CN101125916B - Biodegradation polymer and its preparing process and application - Google Patents

Abstract

The invention relates to a polylactic polymer with organic phosphate bond in the main chain of biological degradation, which can change into innocuity residue by internal degradation. The solidity and hydrophobicity of lactic acid or glycollic acid prepolymer are strengthened by adding a circularity compound that potentially improves the final polymer Tg containing phosphorus, redudeces the need of high molecular weight prepolymer, and the internal degradation time is quickened by using low molecular weight preolymer and improving organic phosphate contents, which improves the encapsulating ratio between polymer and a plurality of aquosity medicines (such as paclixtel or docetaxel). Finally, practical matrices formed by medicine and polymer have much better mixing compatibleness without phenomena of medical phasic demixing and independent crystallization.

Description

A kind of biological degradation polyalcohol and its preparation method and application

Technical field

It is the polylactic acid polymer containing phosphoric acid ester bond in nontoxic residue, biological degradability main chain the present invention relates to degradation in vivo.Medical treatment device that polymer provided by the present invention can be used in implantation, can the purposes such as sustained and controlled release medicament release system, it may also be used for suture, fabric fibre, the engineering material such as foam, plastics.

Background technology

The polymeric material of bio-compatibility is widely used to the application of release of therapeutic agents and medical implant apparatus.But the course for the treatment of, to finally, medical personnel are needed for completion drug delivery or the biocompatible polymeric without pharmaceutical value is taken out from the patient, so, optimal polymeric material is Biodegradable polymer material.

Generally frequently cyclical administration mode is undesirable in many situations.For example when the cyclical administration mode using some toxicity very strong medicine, long term frequent can cause patient to be in high dose state initial stage in administration, even up to intimate dangerous level；To between post-drug period or each administration, actual dosage can be decreased below the state of effective dose, and drug effect can not be played by causing.But, the dosage that the purpose of controlled release drug delivery is desirable to convey medicine can be chronically at performance drug effect and atoxic level.So, if biological degradability medical implant apparatus or medicine insoluble drug release to be used as or other controlled release durg delivery systems, it is a kind of effective method that medicine is discharged with local controlled manner to use polymer support.Referring to Langer etc., " being used as the chemically and physically structure of the polymer of bioactivator control release carrier ",《Macromolecular science magazine》, macromolecular chemistry and physics comment, (J.Macro.Science, Rev.Macro.Chem.Phys.), C23 (1), 61-126 (1983).As a result, it is only necessary to the less medicine of total amount, and toxic side effect can be reduced to minimum.Had been used as in sometimes polymer by local and sustained release the carrier of therapeutic agent.Referring to Leong etc., " polymer controls insoluble drug release ",《Advanced Drug release comment》(Advanced Drug Delivery Reviews), 1：199-233(1987)；Langer etc., " new medicine release method ",《Science》249：1527-33 (1990), and Chien etc.,《New drug delivery system》(NovelDrug Delivery Systems)(1982).Such release system provides enhancing therapeutic efficiency and reduces the possibility of overall toxicity.

For a non-biodegradable polymers matrix, in the step of active medicine discharges is water diffusion matrix, active medicine dissolving, and the active medicine are diffused out by the passage of the matrix.As a result, the mean residence time of the active medicine existed with soluble state is to be more than in non-biodegradable matrix in biodegradable matrices, because when matrix is biodegradable, in this way it is no longer necessary to pass through the path of the matrix channel.Due to the half-life short of many medicines, before they discharge, the active medicine in non-biodegradable matrix will decompose or lose activity.This problem especially significantly, because these molecules are usually hydrolytically unstable, and has relatively low permeability for polymer substrate for many large biological molecules and less polypeptide drugs.In fact, in non-biodegradable matrix, many large biological molecule aggregations and precipitation are diffused into passage required outside carrier matrix so as to block.

These problems are alleviated by using biodegradable matrix, i.e., in addition to a certain degree of dispersal events, mainly make therapeutic agent by control release by the degraded of the polymer substrate.Being studied as the example of a few class synthetic polymers of possible degradable chemical includes polyester (Pitt etc., " the biodegradable medical release system based on aliphatic polyester：For contraceptive and narcotic antagonists ",《The control release of bioactive substance》(Controlled Release of Bioactive Materials), 19-44 (RichardBaker is compiled, 1980))；Polyaminoacid and puppet-polyaminoacid (Pulapura etc., " development trend of the biologically absorbable polymer of medical applications ", biomaterial application magazine (Jorunal of Biomaterials Appl ications) 6：1,216-50 (1992))；Polyurethanes (Bruin etc., " the biodegradable lysine diisocyanate base PGA-e caprolactone polymers urethanes reticulated structure in artificial skin ", biomaterial (Biomaterials), 11：4,291-95 (1990))；Poly- (ortho esters) class (Heller etc., " the norethindrone release in poly- (ortho esters) ", polymer engineering science (Ploymer Engineering and Science), 21：11,727-31 (1981))；Polyanhydrides (Leong etc., " polyanhydride for being used for the control release of bioactivator ", biomaterial (Biomaterials), 7：5,364-71 (1986).The specific example of the Biodegradable material for making medical usage of being used as implanting has polylactide, PGA, poly- diethyleno dioxide ketone (polydioxanone), lactide coglycolide polymer, glycolide-dioxaneone polymer, polyanhydride, glycolide-trimethylene carbonate methyl ester polymer and glycolide-caprolactone polymers.

Some known polymer with phosphoric acid ester bond, i.e. polyphosphate, polyphosphonates and poly- phosphite ester.Referring to Penczek etc.,《Macroscopic single crystal handbook》(Handbook of Polymer Synthesis) the 17th chapter：" phosphorous polymer ", 1077-1132, (HansR.Kricheldorf is compiled, 1992).This three classes compound respectively has the different side chains connected from phosphorus atoms, and its respective structure difference is as follows：

The poly- phosphite ester of polyphosphate polyphosphonates

The multipurpose of these polymer derives from the mutability of phosphorus atoms, it is known that these are relevant with the multiplicity of reaction.Its bonding orbital includes 3p tracks or multiple 3s-3p hybrids；Due to there is enterable d tracks, spd hybrids are also possible.Therefore, the physical-chemical characteristic of polyphosphate can just be changed easily by changing R or R1 groups.The biological degradability of the polymer stems primarily from the unstable phosphoric acid ester bond of physiology present in the polymer backbone.By handling its skeleton or side chain, different biological degradation rates can be obtained.(Kadiyala etc., " polyphosphate：Synthesis, physicochemical characteristics description and physiological reaction "《The biomedical applications of synthesising biological degradable polymer》(Biomedical Applications of Synthetic Biodegradable Polymers) the 3rd chapter：33-57 (Jeffrey O.Hollinger are compiled, nineteen ninety-five).

Another characteristic of polyphosphate is the utilizability of official's energy side base group.Because phosphorus atoms can be pentavalent, drug molecule or other bioactive substances can be chemically bonded on the polymer.For example, the medicine with-O- carboxyls can be coupled through ester bond and the phosphorus atoms, the ester bond can be hydrolyzed.P-O-C groups in skeleton can reduce the glass transition temperature (Tg) of polymer, it is often more important that, this changes dissolubility of the polymer in conventional organic solvent, and the dissolubility is that beneficial characteristic describes and processes desired.

Polyphosphate-polyester polymers are disclosed in Friedman (United States Patent (USP) 3,442,982), there is following asymmetric group as its ester moiety：

It is all stable (the 1st column, 42-44 rows and the 3rd column, 74-75 rows) in the environment of high temperature, strong light and hydrolysis that the polymer for which describing Friedman, which is,.

Polyphosphonates are disclosed in Starck etc. (Canadian Patent 597,473), according to stating, the introducing of phosphorus imparts the noninflammability (the 6th column, 1-2 rows) of resulting polymers.Engelhardt etc. (United States Patent (USP) 5,530,093) discloses various fabrics finish composition, and this based composition has the various condensation polymer structures with phosphate and ester repetitive.Mentioned by Starck etc. and Engelhardt etc. to ester moiety be arranged as follows：

-O-CO-R₃-CO-O-

The organophosphorus polymer prepared with dialkyl group or diaryl phosphorous acid hydrogen salt and some diol compounds such as cyclohexanedimethanol of Isosorbide-5-Nitrae one is disclosed in Coover et al. United States Patent (USP) 3,271,329 referring to the 1st column, 24--31 rows.The phosphorus polymer of the cycling element represented with least one following formula is disclosed in Van denberg et al. United States Patent (USP) 3,655,585：

Wherein R can be alkyl, and z can be alkylidene such as cyclohexylidene referring to the 1st column, 28--55 rows.Being disclosed in Herwig et al. United States Patent (USP) 3,875,263 with ring alkylene moiety such as Isosorbide-5-Nitrae -- two phosphinate of methylene-cyclohexane are referring to the 1st column, 18-37 rows, and the 2nd column, the 13rd row.

However, all these patents are all proposed, these materials and the polymer composition prepared with these materials should extrude or be molded as product or be woven into fiber (coover et al.)；Additive (vandenberg et al., and Herwig et al.) as lubricating oil, gasoline and synthetic resin or other polymers；Or as coating compound (Herwig etc.)

The organophosphorus polymer with such as cyclohexanedimethanol of Isosorbide-5-Nitrae one preparation of some diol compounds, structural formula are disclosed in refined et al. the Chinese patent 98805636.4 of party's text：

Wherein：R and R ', is each independently straight or branched fatty group, is unsubstituted or is replaced by one or more non-interfering substituents；L is divalence cycloaliphatic base；R ' is selected from H, alkyl, alkoxy, aryl, aryloxy group, heterocycle or heterocyclic oxy group；It is 5--1,000 with n.

Similar biological degradation polymer is bio-compatible before biodegradation and when biodegradable described in disclosed in the Chinese patent 98805193,98805196 of hair Haiquan etc. and 98805196, Dang Wenbin Chinese patent application 99816287 and 00806972.Also describe the preparation method of the polymer, the composition containing the polymer and bioactive substance, by the composition be made for the product for being implanted into or being injected in vivo and the method with the polymer controls release of bioactive substances.

The various sustained drug method for releasing for patient have been developed.These controlled release drug delivery systems can reach some targets, including protect medicine to be influenceed before release from biotic environment, and allow medicine to a target area control release.

It is used in recent years among the Biodegradable polymer of controlled release drug delivery system and polymer, polylactide (PLA) and polymer P LGA that it is synthesized with glycolide and the polymer (PPE) containing phosphate, are all to be studied among polymer and tested most classifications.PLA and PLGA, which is used for principal part and topical remedy's controlled release, the examination ＆ approval history of very long safety of medicine and effect.PLGA, which can degrade, makees lactic acid and glycolic, it is a part for citrate cycle in human body, sometimes PLGA will degrade the soluble form for making oligomer poly (lactic acid) and poly (glycolic acid), and be excreted before respective monomer is finally resolved into.Current PLA and PLGA is utilized as pharmaceutical carrier, including Leuprorelin, human growth hormone, steroids etc. in some medicament slow release formulas.The disadvantage of these polymer, which includes these polymer, may need the forming temperature of long degradation time and medicament slow release formula higher.

Recently, polyphosphate (PPE) starts to be increasingly being used to the pharmaceutical carrier of biological absorbable to reach shortening degradation time, and the forming temperature that reduction medicament slow release is formulated.The polymer that one type is made up of the monomer of lactide (lactic acid that lactone form is made up of two parts) and etherophosphoric acid has widely been tested as a pharmaceutical carrier, and the ovarian cancer patients in the U.S. are treated (referring to KhanW.Li etc. " distribution of the taxol phosphoric acid ester microsphere in central nervous system malignant tumour " Clinical CancerResearch in the preclinical and clinical test I phases, Vol.9,3441-C3447, August15,2003.ElizabethHarper etc. " a kind of novel slow controlled release taxol locally plants the influence of lung cancer tumor root nodule metastatic lesion to mouse " ClinicalCancerResearchVol.5,4242-C4248, December1999).So the polymer of this special category of PLGA-PPE can be expected to taxol to be wrapped in microballoon, and the controllable medicine is discharged from microballoon.But, BIOLOGICAL EVALUATIONIn shows that the glass transition temperature (Tg) of polymer is decreased relative to polylactide, so as to make polymer shorten in the pot life at room temperature phase.It can increase the molecular weight of last polymer for the low Tg of compensation and further selectively reduce the content of etherophosphoric acid, the effect joined together can make the polymer and PLA or PLGA of phosphate ester-containing more similar, make polymer retain time longer in vivo and the administration that need not be repeated.

Therefore it is the glass transition temperature that there is a need to improve polymer, without substantially increase PLA content or the content of reduction phosphoric acid.

The content of the invention

The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art there is provided a kind of polymer having compared with high glass transition temperature, without substantially increase PLA content or reduction phosphorus acid content, with the hydrophobic biological degradation polyalcohol of enhancing.

It is a further object to provide the preparation method of above-mentioned polymer.

It is also another object of the present invention to provide the application of above-mentioned polymer.

To achieve the above object, the first aspect of the invention is to provide a kind of biodegradable polymer, includes following repeated monomer unit (structural formula I or formula II)：

Structural formula I

Formula II

Wherein：

X be selected from-O- or-NR '-, wherein R ' can be H or alkyl；

M₁、M₂Selected from each independent, (1) has a side chain or aliphatic groups of 1-20 carbon atoms, or (2) have 1-20 carbon atoms side chain or straight chain epoxide-, carboxyl-or amino-aliphatic group；

L is selected from any alicyclic hydrocarbon containing 2-30 carbon atom, aromatic rings or heterocycle, and form that is direct or being connected by the side chain or aliphatic groups of 1-10 carbon atoms is passed through including two cyclic structures；

R is selected from a side chain or aliphatic groups for having 1 to 20 carbon atom；Or one have the side chain or straight chain of 1 to 10 carbon atom, and contain the aliphatic group of epoxide, carboxyl or amino；Or an aromatic part for having aliphatic or a ring-type.

x:Y mol ratio can change according to the characteristic of polymer, but typically about 1；

X or y is from the arbitrary integer between 1 to 200；

n:The mol ratio of (x or y) is about 1:200 to 200:Between 1；And

q:R mol ratio is 1:99 to 99:Between 1.

Wherein described biological degradation polyalcohol is bio-compatible before biodegradation and when biodegradable.

It can be used as being implanted into, inject, insert internal product in whole or in part there is provided a kind of in another embodiment of the present invention, the product includes structural formula I or II biological degradation polyalcohol or above-mentioned polymer composition.

In another embodiment, the present invention includes a kind of method for preparing Biodegradable polymer, and this method comprises the following steps：

(a) by formula II I, IV or V heterocyclic compound, with initiator H-O-CH₂-L-CH₂- O-H reacts, generation such as structural formula VI or VII prepolymer：

Formula II I structural formulas IV

Structural formula V

Structural formula VI

Structural formula VII

Wherein X, L, M₁、M₂It is as defined above with x, y, q, r；

(b) reacted again with the structural formula VI or VII prepolymers and following structural formula VIII dihalo- substituted phosphate (phosphorodihalidate)：

Structural formula VIII

Wherein " halo " can be Br, Cl or I；And R is as defined above, the polymer of the structural formula I or II is synthesized.

In another embodiment of the invention there is provided a kind of application of biological degradation polyalcohol composition, for control release bioactive substance, comprise the steps：

(a) bioactive substance is made to be mixed to form mixture with the biodegradable polymer with the repeated monomer unit shown in structural formula I or II；

(b) mixture is made to be shaped to the solid articles of definite shape；

(c) in previously selected position et al. Ke or the solid articles are injected, makes that the solid is implanted into or the product of injection is at least contacted with biofluid part.

The present invention points out to be used as the initiator of chemical reaction by adding the compound of aliphatic group or cyclic aromatic, or by the ring-opening reaction of lactide (or mixture of lactide and glycolide), increase hydrophobicity and potential high Tg poly- (phosphoric acid-lactide) polymer can be prepared.

The polymer of the present invention is different from previously known PLA/PPE polymer, and key is to add a kind of cyclic compound, makes polymer improve flintiness and hydrophobicity, particularly possesses following advantage：

● the flintiness and hydrophobicity of enhancing lactic acid or glycolic prepolymer, and the final polymer Tg containing phosphorus of potential raising.

● because prepolymer and polymer improve hydrophobicity, improve the envelop rate of polymer and some hydrophobic drugs (such as taxol or docetaxel), it is last that substantive matrix is formed by medicine and polymer, there is it and preferably mix compatibility, without the layering of medicine phasic property and single crystalline polamer.

● medicine is preferably mutually compatible with polymer, can extend the term of validity of slow release formulation, this effect can more be strengthened by improving Tg polymer.Microballoon or other form of administration can also be made in holding shape in vivo and be easier to predict the release dynamics of medicine.

● the present invention can improve Tg, the need for can reducing to HMW prepolymer, it is possible to the prepolymer and raising phosphate ester element content of low molecule amount, to accelerate internal degradation time.

● this high hydrophobicity and the close new PLA/PPE polymer of molecular weight are utilized, the medicine for making half-life period shorter becomes possible to as whole body and local controlled release drug administration.

Brief description of the drawings

Fig. 1 be Inventive polymers (LAEG-CHDM-EOP)Infared spectrum；

Fig. 2 show in the form of a graph Inventive polymers (LAEG-CHDM-EOP)Gpc analysis result；

Fig. 3 show Inventive polymers (LAEG-CHDM-EOP)Means of differential scanning calorimetry data；

Fig. 4-A show Inventive polymers (LAEG-CHDM-EOP)'s¹H-NMR is composed；

Fig. 4-B show Inventive polymers (LAEG-CHDM-EOP)'s¹H-NMR is composed；

Fig. 5 show Inventive polymers (LAEG-CHDM-EOP)'s³¹P-NMR is composed；

Fig. 6 show Inventive polymers (LAEG-CHDM-EOP)'s¹³C-¹H-NMR is composed；

Fig. 7 shows the storage stability data of the polymer of the present invention at room temperature；

Fig. 8 shows the microballoon outward appearance of the Inventive polymers prepared using solvent evaporation process；

Fig. 9 show by Inventive polymers (LAEG-CHDM-EOP)Release profiles of the taxol microballoon of manufacture in 37 DEG C of PBS.

Embodiment

Term " aliphatic " mentioned by the present invention refers to the alkane, alkene or alkynes of straight chain, side chain or ring-type.Preferred fatty group is the straight or branched group with 1 to 10 carbon atom, the straight chain group of preferably 1 to 7 carbon atom in the phosphate -ester polymer that the present invention is referred to.

Term " aryl " mentioned by the present invention refers to that some have the unsaturated cyclic carbon compound of 4n+2 pi-electrons.

Term " heterocycle " mentioned by the present invention is that have one or more non-carbon, the saturation or unsaturated cyclic compounds of such as nitrogen, oxygen or sulphur atom in finger ring.

Signified biodegradable polymer of the invention includes the repeated monomer unit shown in following structural formula I or II：

Structural formula I

Formula II

Wherein X be-O- or-NR '-, wherein R ' can be H or alkyl.

L can be the group of the alicyclic hydrocarbon, aromatic rings or heterocycle of any 2-30 carbon atom, and form that is direct or being connected by the side chain or aliphatic groups of 1-10 carbon atoms is passed through including two cyclic structures；As long as it does not disturb the polymerisation or bio-degradation reactions of polymer.Clearly L can be following structure, or other approximations：

L is selected from following sub- functional group

R3, R4, R5, R6 are H, the straight chain of 1-10C compositions or the saturated alkane base containing side chain

R7 is 1-10 C straight chain or the saturated alkane base containing side chain

But it is preferred that L contains independent cyclic structure；More preferably L is the cycloalkane containing 4-10 carbon atom.Even more preferably still L is to 6 yuan of substituted cycloalkyl；Most preferably L is hexamethylene.

M in structural formula₁And M₂It is side chain or aliphatic groups that (1) has 1 to 20 carbon atom independently of one another to be, or (2) have 1 to 20 carbon atom side chain or straight chain epoxide-, carboxyl-or amino-aliphatic group.The aliphatic group of both the above situation, side chain or straight chain can be any bivalent aliphatic part for having 1 to 20 carbon atom, be preferably made up of 1 to 7 carbon atom, polymerisation, copolyreaction or bio-degradation reactions without disturbing polymer.Clearly state, work as M₁Or M₂When being the aliphatic group of side chain or straight chain for having 1 to 20 carbon atom, they can be, such as alkylidene, such as methylene, ethylidene, 1- methyl ethylidene, 1,2- dimethylethylenes, sub- n-propyl, trimethylene, isopropylidene, 2,2- dimethylpropylidenes, the sub- tert-butyl group, sub- n-pentyl, sub- tertiary pentyl, sub- n-hexyl, sub- n-heptyl, sub- n-octyl, sub- n-nonyl, sub- positive decyl, sub- n-undecane base, sub- dodecyl or other approximations；Alkylene group, such as sub- positive acrylic, 2- vinyl propylidene, sub- n-butene base, 3- vinyl butylidene, sub- n-pentene base, 4- (3- acrylic) hexylidene, sub- positive octenyl, 1- (4- cyclobutenyls) -3- methyl decylene, 2- (3- acrylic)-Asia dodecyl, sub- hexadecylene base or other approximations；Alkynylene, such as acetenyl, sub- propinyl, 3- (2- acetenyls) pentylidene, sub- positive hexin base, 2- (2-propynyl) decylenes or other approximations；Or alkylidene, alkylene group or the alkynylene replaced by non-interfering substituent, such as hydroxyl, halogen or nitrogen base, such as：Sub- dodecyne base of the chloro- sub- positive decyls of 2-, 1- hydroxyl -3- vinyl butylidene, 2- propyl group -6- nitros -10- etc..

Work as M₁Or M₂When being epoxide-aliphatic group of a side chain for having 1 to 20 carbon atom or straight chain, it can be the alkylene oxide group of such as divalence, such as inferior ethoxyl, 2- methyl inferior ethoxyl, sub- propoxyl group, Aden's epoxide, sub- amoxy, sub- dodecyloxy, sub- hexadecane epoxide.Work as M₁Or M₂When being epoxide-aliphatic group of side chain or straight chain, preferably it has-O- (CH2)_a-, wherein a is 1 to 7.

Work as M₁Or M₂When being the epoxide-aliphatic group of side chain or straight chain for having 1 to 20 carbon atom, it can also be such as alkylene dioxo base, such as methylene-dioxy, ethylenedioxy, 1,3- sub- the third two epoxide, 2- methoxyl groups -1,3- sub- the third two epoxide, 2- methyl isophthalic acids, 3- sub- the third two epoxide, sub- positive penta 2 epoxide, the sub- epoxide of n-octadecane two, methylene epoxide-methylene epoxide, inferior ethoxyl-methylene epoxide, inferior ethoxyl-inferior ethoxyl, the sub- propoxyl group of inferior ethoxyl -1-, Aden's epoxide-Asia positive propoxy, Asia pentadecane epoxide-methylene epoxide or other approximations.Work as M₁Or M₂It is dioxo-aliphatic group of side chain or straight chain, preferably it has-O- (CH₂)_a- O- or-O- (CH₂)_a-O-(CH₂)_b- O- structural formula, wherein a and b are individually 1 to 7.

Work as M₁Or M₂When being the carboxyl -ester race's group of side chain or straight chain for having 1 to 20 carbon atom, it can be such as dibasic carboxylic acid ester, divalent group as described below：Methyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, ro-butyl acetate, ethyl propionate, propionic acid allyl ester, n-butylacrylate, butyric acid n-butyl, vinyl chloroacetate, 2- methoxycarbonyl hexamethylenes alkanone, 2- acetoxyl group hexamethylene alkanones etc..Work as M₁Or M₂When being carboxyl -ester race's group of side chain or straight chain, preferably it has formula-O-CHR₂-CO-O-CHR₃- structure, wherein R₂And R₃It is each independently H, alkyl, alkoxy, aryl, aryloxy group, heterocyclic radical or heterocyclic oxy group.

Work as M₁Or M₂It is the amino-ester race group of the side chain or straight chain that have 1 to 20 carbon atom, it can be divalent amines, such as-CH₂NH-、-(CH₂)₂N-、CH₂(C₂H₅)N-、-n-C₄H₉NH-、-t-C₄H₉NH-、-CH₂(C₃H₇)N-、-C₂H₅(C₃H₇)N-、-CH₂(C₈H₁₇) N- or other approximations.Work as M₁Or M₂When being the amino-ester race group of side chain or straight chain, preferably it has-(CH₂)_a- NR '-structural formula, wherein R ' is H or low alkyl group.

Work as M₁And/or M₂Preferably there is-O- (CH₂)_aThe alkylidene of-structural formula, wherein a are 1 to 7, more preferably the ethylidene of divalence.In a special embodiment, M₁And M₂All exist simultaneously；M₁It is not identical chemical group with M2；And M₁And M₂It is sub- n-pentyl and the methyl acetate base of divalence respectively.

R in Inventive polymers is H, alkyl, alkoxy, aryl, aryloxy group, heterocyclic radical or heterocyclic oxy group residue.Useful alkyl R embodiment includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group and-C₈H₁₇Deng；By non-interfering substituent, such as hydroxyl, halogen, alkoxy or the alkyl of nitro substitution；Corresponding alkoxy and bioactive substance combine to form the alkyl of pendency (pendant) drug delivery system.

When R is aryl or corresponding aryloxy group, typically it contains about 5 to about 14 carbon atoms, and preferably from about 5-12 carbon atom can also arbitrarily include one or more rings condensed each other.The example of particularly suitable aryl includes phenyl, phenoxy group, naphthyl, anthryl and phenanthryl etc..

When R is heterocyclic radical or heterocyclic oxy group, typically it includes about 5-14 annular atom, preferably comprises about 5-12 annular atom, and one or more hetero atoms.Suitable heterocyclic radical example includes furans, thiophene, pyrroles, different pyrroles, the different pyrroles of 3-, pyrazoles, the different imidazoles of 2-, 1,2,3-triazoles, 1,2,4- triazole, oxazole, thiazole, isothiazole, 1,2,3- oxadiazole, 1,2,4- oxadiazole, 1,2,5- oxadiazole, 1,3,4- oxadiazole, 1,2,3,4- oxatriazole, 1,2,3,5- oxatriazole, 1,2,3- bis- oxazoles, 1,2,4- bis- oxazoles, 1,3,2- bis- oxazoles, 1,3,4- bis- oxazoles, 1,2,5- oxatriazole, 1,3- Evil thiophenes phenol (oxathiole), 1,2- pyrans, Isosorbide-5-Nitrae-pyrans, 1,2- pyranone, Isosorbide-5-Nitrae-pyranone, 1,2-dioxin, 1,3-dioxin, pyridine, N- alkyl pyridines drone, pyridazine, pyrimidine, pyrazoles, 1,3,5-triazines, 1,2,4- triazine, 12,3- triazines, 1,2,4- oxazine, 1,3,2- oxazine, 1,3,5- oxazine, the oxazine of Isosorbide-5-Nitrae-, Lin Yi oxazines, Dui Yi oxazines, 1,2,5- Evil thiazines, 1,2,6- Evil thiazines, Isosorbide-5-Nitrae, 2- oxadiazines, 1,3,5,2- oxadiazine, oxa-

(oxepin), azepine, thia

(thiepin), 1,2,4- diazas

, indenes, different indenes, benzofuran, isobenzofuran, benzo-thiophene, isothianaphthene, indoles, indolenine, the different benzazoles of 2-, 1, 4- benzazoles, pyrans simultaneously [3, 4-b]-pyrroles, different indazole, indoxazine, benzoxazole, anthranil, 1, 2- chromenes, 1, 2- benzopyrones, 1, 4- benzopyrones, 2, 1- benzopyrones, 2, 3- benzopyrones, quinoline, isoquinolin, 1, 2- benzodiazines, 1, 3- benzodiazines, 1, 5- benzodiazines, pyrido [3, 4-b]-pyridine, pyrido [3, 2-b]-pyridine, pyrido [4, 3-b]-pyridine, 1, 3, 2- benzoxazines, 1, 4, 2- benzoxazines, 2, 3, 1- benzoxazines, 3, 1, 4- benzoxazines, 1, 2 Ben Bing Yi oxazines, 1, 4- Ben Bing Yi oxazines, carbazole, xanthrene, acridine and purine or other approximations.When R is heterocyclic radical or heterocyclic oxy group, it is preferably selected from furans, pyridine, N- alkyl pyridines, 1,2,3-triazoles, 1,2,4- triazoles, indenes, anthracene and purine ring.

In particularly preferred embodiment party, R is alkyl, alkoxy, phenyl, phenoxy group or heterocyclic oxy group, the even more preferably alkoxy containing 1-7 carbon atom.R is most preferably ethyoxyl.

n:The mol ratio of (x or y) can be according to needed for polymer biological degradability and release characteristics change in relative broad range, but typically be about 200:1~1:200, preferably about 100:1~1:100, most preferably from about 50:1~1:50.

q:R mol ratio can be according to needed for polymer biological degradability and release characteristics change in relative broad range, but typically be about 1:200~200:1.q:R ratio is preferably from about 1:150~150:1, most preferably from about 1:99~99:1.

x:Y mol ratio also can be according to needed for polymer biological degradability and release characteristics change in relative broad range, but typically about 1.

Biological degradation polyalcohol is different from non biodegradable polymer, i.e., they can be degraded during treating in vivo.The process, which is usually directed to, makes polymer fracture be monomer subunit.In principle, the final hydrolytic cleavage product of polyphosphate is phosphate, cycloaliphatic ring dimethanol or fragrant dimethanol, and these products are avirulent.The middle oligomerization product of hydrolysis has different characteristics, but is typically the toxicology that the biological degradation polyalcohol for being implanted into or injecting, or even the polymer synthesized by substantially nontoxic monomer structure are determined after the analysis of one or many in vitro toxicities.

The preferred thing of polymer of the present invention dissolves in one or more common organic solvents, in order to manufacture and process.Common are machine solvent includes chloroform, dichloromethane, acetonitrile, ethyl acetate, DMA, 1-METHYLPYRROLIDONE, DMF and dimethyl sulfoxide.Polymer is preferably soluble at least one above-mentioned solvent.

In a preferred embodiment of the present invention, structural formula I or II biological degradation polyalcohol can be prepared by the method comprised the steps：

(a) at least one formula II I, IV or V heterocyclic compound are made：

Formula II I structural formulas IV

Structural formula V

And with initiator H-O-CH₂-L-CH₂- O-H reacts, and forms structural formula VI or VII prepolymer：

Structural formula VI

Structural formula VII

Wherein X, M₁、M₂, L, R, x, y, q and r be as defined above；

(b) said structure Formula IV or VII prepolymer is further made to be reacted with structural formula VIII dihalo- substituted phosphate：

Structural formula VIII

Wherein " halo " is Br, Cl or I；And R is as defined above, said structure Formulas I or II polymer are formed.

(a) step is in the preparation of polyglycols ester, and the most frequently used formula reaction is the esterification by ring opening polymerisation between glycol and lactide according to following formula：

The advantage of melt polycondensation reaction is that it can avoid using solvent and substantial amounts of other additives, and being achieved in that can more easily purification effect.It can also obtain the polymer of reasonable HMW.But chain acidolysis (or hydrolyzable in the presence of water) can just be made by usually requiring more violent condition.If polymer backbone is easy to be taken away hydrogen atom or because subsequent big free radical is compound and aoxidizes, that may occur undesirable, thermal initiation side reaction, such as cross-linking reaction.

The effect of first step reaction (a) is to use initiator Unclosing structure formula III, the ring of IV or V heterocyclic compounds.Useful formula II I, IV or the example of V heterocyclic compounds include caprolactone, caprolactam, amino acid anhydrides, such as glycine anhydride, cycloalkylidene carbonic ester, diethyleno dioxide ketone (dioxanone), glycolide and lactide.

When the compound of the present invention is Compounds of structural formula I, it can only be used in step (a) and contain M₁Formula II I heterocyclic compound preparation structure Formula IV prepolymers.When the compound of the present invention is compounds of formula II, it can be used in step (a) and contain M₁Formula II I heterocyclic compounds and containing M₂Structural formula IV heterocyclic compounds mixture.Or, when the compound of the present invention is compounds of formula II, it can be used simultaneously containing M in step (a)₁And M₂Single structure Formula V heterocyclic compound.

Suitable initiator example includes the various compound (H-O-CH for carrying at least two reactive hydrogens₂-L-CH₂- O-H), wherein L is linking group and is as defined above.Linking group L can be the group of the alicyclic hydrocarbon containing two divalent methylene cardinal extremities, aromatic rings or heterocycle, pass through form that is direct or being connected by the side chain or aliphatic groups of 1-10 carbon atoms including two cyclic structures, such as cyclic hydrocarbon dimethylene, the methylene respectively comes with active hydrogen moieties-OH.So, various branched polymers can be prepared using the active hydrogen initiators of side chain, to design the polymer with required characteristic.But when these branched polymers and acyl chloride reaction, cross-linked polymer will be obtained.

Reactions steps (a) can be carried out at a temperature of various change, and this depends on the sensitiveness of solvent, required molecular weight, reactant the formation side reaction used and there is the difference of one or more catalyst.But reactions steps (a) are carried out preferably under about 0~+235 DEG C of melting temperature, carried out most preferably under about 110~+235 DEG C of melting condition.In the case where using cation or anionic catalyst, relatively low reaction temperature can be used.

Reaction time alterable needed for reactions steps (a) is larger, and this depends on the reaction type and required molecular weight used.But reactions steps (a) are preferred to be carried out about 1 hour~7 days.

When reactions steps (a) can be polymerisation in bulk, polymerisation in solution, interfacial polycondensation reaction or any convenient other polymerisation process, reactions steps (a) are carried out preferably under melting condition.

The example of particularly useful structural formula VI prepolymers includes：

(i) the OH- blocked prepolymers as derived from polycaprolactone：

H-[-O(CH₂)₅-CO-]_x-O-CH₂-L-CH₂-O-[-CO-(CH₂)₅-O-]_y-H；

(ii) the OH- blocked prepolymers as derived from polylactide：

H-[-OCH(CH₃)-CO-]_x-O-CH₂-L-CH₂-O-[-CO-CH(CH₃)-O-]_y-H；Or

(iii) the OH- blocked prepolymers as derived from poly (trimethylene carbonate)：

H-[-O(CH₂)₃-O-CO-]_x-O-CH₂-L-CH₂-O-[-CO-O-(CH₂)₃-O-]_y-H。

The example of particularly useful structural formula VII prepolymers includes：

(i) the OH- terminated polymers as derived from lactide and glycolide：

H-{-[-OCH(CH₃)-CO-]_q-[-OCH₂-CO-]_r}_x-O-CH₂-L-CH₂-O-{[-OC-CH₂O-]_r-[CO-CH(CH₃)-O-]_q}_y-H；

(ii) the OH- terminated polymers as derived from lactide and caprolactone：

H-{-[-OCH(CH₃)-CO-]_q-[-O(CH₂)₅-CO-]_r}_x-O-CH₂-L-CH₂-O-{[-OC-(CH₂)₅O-]_r-[CO-CH(CH₃)-O-]_q}_y-H；Or

(iii) the OH- terminated polymers as derived from glycolide and caprolactone

H-{-[-O(CH₂)₅-CO-]_q-[-OCH₂-CO-]_r}_x-O-CH₂-L-CH₂-O-{[-OC-CH₂O-]_r-[CO-(CH₂)₅-O-]_q}_y-H；

The purpose of the polymerisation of step (b) is to form polymer, the phosphorylation unit that the prepolymer (VI) or (VII) that the polymer is produced comprising step (a) are connected with each other.Result is probably the block polymer with microstructure, and this polymer is particularly suited for use as control release medium.

Most of polyphosphates can be obtained by the condensation reaction between the dichloride and glycol polymeric precursors that suitably replace.

Structural formula：

Poly- phosphite ester can be prepared by dihydric alcohol with two step condensation reactions.To reduce these side reactions to greatest extent, polymerisation is carried out in the solution.Solution polycondensation requires that prepolymer and phosphorus component are dissolved in common solvent.Typically use chlorinated organic solvent, such as chloroform, dichloromethane or dichloroethanes.Solution polymerization must be carried out in the presence of the reactant of equimolar amounts and the acid acceptor of stoichiometric amount, and common acid acceptor is tertiary amine, such as pyridine, triethylamine, trimethylamine, the aniline and substituted aminopyridine or two or more mixtures of substitution.Then typically separate by being precipitated product in non-solvent from solution, and hydrochloride is removed by routine techniques known to persons of ordinary skill in the art purifying, such as by using acidic aqueous solution, such as watery hydrochloric acid washing removing hydrochloride.

Reaction time needed for solution polymerization is longer than melt polymerization.But the reaction condition used is much gentle, so as to farthest reduce side reaction, and more sensitive functional group can be introduced into polymer.Can be using interfacial polycondensation reaction when needing to obtain heavy polymer with high reaction rate.Gentle reaction condition farthest reduces side reaction.Also eliminate dependence of the HMW intrinsic in solution methods to the Chemical Calculation equivalent between glycol and dichloride (dichloridate).

The polymerization procedure (b) of the present invention is often carried out at the temperature slightly lower compared with step (a), but the change of reaction temperature can also be larger, this depends on the type of polymerisation used, presence, required molecular weight and the reactant of one or more catalyst and occurs the sensitiveness of undesirable side reaction.When using melting condition, the change of temperature turns to about 0-150 DEG C.But when polymerization procedure (b) is being carried out under the conditions of solution polymerization, it is typically carried out at about -40-100 DEG C.Typical solvent includes dichloromethane, chloroform or any various inert organic solvents.Time needed for the polymerisation of step (b) can also change in wider scope, this depend on the molecular weight of material requested and typically also depend on the different drastic conditions of degree of adoption make reaction reach needed for completeness this needs.But polymerization procedure (b) is typically progress about 30 minutes to 48 hours.

When using solution polymerization condition, it is particularly advantageous for there is acid acceptor during polymerization procedure (b).A particularly suitable class acid acceptor includes tertiary amine, such as pyridine, trimethylamine, triethylamine, the aniline and substituted aminopyridine or its two or more mixture of substitution.Most preferred acid acceptor is triethylamine or substituted aminopyridine DMAP (" DMAP ").

Structural formula I and II polymer can be separated using routine techniques from reactant mixture, such as by precipitation, with unmixing solvent extraction, evaporation, filtering and crystallization.But structural formula I and II polymer typically use non-solvent or partly soluble solvent, such as ether or petroleum ether make above-mentioned polymer solution impregnate and while separating and purifying.

Structural formula I and II polymer are generally characterised in that the rate of release of bioactive substance in vivo, the speed due to biodegradation during the hydrolysis of phosphoric acid ester bond of polymer at least partly controlled.In addition, the bioactive substance being released can combine to form pendant drugs release system with phosphorus side chain R '.In addition, other factorses are also important.

The life-span of biological degradation polyalcohol in vivo also depends on its molecular weight, crystallinity, biological stability and the degree of cross linking.Generally, molecular weight is bigger, crystallinity is higher and biological stability is higher, then biodegradable slower.

Therefore, the structure of side chain can influence the release behavior of the composition of matters of containing biological activities.For example, it is contemplated that phosphate side chain will slow down degradation process towards the group conversion that lipophilicity is stronger, hydrophobicity is stronger or bigger.Therefore, it is generally fast compared with from the polymer composition with larger aromatic side chains from the release in the polymer composition with smaller aliphatic group side chain.

The molecular weight of polymer used in the present composition can change, and polymer needed for this is depended primarily on is rigidity (higher molecular weight) or flowable or deformable state (lower molecular weight).The molecular weight that can be surveyed with ability with standard well-known to the ordinarily skilled artisan and input GPC and light scattering method.Generally, weight average molecular weight (Mw) changes typically in the range of 2,000-500,000 dalton, preferably from about 5,000-200,000 dalton, more preferably 10,000-150,000 dalton.

Structural formula I and II polymer can be used alone or forms various biodegradation materials as the also composition containing bioactive substance in addition and use.Even in the presence of no bioactive substance, such as structural formula I and II polymer can also be used to produce bioerodible suture, repair apparatus for correcting or bone cement, degradable or non-degradable fabric layered product or implanted device the external coating of bone or connective tissue damage.

However, biological degradation polyalcohol composition is preferably included simultaneously：(a) at least one bioactive substance, and (b) have the polymer of the repeated monomer unit shown in structural formula I or II, its Shen X, M₁、M₂, L, R, Y, x, y, q, r and n be as defined above.

The bioactive substance of the present invention can be widely varied according to the purpose of composition.Active material can be single one or more mixtures.The release system is designed to discharge the bioactive substance of highly-water-soluble and low aqueous solubility, to produce the release system with control release speed.Term " bioactive substance " includes, but not limited to medicine；Vitamin, mineral supplements；For treating, preventing, diagnose, cure or alleviate disease or the material of illness；Or influence body structure or the material of function；Or prodrug, they produce bioactivity after predetermined physiological environment is placed in or become more effective.

The tool of the bioactive substance of applicable above-mentioned classification, which stops example, includes (a) antitumor agent, such as inhibitor for androgen, antimetabolite, cytotoxic agent, immunomodulator；(b) anti-tussive agents, such as dextromethorphan, dextromethorphan hydrobromide, narcotine, carbetapentane citrate and chlorphedianolhydrochloride；(c) antihistamine, such as chlorpheniramine, phenindamine tartrate, Pyrilamine, the sour benzene ton carbinolamine of bat and citric acid Phenyltoloxamine are bluffed；(d) decongestant, such as meta-synephrine hydrochloride, phenylpropanolamine HC1, pseudoephedrine hydrochloride and ephedrine；(e) various alkaloids, such as codeine phosphate, codeine sulfate and morphine；(f) mineral supplements, such as potassium chloride, zinc chloride, calcium carbonate, magnesia and other alkali and alkaline earth metal ions salt；(g) ion exchange resin, such as cholestyramine；(h) antiarrhymic, such as N-Acetylprocainamide；(i) analgesic-antipyretic, such as paracetamol, aspirin and brufen；(j) appetite inhibitor, such as phenylpropanolamine HC1 or caffeine；(k) Eradicates phlegm agent, such as sweeter ether；(1) antacids, such as aluminium hydroxide and magnesium hydroxide；(m) biological agent, such as peptide, polypeptide, egg are from matter and amino acid, hormone, interferon or cell factor and other bioactivity peptides compound, such as hGH, tPA, calcitonin, ANF, EPO and insulin；Anti-infective, such as antifungal agent, antivirotic, preservative and antibiotic (n).

Bioactive substance is preferably selected from polysaccharide, growth factor, hormone, anti-angiogenesis, interferon and cell factor, and prodrug.Say that the non-limiting examples of useful bioactive substance include following treatment category class medicines in more specific 7 ground：Antalgesic, such as nonsteroidal anti-inflammatory agent, opiate agonist and salicylic acid esters；Antihistamine, such as H1- blocking agents and H2- blocking agents；Anti-infective, such as anti-anthelminthic, anaerobe resistant agent, antibiotic, aminoglycoside antibiotics, antifungal antibiotic, head embrace rhzomorph antibiotic, macrolide antibiotics, various beta-Lactam antibiotics, penicillin antibiotics, carbostyril antibiotic, sulfa antibiotics, tetracycline antibiotics, Antimycobacterial agent, Ad tuberculosis agent, antiprotozoan agent, antiplasmodial agent, antivirotic, antiretroviral agent, scabicide and anti-urinary tract infection medicine；Antitumor agent, such as alkylating agent, nitrogen mustards alkylating agent, nitrosoureas alkylating agent, antimetabolite, purine analogue antimetabolite, pyrimidine analogue antimetabolite, steroids antitumor agent, natural antitumor agent, the agent of antibioticses natural antitumor and vinca alkaloids natural antitumor agent；Autonomous medicine (autonomic agents), such as anticholinergic drug, antimuscarinics anticholinergic drug, peptide, parasympathomimetics, cholinergic agonist class parasympathomimetics, anticholinesterase parasympathomimetics, antisympathetic, alpha block agent class antisympathetic, beta blocker class antisympathetic, sympathetic transmitter releasers and 2-adrenergic agonist components sympathetic transmitter releasers；Cardiovascular drug, such as antianginal drug, beta blocker class antianginal drug, calcium channel blocker class antianginal drug, nitrate esters antianginal drug, antiarrhymic, cardiac glycosides antiarrhymic, I class antiarrhymics, II class antiarrhymics, Group III antiarrhymic, IV class antiarrhymics, antihypertensive, alpha block agent class antihypertensive, angiotensin converting enzyme inhibitors (Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe) class antihypertensive, beta blocker class antihypertensive, calcium channel blocker class antihypertensive, the adrenergic antihypertensive of central action, diuretics class antihypertensive, peripheral vasodilator agent class antihypertensive, antilipemic, bile acid chela replaces mixture antilipemic, HMG-CoA reductase inhibitor class antilipemic, contraction of muscle agent, the agent of cardiac glycosides contraction of muscle and thrombolytics；Dermatologic, such as antihistamine, anti-inflammatory agent, steroidal anti-inflammatory, antipruritic/local anesthetic, local anti-infective, antimycotic local anti-infective, antiviral local anti-infective and local antitumor agent；Electrolyte and renal drug, for example, be acidified medicine, alkalization medicine, diuretics, carbonic anhydrase inhibitor class diuretics, compensatory (loop) diuretics, osmotic diurtc, potassium deficiency diuretics, thiazide diuretic, electrolyte replacement and uricosuric；Enzyme, such as pancreatin and streptokinase；Gastrointestinal drug, such as antidiarrheal agent, antiemetic, intestines and stomach antiphlogistic, salicylic acid esters intestines and stomach antiphlogistic, antiacid class anti-ulcer agent, hydrochloric acid in gastric juice pump inhibitor class anti-ulcer agent, the anti-ulcer agent for acting on gastric mucosa, H2- blocking agent classes anti-ulcer agent, molten cholelith medicine, digestant, emetic, laxative and manure bate and rush digestive tract power reinforcing medicine；Anesthetic,general, such as inhalation anesthetic, halogenation species inhalation anesthetic, Intravenous Anesthesia agent, barbiturates Intravenous Anesthesia agent, benzene phenodiazine

Class Intravenous Anesthesia agent and opiate agonist class Intravenous Anesthesia agent；Hematologic drug, such as Antianemic Agents, hematopoietic Antianemic Agents, coagulant, anticoagulation, hemostatic coagulant, platelet suppressant drug class coagulant, thrombolysis enzyme coagulant and Plasma volumes expand agent；Hormone and hormone regulator, such as aborticide, adrenal gland medicine, corticosteroid adrenal gland medicine, androgen, antiandrogen, antidiabetic, sulfonyl urea antidiabetic medicine, antihypoglycemic, oral contraceptive, progestogens contraceptive, estrogen, the agent of antisterility disease, ocyodinic, parathyroid gland medicine, pituitrin, progestational hormone, antithyroid drug, thyroid hormone and tocolytic agent；Immunology medicine, such as immune globulin from, immunodepressant, toxoid and vaccine；Local anesthetic, such as amide-type local anesthetic and esters local anesthetic；Muscle skeleton medicine, such as antigout anti-inflammatory agent, corticosteroid anti-inflammatory agent, gold compound anti-inflammatory agent, immunodepressant AID, nonsteroidal anti-inflammatory agent (NSAIDs), salicylate AID, skeletal muscle relaxant, neuromuscular blocking agents class skeletal muscle relaxant and inverse neuromuscular blocking agents class skeleton muscle relaxant；Neurology medicine, such as anticonvulsant, barbiturates anticonvulsant, benzene phenodiazine

Class anticonvulsant, antimigraine, antiparkinsonian drug, antivertigo drug, opiate agonist and opiate antagonist；It is ophthalmic remedy, such as Betimol, beta blocker class Betimol, miosis Betimol, mydriatic, 2-adrenergic agonist components class mydriatic, anti-

Malicious bases mydriatic, ophthalmology anesthetic, ophthalmology anti-infectious agent, ophthalmology aminoglycoside anti-infectious agent, ophthalmology macrolides anti-infectious agent, ophthalmology quinolones anti-infectious agent, ophthalmology sulfamido anti-infectious agent, ophthalmology tetracycline anti-infectious agent, ophthalmic anti-inflammatory agent, ophthalmology corticosteroid anti-inflammatory agent and ophthalmology nonsteroidal anti-inflammatory agent (NSAIDs)；Chlorpromazine, such as antidepressants, heterocyclic antidepressants, MAOI (MAOIs), selective serotonin reuptaking inhibitor (SSRIs), tricyclic antidepressant, antimanic drug, antipsychotic drug, phenothiazines antipsychotic drug, solution anxiety agent, sedative, somnifacient, Barbiturates and urge medicament for the eyes and incitantia；It is respiratory drugs, such as anti-tussive agents, bronchodilator, 2-adrenergic agonist components class bronchodilator, anti-

Malicious bases bronchodilator, the agent of Eradicates phlegm, mucolytic, respiratory tract anti-inflammatory agent and respiratory tract corticosteroid respiratory tract anti-inflammatory agent；Toxicology medicine, example button antidote, heavy metal antagonist/chelating agent, drugs (substance abuse agents), poisonous substance prevent agent (deterrent substance abuse agents) and drug-breaking medicine；Mineral matter；And vitamin, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E and vitamin K.

The preferred classes of useful organisms active material in above range include：(1) nonsteroidal anti-inflammatory agent (NSAIDs) analgestic, such as Diclofenac, brufen, Ketoprofen and naproxen；(2) opiate agonist antalgesic, such as codeine, fentanyl, Hydromorphone and morphine；(3) salicylic acid esters analgestic, such as aspirin (ASA)；(4) H1- blocking agents class antihistamine, such as chlorine Ma Siting and RMI 9918；(5) H2- blocking agents class antihistamine, such as former times miaow replace fourth, famotidine, nizatidine and ranitidine；(6) anti-infectious agent, such as mupirocin；(7) anaerobe resistant class anti-infectious agent, such as chloramphenicol and lindamycin；(8) antifungal antibiotic class anti-infectious agent, such as amphotericin B, clotrimazole, fluorine health and ketone health；(9) macrolides antibiotics anti-infectious agent, such as azithromycin and erythromycin；(10) various beta-Lactam antibiotic class anti-infectious agents, such as AZT and Imipenem；(11) penicillin antibiotic class anti-infectious agent, example naphthlazole and OXA, benzyl penicillin and ospen；(12) quinolone antibiotic class anti-infectious agent, such as Ciprofloxacin and orfloxacin；(13) tetracycline antibiotics anti-infectious agent, such as Doxycycline, minocycline and tetracycline；(14) anti-mycobacterium tuberculosis class anti-infectious agent, such as isoniazid (INH) and rifampin；(15) antiprotozoan anti-infectious agent, such as Atovaquone and dapsone；(16) antiplasmodial class anti-infectious agent, chloroquine and pyrimethamine；(17) ARV class anti-infectious agent, such as Ritonavir, VX-478, Nai Feinawei, SQV and Zidovudine；(18) antiviral class anti-infectious agent, such as ACV, Cymevan, interferon-' alpha ' and Rimantadine；(19) alkylating agents antitumor agent, such as carboplatin and cis-platinum；(20) nitrosourea alkylating agents antitumor agent, such as carmustine (BCNU)；(21) antimetabolic antitumor agent, such as methotrexate (MTX)；(22) pyrimidine analogue antimetabolic antitumor agent, such as fluorouracil (5-FU) and gemcitabine；(23) steroids antitumor agent, such as Coserelin, Leuprorelin and TAM；(24) natural antitumor agent, such as Aldesleukin, proleulzin, docetaxel, etoposide (VP-16), interferon-' alpha ', taxol and Tretinoin (ATRA)；(25) antibioticses natural antitumor agent, such as bleomycin, actinomycin D, daunorubicin, adriamycin and mitomycin；(26) agent of vinca alkaloids natural antitumor, such as vincaleukoblastinum and vincristine；(27) from main ingredient, such as nicotine；(28) anticholinergic is from main ingredient, such as benzatropine and benzhexol；(29) antitoxin mouth bases anticholinergic is from main ingredient, such as atropine and light Dingning；(30) ergot alkaloids is from main ingredient, such as bromocriptine；(31) cholinergic agonist class parasympathomimetics, such as pilocarpine；(32) cholesterase inhibitor class parasympathomimetics, such as pyridostigmine；(33) alpha block agent class antisympathetic, such as prazosin；(34) beta blocker class antisympathetic, such as atenolol；(35) 2-adrenergic agonist components sympathetic transmitter releasers, such as salbutamol and dobutamine；(36) cardiovascular drug, such as aspirin (ASA)；(37) beta blocker class antianginal drug, such as atenolol and naphthalene；(38) calcium channel blocker class antianginal drug, such as Nifedipine and Verapamil；(39) nitrate esters antianginal drug, such as ISDN (ISDN)；(40) cardiac glycosides antiarrhymic, such as digoxin；(41) I classes antiarrhymic, such as lidocaine, mexiletine, phenytoinum naticum, procainamide and quinindium；(42) II classes antiarrhymic, such as atenolol, metoprolol, propranolol and timolol；(43) Group III antiarrhymic, such as amiodarone；(44) IV classes antiarrhymic, such as Diltiazem and Verapamil；(45) alpha block agent class antihypertensive, such as prazosin；(46) angiotensin converting enzyme inhibitors (Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe) class antihypertensive, such as captopril and Yi Na sounds profit；(47) beta blocker class antihypertensive, atenolol, metoprolol, Nadolol and propranolol；(48) calcium channel blocker class antihypertensive, such as that sulphur mouthful and Nifedipine；(49) the adrenergic antihypertensive of central action, such as clonidine and ethyldopa；(50) diuretics class antihypertensive, such as amiloride and frusemide, Hydrochioro (HCTZ) and spirolactone；(51) peripheral vasodilator agent class antihypertensive, such as hydrolazine and minoxidil；(52) antilipemic, such as Gemfibrozil and probucol；(53) bile acid sequestrant antilipemic, for example, bake and carry out enamine；(54) HMG-CoA reducing agents enzyme inhibitor class antilipemic, such as Lovastatin and Pravastatin；(55) contraction of muscle agent, such as ammonia power are dense, dobutamine and dopamine；(56) agent of cardiac glycosides contraction of muscle, such as digoxin；(57) thrombolytics, such as alteplase (TPA), Anistreplase, streptokinase and urokinase；(58) dermatologic, such as colchicin, isotretinoin, methotrexate (MTX), minoxidil, Tretinoin (ATRA)；(59) dept. of dermatology's steroidal anti-inflammatory, such as betamethasone and dexamethasone；(60) antimycotic local anti-infective, such as amphotericin B, clotrimazole, Miconazole and nystatin；(61) antiviral local anti-infective, such as ACV；(62) local anti-tumor agent, such as fluorouracil (5-FU)；(63) electrolyte and renal drug, such as lactulose；(64) compensatory diuretics, such as furosemide；(65) potassium deficiency diuretics, such as triamterene；(66) thiazide diuretic, such as Hydrochioro (HCTZ)；(67) uricosuric, such as probenecid；(68) enzyme, such as RNase and DNA enzymatic；(69) streptokinase, such as alteplase, Anistreplase, streptokinase and urokinase；(70) antidiarrheal agent, prochlorperazine；(71) salicylic acid esters intestines and stomach antiphlogistic, such as Liu Qing sulfapryidines；(72) hydrochloric acid in gastric juice pump inhibitor class anti-ulcer agent, such as Omeprazole；(73) H2- blocking agents class anti-ulcer agent, such as Cimetidine, famotidine, ZL-101 and ranitidine；(74) digestant, such as pancreatic lipase；(75) digestive tract power reinforcing medicine, such as domperidone are promoted；(76) opiate agonist class Intravenous Anesthesia agent, such as fentanyl；(77) hematopoietic Antianemic Agents, such as hematopoietin, filgrastin (G-CSF) and salad this (GM-CSF)；(78) coagulant, such as Antihemophilic Globulin 1-10 (AHF1-10)；(79) anticoagulation, such as warfarin；(80) thrombolysis enzyme coagulant, such as alteplase (TPA), Anistreplase, streptokinase and urokinase；(81) hormone and hormone regulator, such as bromocriptine；(82) aborticide, such as methotrexate (MTX)；(83) antidiabetic, such as insulin；(84) oral contraceptive, such as estrogen and progestational hormone；(85) progestogens contraceptive, such as Levonorgestrel and norgestrel；(86) estrogen, such as premarin, such as diethylstilbestrol (DES), estrogen (estradiol, oestrone and oestrone sulphate piperazine (estropipate)；(87) antisterility disease medicine, such as Clomifene, physex (HCG) and follicle-stimulating hormone (FSH)；(88) parathyroid gland medicine, such as calcitonin；(89) pituitrin, such as minirin, Coserelin, oxytocin and pitressin (ADH)；(90) progestational hormone, such as Medroxyprogesterone, norethindrone and progesterone；(91) thyroid hormone, such as Levothyroxine；(92) biological medicament, such as interferon beta-1b and interferon α-1b is immunized；(93) immune globulin is from, such as immune globulin from IM, IMIG, IGIM and immune globulin from IV, IVIG, IGIV；(94) amide-type local anesthetic, such as lidocaine；(95) esters local anesthetic, such as benzocainum and procaine；(96) muscle skeleton corticosteroid anti-inflammatory agent, such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone and metacortandracin；(97) skeletal muscle immunodepressant anti-inflammatory agent, such as imuran, endoxan and methotrexate (MTX)；(98) muscle skeleton nonsteroidal anti-inflammatory agent (NSAIDs), such as double chlorine go out sweet smell, brufen, Ketoprofen, ketorolac, naproxen；(99) skeletal muscle relaxant, such as Baclofen, cyclobenzaprine and the western Pan in ground；(100) inverse neuromuscular blocking agents class skeletal muscle relaxant, such as pyridine it is bright；(101) neurology medicine, such as Nimodipine, Riluzole, Tacrine and plug chloropyridine；(102) anticonvulsant, such as carbamazepine, Gabapentin, Lamotrigine, phenytoinum naticum and valproic acid；(103) barbiturates anticonvulsant, such as phenobarbital and Primidone；(104) benzene phenodiazine

Class anticonvulsant, such as chlorine nitre dissolve, diazepam and Laura dissolve；(105) antiparkinsonian drug, such as bromocriptine, levodopa, carbidopa and pergolide；(106) antivertigo drug, such as Meike profit piperazine；(107) opiate agonist, such as codeine, fentanyl, hydromorphone, methadone and morphine；(108) opiate antagonist, such as naloxone；(109) beta blocker class Betimol, such as timolol；(110) miosis Betimol, such as pilocarpine；(111) ophthalmology aminoglycoside anti-infectious agent, such as gentamicin, neomycin and TOB；(102) ophthalmology quinolones anti-infectious agent, such as Ciprofloxacin, Norfloxacin and Ofloxacin；(113) ophthalmology corticosteroid anti-inflammatory agent, such as dexamethasone and prednisolone；(114) ophthalmology nonsteroidal anti-inflammatory agent (NSAIDs), such as double chlorine go out sweet smell；(115) antipsychotic drug, such as Clozapine, haloperole and risperidone；(116) benzene phenodiazine

The agent of class solution anxiety, sedative and somnifacient, such as Clonazepam, diazepam, Lorazepam, Oxazepam and prazepam；(117) incitantia, such as methylphenidate and pemoline；(118) anti-tussive agents, such as codeine；(119) bronchodilator, such as theophylline；(120) 2-adrenergic agonist components class bronchodilator, such as salbutamol；(121) corticosteroid respiratory tract anti-inflammatory agent, such as dexamethasone；(122) antidote, such as Flumazenil and naloxone；(123) heavy metal antagonist/chelating agent, such as penicillamine；(124) poisonous substance prevents agent, such as disulfiram, naltrexone and nicotine；(125) mineral matter, such as iron, calcium and magnesium；(126) vitamin B compound, such as cyanocobalamin (vitamin B₁₂) and nicotinic acid (vitamin B₃)；(127) vitamin C compounds, such as ascorbic acid；(128) vitamin D compounds, such as calcitriol.

In addition to above-mentioned, it is possible to use following medicines less commonly used：Wash the oil solution than safe, ring malonic acid estradiol；The oil solution of Estradiol Valerate；Flurbiprofen；Flurbiprofen sodium；Ivermectin HCL；Levodopa；Nanofarad Rayleigh and somatropin.

In addition, the medicine of following intravenously administrables can be used：Acyclovir sodium；Aldesleukin；Atenolol；Bleomycin Sulphate, human calcitonin；Salmon calcitonin；Carboplatin；Karma STING；Actinomycin D, daunorubicin hydrochloride；Erythromycin；Docetaxel；Doxorubicin hydrochloride；Epoetin beta α；Etoposide (VP-16)；Fluorouracil (5-FU)；Cymevan sodium；Gentamicin sulphate；Interferon-' alpha '；TAP-144；Spasmedal；Methadone hydrochloride；Methotrexate sodium；Taxol；Ranitidine hydrochloride；Vinblastine sulfate；With Zidovudine (AZT).

In addition, it is also possible to use following peptide, egg from matter and other macromolecular substances, such as from interleukin 1-18, including its mutant and analog；Interferon-' alpha ', β and γ；Luteinising hormone-releasing hormo (LHRH) and its analog；Promoting sexual gland hormone, which is translated, puts hormone (GnRH), transforming growth factor-β (TGF-β)；Fibroblast growth factor (FGF)；Tumor necrosis factor-alpha and β (TNF-α and β)；Nerve growth factor (NGF)；Somatotropin releasing factor (GHRF)；EGF (EGF)；Fibroblastic growth factor autofactor 1 (FGFHF)；HGF (HGF)；Insulin-like growth factor (IGF)；Invade inhibiting factor -2 (IIF-2)；Bones morphology forms egg from 1-7 (BMP1-7)；Somatostatin；Thymosin extrasin-α a-1；Gamma- balls egg is certainly；Superoxide dismutase (SOD)；And complement factor.

Or, bioactive substance can be radiosensitizer, such as Metoclopramide, sensamide or neusensamide (being manufactured by Oxigene)；Profiromycin (is manufactured) by Vion；RSR13 (is manufactured) by Allos；Thymitaq (is manufactured) by Agouron；Etanidazole or lobenguane (being manufactured by Nycomed)；Gadoliniumtexaphrin (is manufactured) by Pharmacyclics；BuDR/Broxine (is manufactured) by Neopharm；IPdR (is manufactured) by Sparta；CR2412 (being manufactured by CellTherapeutic) or L1X (being manufactured by Terrapin) etc..

In particularly preferred embodiments, bioactive substance is medicine or prodrug, the most preferably medicine selected from following classifications：Chemotherapeutics and other antitumor agents, antibiotic, antivirotic, antifungal agent, anti-inflammatory agent and anti-coagulants.Bioactive substance is most preferably taxol and docetaxel.

The consumption of bioactive substance is therapeutically effective amount.The effective dose of bioactive substance depends on used certain material, is easy to be incorporated into the release system of the present invention when the amount of bioactive substance is about 1%-65%, obtains control release effect.For some bioactive substances, less consumption can obtain the level of significance for the treatment of.

Pharmaceutical acceptable carrier can be prepared with various materials.They are such as, but not limited to, diluent, adhesive and adhesive, lubricant, disintegrant, colouring agent, filler, aromatic, sweetener and various materials for preparing specific drugs composition, such as buffer and adsorbent.

The simplest form of biodegradable therapeutic agent release system is made up of the dispersion of therapeutic agent in the polymer matrix.When polymer substrate in vivo it is biodegradable for can be from the soluble product discharged in vivo when, therapeutic agent is released.

In particularly preferred embodiments, product is used to be implanted into, inject or completely or partially insert in vivo, and the product includes the biological degradation polyalcohol composition of the present invention.The bioactive substance and polymer of the present composition can form uniform matrix, or bioactive substance can be encapsulated in the polymer using some modes.For example, bioactive substance can be encapsulated in microballoon first, then combined in the way of at least holding part micro-sphere structure with polymer.Or bioactive substance can be fully unmixing in the polymer of the present invention, i.e., be scattered in droplet form in polymer, without being dissolved in polymer.Both forms are all subjected to, however, the hydrolysis that the uniformity of composition how, is preferably due to phosphoric acid ester bond of the polymer during biodegradation makes the rate of release of bioactive substance in vivo remain at least partly controlled.

In preferred embodiments, designed inventive article is for being implanted into or being injected into animal body.Particularly importantly this product only produces minimum tissue stimulation effect when being implanted into or being injected into vascular tissue.

As structural type medical apparatus, polymer composition of the invention is provided with the composition that specified chemical, the physical form of physical and mechanical property and degradation in vivo are non-toxic residues.Typical structural type medical product includes implant, such as orthopedic fixator, ventricular shunt device, degradable fabric layered product, pharmaceutical carrier, bioerodible suture, burn dressing and the outer membrane that is placed on other implanted devices.

As orthopedic product, composition of the invention can be used for repairing bone and connective tissue damage.It can for example be formed with Bones morphology and each be carried on the bone graft formed on biodegradable porous material for even larger segmental defect.In vessel graft application, the biodegradation material of woven fabric form can be used for promotion organization ingrowing.The polymer composition of the present invention, which can be used as provisional barrier, to be used to prevent tissue adhesion, such as in abdominal postoperative.

On the other hand, as nerve regneration product, the presence of biodegradable supported matrix contributes to cell adherence and propagation.When by polymer composition be made for nerve produce pipe when, for example functional rehabilitation guidance in the tubular body also can as axon elongation geometry guide.

As drug release device, polymer composition of the invention provide the polymer substrate that can chelate bioactive substance and can predetermined control discharge the material.Then polymer substrate degradation is nontoxic residue.

Biodegradable medical embedded device and insoluble drug release product can be prepared using several means.Can be using conventional extrusion or injection molding technology melt processable polymer, or these products can be by dissolving a polymer in appropriate solvent, forming apparatus, then removes solvent to prepare by evaporation or extraction.

Once medical embedded product enters position, it at least answers holding part and biofluid, is contacted such as blood, internal's secretion, mucous membrane and cerebrospinal fluid.

[embodiment]

Embodiment 1：It is that starting material synthesizes poly- (L- lactides-cyclohexanedimethanol-etherophosphoric acid with 1,4-CHDM (CHDM) LAEG-CHDM-EOP) polymer

By 20g (0.139mol) (3S)-cis- 3,6- dimethyl -1,4- dioxane -2,5- diketone (L- lactide LAEG) (is bought from Aldrich Chemical Company, with re-crystallizing in ethyl acetate, distil and again with re-crystallizing in ethyl acetate) and 2.0g (13.9mmol) 1,4-CHDM be placed on 250ml be full of dry argon gas round-bottomed flask in.The flask is sealed and is placed under vacuo and is heated in 140 DEG C of baking oven.Under intermittent oscillating, the flask is set to keep at such a temperature about 48 hours.

Then take out flask and be reduced to room temperature, add 200ml chloroform stirring and dissolvings, be put into ice salt bath and cool, add 4ml triethylamines.Under argon gas stream and stirring, kept for 20-30 DEG C, be slowly added into 2.26g dichloro- etherophosphoric acids.After stirring 1 hour, polymer solution is quenched into refining twice in one liter of ether, near-white precipitation is obtained, is dried under vacuum.

Embodiment 2：Poly- LAEG-CHDM-EOP property is prepared described in embodiment 1

The polymer prepared as described in Example 1, wherein (x or y)/n=10：1.Gained it is poly- (LAEG-CHDM-EOP) polymer is used as standard with polystyrene by GPC and analyzed, the bright Mw of chart of gained is 18856 for 38341, Mn, as shown in Figure 2.

This is 37.67 DEG C by the DSC Tg measured, as shown in Figure 3.

Embodiment 3：With terephthalyl alcohol(Isosorbide-5-Nitrae-Benzenedimethanol)Poly- (LAEG-BZDM-EOP) polymer is synthesized for starting material

By 20g (0.139mol) L- lactides (being bought from Aldrich Chemical Company, with re-crystallizing in ethyl acetate, distil and again with re-crystallizing in ethyl acetate) and 1.92g (13.9mmol)Terephthalyl alcoholIt is placed in round-bottomed flasks of the 250ml full of dry argon gas.The flask is sealed and is placed under vacuo and is heated in 140 DEG C of baking oven.Under intermittent oscillating, the flask is set to keep at such a temperature about 48 hours.

Then it is placed on and is heated in 135 DEG C of oil bath in flask.Under argon gas stream and stirring, 2.26g dichloro- etherophosphoric acids are added.After stirring 1 hour, relatively low vacuum (about 20mmHg) is applied to the system, it is stood overnight.1 hour before post processing, using high vacuum.After cooling, dissolve a polymer in 200ml chloroforms and refining is quenched in one liter of ether twice, obtain near-white precipitation, be dried under vacuum.

Embodiment 4：With4,4 '-biphenyl is to dimethanol (4,4 '-Bis (hydroxymethyl) biphenyl)Poly- (LAEG-BHMBP-EOP) is synthesized for starting material Polymer

By 20g (0.139mol) L-3,6- dimethyl -1,4- dioxane -2,5- diketone (L- lactides) (is bought from Aldrich ChemicalCompany, with re-crystallizing in ethyl acetate, distil and use re-crystallizing in ethyl acetate again) and 2.97g (13.9mmol) 4,4 '-biphenyl is placed on 250ml to dimethanol and is full of in the round-bottomed flask of dry argon gas.The flask is sealed and is placed under vacuo and is heated in 140 DEG C of baking oven.Under intermittent oscillating, the flask is set to keep at such a temperature about 48 hours.

Then take out flask and be reduced to room temperature, add 200ml chloroform stirring and dissolvings, be put into ice salt bath and cool, add 4ml triethylamines.Under argon gas stream and stirring, kept for 20-30 DEG C, be slowly added into 2.26g dichloro- etherophosphoric acids.After stirring 1 hour, polymer solution is quenched into refining twice in one liter of ether, near-white precipitation is obtained, is dried under vacuum.

Embodiment 5：It is that starting material synthesizes poly- (DLAEG-CHDM-EOP) with 1,4-CHDM (Isosorbide-5-Nitrae-Cyclohexanedimethanol) Polymer

By 20g (0.139mol) DL-3,6- dimethyl-Isosorbide-5-Nitrae-dioxane -2,5- diketone (DL- lactides DLAEG) (being bought from AldrichChemical Company, with re-crystallizing in ethyl acetate, distil and again with re-crystallizing in ethyl acetate) and 2.0g (13.9mmol)1,4-CHDMIt is placed in round-bottomed flasks of the 250ml full of dry argon gas.The flask is sealed and is placed under vacuo and is heated in 140 DEG C of baking oven.Under intermittent oscillating, the flask is set to keep at such a temperature about 48 hours.

Then it is placed on and is heated in 135 DEG C of oil bath in flask.Under argon gas stream and stirring, 2.26g dichloro- etherophosphoric acids are added.After stirring 1 hour, relatively low vacuum (about 20mmHg) is applied to the system, it is stood overnight.1 hour before post processing, using high vacuum.After cooling, dissolve a polymer in 200ml chloroforms and refining is quenched in one liter of ether twice, obtain near-white precipitation, be dried under vacuum.

Embodiment 6：The preparation of microballoon

(double emulsions) or solvent dilution method are evaporated by solvent, with ethyl acetate as solvent byPoly- (L- lactides-etherophosphoric acid) gathers CompoundPrepare microballoon.As a result it is as shown in Figure 8.

Embodiment 7：The preparation of the polymer microballoon of taxol containing 15% theoretical load level

The 0.5%PVA aqueous solution is used as aqueous phase, taxol and polymerLAEG-CHDM-EOP(taxol accounts for 15%) is made into 30% dichloromethane solution as oil phase.Aqueous phase and oil phase form microballoon by vortex mixing according to a certain percentage.Emulsion after emulsification imports round-bottomed flask, adds purified water to be diluted while stirring, until microballoon hardening, and continue to stir 2 hours.Microballoon is filtered out using screen cloth, and is rinsed with purified water, is finally freeze-dried.

Embodiment 8：The polymer of FITC-BSA containing 10% theoretical load level(LAEG-CHDM-EOP) the preparation of microballoon

100ml FITC-BSA solution (the 100mg/ml aqueous solution) is added to 100mgPoly- (LAEG-CHDM-EOP)0.5ml dichloromethane solutions in, on ice passing through sound wave emulsify 15 seconds.In 5% sodium chloride solution that gained emulsion is poured into 1% polyvinyl alcohol (PVA) of 5ml vortexs immediately, and continue to be vortexed 1 minute.Then the emulsion of formation is poured into 20ml0.3%PVA 5% sodium chloride solution Shen, is stirred vigorously simultaneously.25ml2% aqueous isopropanols are added, make the mixture continue to be kept stirring for 1 hour, to ensure that extraction is complete.By the way that thus obtained microsphere is collected by centrifugation under 3000Xg, it is washed with water 3 times and freezes.

By using 5% sodium chloride solution or 5% sodium chloride solution containing 1%PEG8000 prepares the microballoon of different formulations as the second aqueous phase.Another technology evaporation solvent can be used, i.e., by the way that the mixture was stirred overnight, so evaporates to form microballoon by solvent.

Embodiment 9：Taxol is from polymer(LAEG-CHDM-EOP) the release in vitro in microballoon

Taxol release in vitro from microballoon is carried out using USP4 methods digestion instrument in phosphate buffer (PH7.4) at 37 DEG C.With ultraviolet spectrometry detector at 228nm on-line checking.Analyzed by absorption value, taxol powder and taxol microballoon vitro cumulative release taxol situation.As a result it is as shown in Figure 9.

Claims (14)

1. a kind of biological degradation polyalcohol, includes the repeated monomer unit shown in following formula II：

Wherein：

X be selected from-O- or-NR '-, wherein R ' is H or alkyl；

M₁、M₂Selected from each independent, (1) has a side chain or aliphatic groups of 1-20 carbon atom, or (2) have the side chain of 1-20 carbon atom or amino-aliphatic group of straight chain；

L is selected from sub- cyclohexyl；

R is selected from alkoxy, aryloxy group or heterocyclic oxy group；

X or y is from the arbitrary integer between 1-200；

X: y mol ratio is 1；

N: the mol ratio of (x or y) be 1: 200 to 200: 1 between；And

Q: r mol ratio be 1: 200 to 200: 1 between；

The weight average molecular weight of GPC or light scattering determining polymer is 2000-500000 dalton.

2. biological degradation polyalcohol according to claim 1, it is characterised in that：Described R is selected from alkoxy, phenoxy group or heterocyclic oxy group.

3. biological degradation polyalcohol according to claim 1, it is characterised in that：Described n: the mol ratio of (x or y) be 100: 1~1: 100 between.

4. biological degradation polyalcohol according to claim 1, it is characterised in that：Q: r described mol ratio is 1: 150~150: 1.

5. the preparation method of biological degradation polyalcohol according to claim 1, it is characterised in that comprise the steps：

(a) by least one formula II I, structural formula IV, structural formula V heterocyclic compound and initiator H-O-CH₂-L-CH₂- O-H reacts, and forms structural formula VII prepolymer,

Wherein X be selected from-O- or-NR '-, wherein R ' is H or alkyl；

M₁、M₂Selected from each independent, (1) has a side chain or aliphatic groups of 1-20 carbon atom, or (2) have the side chain of 1-20 carbon atom or amino-aliphatic group of straight chain；

L is selected from sub- cyclohexyl；

X or y is from the arbitrary integer between 1-200；

X: y mol ratio is 1；

N: the mol ratio of (x or y) be 1: 200 to 200: 1 between；And

Q: r mol ratio be 1: 200 to 200: 1 between；

The weight average molecular weight of GPC or light scattering determining polymer is 2000-500000 dalton；

(b) structural formula VII prepolymer is reacted with structural formula VIII dihalo- substituted phosphate, form the polymer for including formula II described in claim 1,

Wherein " halo " is Br, Cl or I；

R is selected from alkoxy, aryloxy group or heterocyclic oxy group.

6. the preparation method of biological degradation polyalcohol according to claim 5, it is characterised in that：The step (a) is carried out under 110~+235 DEG C of melting condition.

7. the preparation method of biological degradation polyalcohol according to claim 5, it is characterised in that：When the step (b) under the conditions of solution polymerization using carrying out, temperature is -40-100 DEG C.

8. the preparation method of biological degradation polyalcohol according to claim 5, it is characterised in that：In the step (a), formula II I, IV uses caprolactam, caprolactone；Structural formula V heterocyclic compounds use glycolide or lactide.

9. the preparation method of biological degradation polyalcohol according to claim 5, it is characterised in that：In the step (b), solution polymerization is carried out in the presence of the reactant of equimolar amounts and the acid acceptor of stoichiometric amount.

10. the preparation method of biological degradation polyalcohol according to claim 9, it is characterised in that：The acid acceptor is mixture more than one or both of pyridine, triethylamine, trimethylamine, the aniline of substitution or substituted aminopyridine.

11. a kind of biological degradation polyalcohol composition, it is characterised in that include：

(a) at least one bioactive substance, and

(b) polymer as claimed in claim 1 with formula II repeated monomer unit.

12. biological degradation polyalcohol composition according to claim 11, it is characterised in that：Described bioactive substance includes：For treating, preventing, diagnose, cure or alleviate disease or the material of illness；Or influence body structure or the material of function；Bioactivity is either produced after predetermined physiological environment is placed in or becomes more effective prodrug.

13. biological degradation polyalcohol composition according to claim 11, it is characterised in that：The amount of the bioactive substance accounts for the 1%-65% of composition total weight.

14. biological degradation polyalcohol composition according to claim 11, it is characterised in that：Polymer composition is the solid form or powdered coating materials form of microspheres form, as needed compacting or film tool injection.

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