生物降解左旋-18甲基长效避孕埋植剂载体材料的生物相容性研究

采用生物降解的嵌段型聚己内酯丙交酯(CL-b-LA)高分子材料为载体制成的左旋-18甲长效避孕埋植剂是一种新型的皮下埋植剂。为尽快在临床推广使用,按照中国药品生物制品鉴定所等单位制定的标准对这一材料进行了详细的生物相容性研究,包括皮肤刺激试验、皮肤致敏试验、体外溶血试验、急性毒性试验、细胞毒性试验、鼠伤寒沙门氏菌回复突变试验-Ames试验、哺乳动物培养细胞染色体畸变试验、小鼠骨髓多染红细胞微核试验、致畸胎试验和肌内长期埋植试验等。所有结果表明,生物降解左旋-18甲长效避孕埋植剂载体材料CL-b-LA是可以植入体内的,无任何毒副作用的,具有良好生物相容性的医用高分子材料。     

生物降解左旋—18甲基长效避孕埋植剂载体材料的生物相容…

采用生物降解的嵌段型聚己内酯丙交酯高分子材料为载体制成的左旋－１８甲长效避孕埋植剂是一种新型的皮下埋植剂，为尽快在临床推广使用，按照中国药品生物制品鉴定所等单位制定的标准对这一材料进行了详细的生物相容性研究，包括皮肤刺激试验、皮肤致敏试验、体外溶血试验、急性毒性试验、细胞毒性试验、鼠伤寒沙门氏菌回复突变试验－Ａｍｅｓ试验、哺乳动物增减功能染色体畸变 试验小、小鼠骨髓多染红细胞微核试验、致畸胎试验和     

可生物降解皮下埋植剂CaproF的临床初步研究

<正> 多年来研究人员对缓释皮下埋植避孕系统进行了大量、广泛的研究,其中成功地开发和推广使用了释放左旋18甲基炔诺酮(LNG)皮下埋植避孕剂Norplant。经临床研究证实,Norplant是一种高效、安全、可逆、接受性高的长效避孕方法,但放置有效期满5年后必须取出,增加使用者痛苦和花费,而且难于保证所有使用者均能按期取出从而增加避孕失败的危险。由此引发了可生物降解皮下埋植避孕剂的研究,即以一种兼具生物降解性和甾体药物通透性的聚合物,代替硅胶作为释放孕激素的载体,孕激素释放完毕后载体在体内降解吸收而无须取出。研究证实,具有可生物降解性的高分子材料中聚     

国产长效皮下埋植避孕剂的临床应用

1992年我院用国产长效皮下埋植避孕剂(左旋18-甲基炔诺酮),对600例育龄妇女进行皮下埋植,经1年随访,结果显示:国产长效皮下埋植剂的避孕效果达100％。600例中10例因出现月经异常而终止使用,其持续使用率为98.33％,获得了与进口长效皮下埋植避孕剂相同的效果。     

释放甾体药物的皮下埋植避孕法

皮下埋植避孕法是一种新的避孕给药途径。它以医用硅橡胶为载体,将甾体药物充填在载体之中,或与载体均匀混合制成皮下埋植剂。目前广泛使用的皮下埋植剂商品名为Norplant,包括NorplantⅠ系统,释放左旋18-甲基炔诺酮(LNG)30μg/日;NorplanⅡ系统,释放LNG50μg/日。避孕效果可靠,有效时间长,取出后生育力恢复快,对全身健康无影响等优点。其缺点在植入初期有不规则阴道出血。可生物降解缓释系统也在研究之中,可望成为一种更理想的埋植系统。男用埋植避孕剂也在进行实验研究。     

皮下埋植避孕剂的回顾与进展

利用硅橡胶的缓释机制长期恒定地释放小量孕激素——左旋18甲基炔诺酮的皮下埋植避孕剂Norplant,经过20多年的临床研究取得良好效果,5年累积妊娠率3.5％。其作用长效、高效、可逆、可接受性高,受到欢迎。根据此机理正在研制的还有释放孕酮、ST-1435、地索高诺酮及可生物降解的埋植剂。预期到本世纪末将有更多种类、作用时间不等、适于不同避孕要求人群的皮下埋植剂问世。     

聚三亚甲基碳酸酯-丙交酯共聚物微球长效避孕体系的研究

目的:用可生物降解共聚物聚三亚甲基碳酸酯-丙交酯(PTMC-co-DL-LA)为载体,制备含左旋18甲基炔诺酮(LNG)的载药微球,初步考察不同共聚组成聚合物制得的微球性能及体外释放行为,探讨该共聚物微球作为LNG的长效避孕释放载体的可行性。方法:采用溶剂挥发法(O/W),用不同共聚组成比的PTMC-co-DL-LA及其相应均聚物聚三亚甲基碳酸酯(PTMC)和聚丙交酯(PDLLA)制备含LNG的可生物降解微球,表征制得微球的粒径大小及分布、表面形态等性能,考察不同共聚组成聚合物微球对LNG的体外释放行为。结果:粒径均匀分布较窄,平均粒径<5μm:含LNG的微球表面平整光滑,其包封率均>90%。共聚物微球的LNG释放速率均较PTMC和PDLLA均聚物低,体现出良好的长效释放行为。结论:不同共聚组成聚合物制得的微球LNG的释放速率不同,均具有对LNG的长效释放作用,有望通过体内研究,使载有LNG的PTMC-co-DL-LA共聚物微球用于长效避孕。     

Ⅱ期临床——可生物降解的皮下埋植避孕剂Capronor~R的临床研究

应用单纯孕激素避孕的研究已近20年,最常使用的为肌注剂如醋酸甲孕酮(DMPA)及炔诺酮庚酸酯(NET-EN)。为了避免注射剂所见到的很高的初始血药浓度,发展了新的药物释放系统如皮下埋植剂Norplant~R(6支胶囊)及Norplant Ⅱ(2支棒)。Norplant为非生物降解的埋植剂,因所含左旋18甲基炔诺酮(LNG)对硅橡胶的穿透力小,故需要较大的表面积以释放足够的药物从而达到避孕有效浓度,并维持3～5年。另一种含3-酮地索高诺酮(单支)的非生物降解皮下埋植剂也正在研究中,有效期为1年。Capronor为可生物降解的避孕系统,由于其LNG释放率10倍于硅橡胶,所需表面积就少。埋植剂的外层暴露在组织液中一定时间后即分解成为6-羟乙酸,最终成为CO_2与水,因而使用超过有效期后不必手术取出。现对     

聚己内酯-b-丙交酯共聚物微球免疫避孕体系的研究

目的：初步探讨含β-人绒毛膜促性腺激素（β-hCG）的可生物降解嵌段共聚物聚己内酯-b-丙交酯（PCL-b-DLLA）微球作为免疫避孕释放体系的可行性。方法：采用双乳溶剂挥发法（W1/O/W2）,用共聚组成为40/60的PCL-b-DLLA嵌段共聚物制备含β-hCG的可生物降解微球,表征微球的粒径大小及分布、表面形态等性能,建立毛细管电泳测定微球中β-hCG含量的方法,初步考察聚合物微球在小鼠体内的免疫效果。结果：微球表面平整光滑,粒径呈正态均匀分布;平均粒径为6.45m,载药量为1.49%;微球在动物体内一次注射,不经强化即可在相当一段时间内产生相应抗体。结论：聚合物微球对β-hCG具有佐剂效应,该嵌段共聚物有望用作免疫避孕疫苗β-hCG的释放载体。     

皮下埋植避孕的临床观察

目的 探讨皮下埋植的避孕效果。方法 以皮埋剂（左旋18-甲）在育龄妇女上臂内侧进行皮下埋植避孕。结果 在皮埋对象中6年内避孕效果达100％。结论 皮埋避孕可以说是日前唯一、可逆、高效、安全、长效的首选方法。对人口计划生育有着重大的意义。     

A biodegradable levonorgestrel-releasing implant made of PCL/F68 compound as tested in rats and dogs

PURPOSE: Our objective was to report preclinical studies on a biodegradable long-acting contraceptive implant. METHODS: A poly (epsilon-caprolactone) (PCL)/pluronic F68 (F68) compound was used to construct an implant, which was filled with dry levonorgestrel (LNG) powder (PCL/F68/LNG). LNG release rate, contraceptive efficacy and polymer degradation were evaluated in rats and followed for 2 years. A 2-year toxicity study was conducted in dogs. RESULTS: The in vitro and in vivo release of LNG from the implant followed zero-order release kinetics. Serum LNG level in rats was very stable during the 2-year period. Studies on polymer degradation indicated that the molecular weight of PCL dropped from 66,000 to 15,000 Da, but the implant was still in good shape by the end of 2 years. CONCLUSION: Toxicological study demonstrated that the PCL/F68 polymer had no adverse effect in all aspects. The contraceptive efficacy in rats showed dose response. The implant was physically and chemically stable for up to 3 years in airproof aluminum foil packing at room temperature.     

Biodegradation and biocompatibility of contraceptive-steroid-loaded poly (DL-lactide-co-glycolide) injectable microspheres: in vitro and in vivo study

PURPOSE: A controlled-release drug delivery of contraceptive steroids levonorgestrel (LNG) and ethinyl estradiol (EE) has been developed by successful encapsulation of LNG and EE in poly (lactide-co-glycolide) (PLG) microspheres. MATERIALS AND METHODS: Smooth, spherical, steroid-loaded PLG microspheres with a mean size of 10-25 microm were prepared by using the water/oil/water double-emulsion solvent evaporation method. RESULTS: In vitro release profiles showed an increased burst release of LNG/EE on Week 1; thereafter, the release was sustained. At the end of Week 7, the release of LNG/EE from 1:5 and 1:10 PLG microspheres was 75.64% and 62.55%. respectively. In vitro degradation studies showed that the PLG microspheres maintained surface integrity up to Week 8 and then eroded completely by Week 20. In an in vivo study, the serum concentration of LNG/EE in rats showed a triphasic release response, with an initial burst release of 8 ng/mL LNG and 14 pg/mL EE on Day 1; thereafter, a controlled release of the drugs to the systemic circulation was maintained until Week 15, maintaining constant drug levels of 2 ng/mL LNG and 3-4 pg/mL EE in the blood. Histological examination of steroid-loaded PLG microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that contraceptive-steroid-loaded microspheres were biocompatible. CONCLUSION: This controlled-release and biocompatible nature of the PLG microspheres may have potential application in contraceptive therapy.     

左旋18-甲基炔诺酮生物降解长效避孕埋植剂抗生育作用的研究

三组成年SD雌性大鼠埋植载药量为30％(16.11mg/cm)的左旋18-甲基炔诺酮生物降解埋植剂,长度分别为1.2cm、0.8cm及0.5cm;另三组分别为阳性对照组(埋1根Norplant-Ⅰ型制剂)、空白对照组、空管组。埋植后观察动情周期的变化及3周后的抗生育效果,并对子宫内膜及埋植物周围组织的形态学变化进行了观察。结果表明,阳性对照组及1.2cm和0.8cm埋植组大鼠在埋植6天后出现持续间情期,埋植3周后无1例妊娠。0.5cm埋植组部分大鼠呈现持续间情期,埋植3周后,有57％的大鼠不育。说明1.2cm与0.8cm埋植剂量能达到100％抗生育效果,排卵可能被完全抑制。     

Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women

The release of contraceptive steroids through different drug delivery systems into serum and breast milk was investigated in a group of lactating women. Four women in each group were taking either a low dosage progestogen compound like norethisterone (NET) 350 μg or d-norgestrel (d-Ng) 50 μg alone or low dosage combination pills containing NET 1 mg or d-Ng 150 μg with 30 μg ethinyl estradiol (EE₂) or a biodegradable implant containing 25 mg NET or d-Ng. Peak levels in plasma and milk were seen in oral contraceptive users around 2 hours. Of the two low dosage progestogen compounds, d-Ng was below the detection limit in milk within 4 hours whereas NET was still detectable at the 24-hour interval. In contrast to this, because of the larger quantity of steroids in the combination pills, the NET/d-Ng levels in serum as well as in milk were high throughout the 24-hour period. With the subdermal route because of the sustained low release of the drug from the biodegradable implants, the levels in milk were below the detection limit within a day with d-Ng and within a week with NET.     

国产去除爆破效应CLa皮下埋植避孕剂人体药代动力学研究

对10例埋植国产去除爆破效应(本文简称除爆)的CLa皮下埋植剂(左旋18-甲基炔诺酮,本文简称皮埋剂)的妇女进行5年血药水平、释药速率及药物清除等药代动力学观察,结果显示:埋植除爆CLa皮埋剂后,24h血药水平是稳态水平的4.5倍左右,5年时平均血药水平为0.96±0.41nmol/L,释药速率36.21μg/d,足以达到避孕有效浓度,埋植除爆CLa皮埋剂后,各个时期平均血药水平基本恒定,用药5年时平均血药水平比用药早期略低,释药速率与血药浓度变化趋势相似。1～5年平均释药速率为43.96μg/d。经过5年埋植,埋植剂内剩余LNG为总含量的52.13％。取出埋植剂后,消除半衰期为44.55h,廓清率为334.00L/d。     

Development of a polymeric releasing device for 2'-carbomethoxyphenyl 4-guanidinobenzoate (a proteinase inhibitor): release rate, in vitro antifibrinolytic activity and in utero contraceptive effect

A polymeric delivery system consisting of ethylene-vinyl acetate copolymer (EVAc) was developed for 2'-carbomethoxyphenyl 4-guanidinobenzoate (MSGB), a potent inhibitor of the sperm enzyme acrosin. The optimal device consists of copolymer with 40% vinyl acetate by weight (EVAc/40), 65% drug loading and MSGB with a particle size of 250-499 micron. This formulation yields a device that is highly flexible and can be shaped to many forms and sizes. Construction of the device does not alter the properties of MSGB. Well controlled release of MSGB from the device occurs in vitro and in the uteri of rats. The in vitro release rate under "infinite sink" conditions is essentially the same as the in vivo release rate. The contraceptive effect of the MSGB-releasing device was tested in rabbits by placing a blank (control) device in one uterine horn and an MSGB-releasing device in the contralateral horn. In contrast to blank devices, MSGB-releasing devices completely prevent pregnancy, not only by inhibiting fertilization but also by decreasing implantation. MSGB possesses high in vitro antifibrinolytic activity. These results indicate that a very flexible device can be constructed for uterine application which retains its contraceptive effect by release of MSGB. The antifibrinolytic activity of MSGB may further decrease the menorrhagia that can be associated with IUD use.