CN1348383A - Prolonged release microsphere encapsulating luteinizing hormone-releasing hormone analogues and method for preparing the same - Google Patents

Prolonged release microsphere encapsulating luteinizing hormone-releasing hormone analogues and method for preparing the same Download PDF

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CN1348383A
CN1348383A CN 99815239 CN99815239A CN1348383A CN 1348383 A CN1348383 A CN 1348383A CN 99815239 CN99815239 CN 99815239 CN 99815239 A CN99815239 A CN 99815239A CN 1348383 A CN1348383 A CN 1348383A
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microspheres
release
dissolved
releasing hormone
emulsified
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CN 99815239
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Chinese (zh)
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白洛基
朴真圭
朴木淳
朴泰宽
崔丞镐
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东国制药株式会社
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

公开一种缓释微球体,它可以稳定地释放药物,例如黄体素-释放激素类似物,并且包裹着高含量比率的药物。 Discloses a sustained release microsphere, which can stably release the drug, e.g. lutein - releasing hormone analogues, pharmaceutical and wrapped in a high content ratio. 它的制备方法是将丙交酯和乙醇酸交酯的共聚物溶解于二氯甲烷并且将黄体素释放激素类似物和释放控制物质溶于辅助溶剂中,并将上述的两种溶液合并产生乳化相,将乳化相分散到聚乙烯醇(溶于蒸馏水中)的溶液中得到单一的乳化体系,再将乳化相的混合溶剂除去,产生一种聚合物微球体,然后再冻干该聚合物微球体。 Its preparation method is a copolymer of lactide and glycolic acid lactide is dissolved in dichloromethane and the LHRH analogue and a release controlling substance is dissolved in an auxiliary solvent, and the resulting emulsion two kinds of the above-described solutions were combined obtained in phase, the emulsified phase dispersed in a polyvinyl alcohol (dissolved in distilled water) was emulsified in a single system, and then emulsified with a mixed solvent removed to produce a polymer microspheres, polymer microspheres and then lyophilized sphere. 所制备的微球体有精细得多的内部结构,由于如此,该微球体保证稳定的释放速度。 The microspheres are prepared much finer internal structure, because of this, the microspheres ensure a stable release rate. 单一乳化体系简化了制备,维持药物含量在10%或更多。 Single emulsifying system simplifies the manufacturing, drug content is maintained at 10% or more. 与聚合物相关的释放控制物质带电基团降低带有相反电荷的药物在初阶段的过量释放,在保持释放速度恒定方面起着重要的作用。 Associated with the release controlling polymer material to reduce the excessive release of charged groups of opposite charge in the early stages of the drug, it plays an important role in terms of maintaining a constant release rate.

Description

包裹黄体素-释放激素类似物的缓释微球体和制备这种微球体的方法 Wrapping lutein - microsphere sustained release hormone analogs and methods for preparing such microspheres

技术领域 FIELD

该发明涉及一种微球体,它包裹黄体素-释放激素(下文以“LHRH”指代)类似物。 The invention relates to a microsphere that wrap lutein - releasing hormone (hereinafter to "LHRH" refers to) the like. 并且能长时间持续释放这种激素。 And can be long-lasting release of this hormone. 本发明还涉及制备这种缓释微球体的方法。 The present invention further relates to a process for preparing such a sustained release microspheres.

LHRH类似物对垂体腺作用以在机体中抑制LH的分泌,从而导致阻抗雌性激素和雄性激素释放进入血液中。 LHRH analogues effect on pituitary gland to inhibit LH secretion in the body, leading to the impedance of male and female hormone releasing hormone into the bloodstream. 采用这些阻抗作用的优势,雄激素或雌激素引起的疾病,例如前列腺癌,乳腺癌,子宫内膜异位,以及相似的疾病最近得到了治疗。 With these advantages impedance effect, androgen or estrogen-induced diseases, such as prostate cancer, breast cancer, endometriosis, and similar diseases has recently been treated.

然而,像一般的多肽药物,LHRH在肠-胃消化道中十分不稳定并且吸收效率很低。 However, as a general peptide drugs, LHRH in the intestine - is very unstable in the stomach and digestive tract absorption efficiency is very low. 因而,LHRH给药方式通常是用注射形式。 Thus, LHRH administration is generally in the form of injection. 通过注射给药同样有个显著的缺点,即它的生物利用率十分低,从而需要每天注射LHRH,这样的注射给药也需要一段长的治疗时间,从而使病人在适应药物,治疗效果和治疗方面有一定的困难。 By injection also has a significant disadvantage that its bioavailability is very low, thus requiring a daily injection of LHRH, such injection also requires a long treatment time, so that the patient adaptation of drug treatment and therapeutic have certain difficulties.

针对聚(丙交酯-共聚-乙醇酸交酯)(PLGA)的应用已进行了大量的研究,它在体内是一种可降解的聚合物,以含有蛋白质或多肽并可控制释放剂量的形式存在。 For poly (lactide - co - glycolide) (PLGA) have been applied to a lot of research, it is an in vivo degradable polymer and containing a protein or polypeptide in the controlled release dosage form presence. 高分子量蛋白的释放形式和结构的稳定是将它们成为商业化药物的最大障碍。 Release form high molecular weight proteins and stable structure that they will become the biggest obstacle to the commercialization of the drug. 结果,针对开发各种添加物和新的制备过程进行了且在继续许多研究,由此获得的蛋白可以商业化生产并且保持了它们的活性。 As a result, for the development of various additives and new preparation process was continuing and in many studies, the protein thus obtained can be commercially produced and maintained their activity.

对于多肽药物,商业化相对比较容易,因为多肽比蛋白质小且更稳定。 For polypeptide drugs, commercial relatively easy, since the polypeptides of smaller and more stable than proteins. 商业化的例子如,有可持续释放DOS的制剂,其包含LHRH类似物,该类似物为分子量1.2KDa的多肽。 Examples of such commercially, there is a sustained releasable DOS formulation comprising LHRH analogs, the analog is the molecular weight polypeptides 1.2KDa.

由PLGA组成的微球体在体内通过水解分解成乳酸和乙醇酸并且被代谢。 PLGA microspheres composed of in vivo hydrolysis into lactic acid and glycolic decomposed and metabolized by. 换句话说,PLGA对人体没有毒害且降解产物没有副作用。 In other words, PLGA is not toxic to the human body and the degradation products no side effects. 更好的是,由PLGA制成的微球体可以在所需的时间以恒定的速度释放它们的内含物,例如有治疗效果的成分。 More preferably, the PLGA microspheres can be made at a constant rate release their contents at a desired time, for example, therapeutically effective ingredients.

关于这一点,美国专利4,711,782介绍了一种技术,由相似的聚合物通过W/O/W(水包油包水)的2次乳化作用。 In this regard, U.S. Patent No. 4,711,782 describes a technique similar to the polymer W / O 2 times emulsification / W (water-oil-water) through. 产生微多孔的微胶囊。 Microporous produced microcapsules. 这种技术通常用来将水溶性药物制成胶囊。 This technique is often used to water-soluble drugs into capsules. 在这项技术中,水溶性药物溶于水后,加入动物胶用于维持药物,这种含水层通过匀浆器的帮助分散到含有聚合物的一种有机层中,从而获得初步乳化。 In this technique, a water-soluble drugs dissolved in water, gelatin is added for maintaining the drug, with the help of this aqueous layer is dispersed in a homogenizer organic layer containing the polymer, thereby obtaining a preliminary emulsification. 这初步乳化液再分散到有聚乙烯醇作为表面活性剂的水中,从而获得二次乳化。 This preliminary emulsion was redispersed in water with a polyvinyl alcohol as a surfactant, to obtain a secondary emulsification. 有机溶剂扩散到水相层中并且蒸发,从而聚合物固化形成了微胶囊。 The organic solvent diffuses into the aqueous phase and evaporated layer, thereby forming a microcapsule polymer solidifies. 然后将其冻干。 Then freeze-dried.

需指出,水用来溶解水溶性多肽并且所获得的微胶囊是孔状结构。 It is pointed out to dissolve the water-soluble polypeptide and the obtained microcapsules porous structure. 因而,这些微胶囊存在问题,释放多肽药物初速度高,药物含量低。 Accordingly, there is a problem with these microcapsules, the release of polypeptide drugs early high speed, low drug content.

因而,该发明的目的是提供一种缓释微球体,它可以在一段持久的时间内控制药物的释放。 Accordingly, the object of the invention is to provide a sustained-release microsphere which can control the release of the drug over a period of time lasting.

本发明的另外一个目的是提供一种缓释微球体,它使治疗有效成分的含量很高。 Another object of the present invention is to provide a sustained-release microsphere which the therapeutic active ingredient content is high.

本发明的更进一步的目的是提供一种方法,简单和高效率制备这样一种缓释微球体。 A further object of the present invention to provide a method, simple and efficient preparation of a sustained-release microspheres.

依照本发明的一方面,提供了一种缓释微球体,它由一种聚(丙交酯-共聚-乙醇酸交酯)共聚物组成,包裹着一种黄体激素-释放激素类似物。 In accordance with an aspect of the present invention, there is provided a sustained release microsphere, which consists of a poly (lactide - co - glycolide) copolymer, wrapped in a kind of luteinizing hormone - releasing hormone analog.

依照本发明的另一个方面,提供了一种方法来制备一种缓释微球体,包括的步骤为:将丙交酯和乙醇酸交酯共聚物,溶于二氯甲烷。 According to another aspect of the present invention, there is provided a method for preparing a sustained-release microspheres, comprising the steps of: a lactide and glycolide copolymer was dissolved in dichloromethane. 将黄体激素-释放激素类似物和释放控制物质溶于二氯甲烷,一种辅助溶剂中。 The luteinizing hormone - releasing hormone analogue and a release-controlling substance was dissolved in dichloromethane, an auxiliary solvent. 合并以上两种溶液产生一种乳化相;将这种乳化相分散到聚乙烯醇蒸馏水溶液中,获得单一的乳化体系,除去乳化相中的混合溶剂,产生一种聚合物的微球体;并且将该聚合物微球体冻干。 Combining two or more solutions to produce an emulsion phase; such emulsified phase dispersed in a polyvinyl alcohol solution in distilled water to give a single emulsion system, the mixed solvent was removed emulsified phase, to produce microspheres of a polymer; and the freeze-dried polymer microspheres.

进行本发明的最好模式本发明中,含有治疗有效药物并在一段长时间内持续释放它们的一种微球体由生物可降解聚合物的混合物制备。 The best mode of the present invention, the present invention, the medicament comprising a therapeutically effective and sustained release thereof over an extended period of time the microspheres prepared from a biological degradable polymer mixture. 作为有疗效的药物,LHRH类似物引起特别的兴趣。 As drug efficacy, LHRH analogues of particular interest. 因而,如果含有LHRH类似物的微球体被给药后,它们长时间内释放药物,从而睾酮和雌激素可以在血液中维持较低浓度,从而提高治疗效果并且使病人对药物产生适应性。 Thus, if the microspheres containing LHRH analogues are administered, they are a long time to release the drug, so that testosterone and estrogen in the blood concentration can be maintained low, thereby improving the therapeutic effect and the adaptability of the patient to produce the drug.

包裹着LHRH类似物的缓释微球体有aporous,精细和一致的内部结构,从而它的药物含量比率被提高。 LHRH analogues wrapped with a sustained-release microspheres aporous, a fine and uniform internal structure, so that its drug content ratio is increased.

微球体可以用单一乳化过程制备。 The microspheres may be prepared using a single emulsion process. 详细地,LHRH类似物,包括醋酸戈舍瑞林,醋酸那法瑞林,醋酸布舍瑞林(buserelin acetate)和醋酸亮丙瑞林,溶于辅助溶剂并加入到含有聚合物的有机溶剂中,产生一种油相,随后将该油相分散到水相中。 In detail, of LHRH analogs, including goserelin acetate, nafarelin acetate, buserelin acetate (buserelin acetate), and leuprolide acetate dissolved in a solvent and added to an auxiliary organic solvent containing the polymer to produce an oil phase, the oil phase was then dispersed into the aqueous phase.

优选的在本发明中使用的有机溶剂是二氯甲烷。 Preferred organic solvents used in the present invention is dichloromethane. 水相通过溶解聚乙烯醇而获得。 The aqueous phase was obtained by dissolving polyvinyl alcohol.

溶解LHRH的辅助溶剂要与有机溶剂(二氯甲烷)和水都混溶。 LHRH was dissolved in an auxiliary solvent to the organic solvent (methylene chloride) and water are miscible. 辅助溶剂的例子有N-甲基-2-吡咯烷酮(NMP),二甲基亚砜(DMSO),二甲基甲酰胺(DMF),丙酮,乙醇,乙酸乙酯和甲基乙基酮(MEK),最优选的是NMP。 Examples of the auxiliary solvents include N- methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetone, ethanol, ethyl acetate and methyl ethyl ketone (MEK ), most preferably NMP. 这种辅助溶剂在提供具有aporous精细结构的微球体中起重要作用。 Such auxiliary solvent plays an important role in providing microspheres having aporous fine structures.

在本发明中,LHRH类似物的释放通过官能团作用以两种方式控制,所述官能团即是羧基基团和十二烷基基团,附在组成微球体的两种聚合物末端。 In the present invention, the release of the LHRH analogues controlled in two ways by the action of functional groups, i.e., the functional group is a carboxyl group and a dodecyl group, consisting of the two polymers attached to the end of the microspheres. 羧基与LHRH类似物形成疏水性离子对,从而释放的速率受到阻碍,十二烷基抑制酶降解微球体的作用,从而维持生物可降解微球体的整体性。 LHRH analogues with carboxyl forming a hydrophobic ion pair, whereby the rate of release is hindered, dodecyl inhibiting enzymatic degradation of the microspheres, thereby maintaining the integrity of the biodegradable microspheres. 因而,包含在微球体中的药物以突然爆发的形式释放。 Thus, the drug is contained in the microspheres is released in the form of a sudden outbreak.

适合阻止LHRH类似物释放速度的化合物必须和LHRH类似物形成疏水性离子对,并且还可以溶于有机溶剂中。 LHRH analogues for preventing the release rate of the compound is necessary to form a hydrophobic ion pair and LHRH analogs, and may also be dissolved in an organic solvent. 适合这些标准的优选的例子包括油酸钠,脱氧胆酸,胆酸,脂肪酸,和磷脂酸。 Suitable examples of these preferred criteria include sodium oleate, deoxycholic acid, cholic acid, a fatty acid, and phosphatidic acid.

本发明中生物可降解微球体是aporous有超精细的内部结构。 In the present invention, biodegradable microspheres are aporous super fine internal structure. 如图1和2所示。 1 and 2 shown in FIG. 体外释放试验数据证明,LHRH从本发明的微球体中以相对恒定的速度释放,如图3所示。 In vitro release data demonstrate that, at a relatively constant rate of LHRH is released from the microspheres of the present invention, as shown in FIG. 测定微球体减少的重量是为了获得它们生物降解速度的有关信息,最终表明微球体在试验后第45天左右完全被降解,如图4所示。 Determination of microsphere reduced weight in order to obtain information on their rate of biodegradation of the microspheres ultimately show completely degraded at about day 45 after the test, as shown in FIG. 体内释放试验所获得的数据如图5所示,与图4数据完全一致。 Data obtained in vivo release test shown in FIG. 5, 4 fully consistent with the data in FIG.

为了对本发明有一个较好的了解,可以看看随后阐述的实施例,但这些实施例并不是用来限制本发明的。 In order to have a better understanding of the present invention, we can look at the subsequent embodiments set forth, but these examples are not intended to limit the present invention.

实施例I:制备含有醋酸亮丙瑞林(Leuprorelin acetate)的生物可降解的微球体一种微球体以生物可降解的PLGA为材料,用一种O/W(水包油)的单一乳化方法制备。 Example I: Preparation of Bio-containing Leuprolide acetate (Leuprorelin acetate) biodegradable microspheres to one kind of microspheres of PLGA is a biodegradable material, with one O W (oil in water) emulsification process single / preparation.

在3毫升二氯甲烷中,溶解PLGA各350毫克,一种所述PLGA末端有十二烷基基团,分子量为12,000,丙交酯部分∶乙醇酸交酯部分为50∶50,例如由Boehringer Ingelheim售出,商品名RH502,另一种PLGA为其末端有羧基,分子量为8,600,丙交酯部分∶乙醇酸交酯部分为50∶50,例如由Boehringer Ingelheim售出,商品名RH502H。 3 ml of methylene chloride was dissolved 350 mg of PLGA each, one of the end PLGA has a dodecyl group, molecular weight 12,000, partially lactide: glycolide moiety is 50:50, by Boehringer e.g. Ingelheim sold under the trade name RH502, the other end a carboxyl group PLGA, molecular weight 8,600, part lactide: glycolide 50:50 moiety is, for example sold by the Boehringer Ingelheim under the trade name RH502H. 这种二氯甲烷溶液与含有100毫克醋酸亮丙瑞林的1毫升N-甲基-2-吡咯烷酮溶液充分混合。 This methylene chloride solution was mixed with 100 mg of leuprorelin acetate in 1 ml of N- methyl-2-pyrrolidone solution containing mixed thoroughly. 将250毫升0.5%(重量百分比)聚乙烯醇(溶于蒸馏水中,含有2克二氯甲烷)加到有聚合物和药物的饱和溶液中,然后用搅拌器700rpm速度,乳化30分钟。 The 250 ml of 0.5% (by weight) of polyvinyl alcohol (dissolved in distilled water containing 2 g of methylene chloride) was added with a saturated solution of polymer and drug, and then with a stirrer speed of 700rpm, emulsified for 30 minutes. 乳化液在大气压下再搅拌3个小时,N-甲基-2-吡咯烷酮被水给抽提出来,蒸发二氯甲烷,从而获得固化的微球体。 Emulsion was stirred for 3 hours at atmospheric pressure, N- methyl-2-pyrrolidone to be extracted out of the water, methylene chloride was evaporated to obtain a solidified microspheres. 然后8,000rpm离心30分钟,收集微球体后,微球体再用水洗离心2次,除去残余的溶剂和药物,然后冻干。 Then centrifuged at 8,000rpm for 30 minutes, microspheres were collected, then washed microspheres centrifugation twice to remove residual solvent and the drug and then lyophilized.

实施例II:含有醋酸戈舍瑞林(Goserelin acetate)的生物可降解微球体的制备RG502H和RG502各100毫克溶于3毫升二氯甲烷,该溶液与1ml N-甲基-2-吡咯烷酮(含有25毫克醋酸戈舍瑞林)溶液充分混合。 Example II: Biological containing goserelin acetate (Goserelin acetate) biodegradable microspheres prepared RG502H and RG502 100 mg of each was dissolved in 3 ml of dichloromethane, the solution with 1ml N- methyl-2-pyrrolidone (containing goserelin acetate 25 mg) was thoroughly mixed. 200毫升0.3%(重量百分比)聚乙烯醇(溶于蒸馏水中,含有2克二氯甲烷)溶液加到有聚合物和药物的饱和溶液中,然后,用搅拌器700rpm乳化30分钟,然后根据实施例I的余下步骤制备微球体。 200 ml of 0.3% (by weight) of polyvinyl alcohol (dissolved in distilled water containing 2 g of methylene chloride) was added with a saturated solution of polymer and drug, and then, emulsified 700rpm using a stirrer for 30 minutes and then according to the embodiment Example I preparation of microspheres remaining steps.

实施例III:含有醋酸那法瑞林(Nafarelin acetate)的生物可降解微球体的制备RG502H和RG502各200毫克溶于5毫升二氯甲烷,这种溶液与1mlN-甲基-2-吡咯烷酮(含有50毫克醋酸那法瑞林)溶液充分混合。 Example III: That nafarelin acetate (Nafarelin acetate) containing a biologically degradable microspheres prepared RG502H and RG502 200 mg of each was dissolved in 5 ml of methylene chloride, and this solution was 1mlN- methyl-2-pyrrolidone (containing nafarelin acetate 50 mg) was thoroughly mixed. 250毫升0.3%(重量百分比)聚乙烯醇(溶于蒸馏水,含有2克二氯甲烷)溶液加到有聚合物和药物的饱和溶液中。 250 ml of 0.3% (by weight) of polyvinyl alcohol (dissolved in distilled water containing 2 g of methylene chloride) was added with a saturated solution of polymer and drug. 然后以500rpm用一个搅拌器乳化30分钟。 500rpm using a stirrer and then emulsified for 30 minutes. 随后,根据实施例I的余下的步骤制备微球体。 Subsequently, according to the remaining steps of Example I Preparation of microspheres.

实施例IV:用匀浆器制备含有醋酸亮丙瑞林的生物可降解微球体RG502H和RG502各200毫克溶于5毫升二氯甲烷中。 Example IV: with a homogenizer prepared containing leuprolide biodegradable microspheres 200 mg of each of RG502H and RG502 was dissolved in 5 ml of dichloromethane. 这种二氯甲烷溶液与1毫升N-甲基-2-吡咯烷酮(含有50毫克醋酸亮丙瑞林)溶液中充分混和。 This solution was mixed with 1 ml of dichloromethane-methyl-N- (containing 50 mg leuprolide) was mixed well. 250毫升0.5%(重量百分比)聚乙烯醇(溶于蒸馏水,含有2克二氯甲烷)溶液加入到含有聚合物和药物的饱和溶液中,然后用匀浆器,700rpm乳化30分钟。 250 ml of 0.5% (by weight) of polyvinyl alcohol (dissolved in distilled water containing 2 g of methylene chloride) was added to a saturated solution containing the polymer and the drug, and then using a homogenizer, emulsification 700 rpm for 30 minutes. 然后根据实施例I的余下的步骤制备微球体。 Then microspheres are prepared according to Example I of the remaining steps.

实施例V:使用油酸钠制备含有醋酸亮丙瑞林的生物可降解微球体RH502和RG502各200毫克溶于1毫升二氯甲烷,这种二氯甲烷溶液与含有50毫克醋酸亮丙瑞林和3.105毫克油酸钠的1ml N-甲基-2-吡咯烷酮的溶液充分混合。 Example V: Preparation of an oil containing sodium leuprolide biodegradable microspheres RH502 and RG502 200 mg of each was dissolved in 1 ml of methylene chloride, the methylene chloride solution containing 50 mg of leuprolide acetate and 1ml N- methyl-2-pyrrolidone 3.105 mg of sodium oleate solution was mixed well. 250毫升0.3%(重量百分比)聚乙烯醇溶液(溶于蒸馏水,含有2克二氯甲烷)加入到含有聚合物和药物的饱和溶液中,然后,用匀浆器,700rpm乳化30分钟。 250 ml of 0.3% (by weight) polyvinyl alcohol solution (dissolved in distilled water containing 2 g of methylene chloride) was added to a saturated solution containing the polymer and the drug, and then, using a homogenizer, emulsification 700 rpm for 30 minutes. 然后根据实施例I的余下的步骤制备微球体。 Then microspheres are prepared according to Example I of the remaining steps.

实施例VI:含有油酸钠/亮丙瑞林复合物的生物可降解微球体的制备17.5毫克油酸钠和50毫克醋酸亮丙瑞林在蒸馏水中反应产生沉淀。 Example VI: Biological containing sodium oleate / leuprolide composite biodegradable microsphere preparation 17.5 mg of sodium and 50 mg of an oil leuprolide acetate precipitation reaction in distilled water. 然后收集该沉淀并冻干。 The precipitate was collected and then freeze-dried. 将它们溶于0.66毫升N-甲基-2-吡咯烷酮和1.33毫升二氯甲烷混合溶液(含有RG 502H和RG 502各200毫克)中250毫升0.3%(重量百分比)聚乙烯醇溶液(溶于蒸馏水中,含有2克二氯甲烷)加入到含有聚合物和药物的饱和溶液中,然后使用匀浆器700rpm乳化30分钟。 They were dissolved in 0.66 ml N- methyl-2-pyrrolidone and 1.33 ml of methylene chloride mixed solution (RG 502H and RG 502 containing each 200 mg) in 250 ml of 0.3% (by weight) polyvinyl alcohol solution (dissolved in distilled water in methylene chloride containing 2 g) was added to a saturated solution containing the polymer and the drug, and then emulsified using a homogenizer 700rpm for 30 minutes. 然后根据实施例I的余下的步骤制备微球体。 Then microspheres are prepared according to Example I of the remaining steps. 表1微球体的药物含量和平均颗粒大小 Table drug content and an average particle size of the microspheres 1

试验实施例I:体外微球体药物释放实施例制备的生物可降解微球体如下进行体外释放测试。 Test Example I: In vitro drug release microspheres prepared in Example biologically degradable microspheres in vitro release testing was performed as follows. 5毫克冻干微球体分散到一个管瓶中。 5 mg of microspheres dispersed in a lyophilized vial. 所述管瓶中含有10毫升0.333M磷酸缓冲液中0.05%TWEEN 80的溶液,并且在37℃贮存28天。 The vials containing 10 ml of 0.333M phosphate buffer, 0.05% TWEEN 80, and stored at 37 ℃ 28 days. 从第一天到第三十天每隔三天取一个测试样品,这十个样品离心。 A test sample taken every three days from the first day to the thirtieth day, ten samples were centrifuged. 去除上清,用流动相3∶1醋酸铵∶甲醇,流速1.0毫升/分,280纳米下,通过HPLC定量测定微球体中的药物,结果如图3所示。 The supernatant was removed, 3:1 ammonium acetate mobile phase: methanol, flow rate of 1.0 ml / min, at 280 nm, by HPLC quantitative determination of the drug in the microspheres, results shown in Figure 3.

试验实施例II:微球体的降解在与试验实施例I相同的条件下,每四天取一个试验样品。 Experimental Example II: Degradation of microspheres under the same conditions as in Example I and test embodiment, a test sample taken every four days. 将样品离心,除去上清。 The samples were centrifuged, the supernatant was removed. 干燥所获得微球体,然后精确测量其重量。 The obtained microspheres are dried, and then accurately measure the weight thereof. 根据测量结果,计算微球体降解的速率,如图4所示。 According to the measurement results, the rate of degradation of the microspheres is calculated, as shown in FIG.

试验实施例III:体内微球体药物的释放对根据实施例制备的生物可降解微球体,如下测试体内释放。 Experimental Example III: the microspheres release the drug in vivo biological degradable microspheres prepared according to Example, the following in vivo release test. 通过肌内注射微球体到大鼠股区域,通过在每第五天切开,从股区域取出剩余的微球体。 By intramuscular injection of microspheres into the femoral region in rats, removed from the femoral microspheres remaining region by the fifth day of each cut. 所获得的微球体在10毫升0.02%(重量百分比)TWEEN80(聚环氧乙烷20油酸酯,Junsei化学公司)(溶于0.333M磷酸缓冲液pH7.0)中进行匀浆,再加10毫升缓冲溶液和10毫升二氯甲烷之后,药物被抽取到水相层中。 The obtained microspheres (, Junsei Chemical Co., polyoxyethylene 20 oleate) (dissolved in 0.333M phosphate buffer, pH7.0) were homogenized in a (weight percent) in 10 ml of 0.02% TWEEN 80, plus 10 after ml of buffer solution and 10 ml of methylene chloride, the aqueous phase is drawn into the drug layer. 这些抽提物可以在和体外释放试验相同条件下用HPLC定量测定,结果如图5所示。 These extracts can be quantitatively determined by HPLC under the same conditions and in vitro release tests, the results as shown in FIG.

附图简要描述图1是一张电子扫描显微镜图(SEM),显示本发明的微球体结构;图2是一张电子扫描显微镜图,显示本发明微球体的横界面结构。 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a scanning electron micrograph (SEM), showing the structure of the microspheres of the present invention; FIG. 2 is a scanning electron microscope showing a cross-interface structure of the microspheres of the present invention.

图3是一张平面图,表明微球体随时间的体外释放速度。 FIG 3 is a plan view showing the microspheres in vitro release rate over time.

图4是一张平面图,表明微球体随时间的重量失去速度。 FIG 4 is a plan view showing the weight of the microspheres to lose velocity with time.

图5是一张平面图,表明微球体随时间的体内释放速度。 FIG 5 is a plan view showing the microspheres in vivo release rate over time.

工业适用性如上所述,依照本发明制备的微球体有比传统微球体更为精细的内部结构,因此这样的微球体保证一个恒定的释放速度。 Industrial Applicability As described above, the microspheres prepared in accordance with the invention have a more fine than a conventional internal structure of the microspheres, such microspheres thus ensure a constant release rate. 本发明单一的乳化体系简化了微球体制备的过程。 Single emulsifying system of the present invention simplifies the preparation of microspheres. 使它维持药物含量在10%或更多。 Maintain drug content at 10% or more. 另外,与聚合物相关的释放控制物质带电基团降低了在最初阶段带相反电荷的药物的过量释放,在保持释放速度恒定方面起了重要的作用。 Further, associated with the polymer substance release control of the charged groups reduced the excessive release of drugs of opposite charge in the initial stage, play an important role in terms of maintaining a constant release rate.

本发明已经以给出实施例的方式进行了描述,要明白的是所用的术语是为了更好的描述该发明的本质,而不是局限它。 The present invention has been given by way of example of the embodiment to be described, to be understood that the term is to better describe the essence of the invention, not limitation of it. 本发明的许多修饰和突变体在上述指导下是可能的。 Many modifications and mutants of the present invention under the above teachings are possible. 因而要明白,在附加的权利要求范围内本发明可以用其他的方式实施,并不是只局限于所描述的特定的几种。 Therefore to be understood that the present invention may be used in other embodiments within the scope of the claim appended claims, it is not limited to particular ones described.

Claims (8)

1.缓释微球体,它由聚(丙交酯-共聚-乙醇酸交酯)共聚物组成,并且包裹黄体素-释放激素类似物。 1. sustained release microsphere, which is composed of poly (lactide - co - glycolide) copolymer, and the entrapped lutein - releasing hormone analog.
2.如权利要求1所述的缓释微球体,其中黄体素-释放激素类似物选自醋酸戈舍瑞林,醋酸那法瑞林,醋酸布舍瑞林和醋酸亮丙瑞林。 Nafarelin acetate, buserelin acetate and leuprolide-releasing hormone analogue is selected from goserelin acetate, - sustained release microsphere as claimed in claim 1, wherein the lutein.
3.如权利要求1所述的一种缓释微球体,其中共聚物由一种聚丙交酯和一种聚乙醇酸交酯组成,这两者任何一个在末端有一个十二烷基和一个羧基。 3. An extended release microsphere according to claim 1, wherein the copolymer from a polylactide polyglycolide and one composition, both of which have at the end of any one of a and a dodecyl carboxyl.
4.制备一种缓释微球体的一种方法,包括以下几步:将丙交酯和乙醇酸交酯的共聚物溶于二氯甲烷;将黄体素-释放激素类似物和释放控制物质溶于二氯甲烷和一种辅助溶剂中;合并上述两种溶液产生一种乳化相;将乳化相分散到聚乙烯醇的蒸馏水溶液中,从而获得单一的乳化体系;除去乳化相中的混合溶剂,产生一种聚合物微球体;冻干该聚合物微球体。 4. A method for preparing a sustained-release microspheres, comprising the steps of: a copolymer of lactide and lactide of glycolic acid was dissolved in dichloromethane; the lutein - releasing hormone analogue and a release controlling substance solution dichloromethane and an auxiliary solvent; the two solutions were combined to produce an emulsion phase; the emulsified phase is dispersed into a distilled water solution of polyvinyl alcohol so as to obtain a single emulsion system; emulsified mixed solvent phase is removed, produce a polymer microspheres; lyophilized polymeric microspheres.
5.如权利要求4所述的方法,其中单一的乳化体系包含75.0-99.0%(重量百分比)的水相和0.3-0.5%(重量百分比)的聚乙烯醇和含有0.50-10.0%(重量百分比)的二氯甲烷和0.2-10.0%(重量百分比)的辅助溶剂的乳化相。 5. The method according to claim 4, wherein the emulsifying system comprises the single 75.0-99.0% (by weight) of the aqueous phase and 0.3-0.5% (by weight) polyvinyl alcohol containing 0.50-10.0% (by weight) dichloromethane and emulsified 0.2-10.0% (by weight) of co-solvent phase.
6.如权利要求4或5所述的方法,其中辅助溶剂是N-甲基-2-吡咯烷酮。 6. A method as claimed in claim 4 or claim 5, wherein the auxiliary solvent is N- methyl-2-pyrrolidone.
7.如权利要求5所述的方法,其中,释放控制物能和黄体素-释放激素类似物形成疏水性离子对并且溶解于有机溶剂。 7. The method according to claim 5, wherein the release controlling substance can lutein and - releasing hormone analogue form a hydrophobic ion pair and dissolved in an organic solvent.
8.如权利要求5或7所述的方法,其中释放控制物质是油酸钠,以黄体素-释放激素类似物的摩尔计,以75-100%(摩尔百分比)的量使用油酸钠。 8. The method of claim 5 or claim 7, wherein the release controlling substance is sodium oleate to lutein - releasing hormone analogs moles, in an amount of 75-100% (mole percent) using sodium oleate.
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