to 8 heteroatomic alkyl that is selected from O and N at the most.

R at formula II ₄Another kind change the R of at least one unit ₉Contain side group (pendant) COOR ₁Group, wherein in each unit of its appearance, subunit R ₁Independently for hydrogen or contain 0 to 5 and be selected from the heteroatomic of O and N from 1 alkyl to about 18 carbon atoms.

R at formula II ₄Another kind change R ₉Have following structure independently:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a, wherein R ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n, wherein a and n (comprise 0 and 8) independently between 0 and 8; And J ₁And J ₂Be Br or I independently; And Q is selected from hydrogen, free carboxylic acid groups and carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

R wherein _5aFor containing 18 carbon atoms and 0 to 5 heteroatomic alkyl that is selected from O and N at the most; And wherein m is 1 to 8 integer (comprising 1 and 8); And R ₁Independently for hydrogen or contain 0 to 5 and be selected from the heteroatomic of O and N from 1 alkyl to about 18 carbon atoms.

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently, and R ₁Independently for hydrogen or contain 0 to 5 and be selected from the heteroatomic of O and N from 1 alkyl to about 18 carbon atoms.

In some embodiments of embolotherapy product of the present invention, polymer can with poly-(C ₁-C ₄Aklylene glycol) copolymerization.Preferably, poly-(C ₁-C ₄Aklylene glycol) parts by weight that account for are less than about 75wt%.More preferably, poly-(aklylene glycol) is poly-(ethylene glycol).

In the another kind of polymer disclosed herein changed, side group-COOH group was contained in about 0.01% to about 0.99% described polymer unit.

In the another kind of formula II changes, R ₄Can be aryl or alkaryl.Preferably, select R ₄Aryl or alkaryl are so that polymer unit is a diphenol.

In another preferred embodiment of embolotherapy product, polymer can contain the unit that one or more formula IIIs are described:

Wherein the X of each polymer unit is Br or I independently, and Y1 and Y2 (comprise 0 and 4) independently of one another between 0 and 4, and the Y1+Y2 of each unit (comprises 1 and 8) independently between 1 and 8, and the R of each polymer unit ₂Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most.

In the advantageous variant of formula III, all X groups all are ortho-orientation.Preferably, Y1 and Y2 are below 2 or 2 independently, and Y1+Y2=1,2,3 or 4.

In the another kind of formula III changes, the R of at least one unit ₂Can contain side group COOR ₁Group is wherein at COOR ₁Each unit that group exists, subunit R ₁Independently for hydrogen or contain 0 to 5 and be selected from the heteroatomic of O and N from 1 alkyl to about 18 carbon atoms.

In the another kind of formula III changes, R ₂Have following structure independently:

In the advantageous variant of formula III, about 0.01% contains side group COOH base to about 0.99% polymer unit.Preferably, polymer and the poly-(C of 75wt% at the most ₁-C ₄Aklylene glycol) copolymerization.More preferably, poly-(C ₁-C ₄Aklylene glycol) is poly-(ethylene glycol).

In another preferred embodiment of embolotherapy product, polymer can contain the unit that one or more formula IV describe:

Wherein each X is I or Br independently, and Y1 of each diphenol unit and Y2 (comprise 0 and 4) independently between 0 and 4, and the Y1+Y2 of each diphenol unit (comprises 1 and 8) between 1 and 8;

Each R and R ₂Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most, wherein R ₂Also contain the side group hydroxy-acid group;

Wherein A is:

P is that parts by weight are about 75% or poly-(C still less ₁-C ₄Aklylene glycol) unit; F is 0 between less than 1, and g (comprises 0 and 1) between 0 and 1; And f+g (comprises 0 and 1) between 0 and 1.

In the advantageous variant of formula IV, P is that parts by weight are about 50% or still less poly-(ethylene glycol).More preferably, P is that parts by weight are about 30% or still less poly-(ethylene glycol).

In other advantageous variant of formula IV, R and R ₂All contain side group COOR ₁Group; Wherein for R, subunit R ₁Be selected from the heteroatomic of O and N for containing 0 to 5 independently from 1 alkyl to about 18 carbon atoms; And wherein for R ₂, subunit R ₁Be hydrogen atom.

In other advantageous variant of formula IV, each R and R ₂Have following structure independently:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a, wherein R ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n, wherein a and n (comprise 0 and 8) independently between 0 and 8; And J ₁And J ₂Be Br or I independently; And R ₂Q contain free carboxylic acid groups, and the Q of each R is independently selected from hydrogen, carboxylate and amide, wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

In other advantageous variant of formula IV, each R ₂Have following structure independently:

R wherein _5aFor containing 18 carbon atoms and 0 to 5 heteroatomic alkyl that is selected from O and N at the most; And wherein m is 1 to 8 integer (comprising 1 and 8); And R ₁Be hydrogen.

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently, and R ₁Be hydrogen.Preferably, each carboxylate of R or amide are ethyl or butyl ester or amide.

In other advantageous variant of formula IV, A is-C (=O)-group.In the another kind of advantageous variant of formula III, A is:

R wherein ₃Be C ₄-C ₁₂Alkyl, C ₈-C ₁₄Aryl or C ₈-C ₁₄Alkaryl.Preferably, select R ₃So that A becomes the part of the metabolite dicarboxylic acids of nature existence.More preferably, R ₃For being selected from-CH ₂-C (=O)-,-CH ₂-CH ₂-C (=O)-,-CH=CH-and (CH ₂-) _zPart, wherein z is 1 to 8 integer (comprising 1 and 8).

In other advantageous variant of formula IV, all X groups all are ortho-orientation.Preferably, Y1 and Y2 are below 2 or 2 independently, and Y1+Y2=1,2,3 or 4.

In other advantageous variant of formula IV, each halogen all is an iodine.

In other advantageous variant of formula IV, f is greater than 0.1 to about 0.3.Preferably, f is greater than 0.2 to about 0.25.

During other preferably changes at formula IV, poly-(C ₁-C ₄Aklylene glycol) parts by weight are less than about 25wt%.

In other advantageous variant of formula IV, g is greater than 0.1 to about 0.35.More preferably, g is greater than 0.2 to about 0.3.

In another embodiment preferred of embolotherapy product, polymer can contain the unit that one or more formula V describe:

Wherein each X is iodine or bromine independently; Each y (comprises 0 and 4) independently between 0 and 4, wherein (comprised 1 and 8) by the sum of cyclosubstituted iodine and bromine between 1 and 8; Each R ₄And R ₆Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most and R ₄Also comprise the side group hydroxy-acid group;

Wherein A is:

R wherein ₃Be saturated or undersaturated, replacement or unsubstituted alkyl, aryl or alkaryl, they contain about at the most 18 carbon atoms and 0 to 5 hetero atom that is selected from O and N;

P is the poly-(C that parts by weight are less than about 75wt% ₁-C ₄Aklylene glycol) unit;

F from greater than 0 to less than 1; G (comprises 0 and 1) between 0 and 1; And f+g (comprises 0 and 1) between 0 and 1.

Preferably, P is poly-(ethylene glycol) unit.

In the advantageous variant of formula V, each R of described polymer ₄And R ₆All contain side group-COOR ₁Base is wherein for each R ₆, each subunit R ₁Be selected from the heteroatomic of O and N for containing 0 to 5 independently from 1 alkyl to about 18 carbon atoms, and for each R ₄, each subunit R ₁It all is hydrogen atom.

In other advantageous variant of formula V, each R of described polymer ₄And R ₆For:

R wherein _5aFor containing 18 carbon atoms and 0 to 5 heteroatomic alkyl that is selected from O and N at the most; And wherein m is 1 to 8 integer (comprising 1 and 8); And for each R ₆, each subunit R ₁Be selected from the heteroatomic of O and N for containing 0 to 5 independently from 1 alkyl to about 18 carbon atoms, and for each R ₄, each subunit R ₁It all is hydrogen atom.

In other advantageous variant of formula V, the R of described polymer ₆Each R ₁Subunit is ethyl or butyl.

In other advantageous variant of formula V, A is-C (=O)-group.Perhaps, A can be:

R wherein ₃Be C ₄-C ₁₂Alkyl, C ₈-C ₁₄Aryl or C ₈-C ₁₄Alkaryl.

In other advantageous variant of formula V, select R ₃So that A becomes the part of spontaneous metabolite dicarboxylic acids.

In other advantageous variant of formula V, R ₃For being selected from-CH ₂-C (=O)-,-CH ₂-CH ₂-C (=O)-,-CH=CH-and (CH ₂-) part of z, wherein z is 1 to 8 integer (comprising 1 and 8).

In other advantageous variant of formula V, all X groups all be ortho-orientation and y be 2 or 3.

In other advantageous variant of formula V, each X group all is an iodine.

In other advantageous variant of formula V, f is greater than 0.1 to about 0.3.

In other advantageous variant of formula V, g is greater than 0.1 to about 0.35.

In the preferred embodiment of embolotherapy product of the present invention, can prepare microparticle formulation and be used for administrated by injection.The polymer particles that preparation contains can be selected from spherical particle, inhomogenous microgranule, small porous particle, hollow minute particle, solid microgranule and eliminating diameter (excludeddiameter) are from about 10 microns extremely about 5,000 microns microgranules and composition thereof geometrically.

Perhaps, preparation can contain polymer hydrogel compositions.

In the preferred embodiment of embolotherapy product, polymer also can contain at least a therapeutic agent of effective dose.Preferably, described at least a therapeutic agent is selected from chemotherapeutant, non-steroidal anti-inflammatory agent or steroidal anti-inflammatory agents.

In another preferred embodiment of embolotherapy product, polymer also can contain the magnetic resonance reinforcing agent of effective dose.

In the preferred embodiment of embolotherapy product, polymer also can contain the radiopaque medium of effective dose, and it is selected from iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten and composition thereof.

In another preferred embodiment of embolotherapy product, polymer also can contain be suitable for promoting selecting biologically biocompatible, can biological re-absorbed polymer coating.Preferably, biologically is selected from thrombosis, cell adhesion, cell proliferation, attraction inflammatory cell and deposition substrate albumen, inhibition thrombosis, inhibition cell adhesion, suppresses cell proliferation, inflammation-inhibiting cell and suppresses the deposition of stromatin or their combination.

In another preferred embodiment of embolotherapy product, polymer can contain formula I:

Wherein X=I or Br; Y1 and Y2 can be independently=0,1,2,3 or 4;

Wherein R and R ₂Can be independently selected from:

Wherein, for R ₂, R ₁Be H, and for R, R ₁Be the long chain aliphatic hydrocarbon;

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently;

Wherein Z is O or S independently;

Wherein A is selected from:

R wherein ₃Be saturated or undersaturated, replacement or unsubstituted alkyl, aryl or alkaryl, they contain about at the most 18 carbon atoms and 0 to 8 hetero atom that is selected from O and N; And

Wherein B is aliphatic linearity or ramose glycol or poly-(aklylene glycol) unit.

Method according to the open thromboembolism body cavity of another preferred embodiment of the present invention.This method comprises the step of the embolotherapy product of effective dose being introduced body cavity, the embolotherapy product comprise contain biocompatible, can biological re-absorbed polymer particulates preparation, the halogen atom that wherein said polymer contains sufficient amount makes the embolotherapy product for inherent radiopaque.

Preferably, by finish the step of introducing through conduit or injector to inject.

In another preferred embodiment of the present invention, openly treat cirso-and/or Aranea venous method.This method comprises that the embolotherapy product with effective dose delivers medicine to described cirso-and/or Aranea intravenous, the embolotherapy product comprise contain biocompatible, can biological re-absorbed polymer particulates preparation, the halogen atom that wherein said polymer contains sufficient amount makes the embolotherapy product for inherent radiopaque.

Preferably, finish the step of administration by conduit or injector to inject.

According to the preferred embodiments of the invention, promote openly that also the therapeutic agent part is released into the method for tissue.This method may further comprise the steps: the embolotherapy product that enough reduces the amount of described tissue blood flow is delivered medicine to and organize relevant blood vessel; Unite separately or with the embolotherapy product therapeutic agent is delivered medicine to blood vessel, discharge so that strengthen the part of therapeutic agent; And fully degrade, repeat to give behind the described blood vessel permission rechallenge step of embolotherapy product and therapeutic agent in embolotherapy product first administration.The embolotherapy product that is used for this method comprise contain biocompatible, can biological re-absorbed polymer particulates preparation, the halogen atom that wherein said polymer contains sufficient amount makes the embolotherapy product for inherent radiopaque.

Also open method for the treatment of body cavity again.This method may further comprise the steps; With enough amounts that in a period of time, reduces tissue blood flow biocompatible, can deliver medicine to the angiosomes relevant by biological re-absorbed polymerization embolotherapy product with described tissue; And in time after a while any embolotherapy product is given and described roughly the same zone of organizing relevant blood vessel, so that described tissue is accepted the intervention again of treatment again or other form.

In an embodiment of embolotherapy product of the present invention, polymer contain non-spontaneous can biological re-absorbed inherent radiopaque polymer.In another kind changes, polymer comprise contain at least a amino acid whose can biological re-absorbed inherent radiopaque polymer.

The accompanying drawing summary

Figure 1A-1C shows the x-roenthenograph of injecting the transplanting Ren sus domestica of radiopaque polymerization embolotherapy compositions according to embodiment preferred.

Fig. 2 shows that according to embodiment preferred under 37 ℃, chemotherapeutics (Ramulus et folium taxi cuspidatae alcohol phenol (Paclitaxel)) sample is the dissolution from poly--DTE-carbonic ester coating (a kind of biocompatible polymerization embolotherapy coating) in containing the PBS of polysorbas20.

Fig. 3 a-b shows according to a preferred embodiment of the invention, and the X ray of radiopaque performance radiopacity of showing of polycarbonate film that can biological re-absorbed triiodide tyrosine-derived relatively.The optical density of poly-(I2DITE-co-20%PEG2k) carbonic ester thin film is equivalent to people's bone.

Implement best mode of the present invention

Openly can biological re-absorbed, inherent radiopaque polymerization embolotherapy product according to the preferred embodiments of the invention.They can be used for, for example temporary transient restriction or blocking-up blood are for example treated hysteromyoma, tumor (being chemoembolization), hemorrhage (when for example accompanying hemorrhage wound) and arteriovenous malformotion, fistula and aneurysm for (generally include by conduit and discharge) treatment tumor and vascular malformation when routine is used.These suppositories also can discharge by alternate manner, for example directly enter body to provide to appearing at lower limb and Aranea vein on the face (hinders attractive in appearance or unwanted venule by syringe or other non-conduit carrier, near skin surface, arborizations shape or spider reticulation, red or blue) or even the beauty therapeutic of cirso-(swelling and swell in skin surface).

According to a preferred aspect of the present invention, the embolotherapy product can have to the following attribute of small part: (a) radiopacity can develop conventional XRF perspective fully; (b) microgranule compressibility, flowability and floatability are convenient to the transmission of embolotherapy medicine and the performance of function fully; (c) ideal surface characteristic or functional can the adjustment according to the needs (for example blood compatibility or thrombosis) of a series of application; (d) ideal biodegradation and biological heavy absorption spectra can comprise the time period of the different length of occluding body lumens according to the needs adjustment of a series of application; (e) ideal in the described organizer intracavity time of staying so that any thromboembolism product can be used for treat again the blood vessel and the described tissue in roughly the same zone after a while or allow other form to treat for example hands art again; (f) enough therapeutic dose with the biology that need to promote and/or physiological effect and/or (g) fully biocompatible, can biological re-absorbed coating to promote biology and/or physiological effect to the needs of thromboembolism body cavity.The body cavity that this paper uses is appointed as lumen of vessels or the blood vessel (being the tremulous pulse and/or the vein of any size) that contains the organism blood circulation.

According to an aspect of the present invention, the embolotherapy product that provides be biocompatible, can biological re-absorbed polymer particles preparation, the halogen atom that wherein said polymer has sufficient amount develops the embolotherapy product under conventional x ray fluorescence perspective.

That the preferred embodiments of the invention relate to is biocompatible by introducing, can biological re-absorbed microgranule polymeric material thromboembolism or the compositions and the method for inaccessible body cavity (preferred blood vessel).Polymeric material adds the radiopaque part in a more preferred embodiment, is preferably halogen, and most preferably is iodine and/or bromine.Biodegrade (effect by water and/or enzyme is by chemical degradation) be appointed as in the term that this paper uses " can biological re-absorbed " and at least some catabolites can be discharged by body and/or re-absorbed polymer.The term that this paper uses " radiopaque " for example means the analytical technology that comprises by in-vivo imaging, but object that the method for x shadowgraph, fluoroscopy, other form lonizing radiation, MRI, electromagnetic energy, structure imaging (for example computer or computerized tomography) and functional imaging (for example ultrasonography) for example of being not limited to is developed or the material that comprises described object.

In addition, the applicant has found that halogenated polymer of the present invention shows unique combination of the characteristic that is particularly conducive to the embolotherapy purposes, comprises radiopacity, biocompatibility and can biologically weigh absorbability.These polymer can comprise for example at U.S. Patent number 6,475, the embodiment (it all is attached to herein by reference) of the kind of describing in 477, and the biocompatible diphenol of more especially iodinating and/or bromination and poly-(aklylene glycol), it shows unique combination of the characteristic that is particularly conducive to the embolotherapy purposes.Importantly, though U.S. Patent number 6,475,477 describe a large amount of different polymer with different qualities and characteristics combination, but the applicant has found that the property combination of some polymer performance obviously and surprisingly is better than those at U.S. Patent number 6 at present, disclosed polymer in 475,477.

In this article, " embolotherapy product " is meant any polymeric preparations that is applicable to thromboembolism body cavity (for example control over bleeding, prevention are lost blood and/or restriction or blocking blood flow).Example comprises for example injectable polymeric preparations of compositions, microgranule, hydrogel etc.

By conventional design preparation embolotherapy product, with disclosed radiopaque, biocompatible, the non-treatment structural material that can biological re-absorbed polymer replaces conventional application according to preferred embodiment.Such product is effectively inherent.By conventional method the embolotherapy product according to preferred embodiment of effective dose is delivered medicine to the thromboembolism position.

That the applicant has found is biocompatible, can biological re-absorbed, inherent radiopaque polymer class can by broad variety biocompatible, can the biological re-absorbed aryl polymer preparation that contains.For example, biocompatible in all of following table 1 record, can biological re-absorbed polymer in, well-known method by those of ordinary skills adopt easily need not too much experiment, radiopacity can be introduced aromatic ring through halogenation (particularly bromination and iodate) effect.In fact, U.S. Patent number 6,475,477 showed in this way a big class inherence of preparation radiopaque, biocompatible, can biological re-absorbed polymer.Available similar fashion is given radiopacity the monomer component of other polymer in this table.

Table 1

United States Patent (USP)	The patent exercise question	Guidance content
United States Patent (USP)	The patent exercise question	Guidance content	6,475,477	Radiopaque polymer biomaterial	● the diphenol monomer that iodo-and bromo-replace is synthetic ● polycarbonate homopolymer that iodo-and bromo-replace and copolymer are synthetic ● polyarylate homopolymer that iodo-and bromo-replace and copolymer are synthetic
5,658,995	The copolymer of the Merlon of tyrosine-based and poly-(alkylene oxide)	● the diphenol monomer of tyrosine-derived and poly-(alkylene oxide) synthetic statistic copolymer	6,475,477	Radiopaque polymer biomaterial
5,658,995			6,048,521	The copolymer of the polyarylate of tyrosine-based and poly-(alkylene oxide)	● the statistic copolymer of Merlon and polyarylate and poly-(alkylene oxide)
6,120,491	Biodegradable anionic polymer derived from aminoacid L-tyrosine	● the block copolymer of poly-(alkylene oxide) group on Merlon and polyarylate (polyarlates) with side group hydroxy-acid group and the main chain synthetic	6,048,521
6,120,491			6,284,862	Monomer and polymer prepared therefrom derived from hydroxy acid	● aliphatic-aromatic dihydroxy monomer and can biological re-absorbed polymer synthetic
4,863,735	Has the active biodegradable polymeric drug delivery system of adjuvant	● synthesizing of poly-(iminocarbonic ester)	6,284,862
4,863,735		● synthesizing of poly-(iminocarbonic ester)	6,238,687	Their method of biodegradable polymer, compositions, product and preparation and use	● on main polymer chain, prepare the method for phosphorus and deaminizating tyrosyl L-tyrosine link
5,912,225	Biodegradable poly-(phosphate ester-co-deaminizating tyrosyl L-tyrosine ester) chemical compound, compositions, product and preparation and their method of use	● preparation contains the method for the polymer of phosphorus and the link of deaminizating tyrosyl L-tyrosine	6,238,687
5,912,225			4,638,045	But non-peptide polyamino acid bio-digestion	● most monomer unit have 2 or 3 kind of amino

	Polymer	The polymer of acid
	Polymer	The polymer of acid	6,602,497	Strict alternative poly-(alkylene oxide ether (alkylene oxide ether)) copolymer	● the polyethers of the monomer recurring unit of strict alternative poly-(alkylene oxide) and tyrosine-derived
5,198,507	But the polymer of the deutero-bio-digestion of synthesizing amino acid	● amino acid derived Merlon and with the polymeric blends of the poly-iminocarbonic ester of the deutero-diphenol initiation material of same amino acid preparation	6,602,497

All United States Patent (USP)s of narration and their preparation method all are attached to herein by reference in table 1.U.S. Patent number 6,602,497 polyethers may need crosslinked before being used for embolotherapy.But suitable to those skilled in the art cross-linking method is conventional basically and need not too much experiment.

The term that this paper uses " ortho-orientation " refers to the orientation with respect to benzene oxygen alcohol radical.

The term that this paper uses " inherent radiopaque " refers to because halogen is covalently bonded in polymer and radiopaque in fact polymer.Therefore, this term does not comprise and halo kind or other radiopaque medium for example metal and the simple blended polymer of complex thereof.

The variation of polymer halo combination generally can be represented by following formula in the table 1.It should be noted that the following combination range of pointing out surpasses the scope that those tables 1 are described.

Should understand the form that different polymer architecture formulas represent and to comprise homopolymer and heteropolymer, and comprise their stereoisomer.Homopolymer used herein refers to comprise all same type polymer of monomers.Heteropolymer used herein refers to comprise two or more dissimilar polymer of monomers, is also referred to as copolymer.Heteropolymer or copolymer may be known block, random and alternative type.Further with regard to the form of different polymer architecture formulas, the embolotherapy product can comprise homopolymer, heteropolymer and/or such mixture of polymers according to embodiments of the present invention.

Preferred polymer

The embolotherapy product is disclosed according to a preferred embodiment of the invention, its contain inherent radiopaque, biocompatible, can biological re-absorbed polymer, comprise similar polymers, copolymer and composition thereof, wherein this polymer contains one or more following units (formula I):

Wherein X=I or Br; Y1 and Y2 can be independently=0,1,2,3 or 4;

Wherein the scope of f and g can according to combination/performance need is defined as from 0 to 1, prerequisite be f less than 1 and f+g between 0 and 1, (comprise 0 and 1);

R and R ₂Can be independently selected from:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a; R wherein ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n; Wherein a and n (comprise 0 and 8) independently between 0 and 8; And J ₁And J ₂Be Br or I independently; And for each R ₂, Q contains free carboxylic acid groups, and for each R, Q is selected from hydrogen and carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

In the preferred embodiment of formula I, R and R ₂Can be independently selected from:

Each R wherein ₂R ₁R for H and each R ₁Be the long chain aliphatic hydrocarbon independently, and in some embodiments, be selected from the heteroatomic of O and N from 1 alkyl to about 18 carbon atoms for containing 0 to 5;

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently;

Wherein Z is O or S independently;

A is:

R wherein ₁As preceding definition;

R wherein ₃Be saturated or undersaturated, replacement or unsubstituted about at the most 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N of containing; And

According to one embodiment of the invention, provide wherein inherent radiopaque, biocompatible, the product that can biological re-absorbed polymer contains the unit that one or more formula II describe:

Wherein the X of each polymer unit is Br or I independently, and Y (comprises 1 and 4) between 1 and 4, and R ₄For containing about at the most 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N.

Work as R ₄During for alkyl, it preferably has following structure:

The R of each unit wherein ₉Independently for containing about at the most 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N; And R ₅And R ₆Be selected from hydrogen independently of one another and have 18 carbon atoms and 0 to 8 heteroatomic alkyl that is selected from O and N at the most.

Each R ₉Preferably contain side group COOR ₁Group, wherein subunit R ₁As preceding definition.In one embodiment, R ₉For:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂) a; R wherein ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n; Wherein a and n (comprise 0 and 8) independently between 0 and 8; And J ₁And J ₂Be Br or I independently; And Q is selected from hydrogen, free carboxylic acid groups and carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

More preferably, each R ₉Have following structure independently:

R wherein _5aAs preceding definition, and COOR ₁Group as defined herein; And wherein m is 1 to 8 integer (comprising 1 and 8).

In a further preferred embodiment, R ₉For:

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently, and COOR ₁Group is as to R ₉Description.

Selection contains R ₄The preferred polymers embodiment of aryl or alkaryl class is so that the unit that formula II describes is a diphenol.

In another preferred embodiment of the present invention, two phenol polymers can contain the diphenol unit that one or more formula IIIs are described:

Wherein X and R ₂Identical with the description of this paper formula I and formula II, Y1 and Y2 (comprise 0 and 4) independently between 0 and 4, and Y1+Y2 (comprises 1 and 8) between 1 and 8.

This polymer embodiment preferred aspect, this two phenol polymer contains the unit that one or more formula IV describe:

Each R and R ₂Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most, wherein R ₂Also comprise the side group hydroxy-acid group;

A is:

R wherein ₃Be saturated or undersaturated, replacement or unsubstituted about at the most 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N of containing; P is poly-(C ₁-C ₄Aklylene glycol) unit; F 0 and less than 1 between (comprising 0 and 1); G (comprises 0 and 1) between 0 and 1, f+g (comprises 0 and 1) between 0 and 1; And the parts by weight of poly-(aklylene glycol) are about 75% or still less.P is preferably poly-(ethylene glycol), and its parts by weight are about 50% or still less, and more preferably from about 30% or still less.

R and R ₂Preferably contain side group COOR separately ₁Group, wherein for R, subunit R ₁Be selected from the heteroatomic of O and N for containing 0 to 5 independently from 1 alkyl to about 18 carbon atoms, and for R ₂, subunit R ₁Be hydrogen atom.

In a preferred embodiment, each R and R ₂Have following structure independently:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a; R wherein ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n; Wherein a and n (comprise 0 and 8) independently between 0 and 8; And J ₁And J ₂Be Br or I independently; And for each R ₂, Q contains free carboxylic acid groups, and for each R, Q is independently selected from hydrogen, carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

More preferably, each R and R ₂Have following structure independently:

R wherein _5aAs previous definition to formula II, and COOR ₁Group such as this paper are to R and R ₂Definition.In a more preferred embodiment, R and R ₂Class can be selected from:

Wherein j and m are 1 to 8 integer (comprising 1 and 8) independently, and COOR ₁The base as to R and R ₂Definition.

In the another kind of polymer changes, each R of R ₁Subunit all is ethyl or butyl.

In another embodiment, A be-C (=O)-.

In another embodiment, A is:

R wherein ₃For saturated or undersaturated, replacement or unsubstitutedly contain about at the most 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N, and more preferably C ₄-C ₁₂Alkyl, C ₈-C ₁₄Aryl or C ₈-C ₁₄Alkaryl.In a further preferred embodiment, R ₃Can be selected from-CH ₂-C (=O)-,-CH ₂-CH ₂-C (=O)-,-CH=CH-and (CH ₂-) z, wherein z is from 0 to 8 integer (comprising 0 and 8).

Polymer according to the present invention comprises the embodiment that wherein iodine and bromine all occur as ring substituents.

According to preferred embodiment on the other hand, provide embolotherapy product by the cyclosubstituted polymer formation that contains the unit that one or more formula V describe:

Wherein each X is iodine or bromine independently; Each y is 1 or 2 independently; Each R ₄And R ₆Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most; And A, P, f and g with above to formula IV describe identical.

R ₄And R ₆Preferably contain side group COOR separately ₁Group is wherein for R ₆, subunit R ₁Independently for contain 0 to 5 be selected from O or N heteroatomic from 1 alkyl to about 18 carbon atoms, and for R ₄, subunit R ₁Be hydrogen atom.More preferably, each R ₄And R ₆For:

R wherein _5aAs previous definition to formula II, and COOR ₁Group such as this paper are to R ₄And R ₆Definition.

The form that is to be understood that different polymer architecture formulas be the formula IV and the V polymer architecture of sketch map and expression be random copolymer for the P position, all different subunits may appear in the random sequence on whole polymer main chain therefore.At most cases, A is connected with P or phenol ring.

Usually, P is that molecular weight is about 10,000 or littler poly-(aklylene glycol) unit, and more preferably from about 4000 or littler.P is preferably molecular weight and is about poly-(ethylene glycol) unit between 1000 and 2000.

When A was carbonyl (C=O), the formula IV polymer of preferred embodiment contains Merlon and formula V polymer contains poly-(amide carbonic ester).When A is:

The formula IV polymer of preferred embodiment contains polyarylate and formula V polymer contains poly-(esteramides).

Formula IV is defined as polyarylate and formula V is defined as in the embodiment of poly-(esteramides), R therein ₃Be saturated or undersaturated, replacement or unsubstituted about at the most 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N of containing.In preferred embodiments, R ₃For containing 2 the alkyl of having an appointment to about 12 carbon atoms.In some preferred embodiments, R ₃Be the straight or branched alkyl.In a more preferred embodiment, R ₃Group is-CH ₂-CH ₂-,-CH ₂-CH ₂-CH ₂-CH ₂-or-CH ₂-CH ₂-CH ₂-CH ₂-CH ₂-CH ₂-.R ₃Group can be replaced by any suitable functional group, and this functional group preferably can or not be not easy to when polymerization and other monomeric compound cross reaction, forms polymer of the present invention otherwise will have a strong impact on by polymerization described below.Under the situation that cross reaction may take place, but those skilled in the art's application method (for example with blocking group or other method known in the art) obtains preferred chemical compound.

In some preferred embodiment, select R ₃So that the A of formula IV and V part is derived from spontaneous metabolite dicarboxylic acids or the chemical compound of high degree of biocompatibility is arranged.For example, in some embodiments, select R ₃So that the polyarylate A of formula III part derived from known be the Krebs circulation intermediate dicarboxylic acids of Cellular respiration approach.Such dicarboxylic acids comprises decanedioic acid, adipic acid, ethanedioic acid, malonic acid, 1,3-propanedicarboxylic acid, 1,5-pentanedicarboxylic acid., suberic acid and Azelaic Acid.Therefore, R ₃More preferably be selected from-CH=CH-and (CH ₂-) part of z, wherein z is 0 to 8 integer, and is preferably for 4 to 8 (comprising 4 and 8).

In certain embodiments, the X of formula IV and V is preferably iodine.In certain embodiments, when P appearred in formula IV and V, then P was preferably poly-(ethylene glycol) unit.In formula IV and V, when f occurred, preferred F was from greater than 0.1 to about 0.3 (comprising 0.1 and 0.3), and more preferably from greater than 0.2 to about 0.25.As described in formula IV and the V, except as otherwise noted, otherwise all be according to dicarboxylic acids in the polymeric unit of formula IV and V or-C (=O)-the integral molar quantity report molfraction of unit, carboxylic acid ester monomer unit, free carboxy acid unit and poly-(aklylene glycol) unit.

The applicant has recognized that in the polymer that can be adjusted at preferred embodiment that the molfraction of free carboxylic acid unit (for example deaminizating tyrosyl-tyrosine (DT) unit) equally also can adjust the degraded/weight absorbability (resorbability) of embolotherapy compositions of the present invention.For example, the applicant has recognized that the polymer that contains the 35% free carboxy acid unit (molfraction is about 0.35) that has an appointment heavily absorbed in about 15 days about 90%, and this may be the clinical needs to the embolotherapy agent.Another kind of mode illustrates that the molfraction of carboxylic acid unit is high more, and this embolotherapy agent is short more in the intravital life-span of machine.The life-span that needs the embolotherapy agent in certain embodiments is several thoughtful some months, just needs the polymer of " g " value from about 0.2 to about 0.3.According to embodiment preferred, the molfraction of the recurring unit of derived from carboxylic acid unit among formula IV and the V, the scope of g be from greater than about 0.1 to about 0.3 (comprising 0.1 and 0.3), preferably from greater than about 0.2 to about 0.3.But the present invention also comprises usefulness wherein slow re-absorbed compositions of polymer manufacture and the device of g=0.

In some preferred embodiment of embolotherapy agent, the weight average molecular weight of used copolymer (Mw) is from about 20,000 to about 200,000, preferably from about 50,000 to about 150,000, and more preferably from about 75,000 to about 100,000.The scope from about 1.5 to about 2.5 of the polydispersity of copolymer (Pd) value and be about 2 usually.Can calculate the corresponding number-average molecular weight (Mn) of the copolymer that is used for the embolotherapy agent as mentioned above, its value is for about 10,000 to about 100,000, and more preferably from about 25,000 to about 75,000, and even more preferably from about 37,500 to about 50,000.By the molecular weight of gel permeation chromatography (GPC) measurement, need not further correction with respect to polystyrene standard.

Preparation method

Can be by the embolotherapy polymer of any method preparation formula IV.As noted above, the polymer that formula IV describes is optional to comprise cyclosubstituted diphenol Merlon or polyarylate, it contains the side group COOR that limits relative quantity ₁The diphenol unit of the diphenol acid esters unit of group, side group COOH group and poly-(aklylene glycol) unit.Therefore, the method for preparing the free carboxylic acid groups polymer comprises and makes poly-(aklylene glycol) and one or more cyclosubstituted diphenol monomeric compounds of desired proportions (comprise a certain amount of side group COOR that has ₁The monomeric compound of group, wherein subunit R ₁Be blocking group, preferred tertiary butyl ester base, this stoichiometrical amount is equivalent to the molfraction of required side group COOH group) polymerization, and then remove tert-butyl ester blocking group by deprotection reaction, form side group COOH group.

Similarly with poly-(aklylene glycol) of desired proportions with have side group COOR ₁The cyclosubstituted aliphatic-aromatic dihydroxy acid esters unit of group (comprises a certain amount of side group COOR that has ₁The monomeric compound of group, wherein subunit R ₁Be blocking group, preferred tertiary butyl ester base, this stoichiometrical amount is equivalent to the molfraction of required side group-COOH group) polymerization, deprotection preparation formula V poly-(amide carbonic ester) and poly-(esteramides) then.

At U.S. Patent number 5,099,060,5,587,507,5,658,995,5,670,602,6,120,491 and 6, disclose in 475,477 and be applicable to the preparation Merlon of preferred embodiment or the embodiment of polyarylate polymer method, these disclosed contents are attached to herein by reference.Other suitable method, relevant catalyst and solvent is known in the art and at Schnell, Chemistry and Physics ofPolycarbonates (chemistry of Merlon and physics), (Interscience, New York 1964) tell about in, its content of telling about is attached to herein by reference.

Also can be used on B.Kohn by Joachim, Durgadas Bolikal, Aaron F.Pesnell, Joan Zeltinger, Donald K.Brandom and Eric Schmid submitted on August 13rd, 2004, but pending trial at the same time still, (commonly owned) U.S. Patent application of owning together (proxy number (Attorney Docket No) P27, disclosed new polymerization prepares Merlon 286USA), this application exercise question is " Radiopaque Polymeric Medical Devices (radiopaque polymerization medical treatment device) ", and its disclosed content all is attached to herein by reference.In brief, this method comprises and makes diphenol monomer and Polyethylene Glycol be dissolved in the dichloromethane that contains 0.1M pyridine or triethylamine.Add the toluene solution of phosgene then with constant rate of speed, follow quencher, and polymer is carried out post processing.Then by stirring strong acid shape resin (AMBERLYST for example ^TM15) oxolane (THF) polymer solution is removed residual pyridine (if using pyridine).This method can be widely used in any Merlon of formula II.

The diphenol monomer methods that preparation is used to prepare polymer of the present invention is disclosed in U.S. Patent number 5,587,507 and 5,670,602 for example.Especially, such document discloses preparation non-ester deaminizating tyrosyl-tyrosine free carboxy acid (DT) and deaminizating tyrosyl-tyrosine ester, comprises the method for ethyl ester (DTE), butyl ester (DTB), hexyl ester (DTH), octyl group ester (DTO), benzyl ester (DTBn) and other ester.Can prepare the diphenol monomer that iodo-and bromo-replace, for example, two phenolic compounds couplings that one of them or two phenol rings replaced by iodine or bromine through any method disclosed herein together, or the diphenol that forms iodate or bromination by coupling through any suitable iodate or bromination process.

At U.S. Patent number 6,284, described preparation formula V poly-(esteramides) and poly-(amide carbonic ester) and they in 862 from the polymerized therein aliphatic-aromatic dihydroxy monomer method of (comprising the monomer that encircles iodinating or bromination), its disclosed content is attached to herein by reference.Disclosed poly-(amide carbonic ester) polymerization is applicable to method discussed above, and wherein the toluene solution of phosgene replaces blistered gaseous phosgene in the whole monomer solution.

Though above-mentioned any method all is applicable to this paper, but in preferred embodiments, when the Merlon that has the side group free carboxylic acid groups by the monomer with free carboxy acid's base (for example DT monomer) preparation, polyarylate, poly-(esteramides) and poly-(amide carbonic ester), the monomeric cross reaction of monomeric carboxylic acids group and copolymerization may take place.Therefore; in some preferred embodiment; the free acid monomer of the polymer of preferred embodiment by making the cyclosubstituted alkyl ester monomer of iodine or bromine and poly-(aklylene glycol) and temporary protection (wherein the functional group of free acid sheltered by the temporary protection group monomer) polymerization prepares; it also can have iodine or bromine ring substituents; to form Merlon, polyarylate, poly-(esteramides) or poly-(amide carbonic ester) polymeric unit; therefrom selectivity is removed the temporary protection group, to produce corresponding free carboxylic acid groups.This method can be widely used in expecting any polymer of the formula II that produces the side group free carboxylic acid groups.

Any suitable protection/deprotection method all is applicable to the polyplant of preparation preferred embodiment, for example comprises at United States Patent (USP) 6,120, and the method for describing in 491 that DTBn partly is converted into the DT part, it is attached to herein by reference.In U.S. Patent number 6,284,862 mentioned above, described similar approach, wherein had poly-(esteramides) and poly-(amide carbonic ester) of free carboxylic acid groups by the corresponding benzyl ester copolymer of hydrogenolysis.In other words, U.S. Patent number 6,120,491 method can extend to any polymer that expectation has the formula II of side group free carboxylic acid groups.In preferred embodiments; with the Application No. of owning together 60/601; 743 deprotection new method prepares the polymer of preferred embodiment; this application is submitted on August 13rd, 2004 by Joachim B.Kohn, Durgadas Bolikal, Aaron F.Pesnell, JoanZeltinger, Donald K.Brandom and Eric Schmid, and exercise question is " Radiopaque Polymeric Medical Devices (radiopaque polymerization medical treatment device) ".Selectivity is removed the tert-butyl ester blocking group on the polymer of hydrolytically unstable, and the novel polymer that replaces tert-butyl ester base with free carboxy acid's base is provided.

By the suitable solvent that polymer is dissolved in the acid that contains effective dose polymer is contacted with acid.Be dissolvable in water wherein any suitable inert solvents by the polymer of deprotection and all can be used for reactant mixture in this method previous step.The example of suitable solvent includes but not limited to chloroform, dichloromethane, THF, dimethyl formamide etc.In some preferred embodiment, solvent contains dichloromethane.

Can use any suitable weak acid according to this method, described weak acid can promote selectivity to remove the tert-butyl group blocking group on the hydroxy-acid group that polymer is provided by acidolysis.Some suitable faintly acid example comprises the acid of pKa from about 0 to about 4, comprises formic acid, trifluoroacetic acid, monoxone etc.In some preferred embodiment, this weak acid is trifluoroacetic acid.

Used faintly acid amount should be and adds behind the solvent the not maximum of impact polymer dissolubility.Wherein weak acid can be used as the solvent of dissolve polymer.In the present embodiment, preferred acid is formic acid.

Contact procedure, or its part, can by acidolysis effectively selectivity remove under any appropraite condition of tert-butyl group blocking group and carry out.Those skilled in the art need not the contact procedure that too much experiment can be easy to take any acid hydrolysis method to be used for preferred embodiment and remove the tert-butyl group with selectivity.For example, in some preferred embodiment, contact procedure is carried out under about 25 ℃ and about 1atm.

In light of the disclosure herein; those skilled in the art will be at an easy rate by the polymer of the hydrolytically unstable of the multiple band free carboxylic acid groups of corresponding polymer manufacture of the free carboxy acid recurring unit of containing tert-butyl group protection; and particularly the polymer of preferred embodiment for example is used for multiple medical treatment device.

Behind polymerization and the deprotection, can realize suitable post processing, be used for the embolotherapy compositions and the device of the method for preferred embodiment with preparation the polymer of preferred embodiment by any known method.For example, in some preferred embodiment, forming polymer is the microgranule that is applicable to compositions, is used for thromboembolism or inaccessible body cavity (preferred blood vessel).The example of preferred microgranule includes but not limited to, spherical particle, inhomogenous microgranule, small porous particle, solid microgranule, hollow minute particle geometrically, and to get rid of diameter be about 10 to about 3000 microns, and more preferably from about 40 to about 2,400 microns microgranule.In other embolotherapy product, polymer can form hydrogel and be used for thromboembolism or inaccessible body cavity.

Can adopt the conventional method of any preparation polymer particles, hydrogel etc. to be used for preferred embodiment.According to disclosing of this paper, those skilled in the art need not the embolotherapy product that too much experiment can be easy to prepare preferred embodiment.

For example, polymer particles normally prepares in the water that contains suitable surfactant by with meticulous gauge needle polymer being joined at the diluent (about 5wt%) that is used for the solvent of polymer (for example dimethyl sulfoxide (DMSO)).Selected gauge needle will determine the polymer particle diameter.Sedimentary polymer drops is separated and air-dry after filtration by Dropping funnel, then cryogrinding and to be chosen in the temperature (about 50 ℃) of raising dry to prevent to form agglomerate under vacuum.

Those skilled in the art need not too much experiment can make the polymer of using in the preferred embodiment be applicable to the known method of preparation embolotherapy polymer particles.The difference of particle size range will depend on the embolotherapy indication.Usually the scope of polymer particle diameter is about 10 to 3000 microns, and more generally be divided into following bunch: about 45 to about 90 microns (μ m), about 90 to about 190 μ m, about 190 to about 300 μ m, about 300 to about 500 μ m, about 500 is to about 710 μ m, about 710 to about 1,000 μ m, about 1,000 is to about 1,400 μ m, about 1,400 to about 2,000 μ m, about 2,000 is to about 2,400 μ m and about 2,400 to about 3,000 μ m.

Found that the polymer that contains PEG that is used for preferred embodiment has the surface characteristic that is very suitable for forming by meticulous gauge needle the micron sized particles.

Polymer formulations

In another preferred embodiment of above-described product and method, with at least a magnetic resonance reinforcing agent preparation of polymer and effective dose.In another preferred embodiment of above-described product and method, with at least a therapeutic agent and the preparation of at least a magnetic resonance reinforcing agent of polymer and effective dose.In another preferred embodiment of above-described product and method, with polymer and radiopaque medium preparation, such as but not limited to iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten and composition thereof.

Aspect preferred, inherent radiopaque, biocompatible, can be prepared into the spherical particle form by biological re-absorbed polymer.Perhaps, polymer can be prepared into inhomogenous geometrically particulate form.Spherical or inhomogenous geometrically microgranule can have the feature of hydrogel, and wherein this microgranule is porous, solid or hollow.The eliminating diameter range that microgranule can have is about 10 to about 5000 microns, preferred about 40 to 3000 microns and more preferably from about 45 to 2,400 microns.Microgranule can add one or more above disclosed therapeutic agents, magnetic resonance reinforcing agent and radiopaque medium.

The example of preferred magnetic resonance reinforcing agent includes but not limited to gadolinium salt for example gadolinium carbonate, Gadolinia., Gadolinium trichloride and composition thereof etc.In compositions that contains the magnetic resonance reinforcing agent and device, used the magnetic resonance reinforcing agent of the radiology imaging of q.s, this also is that those of ordinary skills need not too much experiment and can determine.

In certain embodiments, the embolotherapy compositions of preferred embodiment and device also contain radiopaque medium.In certain embodiments, embolotherapy compositions and device also contain the non-iodate of the useful formula II polymer that has wherein added radiopaque medium and compositions and the device that non-bromination analog forms.Embodiment preferred can comprise that formula II polymer is as such chemical compound analog.Radiopaque medium can add in the formula II polymer, to strengthen their radiopacity.The example of preferred radiopaque medium includes but not limited to iodine metal, organoiodine compound, bromine, barium sulfate, bismuth oxide, gold, platinum, tantalum, tungsten and composition thereof etc.

The embolotherapy method

According to preferred embodiment on the other hand, disclose by the embolotherapy product radiopaque, biocompatible by inherence disclosed herein, can biological re-absorbed polymer manufacture of effective dose is introduced body cavity, thus the method for thromboembolism body cavity.

In above describing another preferred embodiment of product, can prepare the inherent radiopaque compositions of heavily absorbing of biocompatible thromboembolism microgranule and be used for the special treatment of cancerous tumour and treatment again.Heavy absorbable preparation can be used for the treatment of multiple chemical therapy.And preferred embolotherapy product chemical action flexibly allows to adjust heavy absorption spectra, so that be easy to change in the endovascular time of staying by changing polymer architecture as detailed below.For example, the inhibition and generation of exceeding therapeutic agent is applied to cancerous tissue, and chemically being formulated as re-absorbed thromboembolism microgranule of the present invention can unite implantation with chemotherapeutant.For example under the situation of hepatocarcinoma, especially need be to the so concentrated attack of cancerous cell.Chemotherapeutant can be on the microgranule, in microgranule and/or be incorporated into microparticle polymer and/or discharging in the solution and introduce by polymer.Under this form, preparation can have its curative effect.Along with heavily absorbing of suppository and leading to again of blood vessel, then can repeat this method.Inherent radiopaque microgranule makes the release of described microgranule and therapeutic agent control better, and allows through multiple treatment approach, and this is impossible and represents that important treatment need not be met at present.

Therefore, according to preferred embodiment on the other hand, openly strengthen therapeutic agent to the method that the part of tissue discharges, comprise that (1) delivers medicine to the embolotherapy product radiopaque, biocompatible by inherence disclosed herein, can biological re-absorbed polymer manufacture that enough reduces the amount of tissue blood flow and organizes relevant blood vessel; (2) unite separately or with the embolotherapy product therapeutic agent is delivered medicine to blood vessel, discharge so that strengthen the part of therapeutic agent; (3) the embolotherapy product of first administration fully degrade allow to give described blood vessel once more after, repeat the dosing step of embolotherapy product and therapeutic agent.

According to another preferred embodiment of the present invention, the method for open thromboembolism body cavity.This method comprises introduces body cavity with the compositions of effective dose, and that said composition contains is biocompatible, can biological re-absorbed polymer, and wherein this polymer contains the radiopaque part that is selected from iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten and composition thereof.More preferably, this method comprises the step of the embolotherapy microgranule being introduced blood vessel, and that this microgranule contains is biocompatible, can biological re-absorbed polymer, and this polymer contains enough halogen atoms, so that the microgranule radiopaque.

In certain embodiments, when occlusion of bone tumors, vascular malformation, for example when hysteromyoma, tumor (being chemoembolization), hemorrhage (when for example accompanying hemorrhage wound) and arteriovenous malformotion, fistula and aneurysm, these can biological re-absorbed, inherent radiopaque suppository can by conventional delivery system for example guide catheter discharge.In another embodiment, these can discharge by unconventional delivery system by biological re-absorbed, inherent radiopaque suppository, for example be injected directly into body cavity, the beauty therapeutic to Aranea vein and/or cirso-is provided by syringe or other non-conduit system.In fact, be injected directly into surperficial vein place, polymerization embolotherapy product can not need radiopaque.Therefore, for for example application of beauty therapeutic Aranea vein and/or cirso-, using can be effectively according to the non-halogenated polymer of certain embodiments of the invention.Add therapeutic agent and/or be that the basis discharges therapeutic agent and also can help such beauty treatment clinical indication with the polymer.

Preferred embodiment also provides the method for thromboembolism body cavity, comprises introducing body cavity by the embolizing compositions of formula II polymer manufacture.According to some preferred embodiment, use the compositions that contains following one or more materials of effective dose: spherical particle, geometrically inhomogenous microgranule, small porous particle, solid microgranule, hollow minute particle, have the diameter range of eliminating be about 10 to about 3000 microns and more preferably from about 40 to about 2,400 microns microgranule, hydrogel and any combination thereof.The embolotherapy compositions is introduced body cavity all can be used for embodiment preferred with any suitable conventional method of thromboembolism body cavity.For example, available traditional method with PVA embolus introducing body cavity, but replace the PVA embolus with the compositions of embodiment preferred.

Therapeutic agent

According to the preferred embodiment of above-described embolotherapy product and method, described polymer can with at least a therapeutic agent (for example medicine and/or the biological preparation) preparation of the effective dose of enough performance selectivity curative effects.The term that this paper uses " medicine " comprises that expection can alleviate, treatment or prophylactic material, described material incentive special physiological (metabolism) reaction.The term that this paper uses " biological preparation " is included in any material that has structure and/or functional activity in the biosystem, includes but not limited to organ, tissue or based on the derivant of cell, cell, virus, carrier, originate from nucleic acid (animal natural and recombinant and synthetic and any sequence and size, plant, microorganism and virus), antibody, polynucleotide, oligonucleotide, cDNA ' s, oncogene, protein, peptide, aminoacid, lipoprotein, glycoprotein, fat, carbohydrate, polysaccharide, lipid, liposome or other cell component or organelle be receptor and part for example.The term that this paper uses " biological preparation " also comprises virus, serum, toxin, antitoxin, vaccine, blood, blood constituent or derivant, allergen product or similar product or the arsphenamine or derivatives thereof (or the organic arsenical of any trivalent) (according to Public Health Service Act (PHSA) (42U.S.C.262 (a)) 351 (a) chapters and sections) that is used to prevent, treat or cure human diseases or damage.The term that this paper uses " biological preparation " also can comprise 1) " biomolecule ", comprise by the organism of natural existence or reorganization, antibody, tissue or cell line producing and the synthetic analogues of biologically active peptide, protein, carbohydrate, vitamin, lipid or the nucleic acid of purification or such molecule; 2) " hereditary material " as used herein comprises nucleic acid (DNA (deoxyribonucleic acid) (DNA) or ribonucleic acid (RNA)), genetic constitution, gene, the factor, allele, operon, structural gene, regulator gene, operator, gene complement, genome, genetic code, codon, anticodon, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal extrachromosomal genetic constitution, plasmagene, plasmid, transposon, gene mutation, gene order, exon, intron; With 3) as used herein " biological preparation of processing ", for example treated cell, tissue or organ.Therapeutic agent also can comprise vitamin or mineral or other native element.

Preferred enough conduct (but being not limited to) chemotherapeutics of the amount of therapeutic agent, non-steroidal anti-inflammatory agent and/or steroidal class antiinflammatory promote biology and/or the physiological reaction that needs or influence some other states of thromboembolism tissue, for example attract the healing of the cell help thromboembolism body cavity of healing cell or those generation extracellular matrixs.

Can add therapeutic agent at least one zone to the embolotherapy product surface, or add in the product sometimes, thereby provide the part of such preparation to discharge.In some preferred embodiments, discharge therapeutic agent from the lip-deep thin polymer coating of polymer particles.In another kind preferably changes, discharge therapeutic agent by polymer coating.In other preferred embodiment of embolotherapy product, from least one zone or surface release therapeutic agent of embolotherapy product.In other preferred embodiment of embolotherapy product, because therapeutic agent mixes with the polymer blending or by other method well known by persons skilled in the art, so therapeutic agent is included in the embolotherapy product.

Therapeutic agent according to a preferred aspect of the present invention can be according to they site of action classification in the host, and for example they can be in the extracellular or at the specific membrane acceptor site, in plasma membrane, its effect of performance in Cytoplasm and in nucleus.Therapeutic agent can be polar or have clean negativity or positivity or neutral charge; They can be hydrophobic, hydrophilic or zwitterionic or with water high affinity be arranged.Interact by sustained release mechanism, disperse, with other preparation and to finish release by intravenous injection, atomizing or oral release.Also can finish release by applying a magnetic field, electric field or with ultrasonic.

The example of suitable therapeutic agent includes but not limited to chemotherapeutics, non-steroidal anti-inflammatory agent, steroidal class antiinflammatory.The example of preferred chemotherapeutics includes but not limited to that taxanes, taxinine, paclitaxel, Ramulus et folium taxi cuspidatae alcohol phenol, dioxy soften than star, cisplatin, amycin, bleomycin etc.Preferred nonsteroidal anti-inflammatory examples for compounds includes but not limited to aspirin, dexamethasone, ibuprofen, naproxen, Cox-2 inhibitor (for example rofecoxib, celecoxib and valdecoxib) etc.The example of preferred steroidal class anti-inflammatory compound includes but not limited to dexamethasone, beclometasone, hydrocortisone, prednisone etc.

One or more therapeutic agents of available any appropriate amount.Preferably, with the therapeutic agent with local curative effect of effective dose, those of ordinary skills need not too much experiment can easily determine this amount.

Embolotherapy product with surface coatings

The embolotherapy product removes can discharge therapeutic agent, for example the biopolymer on the releasing product is for example outside thrombosis collagen or fibronectin or the repercussive Phosphorylcholine, because the needs of some clinical effectiveness, the embolotherapy product can also can discharge or coating by biological re-absorbed polymer with the biologically in the predetermined promotion thromboembolism body cavity.Coating also can be used for sheltering the surface characteristic of the polymer that is used to comprise the embolotherapy microgranule.Coating can be selected from any non-halo or halogenated, biocompatible, can biological re-absorbed polymer, it can contain or not contain any poly-(aklylene glycol).These polymer can comprise the variation of composition, comprise homopolymer and heteropolymer, stereoisomer and/or such mixture of polymers.These polymer can comprise such as but not limited to Merlon, polyarylate, poly-(esteramides), poly-(amide carbonic ester), trimethylene carbonate, polycaprolactone, poly-dioxane, poly butyric ester, poly-hydroxyl valerate, polyglycolide (polyglycolides), polyactide and stereoisomer and copolymer, for example glycollide/lactide copolymer.In preferred embodiments, bolt base treatment product is used has the polymer coating of high absorption affinity to form to promote clot to Fibrinogen or plasma protein, for example when hemorrhage.For example poly-(DTE carbonic ester) and poly-(I2DTE carbonic ester) promotes the absorption of Fibrinogen high level; Coating also can contain positively charged polymer, and it attracts the negative charge of erythrocyte adventitia, thus the normal freezing process of bringing out body.In a further preferred embodiment, the embolotherapy product has the polymer coating of affinity with pair cell (for example Interstitial cell, fibroblast, stromal cell and parenchyma), to promote healing and to organize reinventing of heavily absorption and thromboembolism tissue, for example when the treatment hysteromyoma.In another preferred embodiment, the embolotherapy product is with repelling the polymer coating that special cells (for example known blood vessel turns to the capillary endothelium of tumor) is adhered to and/or bred, in this case, the polymer coating on the thromboembolism product can slow down or suppress by the further vascularization of occlusion of bone tumors.In a further preferred embodiment, the embolotherapy product is with attracting cell and/or promotion extracellular matrix molecule propagation and/or sedimentary polymer coating, and described molecule helps to form repair tissue (for example granulation tissue).This can comprise for example macrophage of attraction inflammatory cell, causes successfully healing and/or forming fibrous connective tissue.In preferred embodiments, the embolotherapy product is with the polymer coating that promotes tissue deposition, as when arteriovenous malformotion and the aneurysmal situation.

Following non-limiting example explanation some aspect of the present invention of then enumerating.These embodiment are not in order to limit its scope, but preferred embodiment is described for example.Unless otherwise indicated, all umbers and percentage number average by weight and all temperature all be degree centigrade.

Embodiment

Nomenclature and the abbreviation adopted

Below abbreviation is used to discern different iodinated compounds.TE represents tyrosine ethyl ester, and on behalf of desaminotyrosine and DTE, DAT represent deaminizating tyrosyl tyrosine ethyl ester.The polymer that the phosgenation (phosgenation) of poly-(DTE carbonic ester) expression DTE obtains." I " expression monoiod(in)ate (mono-iodination) (for example ITE represents the TE of monoiod(in)ate) before the abbreviation and the I before the abbreviation ₂Represent two iodate (I for example ₂DAT represents two iodinating DAT).In DTE, if " I " before D, if be meant iodine on the DAT and " I " after D, be meant iodine (DI for example on the tyrosine ring ₂TE represents the DTE that 2 iodine atoms are arranged on the tyrosine ring).Figure below further specifies this nomenclature.

The monomeric universal architecture of iodinating DTE

R ₁＝I，R ₂，R ₃，R ₄＝H；IDTE

R ₁，R ₂＝I，R ₃，R ₄＝H；I ₂DTE

R ₁，R ₂＝H，R ₃，R ₄＝I；DI ₂TE

R ₁，R ₃＝I，R ₂，R ₄＝H；IDITE

Heavily absorb test

Material of describing with Abramson etc. and method in vivo with in-vitro measurements depolymerization rate, " Small changes in polymer structure can dramatically increasedegradation rates:the effect of free carboxylate groups on the properties oftyrosine-derived polycarbonates (the little variation of polymer architecture can obviously increase degradation rate: the free carbonic acid ester group is to the influence of the Merlon characteristic of tyrosine-derived); " the 6th world's biomaterial meeting report, the 26th annual meeting of biomaterial association, summary 1164 (2000), its disclosure is attached to herein by reference.

Embodiment 1: the poly-(60%I of preparation ₂DTE-co-20%I ₂The DT-co-20%PEG2K carbonic ester)

With 18.3g (0.03mol) I ₂DTE, 6.38g (0.01mol) I ₂DTtBu, 20g (0.01mol) PEG2000 and 300ml dichloromethane add in the three neck round-bottomed flasks, and flask equipped has mechanical agitator, thermometer, reflux condenser and rubber septum.Obtain the clarification yellow solution by stirring.Add 15.1ml (0.15mol) pyridine.20% toluene solution (0.0576mol) of 30ml phosgene is placed in the gastight plastic injector,, it is added reaction flask with syringe pump through 3 hours.Aliquot by the gpc analysis reactant mixture is determined molecular weight.Need extra phosgene solution (at the most 10%) to reach the molecular weight that needs.With 110mlTHF and 10ml water quencher reactant mixture.Make polymer precipitation by the cold 2-propanol of 1.5L that reactant mixture is added in the high speed Waring blender.

2-propanol with two parts of 0.5L grinds the gelatinous polymer that generates.The granulated polymer microgranule of separate fine and dry in vacuum drying oven after filtration.For removing tert-butyl group blocking group, make polymer be dissolved in trifluoroacetic acid to obtain 20% solution., add the 2-propanol and make polymer precipitation after 4 hours at stirring at room solution, further grind with the 2-propanol then to remove too much TFA.Separated product washes and drying in vacuum drying oven with IPA after filtration.

It will be appreciated by those skilled in the art that can be by the polymer that replaces for the radiopaque bromine of the same preparation of iodine with bromo in initiation material.

Embodiment 2: the poly-(I of preparation ₂The DTE-co-2.5mole%PEG2K carbonic ester)

Be prepared as follows the I that contains 97.5% molar percentage ₂The polymer of the molecular weight 2000 of DTE and 2.5% poly-(ethylene glycol) (poly-(97.5%I ₂The DTE-co-2.5%PEG2K carbonic ester)).With 29.7g (0.0488mol) I ₂DTE, 2.5g (0.00125mol) PEG2000 and 215ml dichloromethane add three neck round-bottomed flasks, and flask equipped has mechanical agitator, thermometer, reflux condenser and rubber septum.Obtain the clarification yellow solution by stirring.To wherein adding 15.1ml (0.15mol) pyridine.20% toluene solution (0.0576mol) of 30ml phosgene is placed in the gastight plastic injector, with syringe pump it was added reaction flask through 3 hours.Aliquot by the gpc analysis reactant mixture is determined molecular weight.Add extra phosgene solution (at the most 10%) to reach the molecular weight that needs.With 110ml oxolane and 10ml water quencher reactant mixture.Make polymer precipitation by the cold 2-propanol of 1.5L that reactant mixture is added in the high speed Waring blender.2-propanol with two parts of 0.5L grinds the polymer that generates.The granulated polymer microgranule of separate fine and dry in vacuum drying oven after filtration.

Embodiment 3: form the embolotherapy microgranule

By making the 0.650g polymer be dissolved in the 5%w/w DMSO solution of the polymer of preparation embodiment 2 among the 12.35g DMSO.Add in the 300ml water by 10vol% aqueous solution (from concentrated solution) and to prepare precipitation solution the ALCONOX surfactant of 3ml.Precipitation solution is placed the 600ml container and slowly stir (＜100RPM).In the mode that drips the DMSO polymer solution is added precipitation solution with syringe by the 26-gauge needle and make the polymer drops precipitation.The 26-gauge needle is ground to any and makes silicone coating come off (buff off).This has reduced surface tension, makes and forms the more polymer of droplet when making up a prescription.

Polymer drops by filtering Dropping funnel precipitation separation is also air-dry.Then with about 20,000RPM in coffee grinder with the CO of ball and adding ₂Cryogrinding.Then the microgranule that will grind is in 50 ℃ of vacuum drying ovens, dried overnight under dynamic vacuum.With hands dry ball is sieved then and is following microgranule scope:

The 90-180 micron diameter

The 180-300 micron diameter

The 300-500 micron diameter

The 500-710 micron diameter

Embodiment 4: assessment or microgranule radiopacity in the body

The renal artery bed that is injected into pig by the embolotherapy microgranule with embodiment 3 is assessed its tangible radiopacity.Microgranule is by inserting the tube injection of renal artery bed tip.

With surpassing 0.035 " the 5F conduit of silk reach the renal artery bed.The conduit intravasation bed tip that profile is tiny is to provide the injection of more secondary selectivity (sub-selective).In film photographs benchmark angiogram.In beaker, mix with 5cc saline and suck the 3cc syringe with every approximately 300mg embolotherapy microgranule.The empty syringe of 3cc syringe that fills up and 1cc is connected in stop,threeway.By suspension is moved around between two syringes to prevent the microgranule sedimentation.

Piston apparatus is connected in 5-Fr (0.038 " ID) multipurpose catheter of placement.Injection injection device content strong fast.Repeat to load with the blood flow of injection operation and stop until target region.Confirm that by injection of contrast medium blood flow stops.

Syringe contents contains following particle mass ^*:

90-180um： 110mg

180-300um： 221mg

300-500um： 233mg ^*

500-710um： 122mg ^*

^*So because conduit stops up each definite amount of these magnitude range of not injection.

When not adding contrast-medium injection under fluoroscopy microgranule all develop.They appear on the fluoroscopy display screen short burst just as white under the black background, and are with contrast agent that the mode that occurs is similar, although contrast agent not in the injection solution.Vascular bed that injection of contrast medium has subsequently shown effective thromboembolism.

Shift out kidney and at the external x of being radiological survey X (Figure 1A and 1B).In Figure 1A, embolotherapy material (arrow) fills up in visible arteriorenal big branch (about fourth stage) (diameter is near 2 to 3 millimeters).Do not develop with the same artery that the polymer drops of buying on the market is filled at the x ray.In Figure 1B, be also shown in little renal artery (arrow) and fill up the 100-300 microparticles.

These figure illustrate that the inherent radiopaque microgranule of preferred embodiment produces visible cast on the x ray, and it is evenly distributed in arteriorenal different branch basically.Quite dangerous also must being close to of thromboembolism operation ideally controlled microgranule release.The microgranule that develops on the x ray better controls than the microgranule that do not develop, because can monitor their expansion in real time, thereby determines to discharge terminal point more accurately.Immediate feedback to Particle Distribution also helps to calibrate particle size distribution, to realize more accurate release.The microgranule of preferred embodiment also helps heavily to absorb the indirect evaluation operation that has replaced biopsy method and used at present by x ray monitoring thromboembolism tissue and polymer afterwards.

The polymer pole of above-mentioned proof preferred embodiment promises to be inherent radiopaque, impermanent bio-compatible embolotherapy agent.Though with the amount that is less than standard, with Dynamic Fluorescence perspective develop still can efficiency confirmed thromboembolism, clearly discerning with the x ray then has inherent radiopaque corpuscular eclipse in the vascular bed.Should be noted that because contrast agent is just injected before thromboembolism and afterwards, so the radiopacity of microgranule is the result of polymer internal characteristics.

Embodiment 5: external medicament elution kinetics

This is in order to determine the drug release of some polymer, based on 37 ℃ under the condition of " sink (sinkings) " plysiochemical feature and solvent extraction need, and stir with assurance solution even.Can be on the surface on thin polymer film surface to the therapeutant in the polymer (seeing the following form) (for example medicine) coating, and its can before press mold, implant polymer or and polymer mixed, it imitates treatment thromboembolism product in these tests.

Adjust the thin film size to adapt to drug load and quantitative detection limit.Typical operation can comprise that chemical compound extracts or precipitation, and is then quantitative with high performance liquid chromatography (HPLC).Use for example phosphate buffered saline (PBS) (PBS) of 3% bovine serum albumin (BSA) or 35%Tween 20 of suitable dissolve medium.Can measure dissolubility from 24 hours to 28 days.After the dissolving, the medicament contg of analysed film and/or culture medium.Calculate the dissolution rate of every kind of medicine with the mass balance of HPLC algoscopy mensuration.The amount that is used in each point in time measurement of all dissolving spectrums is calculated dissolved percent.

Table 2

The test summary of the Merlon coating of tyrosine-derived

Poly-(100%DTE) carbonic ester
Poly-(100%DTE) carbonic ester	Poly-(90%DTE-co-10%DT) carbonic ester ¹
Poly-(76%DTE-co-24%DT) carbonic ester ²	Poly-(90%DTE-co-10%DT) carbonic ester ¹
Poly-(76%DTE-co-24%DT) carbonic ester ²	Poly-(67%DTE-co-33%DT) carbonic ester
Poly-(95%DTE-co-5%PEG 1K) carbonic ester	Poly-(67%DTE-co-33%DT) carbonic ester
Poly-(95%DTE-co-5%PEG 1K) carbonic ester	Poly-(97.5%I ₂DTE-co-2.5%PEG 2K) carbonic ester
Poly-(77.5%I ₂DTE-co-20％I ₂DT-2.5%PEG 2K) carbonic ester	Poly-(97.5%I ₂DTE-co-2.5%PEG 2K) carbonic ester
Poly-(77.5%I ₂DTE-co-20％I ₂DT-2.5%PEG 2K) carbonic ester	Poly-(67.5%I ₂DTE-co-30％I ₂DT-2.5%PEG 2K) carbonic ester
Poly-(70%I ₂DTE-co-20％I ₂DT-10%PEG 2K) carbonic ester	Poly-(67.5%I ₂DTE-co-30％I ₂DT-2.5%PEG 2K) carbonic ester
Poly-(70%I ₂DTE-co-20％I ₂DT-10%PEG 2K) carbonic ester	Poly-(80%I ₂DTE-co-20%PEG 2K) carbonic ester

¹Testing drug eluting in the thin film that the thin film and the medicine of coating are implanted

²Testing drug eluting in the thin film that medicine is implanted only

Coating has proved the eluting of medicine at polymer surfaces or the medicament elution implanting polymer and be pressed into the different polymer (table 2) of thin film.Fig. 2 shows the eluting of embolotherapy agent from poly--DTE-carbonic ester.Other is biocompatible can to can be used for this purpose by biological re-absorbed polymer.In the example of Merlon, can be by on the DAT ring, cutting out (tailored) medicament elution with the iodine modified polymer or with the main chain that PEG adds polymer.

Embodiment 6: the poly-(I of preparation ₂DTE-co-2.5mole%PEG _2kAdipate ester)

With diphenol I ₂DTE (2.97g, 4.87mmol), PEG2000 (0.250g, 0.125mmol) and adipic acid (0.731g, 5.04mmol) and the DPTS (dimethyl list pyridine radicals-tosilate, catalyst) of 0.4g weigh and add in the 100ml brown bottle of band Teflon lid.The 40ml dichloromethane is also added in the bottle, and guarantee that the lid lid is tight.Shook bottle 10-15 minute, and added 2.5ml (2.02g, 16mmol) diisopropyl carbodiimides and continued to shake 2 hours then.Take out the aliquot of sample and suitably use gpc analysis after the processing.The Mw that needs is about 100,000.In case reach the Mw that needs, the 2-propanol with 200ml adds in the reactant mixture while stirring.The collecting precipitation thing is also dry in nitrogen current.Make precipitate be dissolved in the 20ml dichloromethane then and also use the 200ml methanol extraction.Dry polymer under nitrogen is then dry in vacuum drying oven then.

Embodiment 7: poly-(60%I ₂DTE-co-20%I ₂DT-co-20%PEG _2kAdipate ester) polymerization

With glycol (diolic) composition (1.83g, 3.00mmolI ₂DTE, 0.638g, 1.00mmolI ₂DTtB and 2.000g 1.00mmol PEG2000) and diacid (0.731g, 5mmol adipic acid) and 0.4g DPTS weigh and add in the 100ml brown bottle of band Teflon lid.The 40ml dichloromethane is also added in the bottle, and guarantee that the lid lid is tight.Shook bottle 10-15 minute, and added 2.5ml (2.02g, 16mmol) diisopropyl carbodiimides and continued to shake 2 hours then.Take out the aliquot of sample and suitably use gpc analysis after the processing.The Mw that needs is about 100,000.In case reach the Mw that needs, the 2-propanol with 200ml adds in the reactant mixture while stirring.The collecting precipitation thing is also dry in nitrogen current.Make precipitate be dissolved in the 20ml dichloromethane then and also use the 200ml methanol extraction.Dry polymer under nitrogen is then dry in vacuum drying oven then.

Deprotection: make the polymer of generation be dissolved in trifluoroacetic acid (10%W/w/v) and stir and spend the night.Second day, polymer is precipitated in isopropyl alcohol with blended agitator.Grind polymer twice with fresh isopropyl alcohol then, the filter with frit between the flushing filters.Dry polymer under nitrogen is then dry in vacuum drying oven then.

Embodiment 8: the poly-(I of preparation ₂DTE-co-2.5mole%PEG _2kSebacate)

With diphenol I ₂DTE (2.98g, 4.89mmol), PEG2000 (0.250g, 0.125mmol) and decanedioic acid (1.01g, 5.00mmol) and the DPTS of 0.4g weigh and add in the 100ml brown bottle of band Teflon lid.The 40ml dichloromethane is also added in the bottle, and guarantee that the lid lid is tight.Shook bottle 10-15 minute, and added 2.5ml (2.02g, 16mmol) diisopropyl carbodiimides and continued to shake 2 hours then.Take out the aliquot of sample and suitably use gpc analysis after the processing.The Mw that needs is about 100,000.In case reach the Mw that needs, the 2-propanol with 200ml adds in the reactant mixture while stirring.The collecting precipitation thing is also dry in nitrogen current.Make precipitate be dissolved in the 20ml dichloromethane then and also use the 200ml methanol extraction.Dry polymer under nitrogen is then dry in vacuum drying oven then.Embodiment 9: preparation triiodide DTE (I ₂DITE):

By using I ₂DAT replaces DAT and ITE to replace TE, adopts those disclosed in the literature operations to prepare triiodide monomer (I ₂DITE).Typically be operating as, in 1 liter of round-bottomed flask, 85.8g (0.255mol) Iotyrosine I 131 ethyl ester (ITE), 104g (0.250mol) I ₂DAT and 3g (0.025mol) I-hydroxybenzotriazole stirs with the 500ml oxolane.The cooling flask is to 10-18 ℃ in ice-water bath, adds 50g (0.255mol) EDCI and stirs 1 hour at 15-22 ℃.Then ambient temperature stirred reaction mixture 5 hours.Reactant mixture is concentrated into 250m, and 1 stirs with 1L water and 1L ethyl acetate then.Separate the water layer of lower floor and discharge with separatory funnel.Successively with each 500ml flushing organic layer of 0.4M HCl, 5% sodium bicarbonate solution and 20% sodium chloride solution.After dried over sodium sulfate, organic layer simmer down to slurry is also used the hexane agitation grinding.Obtain pale solid.With HPLC and ¹HNMR characterizes product.

Embodiment 10: preparation tetraiodo DTE (I ₂DI ₂TE)

(16.4g 0.046mol) is dissolved in 95% ethanol of 300ml to make DTE.While stirring 46g (0.19mol) PyICl is added in the solution.Agitating solution 2 hours, solid slowly dissolves the generation yellow solution during this period.In 1 premium on currency through while stirring its adding being contained 10g sodium thiosulfate in 30 minutes.Separate pale solid and separate after filtration and with several parts of deionized water rinsings.

Wet agglomerate (approximately 150g) is heated until its dissolving with 1.5L ethanol, be cooled to room temperature then.It is also also dry with 95% alcohol flushing to separate the white crystalline solid that forms after filtration.Obtain 32g (81%) desciccate.With HPLC and ¹H NMR characterizes product.

Embodiment 11: the triiodide polymer that contains poly-(ethylene glycol)

Be prepared as follows and contain 80% mole percent I ₂The polymer of the molecular weight 2000 of DITE and 20% poly-(ethylene glycol) (poly-(80%I ₂The DITE-co-20%PEG2K carbonic ester)).With 6.0g (8.1mmol) I ₂DITE and 4.1g (2.05mmol) PEG2000 and 66ml dichloromethane and 3.1ml (39mmol) pyridine add in the three neck round-bottomed flasks, and flask equipped has mechanical agitator, thermometer, reflux condenser and rubber septum.Obtain the almost colourless solution of clarification by stirring.20% toluene solution (12.5mmol) of 6.5ml phosgene is placed in the gastight plastic injector, by syringe pump it was added reaction flask with 3 hours then.By determining molecular weight with the aliquot of gpc analysis reactant mixture.Obtain molecular weight and be equivalent to 200,000 polystyrene.With 55ml oxolane and 5ml water quencher reactant mixture.Make polymer precipitation by reactant mixture being added in the cold 2-propanol of 1L in the high speed Waring blender.2-propanol with two parts of 0.5L grinds the gelatinous polymer that generates.The granulated polymer microgranule of separate fine and dry in vacuum drying oven after filtration.

Embodiment 12: the tetraiodide polymer that contains poly-(ethylene glycol)

Be prepared as follows and contain 80% mole percent I ₂DI ₂The polymer of the molecular weight 2000 of TE and 20% poly-(ethylene glycol) (poly-(80%I ₂DI ₂The TE-co-20%PEG2K carbonic ester)).With 1.55g (1.80mmol) I ₂DI ₂TE and 0.9g (0.45mmol) PEG2000 and 20ml dichloromethane and 0.68ml (8.6mmol) pyridine add in the three neck round-bottomed flasks, and flask equipped has mechanical agitator, thermometer, reflux condenser and rubber septum.Obtain the almost colourless solution of clarification by stirring.20% toluene solution (2.7mmol) of 1.4ml phosgene is placed in the gastight plastic injector, by syringe pump it was added reaction flask with 3 hours then.By determining molecular weight with the aliquot of gpc analysis reactant mixture.Obtain molecular weight and be equivalent to 25,000 polystyrene.With 18ml oxolane and 2ml water quencher reactant mixture.Make polymer precipitation with magnetic stirring apparatus by reactant mixture being added in the cold 2-propanol of 200ml in the beaker.2-propanol with 200ml grinds the gelatinous polymer that generates.The polymer that obtains still is a colloid, and this may be because the high cause of molecular weight low and poly-(ethylene glycol) content.

Fig. 3 a-b show radiopaque can biological re-absorbed two iodate and the x ray of the polycarbonate film of triiodide tyrosine-derived relatively.Poly-(I ₂DITE-co-20%PEG2k) optical density of carbonic ester 114 micron films is equivalent to people's bone.Poly-(80%I ₂DTE-co-20%PEG2k) optical density of carbonic ester is lower.

Embodiment 13: Fibrinogen is to the absorption of polymeric surface

With the quartz crystal microbalance of band loss monitoring (QCM-D, Q-Sense AB, model D300, Goeteborg Sweden) measures the time course of human fibrinogen to the test polymer surface adsorption.

QCM-D can be used for the instant quality of measuring the liquid material that adheres to the surface for the gravity test technology.The increase that is incorporated into quartz surfaces weight causes crystalline frequency of oscillation to reduce.And this device can be measured the loss of being brought out by the quality of surface adsorption and change.

Make quartz crystal (Q-Sense, Cat#QSX-301) spin coating with polymer solution (1% polymer is in dichloromethane).(Q-Sense is Cat#QSX-304) with making comparisons to comprise the quartz crystal of using thin layer rustless steel coating that can buy on the market.For beginning representational experiment, crystal inserted in the QCM-D instrument and under 37 ℃ in phosphate-buffered saline (PBS) incubation.After reaching steady baseline, frequency and loss that injection fibrinogen solution and instant recording are brought out by the absorption quality change.The incubation fibrinogen solution is until reaching in conjunction with saturated (show as frequency and the loss value does not have further significant change).All rinsing steps all use not the PBS of fibrinogen to remove the unconjugated Fibrinogen of sensor surface after the adsorption process.The human fibrinogen is available from Calbiochem (Cat#341576) and be diluted to final concentration 3mg/ml in PBS.All experiments are all carried out three parts, and standard deviation is less than 12% (standard error average).

Can re-use 10 times at the most by following cleaning method quartz crystal: use by H ₂O ₂(30%), NH ₄The cleaning solution that OH and ultra-pure water are formed with 1: 1: 5 ratio handle quartz crystal (80 ℃, 15min).With ultra-pure water fully wash crystal and dry up with nitrogen thereafter.At last, crystal be exposed to UV and ozone 15 minutes (the UVO cleaner, Jelight Company, Irvine, CA, USA).

The different stent polymer formulations of table 3 general introduction are about the comparative evaluation of external Fibrinogen absorption.Fibrinogen is main blood protein.With artificial surfaces that blood contacts on fibrinogenic degree of absorption generally be counted as the reliability index whether described surface tends to blood compatibility.As the universal law known to the skilled of biomedical engineering field, the level that Fibrinogen is adsorbed in material is low more, and the blood compatibility of this material is high more.

Table 3

Frequency displacement in-vitro measurements Fibrinogen by quartz crystal microbalance (Q-sense) is in the level relatively of test surfaces absorption

With reference to table 3, the clinical material of use of project 1 (rustless steel) expression, known its thrombosis level is low and have a blood compatibility of getting well.Rustless steel in contrast and have an acceptable Fibrinogen adsorption levels.Project 2 in the table 3 is Dacron, a kind of known thrombosis material, and its clinical application only limits to vascular applications.Dacron Fibrinogen adsorption levels in all test materials is the highest.Project 3 is poly-(DTE carbonic esters), the basic material in the polymer that formula I represents.This polymer of the high prompting of its Fibrinogen adsorption levels is not the candidate material likely that is used to contact the medical treatment device of blood.Add iodine (project 4) separately or add DT unit's (project 5) separately and help to reduce the Fibrinogen adsorption levels.

Above-mentioned proof still can satisfy under the PEG level that the polymer of mechanical strength needs are provided, and adds iodine, DT and PEG simultaneously and causes Fibrinogen absorption obviously to descend.Under this universal law, the applicant also provides another unexpected discovery now: contrast project 6 and 7 shows that the atomic little increase of PEG amount in the polymer composition can have not obvious and uncertain influence to protein adsorption.Though Fibrinogen is enough low to the absorption of polymer composition 6, make said composition become candidate material likely and be used for the less application of thrombosis, but the polymer composition that the few polymer composition 7 to 0.9mol%PEG of interpolation provides seems better than the rustless steel of clinical usefulness according to its blood compatibility.

Another significant design principle that polymer composition 7 explanation in the table 3 is confirmed first by the applicant: when iodine and PEG followed the polymer composition that adding formula I covers, the PEG of extremely low molar ratio just was enough to obviously reduce Fibrinogen surface adsorption level.In conjunction with previously described iodine and the PEG influence to the polymer composition mechanical property, the applicant has found to optimize simultaneously the method for the machinery and the biological characteristics of polymer.Therefore, can thrombosis level (being hemocyte and protein and other affinity that increases and reduce with the relevant molecule of thrombosis) be designed into the embolotherapy product by the level relatively that changes iodine and percentage ratio PEG, DT and DTE.

The embolotherapy product can discharge or coating the scheduled biologically that promotes in the required thromboembolism body cavity of some clinical effectiveness of these polymer with other biocompatible can be biological re-absorbed polymer in addition.Coating can be selected from any biocompatible can biological re-absorbed polymer, described polymer can comprise any of following material or its combination: the Merlon of tyrosine-derived, the polyarylate of tyrosine-derived, polyesteramide, polyamide carbonic ester, trimethylene carbonate, polycaprolactone, poly-dioxane, poly butyric ester and poly-hydroxyl valerate, polyglycolide, polyactide and stereoisomer thereof and be used for any biocompatible copolymer that can biological re-absorbed polymer, for example glycollide/lactide copolymer.Coating can cause and/or suppress biologically.

In one embodiment, most of embolotherapy products (being microgranule in this embodiment) can contain high percentage ratio PEG in the iodate polycarbonate compositions, discharge so that pass through the conduit part with microgranule compressibility and the elasticity that need to obtain.Microgranule also can contain coating that Fibrinogen absorbs, and for example chitosan or poly-(DTE carbonic ester) are used for the thrombosis of needs.Such microgranule can be by any method known to those skilled in the art and the technology preparation, for example be used for pharmaceuticals industry standard powder coating method, be used for the top coating method (its available pharmaceutical drying device and spray coating device and soak coating etc.) of medicine equipment industry.

The such method and the example of technology are disclosed in: Ravina etc., " ArterialEmbolization to Treat Uterine Myomata (artery embolization for treatment hysteromyoma), " Lancet, 346,671-672 (Sep.9,1995); Hilal etc., " Therapeutic percutaneousembolization for extra-axial vascular lesions of the head; neck; and spine (the outer vascular lesion of axle of percutaneous embolotherapy head, neck and spinal column); " J.Neurosurg 43 (3), 275-287 (1975); Solomon etc., " Chemoembolization ofhepatocellularcarcinoma with cisplatin; doxorubicin; mitomycin-C; ethiodol; andpolyvinyl alcohol:prospective evaluation of response and survival in a U.S.population (usefulness cisplatin, doxorubicin, Mitomycin-C, ethiodized Oil and polyvinyl alcohol chemoembolization hepatocarcinoma: the reaction of perspective assessment American population and survival rate); " J.Vasc IntervRadiol., 10 (6), 793-8June 1999); Tseng etc., " Angiographicembolization for epistaxis:a review of 114 cases (the angiography thromboembolism of epistaxis: 114 examples are looked back)." Laryngoscope, 108 (4 Pt 1), 615-9 (April 1998); Kerber etc., " Flow-controlled therapeutic embolization:a physiologic and safetechnique (the treatment thromboembolism of flow-control: physiology and safe method); " Am.J.Roentgenol., 134 (3), 557-61 (March 1980); Latchaw etc., " PolyvinylFoam Embolization of Vascular and Neoplastic Lesions of the Head, Neckand Spine (the polyethylene thromboembolism of head, neck and spinal column blood vessel and neoplastic lesion), " Radiology, 131,669-679 (1978); With Tadavarthy etc., " Polyvinyl Alcohol (Ivalon) A New Embolic Material (a kind of new embolism materials of polyvinyl alcohol (Ivalon)); " Am.J.Roentgenol.:Radium Therapy andNuclearMedicine, 125,609-616 (1975).

Though described many preferred embodiments of the present invention and variation thereof in detail, those skilled in the art obviously also will know other modification and using method very much.Therefore, should be appreciated that can make being equal to of different application, modification and replacement substitutes and do not deviate from theme of the present invention or claim scope.

The document of quoting

1) 6,475,477 radiopaque polymer biomaterials

2) 6,358,228 comprise the vascular occluding device of many asymmetrical fibres

3) 6,337,198 are used for the porous polymer support of organizational project

4) 6,319, the copolymer of the polyarylate of 492 tyrosine-based and poly-(alkylene oxide)

5) 6,284,862 derived from the monomer of hydroxy acid and with the polymer of its preparation

6) RE37, the deutero-diphenol monomer of 160 synthetic hydroxyphenylaminopropionic acids

7) 6,120,491 biodegradable anionic polymers derived from aminoacid L-tyrosine

8) 6,117,157 spiral helicine embolic coils

9) 6,103,255 are used for the porous polymer support of organizational project

10) 6,048, the copolymer of the polyarylate of 521 tyrosine-based and poly-(alkylene oxide)

11) 5,877,224 polymeric pharmaceutical preparatioies

12) 5,851,508 are used for the compositions of vascular embolization

13) 5,670, the deutero-diphenol monomer of 602 synthetic hydroxyphenylaminopropionic acids

14) 5,658, the copolymer of the Merlon of 995 tyrosine-based and poly-(alkylene oxide)

15) 5,587, the deutero-diphenol monomer of 507 synthetic hydroxyphenylaminopropionic acids

16) 5,317,077 contains the polyarylate of natural amino acid 1-tyrosine derivative

17) 5,216,115 contain the polyarylate of natural amino acid L-tyrosine derivative

18) 5,198, but the polymer of the deutero-bio-absorbable of 507 synthesizing amino acids

19) 5,099, but the polymer of the deutero-bio-absorbable of 060 synthesizing amino acid

20) 4,819,637 artificial blood vessel's thromboembolism system and operative installationss thereof

21) 4,441,495 discerptible balloon catheter device and usings method

Other publication

1) Interventional Radiology (interventional radiology), Dandlinger etc., ed., Thieme, N.Y., 1990:295-313.

2) " Polyvinyl Alcohol Foam Particle Sizes and ConcentrationsInjectable through Microcatheters (can by the polyvinyl alcohol foam particle diameter and the concentration of microtubular injection) ", JVIR 1998; 9:113-115

3) " Polyvinyl Alcohol Particle Size and Suspension Characteristics (polyvinyl alcohol particle diameter and suspension feature) ", American Journal of NeuroradiologyJune 1995; 16:1335-1343.

4) Ravina etc., Arterial Embolization to Treat Uterine Myomata (artery embolization for treatment hysteromyoma), Lancet, Sep.9,1995; Vol.346, pp.671-672.

5) " Therapeutic percutaneous embolization for extra-axial vascularlesions of the head; neck; and spine (the outer vascular lesion of axle of percutaneous embolotherapy head, neck and spinal column) ", Hilal etc., J.Neurosurg.43 (3), 275-287 (1975).

6) " Chemoembolization of hepatocellular carcinoma with cisplatin; doxorubicin; mitomycin-C; ethiodol, and polyvinyl alcohol:prospectiveevaluation of response and survival in a U.S.population (usefulness cisplatin, doxorubicin, Mitomycin-C, ethiodized Oil and polyvinyl alcohol chemoembolization hepatocarcinoma: the reaction of perspective assessment American population and survival rate).”J Vasc Interv Radiol.1999Jun；10(6)：793-8.Solomon B，Soulen MC，Baum RA，Haskal ZJ，Shlansky-GoldbergRD，Cope C.

7) " Hydrogel embolic agents.Theory and practice of adding radio-opacity (hydrogel suppository suppository.Increase the principle of radiopacity and put into practice).”Link DP，Mourtada FA，Jackson J，Blashka K，Samphilipo MA.Invest Radiol.1994Aug；29(8)：746-51.

8) " Angiographic embolizationfor epistaxis:a review of 114cases (the angiography thromboembolism of epistaxis: 114 examples are looked back).”Tseng EY，Narducci CA，WillingSJ，Sillers MJ.，Laryngoscope.1998Apr；108(4 Pt 1)：615-9.

9) " Supraselective embolization in intractable epistaxis:review of 45cases (the super-selective thromboembolism of intractable epistaxis: 45 examples are looked back).”Moreau S，De RugyMG，Babin E，Courtheoux P，Valdazo A.，Laryngoscope.1998 Jun；108(6)：887-8.

10) " Polyvinyl alcohol particle size and suspension characteristics (polyvinyl alcohol particle diameter and suspension feature) ", Derdeyn CP, Moran CJ, Cross DT, Dietrich HH, Dacey RG Jr., AJNR Am J Neuroradiol.1995Jun-Jul; 16 (6): 1335-43.

11) " Polyvinyl alcohol foam paricle sizes and concentrationsinjectable through microcatheters (can by the polyvinyl alcohol foam particle diameter and the concentration of microtubular injection). ", Barr JD, Lemley TJ, Petrochko CN., J Vasc Interv Radiol.1998Jan-Feb; 9 (1Pt 1): 113-8.

12) " Flow-controlled therapeutic embolization:a physiologic andsafe technique (the treatment thromboembolism of flow-control: physiology and safe practice) ", Kerber CW., AJR Am J Roentgenol.1980 Mar; 134 (3): 557-61.

13) " Polyvinyl alcohol foam:prepackaged emboli for therapeuticembolization (polyvinyl alcohol foam: be used for the treatment of the pre-packing embolus of learning thromboembolism) ", KerberCW, Bank WO, Horton JA., AJR Am J Roentgenol.1978 Jun; 130 (6): 1193-4.

14) Interventional Radiology (interventional radiology), Dandlinger etc., Thieme, N.Y., 1990:295-313.

15) " Polyvinyl Alcohol Foam Particle Sizes and ConcentrationsInjectable through Microcatheters (can by the polyvinyl alcohol foam particle diameter and the concentration of microtubular injection) " JVIR 1998; 9:113-115.

16) " Polyvinyl Alcohol Particle Size and Suspension Characteristics (polyvinyl alcohol particle diameter and suspension feature) ", American Journal of NeuroradiologyJune 1995; 16:1335-1343.

17) " Biodegradable microspheres of poly (DL-lactic acid) containingpiroxicam as a model drug for controlled release via the parenteral route (containing the biodegradable microsphere of piroxicam conduct) " through poly-(the DL-lactic acid) of the model drug of parenteral approach sustained release, Lalla JK, Sapna K., J Microencapsul.1993Oct-Dec; 10 (4): 449-60.

18) " Gelfoam embolization:a simplified technique (Gelfoam thromboembolism: the technology of simplification) ", Bank WO, Kerber CW., AJR Am J Roentgenol.1979Feb; 132 (2): 299-301.

19) R.E.Latchaw, L.H.Gold: " Polyvinyl Foam Embolization ofVascular and Neoplastic Lesions of the Head; Neck and Spine (blood vessel and the neoplastic lesion of polyethylene thromboembolism head, neck and spinal column); " Radiology, 131 (1979), 669-679.

20) S.M.Tadavarthy, J.H.Moller, K.Amplatz: " Polyvinyl Alcohol (Ivalon) A New Embolic Material (a kind of new embolus material of polyvinyl alcohol (Ivalon)); " American Journal of Roentgenology:Radium Therapy and NuclearMedicine, 125 (1975), 609-616.

21) Kerber, CW, " Catheter therapy:fluoroscopic monitoring ofdeliberate embolic occlusion (catheter treatment: the perspective monitoring of meticulous embolus obturation). " Radiology.1977Nov; 125 (2): 538-40.

22) Horak etc., " Hydrogels in endo-vascular embolization.IV.Effectof radiopaque spherical particles on the living tissue (the radiopaque spherical particle of hydrogel .IV. that the vascular peg stay plug forms is to living tissue influence).”Biomaterials 9，367-371，1988.

23) Horak, D etc. " Hydrogels in endovascular embolization.III.Radiopaque spherical particles; their preparation and properties (the radiopaque spherical particle of hydrogel .III. that the vascular peg stay plug forms, their preparation and characteristic).”Biomaterials 8，142-145，1987.

Claims

1. embolotherapy product, it comprise contain biocompatible, can biological re-absorbed polymer and the optional microparticle formulation that comprises its stereoisomer, the halogen atom that wherein said polymer contains sufficient amount makes the embolotherapy product have inherent radiopacity.

2. the embolotherapy product of claim 1, wherein said polymer also contains homopolymer, heteropolymer or its mixture.

3. the embolotherapy product of claim 1, wherein said polymer contain the unit that one or more formula I describe:

Wherein X=I or Br; Y1 and Y2 independently=0,1,2,3 or 4;

Wherein f 0 and less than 1 between; G comprises 0 and 1 between 0 and 1; And f+g comprises 0 and 1 between 0 and 1;

Wherein A is:

R wherein ₁Be H or contain 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N independently;

R wherein ₃Be saturated or unsaturated, replacement or unsubstituted alkyl, aryl or alkaryl, they contain 18 carbon atoms and 0 to 8 hetero atom that is selected from O and N at the most;

Wherein R and R ₂Be independently selected from:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a; R wherein ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n; Wherein a and n between 0 and 8, comprise 0 and 8 independently; J ₁And J ₂Be Br or I independently; And R wherein ₂The Q Q that contains free carboxylic acid groups and each R be independently selected from hydrogen and carboxylate and amide, wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

4. the embolotherapy product of claim 3, wherein R and R ₂Be selected from:

Wherein for each R, R ₁Independently for the alkyl that contains 0 to 5 heteroatomic from 1 to 18 carbon atom that is selected from O and N and for each R ₂, R ₁Be H;

Wherein j and m are 1 to 8 integer independently, comprise 1 and 8; With

Wherein Z is O or S independently.

5. the embolotherapy product of claim 1, wherein said polymer contain the unit that one or more formula II describe:

Wherein the X of each polymer unit is Br or I independently, and Y comprises 1 and 4 between 1 and 4, and R ₄Be 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most.

6. the inspection plug of claim 5 treatment product, wherein all X groups all be ortho-orientation and Y be 1 or 2.

7. the embolotherapy product of claim 5, wherein R ₄Be alkyl.

8. the embolotherapy product of claim 7, wherein R ₄Have following structure:

The R of each unit wherein ₉Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most; And R ₅And R ₆Be selected from hydrogen independently of one another and contain 18 carbon atoms and 0 to 8 heteroatomic alkyl that is selected from O and N at the most.

9. the embolotherapy product of claim 8, the wherein R of at least one unit ₉Contain side group-COOR ₁Group is wherein for each unit that has side group, subunit R ₁Be hydrogen or contain 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N independently.

10. the embolotherapy product of claim 8, wherein each R ₉Have following structure independently:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a, wherein R ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n, wherein a and n between 0 and 8, comprise 0 and 8 independently; And J ₁And J ₂Be Br or I independently; And Q is selected from hydrogen, free carboxylic acid groups, and carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

11. the embolotherapy product of claim 8, wherein each R ₉Have following structure independently:

R wherein _5aFor containing 18 carbon atoms and 0 to 5 heteroatomic alkyl that is selected from O and N at the most; And wherein m is 1 to 8 integer, comprises 1 and 8; And R ₁Be hydrogen or contain 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N independently.

12. the embolotherapy product of claim 8, wherein each R ₉Have following structure independently:

Wherein j and m are 1 to 8 integer independently, comprise 1 and 8, and R ₁Be hydrogen or contain 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N independently.

13. each embolotherapy product among the claim 3-12, wherein said polymer and poly-(C ₁-C ₄Aklylene glycol) combined polymerization.

14. the embolotherapy product of claim 13, wherein said poly-(C ₁-C ₄Aklylene glycol) exists with parts by weight less than 75wt%.

15. the embolotherapy product of claim 14, wherein said poly-(aklylene glycol) is poly-(ethylene glycol).

16. the embolotherapy product of claim 13, wherein side group-COOH group is contained in 0.01 to 0.99% described polymer unit.

17. the embolotherapy product of claim 5, wherein R ₄Be aryl or alkaryl.

18. the embolotherapy product of claim 17, wherein selected R ₄Aryl or alkaryl make that polymer unit is a diphenol.

19. the embolotherapy product of claim 1, wherein said polymer contain the unit that one or more formula IIIs are described:

Wherein the X of each polymer unit is Br or I independently, and Y1 and Y2 between 0 and 4, comprise 0 and 4 independently of one another, and the Y1+Y2 of each unit between 1 and 8, comprises 1 and 8 independently, and the R of each polymer unit ₂Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most.

20. the embolotherapy product of claim 19, wherein all X groups all are ortho-orientation.

21. the embolotherapy product of claim 19, wherein Y1 and Y2 are below 2 or 2 independently, and Y1+Y2=1,2,3 or 4.

22. the embolotherapy product of claim 19, the wherein R of at least one unit ₂Contain side group-COOR ₁Group is wherein for-COOR ₁Group is present in each unit wherein, subunit R ₁Be hydrogen or contain 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N independently.

23. the embolotherapy product of claim 19, wherein each R ₂Have following structure independently:

24. the embolotherapy product of claim 19, wherein each R ₂Have following structure independently:

25. the embolotherapy product of claim 19, wherein each R ₂Have following structure independently:

26. the embolotherapy product of claim 19, wherein side group-COOH group is contained in 0.01 to 0.99% described polymer unit.

27. the embolotherapy product of claim 19, the poly-(C of wherein said polymer and 75wt% at the most ₁-C ₄Aklylene glycol) combined polymerization.

28. the embolotherapy product of claim 27, wherein said poly-(C ₁-C ₄Aklylene glycol) is poly-(ethylene glycol).

29. the embolotherapy product of claim 1, wherein said polymer contain one or more units of being described by formula IV:

Wherein each X is I or Br independently, and Y1 of each diphenol unit and Y2 between 0 and 4, comprise 0 and 4 independently, and the Y1+Y2 of each diphenol unit comprises 1 and 8 between 1 and 8;

Wherein A is:

R wherein ₃For containing at the most heteroatomic saturated or undersaturated, replacement or unsubstituted alkyl, aryl or the alkaryl that 18 carbon atoms and 0 to 8 are selected from O and N;

P has parts by weight 75% or littler poly-(C ₁-C ₄Aklylene glycol) unit; F 0 and less than 1 between; G comprises 0 and 1 between 0 and 1; And f+g comprises 0 and 1 between 0 and 1.

30. the embolotherapy product of claim 29, wherein P is poly-(ethylene glycol), its with 50% or still less parts by weight exist.

31. the embolotherapy product of claim 29, wherein P is poly-(ethylene glycol), its with 30% or still less parts by weight exist.

32. the embolotherapy product of claim 29, wherein R and R ₂All contain side group COOR ₁Group;

Wherein for R, subunit R ₁Independently for containing 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N; And

Wherein for R ₂, subunit R ₁Be hydrogen atom.

33. the embolotherapy product of claim 29, wherein each R and R ₂Have following structure independently:

R wherein ₇Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) a, wherein R ₈Be selected from-CH=CH-,-CHJ ₁-CHJ ₂-and (CH ₂-) n, wherein a and n between 0 and 8, comprise 0 and 8 independently; And J ₁And J ₂Be Br or I independently; And wherein for each R ₂, Q contains free carboxylic acid groups, and for each R, Q independently is selected from hydrogen and carboxylate and amide, and wherein said ester and amide are selected from the ester of the alkyl that contains 18 carbon atoms at the most and alkaryl and amide and biology and the pharmaceutically ester and the amide of reactive compound.

34. the embolotherapy product of claim 29, wherein each R ₂Have following structure independently:

R wherein _5aFor containing 18 carbon atoms and 0 to 5 heteroatomic alkyl that is selected from O and N at the most; Wherein m is 1 to 8 integer, comprises 1 and 8; And wherein for each R ₂, R ₁Be hydrogen, and for each R, R ₁Independently for containing 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N.

35. the embolotherapy product of claim 29, wherein each R ₂Have following structure independently:

Wherein j and m are 1 to 8 integer independently, comprise 1 and 8, and wherein for each R ₂, R ₁Be hydrogen, and for each R, R ₁Independently for containing 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N.

36. the embolotherapy product of claim 34 or 35, each R of the R of wherein said polymer ₁Subunit is ethyl or butyl.

37. the embolotherapy product of claim 29, the A of wherein said polymer be-C (=O)-group.

38. the embolotherapy product of claim 29, the A of wherein said polymer is:

39. the embolotherapy product of claim 38, the wherein R of Xuan Zeing ₃Make that A is the part of spontaneous metabolite dicarboxylic acids.

40. the embolotherapy product of claim 38, the R of wherein said polymer ₃For being selected from-CH ₂-C (=O)-,-CH ₂-CH ₂-C (=O)-,-CH=CH-and (CH ₂-) part of z, wherein z is 1 to 8 integer, comprises 1 and 8.

41. the embolotherapy product of claim 29, wherein all X groups all are ortho-orientation.

42. the embolotherapy product of claim 29, wherein Y1 and Y2 are below 2 or 2 independently, and Y1+Y2=1,2,3 or 4.

43. the embolotherapy product of claim 42, wherein all X groups all are iodine.

44. the embolotherapy product of claim 29, wherein f is greater than 0.1 to 0.3.

45. the embolotherapy product of claim 44, wherein f is greater than 0.2 to 0.25.

46. the embolotherapy product of claim 29, wherein said poly-(C ₁-C ₄Aklylene glycol) parts by weight are less than 25wt%.

47. the embolotherapy product of claim 29, wherein g is greater than 0.1 to 0.35.

48. the embolotherapy product of claim 47, wherein g is greater than 0.2 to 0.3.

49. the embolotherapy product of claim 1, wherein said polymer contain one or more formula V unit:

Wherein each X is iodine or bromine independently; Each y between 0 and 4, comprises 0 and 4 independently, and the sum of wherein cyclosubstituted iodine and bromine comprises 1 and 8 between 1 and 8; Each R ₄And R ₆Independently for containing 18 carbon atoms and 0 to 8 heteroatomic alkyl, aryl or alkaryl that is selected from O and N at the most and R ₄Also comprise the side group hydroxy-acid group;

Wherein A is:

R wherein ₃For containing at the most heteroatomic saturated or unsaturated, replacement or unsubstituted alkyl, aryl or the alkaryl that 18 carbon atoms and 0 to 5 are selected from O and N;

P is the poly-(Cs of parts by weight less than 75wt% ₁-C ₄Aklylene glycol) unit;

F 0 and less than 1 between; G comprises 0 and 1 between 0 and 1; And f+g comprises 0 and 1 between 0 and 1.

50. the embolotherapy product of claim 49, wherein P is poly-(ethylene glycol) unit.

51. the embolotherapy product of claim 49, each R of wherein said polymer ₄And R ₆Contain side group-COOR ₁Group is wherein for each R ₆, each subunit R ₁Independently for to contain 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N, and for each R ₄, each subunit R ₁Be hydrogen atom.

52. the embolotherapy product of claim 49, each R of wherein said polymer ₄And R ₆For:

R wherein _5aFor containing 18 carbon atoms and 0 to 5 heteroatomic alkyl that is selected from O and N at the most; And wherein m is 1 to 8 integer, comprises 1 and 8; And wherein for each R ₄, each subunit R ₁Be hydrogen, and for each R ₆, each subunit R ₁Independently for containing 0 to 5 alkyl that is selected from heteroatomic from 1 to 18 carbon atom of O and N.

53. the embolotherapy product of claim 52, the R of wherein said polymer ₄Each R ₁Subunit is ethyl or butyl.

54. the embolotherapy product of claim 49, wherein A be-C (=O)-group.

55. the embolotherapy product of claim 49, wherein A is:

56. the embolotherapy product of claim 49, the wherein R of Xuan Zeing ₃Make that A is the part of spontaneous metabolite dicarboxylic acids.

57. the embolotherapy product of claim 56, the R of wherein said polymer ₃For being selected from-CH ₂-C (=O)-,-CH ₂-CH ₂-C (=O)-,-CH=CH-and (CH ₂-) part of z, wherein z is 1 to 8 integer, comprises 1 and 8.

58. the embolotherapy product of claim 49, wherein all X groups all be ortho-orientation and y be 2 or 3.

59. the embolotherapy product of claim 58, wherein each X group all is an iodine.

60. the embolotherapy product of claim 49, wherein f is greater than 0.1 to 0.3.

61. the embolotherapy product of claim 49, wherein g is greater than 0.1 to 0.35.

62. the embolotherapy product of claim 1, wherein said microparticle formulation is used for administrated by injection by preparation.

63. the embolotherapy product of claim 1, wherein said preparation contains polymer particles, described polymer particles is selected from spherical particle, inhomogenous microgranule, small porous particle, hollow minute particle, solid microgranule geometrically, and have and get rid of 10 microns of diameters to 5,000 micron microgranule, and their combination.

64. the embolotherapy product of claim 1, wherein said preparation contains polymer hydrogel compositions.

65. the embolotherapy product of claim 1, wherein said polymer also contain at least a therapeutic agent of effective dose.

66. the embolotherapy product of claim 65, wherein said at least a therapeutic agent are selected from chemotherapeutant, non-steroidal anti-inflammatory agent or steroidal class antiinflammatory.

67. the embolotherapy product of claim 1, wherein said microparticle formulation also contain the magnetic resonance reinforcing agent of effective dose.

68. the embolotherapy product of claim 1, wherein said microparticle formulation also contain the radiopaque medium that is selected from iodine, bromine, barium, bismuth, gold, platinum, tantalum, tungsten and composition thereof of effective dose.

69. the embolotherapy product of claim 1, wherein said microparticle formulation also contain be applicable to promote to select biologically biocompatible, can biological re-absorbed polymer coating.

70. the embolotherapy product of claim 69, wherein said biologically are selected from thrombosis, cell adhesion, cell proliferation, attraction inflammatory cell and deposition substrate albumen, inhibition thrombosis, inhibition cell adhesion, suppress cell proliferation, inflammation-inhibiting cell and suppress stromatin deposition or their combination.

71. the embolotherapy product of claim 1, it comprises the microparticle formulation that contains formula I:

Wherein X=I or Br; Y1 and Y2 independently=0,1,2,3 or 4;

Wherein f and g from 0 to 1;

Wherein R and R ₂Be independently selected from:

Wherein for each R ₂, each subunit R ₁Be H, and for each R, each subunit R ₁Be the long chain aliphatic hydrocarbon independently;

Wherein j and m are 1 to 8 integer independently, comprise 1 and 8;

Wherein Z is O or S independently;

Wherein A is selected from:

R wherein ₃For containing at the most heteroatomic saturated or unsaturated, replacement or unsubstituted alkyl, aryl or the alkaryl that 18 carbon atoms and 0 to 8 are selected from O and N; And

72. the embolotherapy product of claim 1 is used for the purposes of the medicine of thromboembolism body cavity in preparation.

73. the embolotherapy product of claim 1 is used for the treatment of purposes in varicosis and/or the Aranea venous medicine in preparation.

74. a combination medicine, described combination medicine comprise the embolotherapy product and the therapeutic agent of claim 1.

75. a combination medicine, described combination medicine comprise embolotherapy product and any other embolotherapy product of claim 1.

76. the embolotherapy product of claim 1, wherein said polymer are not spontaneous.

77. the embolotherapy product of claim 1, wherein said polymer contains at least a aminoacid.