WO2003042277A1 - Polymere contenant des drogues psycho-actives et possedant des acides amines dans sa chaine principale, et son procede de preparation - Google Patents

Polymere contenant des drogues psycho-actives et possedant des acides amines dans sa chaine principale, et son procede de preparation Download PDF

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WO2003042277A1
WO2003042277A1 PCT/CN2001/001622 CN0101622W WO03042277A1 WO 2003042277 A1 WO2003042277 A1 WO 2003042277A1 CN 0101622 W CN0101622 W CN 0101622W WO 03042277 A1 WO03042277 A1 WO 03042277A1
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polymer
drug
acid
polyester
preparation
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PCT/CN2001/001622
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English (en)
French (fr)
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Shujun Cheng
Zhirong Tang
Ju Rao
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East China University Of Science And Technology
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Priority to US10/495,328 priority Critical patent/US20050106120A1/en
Publication of WO2003042277A1 publication Critical patent/WO2003042277A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/685—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen
    • C08G63/6852—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/21—Acids
    • A61L2300/214—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation

Definitions

  • the present invention relates to a high molecular polymer, in particular to a polyester containing an active drug and a preparation method thereof. Background technique
  • Biodegradable polyesters such as poly (lactic acid), PLA, poly (glycolic acid), PGA, polycaprolactone (PCL) and their copolymers
  • FDA US Food and Drug Administration
  • polylactic acid also known as polylactide
  • FDA US Food and Drug Administration
  • polylactide can be used as surgical sutures and microcapsules, microspheres and implants for injection And other preparation materials.
  • the chemical structure of these polyesters determines their performance limitations: they lack reactive groups.
  • Targeting and sustainable release of drugs are currently one of the hottest points of polymer materials in the medical field.
  • Targeted administration can be performed through a catheter, a drug stent, or a specific antibody.
  • the controlled release of drugs includes diffusion and degradation release.
  • the effects of drugs and polymer materials are physical blending and chemical bonding. Due to the relatively stable release of chemically bound drugs, the action time is relatively long, which has attracted people's attention, and has been approved for clinical use.
  • U.S. Patent No. 5,855,618 discloses a pharmaceutical polymer grafted with polyethylene oxide grafting polyurethane (PEO-g-PU) and bonded to heparin.
  • PEO-g-PU polyethylene oxide grafting polyurethane
  • the drug has the following defects:
  • the terminal group of polyethylene oxide is hydroxyl group, which can only undergo esterification reaction with carboxyl group.
  • the polymer drug of the present invention is a polymer having the following structural formula:
  • ⁇ represents the degree of polymerization, which ranges from 1 to 3,000
  • y represents the degree of polymerization, which ranges from 1 to 1,000.
  • the polymer can be divided into two parts, one of which is a polymer matrix material The second is a drug with a reactive group.
  • the molar content of amino acids in the above polymer is 1% ⁇ 49%, which can be analyzed by NMR; the relative number average molecular weight range of the polymer matrix material is 500 ⁇ 200,000, and its molecular weight distribution is 1.2-3.6, which can be characterized by GPC.
  • the polymer described above was prepared as follows:
  • lactide or lactone with polyfunctional amino acids lysine, Lys, serine, Ser
  • aspartic acid Aspartic acid
  • Glu glutamic acid
  • the derivative of morpholine-dione is polymerized in a N 2 atmosphere using stannous octoate as a catalyst; the reaction temperature is 120 to 170 ° C, and the reaction time is 1 to 10 hours.
  • the obtained polymer is catalyzed by Pd / C as catalyst at room temperature for more than 24 to 80 hours or HBr HAc is used. After the protective group is removed for the catalyst, a biodegradable polyester having a reactive side group is obtained, the reaction temperature is 10-35 ° C, and the reaction time is 24-80;
  • the deprotected polymer and the drug are dissolved in a suitable solvent and reacted with dicyclohexylcarbodiimide (DCC) as a catalyst to obtain a fully biodegradable drug polymer (medico-macromolecule) ;
  • DCC dicyclohexylcarbodiimide
  • the reaction temperature is 0 ⁇ 5 ° C, and the reaction time is 18 ⁇ 40h;
  • the solvent is one of tetrahydrofuran, chloroform or tetrahydrofuran / water.
  • the present invention has positive significance.-It is well known that a -L-amino acid is the final product of poly- ⁇ -L-amino acid degradation, and many of the natural amino acids are polyfunctional. Although a-L-amino acid is not toxic, its polymer The oligomers produced during the degradation process have antigenicity.
  • a natural polyfunctional amino acid is randomly introduced into a biodegradable polyester, thereby avoiding the antigenicity of the degradation product, and at the same time, the degradation product can be completely bioabsorbed.
  • the new polyester may contain active groups such as carboxyl group, hydroxyl group, and amino-group. As long as the drug contains functional groups such as carboxyl, hydroxyl, and amino groups, the polyester can be bonded to the polyester. .
  • the obtained drug polymer can work directly or after degradation.
  • the invention can be used as a coating for a medical device, while improving the biocompatibility of the device while carrying a targeted drug, thereby achieving the purpose of targeted continuous administration. It can also be made into implants or other preparations.
  • poly (lactic-co-glycolic acid-aspartic acid) was obtained, with a molecular weight of 50,000 and an amino acid content of 17%.
  • Heparin contains amino and carboxyl groups, and 3 g of poly (lactic-co-glycolic acid-aspartic acid) is dissolved in 100 ml of a mixed solvent of tetrahydrofuran and water (1: 1), also known as 0.5 g (according to the polymer's Gel Permeation Chromatography, GPC molecular weight and amino Sodium heparin is dissolved in a small amount of water, and the pH is adjusted to about 4 with a dilute acid.
  • Penicillin contains a carboxyl group and an amino group.
  • 2 g of poly (lactic-co-glycolic acid-aspartic acid) and lg (based on the GPC molecular weight and amino acid content of the polymer) of penicillin in Example 2 were dissolved in chloroform. An equivalent amount of DCC was stirred at 4 ° C for 24 hours, and the insoluble matter was filtered off. The obtained solution was precipitated with petroleum ether and dried at room temperature for 24 hours to obtain a drug polymer.
  • Poly (lactic-glycolic-glutamic acid) is bonded to heparin.
  • 3 g of poly (lactic-co-glycolic acid-glutamic acid) from Example 1 was dissolved in a mixed solvent of tetrahydrofuran and water, and 0.5 g of sodium heparin (based on the GPC molecular weight and amino acid content of the polymer) was also dissolved in a small amount of water.
  • Poly (lactic-co-glycolic acid-glutamic acid) is bonded to penicillin.
  • Penicillin contains a carboxyl group and an amino group.
  • 2 g of poly (lactic-co-glycolic acid-glutamic acid) and lg (according to the GPC molecular weight and amino acid content of the polymer) of Example 1 were dissolved in chloroform, and an equivalent amount of DCC was added. The mixture was stirred at 4 ° C for 24 hours, and the insoluble matter was filtered off. The obtained solution was precipitated with petroleum ether and dried at room temperature for 24 hours to obtain a drug polymer.
  • Poly (lactic-co-glycolic acid-serine) is bonded to aspirin.
  • poly (lactic-co-glycolic acid-serine) was obtained by replacing glutamic acid with serine.
  • Aspirin contained a carboxyl group. 2 g of poly (lactic-co-glycolic acid-serine) and 1.5g (according to the GPC molecular weight and amino acid content of the polymer) of aspirin was dissolved in chloroform, and an equivalent amount of DCC was added, and the mixture was stirred at 4 ° C for 24 hours. The insoluble matter was filtered off. The resulting solution was precipitated with petroleum ether and dried at room temperature. In 24 hours, a drug polymer is obtained.
  • Poly (lactic-co-glycolic acid-serine) is bonded to penicillin.
  • Penicillin contains a carboxyl group and an amino group.
  • 2 g of poly (lactic-co-glycolic acid-serine) and lg (based on the GPC molecular weight and amino acid content of the polymer) of penicillin in Example 6 were dissolved in chloroform, and an equivalent amount of DCC was added. After stirring at ° C for 24 hours, the insoluble matter was filtered off. The obtained solution was precipitated with petroleum ether and dried at room temperature for 24 hours to obtain a drug polymer.
  • Poly (lactic acid-glycolic acid-serine) is bonded to heparin.
  • 3 g of poly (lactic-co-glycolic acid-serine) from Example 6 was dissolved in a mixed solvent of tetrahydrofuran and water, and another 0.5 g (based on the GPC molecular weight of the polymer and Amino acid content) of sodium heparin is dissolved in a small amount of water, and the pH is adjusted to about 4 with dilute acid.
  • Poly (lactic-glycolic-lysine) bonded to penicillin Using the same method as in Example 1, but replacing glutamic acid with lysine, poly (lactic acid-light acetic acid-lysine) was obtained, and 2 g of poly (lactic acid-glycolic acid-lysine) and lg (According to the GPC molecular weight and amino acid content of the polymer) penicillin was dissolved in chloroform, and an equivalent (equivalentpCC, stirred at 4 ° C for 24 hours, filtered off the insoluble matter, the resulting solution was precipitated with petroleum ether, and dried at room temperature for 24 hours, The drug polymer is obtained.
  • Poly (lactic-glycolic-lysine) bonded to heparin 3g of poly (lactic-co-glycolic acid-lysine) is dissolved in a mixed solvent of tetrahydrofuran and water, and another 0.5g of sodium heparin (based on the GPC molecular weight and amino acid content of the polymer) is dissolved in a small amount of water. Adjust the pH to around 4. Mix the two, add an equivalent amount of DCC, stir at 4 ° C for 24h, remove the solvent under reduced pressure, then add an appropriate amount of chloroform, filter off the insoluble matter, precipitate the solution with petroleum ether, and dry at room temperature for 24h to obtain the drug. molecule.
  • Poly (lactic-glycolic-lysine) bonded to aspirin Dissolve 2 g of poly (lactic-co-glycolic acid-lysine) and 1.5 g of aspirin (based on the GPC molecular weight and amino acid content of the polymer) in chloroform, add an equivalent amount of DCC, and stir at 4 ° C for 24 h The insoluble matter was filtered off, and the resulting solution was precipitated with petroleum ether and dried at room temperature for 24 hours to obtain a drug polymer.

Description

含有活性药物、 主链中具有氨基酸的聚酯及其制备方法 技术领域
本发明涉及一种高分子聚合物， 具体地说涉及一种含有活性药物的聚酯及其制 备方法。 背景技术
随着现代医学的发展， 不断有新的治疗理念及其相关的医疗器械出现， 作为制 作医疗器械的生物材料必须具有一个基本通性， 即生物相容性。 生物降解型聚酯， 如聚乳酸 （poly(lactic acid), PLA)、 聚乙交酯（poly(glycolic acid), PGA), 聚 ε -己内 酯 （polycaprolactone， PCL)及其共聚物由于其具有优良的生物相容性和可生物降解 性而成为近年来生物材料的研究热点。 其中经美国食品与医药管理局 (U.S. Food and Drug Administration, FDA)批准， 聚乳酸 (也称聚丙交酯（ polylactide))可用作医用手术缝 合线和注射用微胶囊、 微球及埋植剂等制剂的材料。 但这些聚酯的化学结构决定了 其性能上的局限性： 缺少可反应性基团。
药物的靶向性 (targetting)及可持续释放性是目前高分子材料在医学领域的最大热 点之一。
靶向给药可以通过导管、 药物支架或特定的抗体 (specified antibody)进行。
药物的控制释放的途径有扩散及降解释放等。 药物与高分子材料的作用有物理 共混 (blending)和化学结合 (bonding), 由于化学结合的药物释放比较稳定， 作用时间 较长， 尤其受到了人们的关注， 已有一些批准用于临床。
美国专利 U.S. 5,855,618公开了一种用聚环氧乙垸接枝聚氨酯 (polyethylene oxide) grafting polyurethane, PEO-g-PU)并与肝素键合的药物高分子。 但该药物存在以下缺 陷：
1 ) 聚氨酯或聚环氧乙烷接枝聚氨酯在体内的生物相容性不理想， 降解产物可能 有毒。
2) 聚环氧乙垸的端基为羟基， 只可与羧基发生酯化反应， 若要键合含氨基或羟 基的药物还需以剧毒的二异氰酸酯为桥梁， 且步骤过多。
因此， 提供一种制备可完全生物降解的无任何毒副作用的高分子药物将具有重 要的意义。 发明的公开
本发明需要解决的技术问题之一是提供一种含有活性药物、 主链中具有氨基酸 的聚酯， 以克服现有技术存在的在体内的生物相容性不理想， 降解产物可能有毒、 只可与羧基发生酯化反应、 需以剧毒的二异氰酸酯为桥梁、 且步骤过多的缺陷； 本发明需要解决的技术问题之二是提供上述主链中含有氨基酸和活性药物的聚 酯的制备方法。
本发明的高分子药物为具有如下结构通式的聚合物：
Figure imgf000004_0001
其中:
代表 CH2OH、 CH2COOH、 CH2CH2COOH或 CH2CH2CH2CH2NH2中的一种， 俗称分别为丝氨酸、 天冬氨酸、 谷氨酸和赖氨酸；
代表具有可反应基团的药物， 即其结构式中含有羟基、 氨基、 羧基等官能团; , 1 4为聚酯的侧基： 包括一 H或一 CH3 ;
n = l~5; α -羟基酸， η=1 ; β -羟基酸， n=2; y -羟基酸， η=3; δ -轻基酸， η=4; ε -羟基酸， η=5;
χ代表聚合度， 其范围为 1~3,000， y代表聚合度， 其范围为 1~1,000； 由上述公开的结构式可见， 所说的聚合物可分为两个部分， 其一为高分子基质 材料， 其二为具有可反应基团的药物。
上述聚合物中氨基酸摩尔含量为 1 %〜49%， 可用 NMR进行分析； 高分子基质材料的相对数均分子量范围为 500〜200,000， 其分子量分布为 1.2-3.6, 可用 GPC进行表征。
上述的聚合物是这样制备的：
(1)聚合：
一定量的交酯或内酯与含多官能团氨基酸 (赖氨酸 (lysine, Lys)、 丝氨酸 (serine, Ser)、 天冬氨酸 (aspartic acid, Asp)及谷氨酸 (glutamic acid, Glu))的吗啉二酮衍生物 (derivative of morpholine-dione)以辛酸亚锡 (stannous octoate)为催化剂， 在 N2气氛下 进行聚合； 反应温度为 120~170°C， 反应时间为 1~10小时， 各物料的配比为： 交酯 或内酯： 含多官能团氨基酸的吗啉二酮单体： 催化剂 = 1 ： ( 0.01-50 ) ： (0.0002-0.002)；
(2)脱保护：
所得聚合物在室温下用 Pd/C为催化剂催化氢化 24~80小时以上或采用 HBr HAc 为催化剂脱去保护基团后， 便得到了具有可反应性侧基的生物降解型聚酯， 反应温 度为 10~35°C， 反应时间为 24〜80；
(3)键合：
再将脱保护后的聚合物与药物溶解在适当的溶剂中， 以二环己基碳二亚氨 (dicyclohexylcarbodiimide, DCC)为催化剂进行反应， 即得到可完全生物降解的药物 高分子 (medico-macromolecule)；
反应温度为 0~5°C， 反应时间为 18~40h;
所说的溶剂为四氢呋喃、 氯仿或四氢呋喃 /水中的一种。
本发明具有的积极意义. - 众所周知， a -L-氨基酸是聚 α -L-氨基酸降解的最后产物， 天然氨基酸中有许多 是多官能团的， 虽然 a -L-氨基酸没有毒性， 但其聚合物在降解过程中生成的低聚物 (oligomer)却具有抗原性 (antigenicity)。 本发明将天然多官能团氨基酸无规地引入生 物降解型聚酯中， 避免了降解产物的抗原性， 同时降解产物可被完全生物吸收。 新 型聚酯可含有羧基 (carboxyl group；)、 羟基 (hydroxyl group)及氨基 (amino-group)等活性 基团， 只要药物中含有羧基、 羟基、 氨基等官能团， 即可键合到该聚酯上。 所得药 物高分子可直接发挥作用， 也可在降解后起作用。
本发明可作为医疗器械的涂层， 在改善器械的生物相容性的同时携带有针对性 的药物， 从而达到靶向持续给药的目的。 也可制成植入体或其他制剂。
实施发明的最佳方式
实施例 1
聚（乳酸-羟基乙酸-谷氨酸） 的制备
称取 O.lmolL-丙交酯及 0.05mol含苄氧基保护谷氨酸的吗啉二酮衍生物单体于 干燥的、 带有搅拌子的聚合瓶中， 用1^2置换 3次， 置于 16CTC油浴中， 待熔化后， 加入 lml、 0.02g/ml辛酸亚锡氯仿溶液， 减压除去氯仿， 搅拌下反应 5h， 聚合物用 氯仿溶解， 乙醇沉淀。 所得聚合物以 Pd/C为催化剂， 氢气鼓泡 40h脱去苄氧基， 即 得到聚（乳酸-羟基乙酸 -谷氨酸）。 其凝胶渗透色谱 (Gel Permeation Chromatography) 分子量，简称 GPC分子量为 50,000， 氨基酸含量为 17%。 实施例 2
采用与实施例 1 相同的方法， 但以天冬氨酸取代谷氨酸， 即可获得聚（乳酸-羟 基乙酸-天冬氨酸）， 其分子量为 50,000， 氨基酸含量为 17%。 肝素中含有氨基、 羧 基，将 3g聚（乳酸-羟基乙酸 -天冬氨酸）溶于 100ml四氢呋喃与水的混合溶剂中（ 1： 1 )， 另称 0.5g (根据聚合物的 Gel Permeation Chromatography,简称 GPC分子量及氨基 酸含量)的肝素钠溶于少量水中， 用稀酸调节 pH为 4左右。 将两者混合， 加入等当 量的二环己基碳二亚氨 (dicyclohexylcarbodiimide, DCC), 在 4°C下搅拌 24h， 减压除 去溶剂， 再加入适量氯仿， 滤去不溶物， 所得溶液用石油醚沉淀， 常温下干燥 24h， 即得到肝素化高分子 (heparinized polymer)。
实施例 3
聚 （乳酸-羟基乙酸 -天冬氨酸） 键合青霉素 (penicillium)。 青霉素中含有羧基、 氨基， 将实施例 2的 2g聚（乳酸-羟基乙酸 -天冬氨酸）及 lg (根据聚合物的 GPC 分子量及氨基酸含量） 的青霉素溶于氯仿 (chloroform)中， 加入等当量的 DCC， 在 4 °C下搅拌 24h， 滤去不溶物， 所得溶液用石油醚沉淀， 常温下干燥 24h， 即得到药物 高分子。
实施例 4
聚 （乳酸-羟基乙酸-谷氨酸）键合肝素。 将实施例 1的 3g聚 （乳酸-羟基乙酸-谷 氨酸）溶于四氢呋喃与水的混合溶剂中， 另称取 0.5g (根据聚合物的 GPC分子量及 氨基酸含量） 的肝素钠溶于少量水中， 用稀酸调节 pH为 4左右。 将两者混合， 加 入等当量的 DCC， 在 4°C下搅拌 24h， 减压除去溶剂， 再加入适量氯仿， 滤去不溶 物， 所得溶液用石油醚沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 5
聚 （乳酸-羟基乙酸-谷氨酸）键合青霉素。 青霉素中含有羧基、 氨基， 将实施例 1的 2g聚（乳酸-羟基乙酸-谷氨酸）及 lg (根据聚合物的 GPC分子量及氨基酸含量） 的青霉素溶于氯仿中， 加入等当量的 DCC， 在 4°C下搅拌 24h， 滤去不溶物， 所得 溶液用石油醚沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 6
聚 （乳酸-羟基乙酸-丝氨酸）键合阿斯匹林 (aspirin)。 采用与实施例 1 相同的方 法， 但以丝氨酸取代谷氨酸， 即可获得聚 （乳酸-羟基乙酸 -丝氨酸)， 阿斯匹林中含 有羧基， 将 2g聚（乳酸-羟基乙酸-丝氨酸） 及 1.5g (根据聚合物的 GPC分子量及氨 基酸含量） 的阿斯匹林溶于氯仿中， 加入等当量的 DCC, 在 4Ό下搅拌 24h， 滤去 不溶物， 所得溶液用石油醚沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 7
聚 （乳酸-羟基乙酸-丝氨酸）键合青霉素。 青霉素中含有羧基、 氨基， 将实施例 6的 2g聚（乳酸-羟基乙酸-丝氨酸）及 lg (根据聚合物的 GPC分子量及氨基酸含量) 的青霉素溶于氯仿中， 加入等当量的 DCC， 在 4°C下搅拌 24h， 滤去不溶物， 所得 溶液用石油醚沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 8
聚 （乳酸-羟基乙酸-丝氨酸）键合肝素。 将实施例 6的 3g聚 （乳酸-羟基乙酸-丝 氨酸）溶于四氢呋喃与水的混合溶剂中， 另称取 0.5g (根据聚合物的 GPC分子量及 氨基酸含量） 的肝素钠溶于少量水中， 用稀酸调节 PH为 4左右。 将两者混合， 加 入等当量的 DCC， 在 4°C下搅拌 24h， 减压除去溶剂， 再加入适量氯仿， 滤去不溶 物， 所得溶液用石油醚沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 9
聚 （乳酸-羟基乙酸-赖氨酸）键合青霉素。 采用与实施例 1相同的方法， 但以赖 氨酸取代谷氨酸， 即可获得聚（乳酸-轻基乙酸 -赖氨酸）， 将 2g聚（乳酸-羟基乙酸- 赖氨酸）及 lg (根据聚合物的 GPC分子量及氨基酸含量） 的青霉素溶于氯仿中， 加入等当量的 (equivalentpCC, 在 4°C下搅拌 24h， 滤去不溶物， 所得溶液用石油醚 沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 10
聚 （乳酸-羟基乙酸-赖氨酸）键合肝素。 将 3g聚（乳酸-羟基乙酸-赖氨酸）溶于 四氢呋喃与水的混合溶剂中， 另称取 0.5g (根据聚合物的 GPC分子量及氨基酸含量） 的肝素钠溶于少量水中，用稀酸调节 PH为 4左右。将两者混合，加入等当量的 DCC， 在 4°C下搅拌 24h， 减压除去溶剂， 再加入适量氯仿， 滤去不溶物， 所得溶液用石油 醚沉淀， 常温下干燥 24h， 即得到药物高分子。
实施例 11
聚 （乳酸-羟基乙酸-赖氨酸）键合阿斯匹林。 将 2g聚（乳酸-羟基乙酸-赖氨酸） 及 1.5g (根据聚合物的 GPC分子量及氨基酸含量） 的阿斯匹林溶于氯仿中， 加入等 当量的 DCC， 在 4°C下搅拌 24h， 滤去不溶物， 所得溶液用石油醚沉淀， 常温下干 燥 24h， 即得到药物高分子。

Claims

权利要求书
1.一种含有活性药物、 主链中具有氨基酸的聚酯， 其特征在于， 该高分子药物 为具有如下结构通式的聚合物：
Figure imgf000008_0001
其中:
Rj代表 CH2OH、 CH2COOH：、 CH2CH2COOH或 CH2CH2CH2CH2NH2中的一种； R2代表具有可反应基团的药物；
， 为一 H或一 CH3 ;
n = 1~5；
X代表聚合度， 其范围为 1 3,000， y代表聚合度， 其范围为 1~1,000;
2.如权利要求 1所述的高分子药物中的聚酯， 其特征在于， 包括 α -羟基酸， e -羟基酸， Y -羟基酸， S -羟基酸， ε -羟基酸的均聚物及其共聚物。
3.如权利要求 1 所述的聚酯， 其特征在于， R2代表其结构式中含有羟基、 氨基 或羧基官能团的药物。
4.如权利要求 1所述的聚酯， 其特征在于， 聚合物中氨基酸摩尔含量为 1 %〜49
%。
5.如权利要求 1 所述的聚酯， 其特征在于， 高分子基质材料的相对数均分子量 范围为 500〜200，000， 其分子量分布为 1.2 3.6。
6.如权利要求 1〜4任一所述的聚酯的制备方法， 其特征在于， 该方法包括如下 步骤-
(1)聚合：
交酯或内酯与含多官能团氨基酸的吗啉二酮衍生物 (derivative ofmorpholine-dione) 以辛酸亚锡为催化剂， 进行聚合； 反应温度为 120~170°C， 反应时间为 1〜10小时； (2)脱保护：
所得聚合物用 Pd/C为催化剂催化氢化 24~80小时以上或釆用 HBr/HAc为催化剂 脱去保护基团后， 便得到了具有可反应性侧基的生物降解型聚酯， 反应温度为 10~35 V， 反应时间为 24~80h; (3)键合：
再将脱保护后的聚合物与药物溶解在溶剂中， 以二环己基碳二亚氨为催化剂进 行反应， 即得到可完全生物降解的药物高分子；
反应温度为 0~5°C， 反应时间为 18〜40h;
7. 如权利要求 6所述的制备方法， 其特征在于， 所说的含多官能团氨基酸包括 赖氨酸、 丝氨酸、 天冬氨酸及谷氨酸。
8.如权利要求 6所述的制备方法， 其特征在于， 步骤 (1)各物料的配比为： 交酯 或内酯：含多官能团氨基酸的吗啉二酮单体：催化剂 = 1： 0.01-50： 0.0002~0.002。
9. 如权利要求 6所述的制备方法， 其特征在于， 步骤 (1)在1¾气氛下进行聚合。
10.如权利要求 6所述的制备方法， 其特征在于， 所说的溶剂为四氢呋喃、 氯仿 或四氢呋喃 /水中的一种。
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