CN1204919C - Long-acting intra-ocular release system of cyclosporin - Google Patents

Long-acting intra-ocular release system of cyclosporin Download PDF

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CN1204919C
CN1204919C CN 00122863 CN00122863A CN1204919C CN 1204919 C CN1204919 C CN 1204919C CN 00122863 CN00122863 CN 00122863 CN 00122863 A CN00122863 A CN 00122863A CN 1204919 C CN1204919 C CN 1204919C
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cyclosporine
delivery system
long
cyclosporin
polymer
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CN1340358A (en )
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王身国
谢立信
贝建中
史伟云
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中国科学院化学研究所
山东省眼科研究所
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本发明提供了一种长效环孢素释放体系,包括环孢素和药物载体,二者的重量比为0.1∶0.9-0.9∶0.1。 The present invention provides a long-term cyclosporin delivery system, comprising cyclosporine and a pharmaceutical carrier, a weight ratio of both 0.1:0.9-0.9:0.1. 药物载体为合成生物降解高分子材料、天然生物降解高分子材料、或合成生物降解高分子材料同天然生物降解高分子材料的共混物。 Pharmaceutical carrier is a synthetic biodegradable polymer materials, natural biodegradable polymers, synthetic biodegradable polymer materials, or natural biodegradable polymer materials with a blend. 本发明的长效环孢素释放体系释药周期为一周到一年,可用于眼科预防和治疗高危角膜移植后的排斥反应,同时也可用于慢性葡萄膜炎、白塞氏病等眼科自身免疫性疾病。 Long period cyclosporine release delivery system of the present invention is a week to one year, it may be used for preventing and treating ophthalmic rejection after corneal transplantation risk, but also can be used for chronic uveitis, Behcet's disease and other autoimmune Ophthalmology diseases.

Description

长效环孢素眼内释药体系 In the long-term cyclosporine ophthalmic drug delivery system

本发明涉及一种体内植入药物制剂,特别涉及到一种以生物降解高分子材料作为药物载体的长效环孢素眼内释药体系。 The present invention relates to a pharmaceutical formulation in vivo implantation, particularly to an intraocular drug delivery system, a kind of biodegradable polymer materials as drug delivery depot cyclosporine.

免疫排斥反应是导致同种异体器官和组织移植失败的首要原因。 Immune rejection is the primary cause of failure of allogeneic transplantation of organs and tissues. 目前,糖皮质激素是防治如角膜移植等组织移植排斥反应的主要手段,但长期应用糖皮质激素不仅可导致多种并发症,而且往往不能有效地抑制高危角膜移植术后的排斥反应。 At present, glucocorticoids are the principal means such as corneal transplantation tissue transplant rejection prevention and treatment, but long-term use of glucocorticoids can lead not only to a variety of complications, and often can not effectively suppress the rejection of high-risk corneal transplantation.

环孢素A(Circlosporin A,CsA,以下简称环孢素)是第三代免疫抑制剂,其特点是高效,无骨髓毒性,CsA是选择性免疫抑制剂,主要抑制某些T淋巴细胞和B淋巴细胞的增殖。 Cyclosporin A (Circlosporin A, CsA, hereinafter referred to as cyclosporine) is a third generation immunosuppressant, which is characterized by high efficiency, no bone marrow toxicity, of CsA selective immunosuppressants, primarily inhibit certain T lymphocytes and B lymphocyte proliferation. 其全身或局部用药对降低角膜移植术后的免疫排斥反应和治疗某些自身免疫性眼病的疗效已得到公认。 Topical or systemic effect in reducing corneal transplant rejection and treatment of certain autoimmune eye disease has been recognized. 但是,CsA全身用药不仅价格昂贵,而且可能引起肝、肾脏毒性损害及高血压等并发症,使其应用受到限制(Palestine A G.,Am.J.Ophthalmol.,1985,99:210)。 However, CsA systemic medication is not only expensive, but also may cause liver and kidney toxicity damage and complications such as high blood pressure, its application is limited (Palestine A G., Am.J.Ophthalmol, 1985,99:. 210).

体内植入药物制剂是一种新型的药物制剂,具有不受体液冲洗、稀释的影响,用药量极少,且能长时间在体内缓慢释放药物的特点;特别是对药物吸收困难的部位,能达到很高的用药效果。 Implantable drug formulation in vivo is a new pharmaceutical formulation, having a rinse fluid free, impact dilution, minimal dosage, and can be prolonged slow release characteristics of the drug in the body; especially difficult for drug absorption site, You can achieve high treatment effect. 药物缓释系统的出现,正受到全世界的瞩目。 Emergence of drug delivery systems, is attracting attention around the world. 然而由于药物载体的问题一直没有解决,因此迄今为止,具有长期释药功能的环孢素体内植入制剂还不能问世。 However, due to the formulation of cyclosporine implanted drug delivery problem has not been resolved, so far, it has a long-term release function can not be published.

眼内植入药物制剂主要由药物及药物载体二种成分组成。 Intraocular implants mainly consists of two kinds of pharmaceutical preparations and pharmaceutical ingredients of the pharmaceutical carrier. 药物载体对药物的释放起保护和控制速度的作用,从而达到可以在眼内长期释放的效果(Jani P.,J.Pharm.Pharmacol.,1990,41:821)。 Pharmaceutical carrier for release of the drug and the protective role of control speed, so as to achieve long-term release in the eye (Jani P., J.Pharm.Pharmacol, 1990,41:. 821). 药物载体必须对药物具有一定的通透性,同药物不发生相互作用,此外,由于药物制剂是长期植入眼内进行药物释放的,因此药物制剂必须具有对机体很好的生物相容性,不对机体产生炎症、刺激、致敏等作用。 Pharmaceutical carrier must have a certain permeability to the drug, the drug does not interact with, in addition, since the pharmaceutical formulation is a long-term drug release intraocular implants, and thus the pharmaceutical formulation must have good biocompatibility on the body, not effect the body to produce inflammation, irritation, sensitization and the like. 能满足这样的药物载体材料又可分为生物惰性高分子及生物降解型高分子材料两类。 Such pharmaceutical carriers can meet the material can be divided into two categories degradable polymer and a biologically inert polymer material organisms. 硅橡胶、聚氨酯等都是在医学领域得到广泛应用的生物惰性高分子材料,具有良好的生物相容性,已被应用于制备心脏瓣膜介入治疗插管等,同时也已被用于长效避孕药等缓释药物的药物载体。 Silicone rubber, polyurethane, etc. in the medical field are obtained bioinert polymer materials widely used, have good biocompatibility, has been applied to the preparation of the heart valve intervention intubation also it has been used long-acting contraceptive drugs and other pharmaceutical sustained release pharmaceutical carrier. 然而用这类生物惰性材料作为药物载体时,虽然可以维持药物的长期缓释效果,且不会对机体产生致炎、刺激和致敏等生物相容性的问题,但是由于随着时日的增加,药剂中含药量的不断减少,药物释放速度及释放量也会不断下降,因此药物的释放剂量随时间在不断减少,因此无法保证恒定的药物剂量;此外由于这些材料的生物惰性,在体内还不会发生变化,因此在药物释放完后,还必须再从体内取出,以免作为异物留在体内会产生不良的影响。 However, when using such a biologically inert material as a drug carrier, although the effect can be maintained long-term release of the drug, and will not have the problem of the body to produce a biocompatible inflammatory, irritation and sensitization and the like, but because of the time with increases, decreasing the dose of medicament contained, the drug release rate and the release will continue falling, thus releasing the dose of drug over time decreasing, and therefore can not ensure a constant drug dose; Furthermore, since these materials are bioinert, in the body will not change, so after the release of the drug, it must then be removed from the body, so as not to leave the body as a foreign substance will have a negative impact.

另一类是生物降解型高分子药物载体。 Another type is a biodegradable polymeric drug carrier. 生物降解型高分子药物载体在药物释放的同时,由于体内的生理环境(体温、体液、酶等)的作用,载体材料也被不断降解,分子量变小,结构变得疏松,以至最终降解为小分子或单体,被机体吸收或代谢,因此用这样的材料为药物载体,当药物释放完后可以不用再手术取出。 Biodegradable polymeric drug carrier of drug release at the same time, due to the in vivo physiological environment (temperature, body fluids, enzymes, etc.), the carrier material is also constantly degraded, the molecular weight becomes smaller, the structure becomes loose, and eventually degraded to small molecule or monomer, absorbed or metabolized by the body, so as a drug carrier, can no longer release the drug when the operation to remove such materials after use. 此外,由于材料随着降解,结构变得疏松且使药物更易从中释放出来,因而有使药物释放量增加的趋势。 Further, since the material degradation as the structure becomes more loose and the drug released therefrom, and thus there is a tendency to increase the drug release. 当由于含药物的减少所引起的药物释放剂量的减少与由降解引起的药物释放量增加的量相一致时,就可以实现药物的恒速释放,这是用生物惰性高分子为药物载体时所不可能实现的药物释放行为(王身国,化学通报1997,2:45)。 When the reduction of drug release due to the reduced dose of medicament-containing and medicament release induced degradation caused by the increased amount coincide, can achieve constant release of the drug, which is a polymer with a biologically inert carrier when the pharmaceutical drug release behavior can not be achieved (Wang Shenguo, chemical informed 1997,2: 45).

近年来,已有用胶原为载体的环孢素释放体系(Chen YF等,Am JOphthalmol,1990,15;109-132),以脂质体为载体的环孢素释放体系(PleyerU等,Curr Eye Res,1994,13:177)等眼用药物释放体系研究报道,表明可以在一定程度上达到药物持续释放,减少给药剂量和次数,提高药物生物利用度,且降低毒性的效果。 In recent years, collagen has been used as the carrier of cyclosporine delivery system (Chen YF like, Am JOphthalmol, 1990,15; 109-132), liposome delivery system as carrier of cyclosporine (PleyerU the like, Curr Eye Res , 1994, 13: 177) and other ophthalmic drug delivery systems research reports, show up to a certain extent, sustained release of the drug, reducing the dosage and frequency increase drug bioavailability and reduce the toxicity effect. 然而它们的持续释药时间都较短,或对视力有一定的影响(如胶原体),或价格昂贵(如脂质体),此外,由于易受泪液冲洗稀释的影响而使药物丧失,因此药效短。 However, their duration is short release time, or to a certain extent (e.g., collagen body) vision, or expensive (such as liposomes), in addition, since the tear susceptible to the flushing impact of the drug dilution loss, so efficacy short.

本发明的目的在于克服上述已有技术中持续时间较短、且药效短的缺点而提供一种长效环孢素释放体系。 Object of the present invention is to provide a long-acting delivery system to overcome the above cyclosporine prior art short duration, and the efficacy of short disadvantages.

本发明的环孢素释放体系包括药物和药物载体,二者按重量比为0.1∶0.9~0.9∶0.1。 Cyclosporine delivery system of the present invention comprises a drug and a pharmaceutical carrier, a weight ratio of both 0.1:0.9 ~ 0.9:0.1. 所述的药物载体为具有良好的生物相容性、具有一定的强度、硬度和弹性的合成生物降解高分子材料、天然生物降解高分子材料、或合成生物降解高分子材料同天然生物降解高分子材料的共混物为药物载体。 The pharmaceutical carriers having excellent biocompatibility and a certain degree of strength, hardness and elastic synthetic biodegradable polymer materials, natural biodegradable polymers, synthetic biodegradable polymer materials with a natural biodegradable polymer blend material is a pharmaceutical carrier. 药物释放体系在药物释放完前可保持一定的强度、弹性和形状,而在体内的生理条件下可以自然降解、从而被吸收或通过代谢而排出体外,因此既不会成为异物对机体产生刺激,也不会使机体产生异物反应,因此不需要再行二次手术将其取出。 Drug delivery systems prior to complete drug release can maintain a certain strength, elasticity and shape, but under physiological conditions in vivo can be natural degradation so as to be absorbed or metabolized and excreted by, the foreign matter thus be neither irritation on the body, nor will the body to produce foreign body reaction, and therefore do not need surgery to remove the second row. 上述的合成生物降解高分子材料可为脂肪族聚酯类高分子,它们可以是聚L-乳酸(PLLA)、聚DL-乳酸(PDLLA)、共聚(L-乳酸/DL-乳酸)(PLLA-co-PDLLA)、聚乙醇酸(PGA)、共聚(乳酸/乙醇酸)(PLGA)、聚己内酯(PCL)、(乙醇酸/乳酸/己内酯)三元共聚物(PLGC)、聚己内酯/聚醚嵌段共聚物(PCE)、聚己内酯/聚醚/聚乳酸三元共聚物(PCEL),以及其它聚羟基酸(PHA)。 The above-described synthetic biodegradable polymer materials may be an aliphatic polyester-based polymer, they may be poly-L- lactic acid (of PLLA), poly-DL- lactic acid (of PDLLA), copolymer (lactic acid L- / DL- lactic acid) (PLLA- co-PDLLA), polyglycolic acid (PGA), copoly (lactic / glycolic acid) (PLGA), polycaprolactone (PCL), (glycolic acid / lactic acid / caprolactone) terpolymers (PLGC), poly caprolactone / polyether block copolymer (PCE), polycaprolactone / polyether / polylactic acid terpolymer (PCEL), and other polyhydroxy acid (PHA). 上述的天然生物降解高分子材料可为壳聚糖、明胶,或它们的共混物。 Above the natural biodegradable polymer materials can be chitosan, gelatin, or blends thereof.

所述的药物载体可以为膜状、片状、粒状、块状、条状。 The pharmaceutical carrier may be a film, sheet, granular, massive, bar-shaped. 它由上述天然或合成的生物降解高分子的无纺织物,也可以是由上述的合成或天然生物降解高分子材料的海绵体。 It degrades the polymer by the above-described non-woven fabric of natural or synthetic biological, sponge may be degraded by the natural biological or synthetic polymer material. 上述的药物载体孔结构的大小和密度由控制溶液挥发速度的方法、或控制致孔剂量的方法、或通过控制织物密度的方法进行控制。 The above-described pharmaceutical carrier pore structure by a method of controlling the size and density of the evaporation rate of the solution, or a method of controlling pore dose, or controlled by the method of controlling the density of the fabric.

所述的环孢素释放体系可以是无孔,或具有相互连通的孔结构,其孔径大小为10纳米-500微米。 The delivery system may be a cyclosporin nonporous, or interconnected pore structure having a pore size of 500 microns size of 10 nanometers.

本发明的环孢素释放体系是长效环孢素释放体系,释药周期为一周到一年;具有不受泪液冲洗、稀释的影响,用药量极少,且能长时间在眼内缓慢释放药物的特点;对于药物吸收困难的部位,能达到很高的用药效果。 Cyclosporine delivery system of the present invention is cyclosporine depot delivery system for the release week to one year period; not having a tear flushing, influence of dilution, minimal dosage, and can slow release in the eye for a long time characteristics of the drug; difficult for drug absorption site, the drug can achieve high effects. 可用于眼科预防和治疗高危角膜移植后的排斥反应,同时也可用于慢性葡萄膜炎、白塞氏病等眼科自身免疫性疾病。 It can be used for preventing and treating ophthalmic rejection risk corneal transplantation, but can also be used for chronic uveitis, Behcet's disease, autoimmune diseases and other eye.

实施例1、共聚(乳酸/乙醇酸)(PLGA)(分子量11万)5份,用二氯甲烷20份溶解后加入环孢素粉末5份,搅拌均匀后注入聚四氟乙烯模具,控制气流速度,使二氯甲烷挥发。 Example 1, copoly (lactic / glycolic acid) (of PLGA) (110,000 molecular weight), 5 parts of dissolved 20 parts of dichloromethane was added with 5 parts of cyclosporin powders, polytetrafluoroethylene injection mold after mixing, the gas flow control speed, to volatile the dichloromethane. 待完全干燥后,将此含有环孢素的共聚(乳酸/乙醇酸)药物释放体系从聚四氟乙烯模具上取下,在室温真空烘箱内保持48小时以完全除尽溶剂,得到厚度为2毫米、呈10纳米小孔结构的片状药剂,再用孔径为2毫米的冲模冲成厚为2毫米、直径为2毫米的环孢素制剂。 After allowing to dry completely, this containing cyclosporine copoly (lactic / glycolic acid) is removed from the drug delivery systems Teflon mold, held in a vacuum oven at room temperature for 48 hours to completely divisible solvent to give a thickness of 2 mm, was 10 nm pore structure of the sheet-like agent, a pore size of 2 mm and then punched into die thickness of 2 mm, a diameter of 2 mm cyclosporine formulation. 将此环孢素制剂用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后植入兔眼的前房。 This formulation of Cyclosporin 24 hours fumigation with ethylene oxide sterilization, and then one week after placement of the implant in the anterior chamber of rabbit eyes.

术后的肉眼观察和局部组织病理学检查结果表明:前房无炎症反应;角膜、晶状体透明度和虹膜反应正常:未发现有角膜水肿、虹膜新生血管、萎缩或坏死的现象,且晶状体保持透明;眼压也正常,手术前后无变化。 And visually observed after local histopathology results show that: the anterior chamber without inflammation; cornea, iris and lens transparency normal reaction: No corneal edema, iris neovascularization, atrophy or necrosis phenomena, and a transparent lens holder; IOP is normal, no change before and after surgery. 此外,从局部组织病理学检查结果所表明的环孢素释放体系所在部位的虹膜、角膜无明显炎性细胞浸润、无组织变性及坏死表现,以及环孢素释放体系所在部位的房角与正常房角结构无明显区别,证明环孢素释放体系的眼内生物相容性良好。 Further, from the local tissue pathology results indicated where the iris portion of cyclosporine release system, no obvious inflammatory cell infiltration of the cornea, anterior chamber angle no degeneration and necrosis of tissue expression, and cyclosporin site where the normal delivery system no significant difference angle structures, prove good intraocular biocompatibility of cyclosporine delivery systems.

此外,在环孢素释放制剂植入后的8周内,房水中一直维持有一定浓度的环孢素,未受泪液冲洗、稀释的影响,有效地防止了高危角膜移植排斥反应。 Further, 8 weeks after the implantation of cyclosporine release formulation, aqueous humor has maintained a concentration of cyclosporine were not tear flushing, influence of dilution, effectively prevents the risk corneal graft rejection. 而在血液中检测不到有环孢素的存在,避免了环孢素对肾脏的毒性损害及引起高血压等并发症。 The detection of the presence in the blood of less than cyclosporine, cyclosporine avoid toxic damage to the kidneys and cause high blood pressure and other complications. 此环孢素释放制剂在植入的8周后完全消失,可以不用再取出。 This formulation of Cyclosporin release completely disappeared after 8 weeks of implantation, can no longer be removed.

实施例2、按实施例1的方法与步骤,但采用聚DL-乳酸(PDLLA)(分子量6万)3份、二氯甲烷20份和环孢素7份、制孔剂15份制得直径为2毫米的药棒,在清除制孔剂后得到直径为2毫米、孔结构为10微米的药棒,在室温真空烘箱内保持48小时以完全除尽溶剂后再截成2毫米长的环孢素释放制剂。 Example 2, according to methods and procedures of Example 1, but with poly DL- lactic acid (of PDLLA) (molecular weight 60,000) 3 parts, 20 parts of methylene chloride and 7 parts of cyclosporin, 15 parts of pore-forming agent prepared in diameter drug rod of 2 mm, pore-forming agent after clearing a diameter of 2 mm, 10 micron pore structure drug rod, and then held for 48 hours to complete the solvent divisible cut into 2 mm long ring in a vacuum oven at room temperature cyclosporin release formulation. 将此环孢素制剂用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后同实施例1方法植入兔眼的前房。 The method of Example 1 implanted in the anterior chamber of the rabbit eye in the same manner after 24 hours fumigation with ethylene oxide sterilization cyclosporin this formulation, and then left for 1 weeks. 术后的肉眼观察和局部组织病理学检查结果表明环孢素释放体系有良好的眼内生物相容性,植入后的14周内环孢素可在房水中维持一定浓度,而在血液中检测不到有环孢素存在,14周后环孢素制剂完全消失,可以不用再取出。 Was visually observed, and local histopathology results show that postoperative cyclosporine delivery system with good biocompatible intraocular, 14 weeks after implantation of cyclosporine to maintain a certain concentration in the aqueous humor, in blood could not be detected the presence of cyclosporine, cyclosporine formulation after 14 weeks completely disappeared, can no longer be removed.

实施例3、按实施例1的方法与步骤,但采用(按中国发明专利申请号99105984.0方法制备的)(乙醇酸/乳酸/己内酯)三元共聚物(PGLC)(分子量8万)3份、二氯甲烷18份和环孢素9份、制孔剂24份制得各边长为10毫米的块状物,在清除制孔剂后得到直径为2毫米、孔结构为100微米的药棒,在室温真空烘箱内保持48小时以完全除尽溶剂后再裁成2毫米见方的环孢素释放制剂。 Example 3, according to methods and procedures of Example 1 but using (glycolic acid / lactic acid / caprolactone) terpolymer (prepared by the method of invention patent application No. 99105984.0 China) (PGLC) (molecular weight 80,000) 3 parts of dichloromethane and 18 parts of 9 parts of cyclosporin, 24 parts of pore-forming agent to prepare each side length of 10 mm lumps, a diameter of 2 mm after removing the pore-forming agent, the pore structure of 100 m medicated sticks, 48 ​​hours after the release of the solvent to completely divisible cut into 2 mm square cyclosporine formulation in a vacuum oven at room temperature. 将此环孢素制剂用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后同实施例1方法植入兔眼的前房。 The method of Example 1 implanted in the anterior chamber of the rabbit eye in the same manner after 24 hours fumigation with ethylene oxide sterilization cyclosporin this formulation, and then left for 1 weeks.

术后的肉眼观察和局部组织病理学检查结果表明环孢素释放体系有良好的眼内生物相容性,植入后的10周内环孢素可在房水中维持一定浓度,而在血液中检测不到有环孢素存在,10周后环孢素制剂完全消失,可以不用再取出。 Was visually observed, and local histopathology results show that postoperative cyclosporine delivery system has good biocompatibility in the eye, cyclosporin 10 weeks after implantation may be maintained at a certain concentration of the aqueous humor, in blood could not be detected the presence of cyclosporine, cyclosporine formulation after 10 weeks completely disappeared, can no longer be removed.

实施例4、与实施例1相同方法与步骤,但采用(按中国发明专利ZL 92113100.3方法制备的)聚己内酯/聚醚嵌段共聚物(PCE)(分子量8万)制备,得到孔结构大小为10纳米的环孢素制剂,在用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后植入兔眼的前房。 Example 4, the same method as in Example 1, Step but with polycaprolactone / polyether block copolymers (the PCE) (molecular weight 80,000) prepared (prepared by the method of Chinese Patent No. 92113100.3 ZL of the invention), the pore structure to give size of 10 nm cyclosporine formulation implanted in the anterior chamber of the rabbit eye after 24 hours fumigation with ethylene oxide sterilization, and then left for 1 weeks.

术后的肉眼观察和局部组织病理学检查结果表明环孢素释放体系有良好的眼内生物相容性,植入后的一年内环孢素可在房水中维持一定浓度,而在血液中检测不到有环孢素存在,一年后环孢素制剂完全消失,可以不用再取出。 Was visually observed, and local histopathology results show that postoperative cyclosporine delivery system has good biocompatibility in the eye, cyclosporin within one year after implant may maintain a certain concentration of the aqueous humor, in blood have not detected the presence of cyclosporine, a year after cyclosporine formulation completely disappear, can no longer be removed.

实施例5、与实施例1相同方法与步骤,但采用(按中国发明专利申请号98102212X方法制备的)聚己内酯/聚醚/聚乳酸三元共聚物(PCEL)(分子量9万)制备,得到孔结构大小为50纳米的环孢素制剂,在用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后植入兔眼的前房。 Example 5 In the same manner as in Example 1, Step but using (prepared by the method of invention patent application No. 98102212X China) Polycaprolactone / Poly / polylactic acid terpolymer (PCEL) (molecular weight 90,000) was prepared to give a size of 50 nanometers pore structure of cyclosporine formulation implanted in the anterior chamber of the rabbit eye after 24 hours fumigation with ethylene oxide sterilization, and then left for 1 weeks.

术后的肉眼观察和局部组织病理学检查结果表明环孢素释放体系有良好的眼内生物相容性,植入后的30周内环孢素可在房水中维持一定浓度,而在血液中检测不到有环孢素存在,40周后环孢素制剂完全消失,可以不用再取出。 Was visually observed, and local histopathology results show that postoperative cyclosporine delivery system has good biocompatibility in the eye, 30 weeks after implantation of cyclosporine to maintain a certain concentration in the aqueous humor, in blood could not be detected the presence of cyclosporine, cyclosporine formulation after 40 weeks completely disappeared, can no longer be removed.

实施例6、与实施例2相同方法与步骤,按实施例4的方法与步骤,但采用聚L-乳酸(PLLA)(分子量6万)(95%重量)与甲壳质(5%重量)的混合物制备,得到孔结构大小为15微米的环孢素制剂,在用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后植入兔眼的前房。 Example 6 Example 2 In the same manner, step, and step as in Example 4, but using poly-L- lactic acid (of PLLA) (molecular weight 60,000) (95 wt%) and chitin (5 wt%) the mixture was prepared to give a 15 micron pore size structure of cyclosporine formulation implanted in the anterior chamber of the rabbit eye after 24 hours fumigation with ethylene oxide sterilization, and then left for 1 weeks.

术后的肉眼观察和局部组织病理学检查结果表明环孢素释放体系有良好的眼内生物相容性,植入后的50周内环孢素可在房水中维持一定浓度,而在血液中检测不到有环孢素存在,一年后环孢素制剂完全消失,可以不用再取出。 Was visually observed, and local histopathology results show that postoperative cyclosporine delivery system has good biocompatibility in the eye, 50 weeks after implantation of cyclosporine to maintain a certain concentration in the aqueous humor, in blood have not detected the presence of cyclosporine, a year after cyclosporine formulation completely disappear, can no longer be removed.

实施例7、同实施例6的方法与步骤,但采用聚DL-乳酸(PDLLA)(分子量6万)(95%重量)与胶原(5%重量)的混合物制备,得到孔结构大小为10微米的环孢素制剂,在用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后植入兔眼的前房。 Example 7 The procedure of Example 6 with the method of the same embodiment, but prepare a mixture (95% by weight) and collagen (5% by weight) using poly DL- lactic acid (of PDLLA) (molecular weight 60,000), obtained pore structure size of 10 microns cyclosporine formulation, after 24 hours fumigation with ethylene oxide sterilization, for one week and then implant the anterior chamber of rabbit eyes.

术后的肉眼观察和局部组织病理学检查结果表明环孢素释放体系有良好的眼内生物相容性,植入后的20周内环孢素可在房水中维持一定浓度,而在血液中检测不到有环孢素存在,20周后环孢素制剂完全消失,可以不用再取出。 Was visually observed, and local histopathology results show that postoperative cyclosporine delivery system has good biocompatibility in the eye, 20 weeks after implantation of cyclosporine to maintain a certain concentration of the aqueous humor, in blood could not be detected the presence of cyclosporine, cyclosporine formulation after 20 weeks completely disappeared, can no longer be removed.

实施例8、同实施例1的方法与步骤,将环孢素药片裁成厚为2毫米、宽为5毫米、长为30毫米的环孢素制剂。 Example 8, with the method the same procedure of Example 1 embodiment, the thickness of cyclosporine tablets cut into 2 mm and a width of 5 mm and a length of 30 mm cyclosporine formulation. 将此环孢素制剂用环氧乙烷熏蒸24小时灭菌消毒、再放置1周后植入兔的肾后部。 This formulation of Cyclosporin 24 hours fumigation with ethylene oxide sterilization, and then placing the rear renal rabbits one week after the implant.

术后的肉眼观察和局部组织病理学检查结果表明:无炎症反应、水肿、新生血管、萎缩或坏死的现象,且血压正常,手术前后无变化。 And visually observed after local histopathology results show that: no inflammation, edema, angiogenesis, atrophy or necrosis phenomena, and normal blood pressure, no change before and after surgery. 证明环孢素释放体系的体内生物相容性良好。 Cyclosporine release in vivo biocompatibility prove a good system. 血液检测结果表明,在血液中无环孢素存在,因此可以避免环孢素对肾脏的毒性损害及引起高血压等并发症。 Blood test results show no presence of cyclosporine in the blood, thus avoiding cyclosporine toxicity damage to the kidneys and cause high blood pressure and other complications. 此环孢素释放制剂在植入的10周后完全消失,可以不用再取出。 This formulation of Cyclosporin release completely disappeared after 10 weeks of implantation, can no longer be removed.

对照例1:以聚氨酯为载体、完全按实例3的制法、用量及步骤制备环孢素释放体系。 Comparative Example 1: A polyurethane carrier, exactly as in Example 3, production method, dosage and the step of preparing cyclosporine delivery system. 术后肉眼观察和局部组织病理学检查表明环孢素释放体系有良好的眼内生物相容性,植入后的15周内可维持环孢素在房水为一定浓度,且在血液中检测不到有环孢素存在;到六个月时房水中也检测不到有环孢素存在。 Was visually observed, and local histopathology after cyclosporine showed a good delivery system biocompatible intraocular, 15 weeks after implantation cyclosporine may be maintained at a constant concentration in the aqueous humor, and detected in the blood cyclosporine has not exist; when six months have not be detected in aqueous humor presence of cyclosporine. 但术后一年制剂仍存在于前房之中,并且外型、大小和强度无变化,因此必须再手术取出。 One year after formulation but still exist in the anterior chamber, and the shape, size and intensity unchanged, it is necessary to remove the reoperation.

对照例2:高危角膜移植大鼠10只,术后1%环孢素滴眼液滴眼,每日4次。 Comparative Example 2: 10 high-risk corneal transplantation in rats, after 1% cyclosporine eye drops four times daily. 排斥反应时间只为10.6±1.90天。 Rejection time was only 10.6 ± 1.90 days.

Claims (7)

  1. 1.一种长效环孢素释放体系,包括环孢素和药物载体,二者的重量比为0.1∶0.9~0.9∶0.1,所述的药物载体为合成生物降解高分子材料、天然生物降解高分子材料、或合成生物降解高分子材料同天然生物降解高分子材料的共混物。 Cyclosporin A long-acting delivery system, comprising cyclosporine and a pharmaceutical carrier, a weight ratio of both 0.1:0.9 ~ 0.9:0.1, the pharmaceutical carrier is a biodegradable synthetic polymer materials, natural biodegradable a polymer material, or a synthetic biodegradable polymer materials with natural biological degradation of the polymer blend material.
  2. 2.按照权利要求1所述的长效环孢素释放体系,其中,所述的合成生物降解高分子材料为脂肪族聚酯类高分子,所述的天然生物降解高分子材料为壳聚糖、和/或明胶。 2. The natural biological depot according to claim 1, said cyclosporine delivery system, wherein said synthetic biodegradable polymer material is an aliphatic polyester-based polymer, said polymer material is degraded chitosan , and / or gelatin.
  3. 3.按照权利要求2所述的长效环孢素释放体系,其中,所述的脂肪族聚酯类高分子是聚羟基酸。 3. A cyclosporin according to claim long-acting delivery system of claim 2, wherein the aliphatic polyester-based polymer is a polyhydroxy acid.
  4. 4.按照权利要求2所述的长效环孢素释放体系,其中,所述的脂肪族聚酯类高分子是聚L-乳酸、聚DL-乳酸、共聚(L-乳酸/DL-乳酸)、聚乙醇酸、共聚(乳酸/乙醇酸)、聚己内酯、(乙醇酸/乳酸/己内酯)三元共聚物、聚己内酯/聚醚嵌段共聚物、和/或聚己内酯/聚醚/聚乳酸三元共聚物。 4. A cyclosporin according to claim long-acting delivery system of claim 2, wherein the aliphatic polyester-based polymer is poly-L- lactic acid, poly-DL- lactic acid, copoly (lactic acid L- / DL- lactic acid) , polyglycolic acid, copoly (lactic acid / glycolic acid), polycaprolactone, (glycolic acid / lactic acid / caprolactone) terpolymers, polycaprolactone / polyether block copolymers, and / or polyhexamethylene lactone / polyether / polylactic acid terpolymers.
  5. 5.按照权利要求1所述的长效环孢素释放体系,其特征在于,所述的长效环孢素释放体系具有相互连通的孔结构,其孔径大小为10纳米-500微米。 5. A cyclosporin according to claim long-acting delivery system of claim 1, wherein said depot delivery system cyclosporine interconnected pore structure having a pore size of 500 microns size of 10 nanometers.
  6. 6.按照权利要求1所述的长效环孢素释放体系,其特征在于,所述的药物载体为膜状、片状、粒状、块状、或条状。 6. A cyclosporin according to claim long-acting delivery system of claim 1, wherein the pharmaceutical carrier is a film, sheet, granular, massive, or strips.
  7. 7.按照权利要求1所述的长效环孢素释放体系,其特征在于,所述的载体为上述天然或合成的生物降解高分子的无纺织物,或者是由上述的合成或天然生物降解高分子材料制成的海绵体。 7. A cyclosporin according to claim long-acting delivery system of claim 1, wherein said carrier is above a biodegradable natural or synthetic polymer non-woven fabric, or by the degradation of synthetic or natural biological the sponge made of a polymer material.
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