Once-a-month injectable microcapsules of leuprorelin acetate]

Leuprorelin (leuprolide, D-Leu6-(des-Gly10-NH2)-LH-RH ethylamide) acetate is a super-active agonist of luteinizing hormone-releasing hormone (LH-RH). We developed once-a-month injectable microcapsules of this agonist by our novel in-water drying method. This depot formulation can release the drug at an apparent zero-order rate over one month with bioerosion of copoly (lactic/glycolic acid) utilized as a wall material of the polycore microcapsules. A dramatic prolonged depression of pituitary-gonadal axis, chemical castration, was achieved by the once-a-month injection in experimental animals; it expects a reliable efficacy for treating hormone-dependent prostatic, breast cancers and endometriosis. Studies on the dosage design of this new delivery system of leuprorelin are summarized.     

缓释醋酸亮丙瑞林微球对大鼠子宫异位内膜的抑制作用

目的观察国内研制的醋酸亮丙瑞林(LE)微球对异位子宫内膜的抑制作用,并与进口醋酸亮丙瑞林微球(enanton)及醋酸亮丙瑞林(LE)注射溶液进行疗效比较.方法以手术方法制备大鼠子宫内膜异位症模型,将动物分为辅料组、原料药组(LE,20μg·kg-1·d-1×28d,sc)、进口微球组(enanton20μg·kg-1·d-1,sc)、国产微球组(国产LE微球2、20、200μg·kg-1·d-1,sc).结果辅料组异位内膜体积呈增长趋势,阳性对照药LE20μg·kg-1(sc×28d)、enanton20μg·kg-1·d-1,及国产LE微球2、20、200μg·kg-1·d-1对异位内膜均有明显抑制作用,且后者具有一定的剂量相关性.结论国产醋酸亮丙瑞林微球20μg·kg-1·     

醋酸亮丙瑞林联合莉芙敏治疗子宫内膜异位症的临床研究

目的研究醋酸亮丙瑞林联合莉芙敏治疗子宫内膜异位症（EM）的疗效和安全性。方法选择2009年12月1日～2010年12月1日于阜新市第二人民医院妇科住院接受治疗的子宫内膜异位症患者60例,随机分为A、B组,每组各30例。A组患者术后月经复潮第1～2天内皮下注射醋酸亮丙瑞林3.75mg,每4周1次,连续6次,疗程24周;B组在使用醋酸亮丙瑞林的基础上配合口服莉芙敏,比较两组患者治疗前、后的血清激素、绝经症状严重程度、骨代谢生化指标及临床疗效。结果 （1）治疗后FSH、LH和E2水平均低于治疗前,差异有统计学意义;治疗后,B组的雌二醇水平高于A组,FSH及LH水平低于A组,但差异均无统计学意义（P〉0.05）。（2）A、B两组患者治疗后的Kupperman评分总平均分别为（19±5）分和（12±2）分,两组间比较,差异有统计学意义（P〈0.05）;两组间潮热出汗、失眠及肌肉关节疼痛的发生率比较,差异均有统计学意义（P〈0.05）;感觉异常的发生率两组间比较,差异均无统计学意义（P〉0.05）。（3）用药后均存在骨代谢生化指标钙、磷明显升高,与用药前差异有统计学意义;用药后B组患者各指标升高程度低于A组,差异有统计学意义;两组患者用药前后腰椎骨密度有显著差异,A组用药后与B组用药后相比也存在差异,B组用药前后无显著差异。（4）两组患者完全缓解率及部分缓解率无差异,复发率为A组略高于B组,推测可能与样本量小有关,有待于扩大样本进一步研究。结论皮下注射醋酸亮丙瑞林对于EM保守性手术后的巩固治疗疗效确切,同时配合口服莉芙敏是能减轻其不良反应,增强患者依从性,同时也是安全有效的。     

胸腺肽α1缓释注射微球的研究

制备胸腺肽α₁(Tα₁)的长效注射微球，并对微球的体外释放特性、体外活性及药效学进行考察。采用复乳法(W/O/W)制备了载Tα₁聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；采用CCK-8法评价微球制备工艺和体外释放过程中Tα₁的生物学活性；体内药效学研究中采用流式细胞仪检测免疫抑制模型大鼠给予Tα₁微球后所产生的CD₄⁺，CD₈⁺因子的量，根据CD₄⁺/CD₈⁺的比值变化评价体内药效。微球球形圆整，分散性好，两个优选处方(外水相中加入5%氯化钠和10%葡萄糖)的微球包封率分别为87.8%和90.2%；Tα₁微球1个月的体外累积释放可达90%以上。使用含10%葡萄糖的PVA溶液作为外水相，较好地保持了制备工艺过程中的Tα₁生物学活性，在体外释放过程中Tα₁的生物学活性略有下降；Tα₁微球可显著提高免疫抑制模型小鼠的免疫力。用可生物降解的聚合物PLGA作为载体材料，可以将Tα₁制备成缓释1个月的注射微球。     

醋酸戈舍瑞林缓释微球的制备及体外释药研究

目的制备醋酸戈舍瑞林缓释微球,考察其一般性质和体外释药特性。方法采用复乳-液中干燥法制备醋酸戈舍瑞林微球,测定微球的外观形态、粒度分布和体外释药曲线。结果微球形态规则,粒径约为85.6μm,微球体外释药规律符合Higuchi方程：Q=16.202t1/2＋1.550 3,r=0.991 0。结论制备的醋酸戈舍瑞林微球具有长时间的缓释作用。     

注射用醋酸亮丙瑞林对特发性中枢性性早熟的疗效观察

目的：观察注射用醋酸亮丙瑞林（GnRHa）对特发性中枢性性早熟（ ICPP ）女童的临床疗效。方法对45例ICPP女童给予注射用醋酸亮丙瑞林治疗,每4周注射1次,治疗12个月。观察分析治疗前后患儿第二性征、子宫、卵巢、雌二醇（E2）、黄体生成素（LH）、促卵泡激素（FSH）、骨龄（BA）,预测成人身高的变化及药物不良反应。结果45例患儿治疗后乳房、子宫、卵巢体积均有缩小, E2、LH、FSH较治疗前显著降低,骨龄成熟减缓,骨龄/年龄（BA /CA）值下降,预测成人身高增加（4.5±0.4）cm,与治疗前相比,差异具有统计学意义（P﹤0.05）。结论注射用醋酸亮丙瑞林能显著有效抑制特发性中枢性性早熟女童性腺轴及第二性征发育,延缓骨龄成熟,达到改善性早熟患儿成年终身高的目的。     

Therapeutic effects of leuprorelin microspheres in prostate cancer

Leuprorelin has demonstrated effectiveness comparable to orchiectomy and oral diethylstilboestrol for the palliation of advanced prostate cancer. Unlike orchiectomy, leuprorelin's effects are reversible; also leuprorelin is not associated with the cardiovascular or thromboembolic adverse effects of oestrogens. For these reasons, leuprorelin has been widely used as an alternative to surgical castration or to oestrogens in the treatment of metastatic prostate cancer. Sustained-release leuprorelin microsphere formulations have been developed which exhibit zero order release of active drug from the injection site, such that in the United States the 7.5 mg dosage strength is recommended to be administered once a month and the 22.5 mg dosage strength once every three months. Although most patients will have suppressed release of pituitary luteinizing hormone by the third or fourth week after the first dose of depot leuprorelin, 4-5% of treated patients have been reported to have delayed responses, taking many more weeks or months to respond. A transient biochemical hormone escape has also been reported, although worsening of clinical symptoms has not accompanied the elevation of serum testosterone levels during treatment. Usually, leuprorelin is initiated as monotherapy when patients with advanced prostate cancer become symptomatic. However, newer studies of combination therapy of luteinizing hormone releasing hormone analogs with antiandrogens suggest that early initiation of therapy, at the time of diagnosis of advanced disease, may be beneficial, particularly in a subgroup of patients with small volume disease and good performance status. Leuprorelin is also undergoing evaluation as neoadjuvant therapy prior to radical prostatectomy for localized prostate cancer. Preliminary studies suggest that neoadjuvant leuprorelin in combination with an antiandrogen may be effective in downstaging prostate tumours. Leuprorelin commonly produces several adverse effects: hot flashes, decreased libido and impotence, and tumour flare.     

贝依联合曼月乐治疗子宫腺肌症的疗效观察及对患者月经的影响

目的 探析贝依联合曼月乐治疗子宫腺肌症的疗效及对月经的影响.方法 选择我院2013年3月至2015年3月收治的81例子宫腺肌症患者作为研究对象,随机分为观察组41例与对照组40例.对照组应用曼月乐进行治疗,观察组在曼月乐基础上联合贝依进行治疗,比较两组治疗前后子宫体积、子宫内膜厚度、痛经、月经量及不良反应发生率.结果 治疗后两组子宫体积、子宫内膜厚度与治疗前相比均大幅降低,组内治疗前后差异有统计学意义(P＜0.05),同时观察组下降幅度更大,组间差异有统计学意义(P＜0.05).观察组不良反应发生率为43.9％(18/41),对照组50.0％(20/40),差异无统计学意义(P＞0.05).结论 贝依联合曼月乐治疗子宫腺肌症疗效满意,利于子宫体积与子宫内膜厚度减小,且痛经与月经量多情况得到明显缓解,不良反应少,具有较大临床价值.     

Therapeutic effects of leuprorelin microspheres on endometriosis and uterine leiomyomata

Uterine leiomyomata and endometriosis are two common hormone-dependent pathologies effecting women of reproductive age. Prior to the introduction of gonadotropin releasing hormone agonists (GnRHa), there was no effective medical therapy for leiomyomata, and the most effective pharmaceutical intervention for endometriosis had unacceptable side effects. Early intranasal and non-depot formulations of GnRHa were effective treatments for these diseases but patient acceptance and compliance was poor. The introduction of depot microspheres of leuprorelin (leuprolide) acetate has provided efficacious and safe medical management of both endometriosis and uterine leiomyomata which is well tolerated by most patients.     

Chitosan/cellulose acetate microspheres preparation and ranitidine release in vitro

New microspheres containing hydrophilic core and hydrophobic coating as a controlled-release system with no toxic reagents were proposed. Water in oil in water (W/O/W) emulsion and solvent evaporation methods were used to make chitosan/ cellulose acetate (CCA) microspheres sized 200 - 400 microm. Ranitidine hydrochloride, as a model drug, was investigated for its release properties in vitro. The loading efficiency and release rate of ranitidine were affected by chitosan concentration and molecular weight. Higher loadings were obtained at lower concentrations in the interval of 1% to 2%. With chitosan at a 2% concentration microspheres could be obtained with more spherical appearance, smaller size, and higher ranitidine loading efficiency microspheres than at other concentrations. Among the different molecular weight chitosan (47, 145, 308, 499, and 1130 KD) microspheres, the high molecular weight chitosan (1130 KD) microspheres had relatively high loading efficiency (10%). Molecular weight and concentration of chitosan as well as the size of microspheres affected the release of ranitidine. Microspheres smaller than 280 microm released the drug faster than did the bigger by about 10%. The optimal condition for the preparation of the microspheres was chitosan concentration 2%, molecular weight 1130 KD. The ranitidine release from the microspheres was 30% during 48 h in phosphate-buffer saline medium.     

注射用醋酸奈西利肽缓释微球的制备及体外释药研究

目的制备注射用醋酸奈西利肽缓释微球,考察其体外释药特性,以达到缓释作用,减少用药次数。方法采用复乳-液中干燥法,以聚乳酸-羟基乙酸(PLGA)为载体,乙酸乙酯为有机溶剂,羧甲基纤维素钠(CMC)水溶液为分散介质,甘露醇为保护剂,通过冷冻干燥制备注射用醋酸奈西利肽缓释微球。以微球粒径、收率、包封率为指标,采用正交实验优化微球的处方和制备工艺。采用透析法考察含药微球的体外释药特性,计算微球累积释药百分率,绘制体外释药曲线。结果通过正交实验筛选出了制备注射用醋酸奈西利肽缓释微球的处方和制备工艺,载药量为37.3%,包封率为91.2%,zeta电位为(-27.8±1.72)m V,含药缓释微球的体外释药过程符合Higuchi方程。结论制备的注射用醋酸奈西利肽缓释微球具有长时间的缓释作用。     

胰高血糖素样肽-1长效注射微球的制备及其体外释放研究

目的:制备载胰高血糖素样肽-1(GLP-1)的长效注射微球,并对微球的体外释放特性和生物活性进行考察。方法:采用复乳法(w/o/w)制备了载GLP-1的聚乳酸-乙醇酸嵌段共聚物(PLGA)微球;考察微球的粒径大小、外观、包封率等理化特性和体外释放特性;采用在体动物法评价了微球制备工艺和体外释放过程中GLP-1的生物学活性。结果:外水相中NaCl浓度为15%(w/v)时微球包封率在85%以上,微球圆整,表面致密,平均粒径30μm。使用低黏度PLGA并在油相中加入10%(w/w)的PEG 6000,显著提高了药物在1个月内的累积释放,可达83%。微球的制备工艺不影响GLP-1的生物学活性,在体外释放过程中GLP-1的生物学活性明显下降。结论:用可生物降解的聚合物PLGA作为载体材料,可以将GLP-1制备成缓释1个月的注射微球。     

醋酸亮丙瑞林的临床应用和制剂研究进展

醋酸亮丙瑞林是视丘下部所产生的黄体生成激素释放激素(LHRH)的高活性衍生物,为合成的两端封闭的水溶性九肽.它可以刺激垂体分泌促性腺激素,诱发生殖器官生成类固醇,长期大量使用会使LHRH受体脱敏,抑制促性腺激素的分泌以及睾丸或卵巢甾类的生成,临床上用来治疗或缓解多种性激素依赖性疾病如前列腺癌、子宫内膜异位症、子宫肌瘤、中枢性性早熟等.但是醋酸亮丙瑞林不易透过生物膜,在胃肠道中不稳定,易被消化酶降解,口服、鼻腔、直肠、阴道途径给药生物利用度极低,所以目前人们针对醋酸亮丙瑞林的非胃肠道给药途径的制剂进行了广泛的研究,有些已经成功开发为上市药品.本文主要就醋酸亮丙瑞林的临床应用及其制剂的研究情况进行综述.     

胰高血糖素样肽-1长效注射微球的研究

目的制备载胰高血糖素样肽-1(GLP-1)的长效注射微球，并对其体外释放特性及药效学进行考察。方法采用复乳法(W/O/W)制备载GLP-1聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；在体动物法评价微球制备工艺和体外释放过程中GLP-1的生物学活性。在糖尿病模型小鼠体内考察了微球的降血糖作用。结果微球球形圆整，分散性好，包封率在80%以上；GLP-1微球1个月的体外累积释放可达85%，其释放行为符合近似零级释放模式；使用明胶溶液作为内水相，较好地保持了制备工艺过程中的GLP-1生物学活性，在体外释放过程中GLP-1的生物学活性略有下降；GLP-1微球可显著降低糖尿病模型小鼠的血糖水平，降糖作用可维持1个月。结论用可生物降解的聚合物PLGA作为载体材料，可以将GLP-1制备成缓释1个月的注射微球。     

Preparation and characterization of injectable microspheres of contraceptive hormones

Present study describes the development of a new formulation of levonorgestrel and ethinylestradiol based on double emulsion-solvent evaporation technique using poly(epsilon-caprolactone) (PCL) as biodegradable polymer. The effect of polymer concentration on microspheres and entrapment of drug into microspheres were studied. PCL was selected because of its hydrophobicity and advantages over other biodegradable polymers. Characterization of biodegradable polymer used for controlled drug delivery is essential to ensure reproducibility of in vitro and in vivo performances. The selected characterisation techniques established for PCL microspheres include its loading and entrapment efficiencies, DSC to analyse thermal behaviour, SEM to observe surface morphology, drug content of microspheres and in vitro release of drugs from microspheres. The SEM reports showed that microspheres were with smooth surface and DSC thermograms revealed no interaction between drug and polymer. The entrapment was found to be 58 and 47% for 1:10 and 1:5 batches and in vitro release studies showed that about 69.7% of LNG and 66.7% of EE from 1:10 batch and about 80% of LNG and 75.5% of EE from 1:5 batch for 150 days.     

An overview of preparation and evaluation sustained-release injectable microspheres

Recently, sustained-release injectable microspheres as a novel parenteral administration system have been interested on for many years, due to the excellent advantages when compared to traditional dosage forms: less administration frequency, lower adverse side effects and no need for a surgical procedure. Therefore, major progresses in the development of another successful marketed sustained-release injectable formation have been made, but most investigations are merely limited in laboratory levels; in addition, few reports focus on giving some positive guidance to launch these novel microspheres into market. This review addressed some commonly used polymers, preparation methods and sterilization processes relating to biodegradable microspheres. Moreover, the processes for measuring the sustained-release behaviour of this novel system are summarized in this report, including the methods to determine the in vitro and in vivo release behaviours and the strategies to analyse the in vitro and in vivo correlations.     

利培酮长效注射剂的药动学特征和临床应用

微球注射剂系采用生物降解聚合物为骨架将药物包裹于微球内的一种可供注射的剂型，它具有长效、安全和用药方便等优点。现综述国内外刚上市的可缓释2周的利培酮微球注射剂（Risperidal Consta^TM，恒德）的药动学特点和临床应用概况。该制剂用药后可以预测的缓释速率释药和较低血药峰谷浓度波动，体现了制剂药动学的优点。用阳性和阴性症状量表（PANSS）平均分值评价结果表明，精神分裂症患者采用本制剂进行短期（12周）和长期（12个月）试验治疗，除具有肯定的疗效外，在耐受性和锥体外系不良反应方面也优于利培酮片剂和目前临床其他常规制剂。由于可减少住院次数和发作所需专业机构护理次数以及缩短了累积住院期间，从药物经济学角度考虑也具有较好的优势。     

Preliminary investigation of the nasal delivery of liposomal leuprorelin acetate for contraception in rats

The purpose of the study was to investigate the nasal route as a non-invasive alternative for delivery of leuprorelin acetate (leuprolide acetate, LEU) and to achieve an effective concentration of leuprorelin acetate in blood after nasal administration for contraception in rats. The plain drug solution, physical mixture (plain drug along with constituents of liposomes), or drug encapsulated in either neutral or charged liposomes containing 5 microg leuprorelin acetate were administered to rats through the nasal route. The plain drug solution was administered subcutaneously (s.c.). Simultaneous evaluation was performed on the influence of a mucoadhesive agent (chitosan) on nasal absorption of the plain drug and the liposome-encapsulated drug. Blood samples were taken at regular time intervals and subjected to luteinising hormone (LH) analysis using a specific immunoassay kit. The plasma luteinising hormone concentration vs time data of nasal and subcutaneous treatments were plotted and compared with that of subcutaneous administration. Relative percentage of bioavailability (F) for nasal treatments was calculated from plasma concentration vs time plots. Sperm count and fertility performance studies were carried out for selected formulations in rats. Neutral liposomes (LLEU) and negatively-charged liposomes (LLEUn) showed higher relative percentage of bioavailability (F 27.83 and 21.30%, respectively) as compared with the plain drug and the physical mixture (F 10.89 and 10.96%, respectively) after nasal administration. Hence, work on neutral liposomes was continued. F was further improved after incorporation of chitosan i.e. 10.89 to 49.13% for plain leuprorelin acetate and 27.83 to 88.90% for liposomal leuprorelin acetate formulations. Liposomal chitosan formulation administered nasally and leuprorelin acetate solution subcutaneously achieved complete azoospermia. No implantation sites were observed after the mating of female rats with treated males. It was observed that in the treated female rats, the estrous cycles ceased with the same formulations from the first treatment cycle. The findings of these investigations demonstrated that the bioavailability of the nasally-administered liposomal leuprorelin acetate with chitosan formulation was comparable with that of the subcutaneously administered drug. Complete contraception was obtained in male and female rats that had been treated with either the nasally administered liposomal leuprorelin acetate with chitosan or the subcutaneously administered drug.     

The choice of lipids and surfactants for injectable extravenous microspheres

Suspensions of lipid microspheres sizing from 1 to 30 microm, whose fluidity and lipid/surfactant composition is suitable for parenteral administration were developed. None of the formulations prepared with Precirol (palmitostearate), as the only lipid, was physically stable during storage, because liquid suspensions formed semisolid gels within one week. Stable 10% (w/w) suspensions of lipid microspheres were produced using saturated triglycerides in combination with medium chain unsaturated triglycerides (Miglyol) as lipids and polysorbate 80 (2% w/w) as a surfactant.