罗替戈汀原位形成植入剂的处方研究

目的通过单因素考察优化处方,制备罗替戈汀原位形成植入剂。方法采用聚乳酸-羟基乙酸共聚物(PLGA)为载体,以体外累积释放度为指标考察PLGA类型、PLGA相对分子质量、PLGA质量浓度和载药量对罗替戈汀原位形成植入剂的影响,优化最佳处方。结果罗替戈汀原位形成植入剂的最佳处方为:以PLGA 7525 5A为载体、N-甲基-2-吡咯烷酮为溶剂的PLGA质量浓度为25%、载药量为50%。制备的罗替戈汀原位形成植入剂体外释药30 d累积释放度达85%以上,具明显的缓释特征。结论罗替戈汀原位形成植入剂结合了缓释注射剂和植入剂的优点,体外具有良好的缓释效果。     

吡喹酮-硬脂酸固体脂质纳米粒的制备及性能评价

目的：制备吡喹酮-固体脂质纳米粒,考察其理化性质和体外释放度。方法：以硬脂酸为脂质材料,聚乙烯吡咯烷酮为乳化剂,利用热熔乳化超声法制备吡喹酮-固体脂质纳米粒,扫描电镜观察纳米粒形态和均匀度,纳米粒度仪测定其粒径、分散指数、Zeta电位、包封率和载药量,并进行体外释放试验。结果：制备的固体脂质纳米粒为类圆球状,粒径分布较均匀、表面光滑。纳米的平均粒径、分散指数、电位、包封率和载药量分别为（316.5±22.8）nm、0.23±0.05、（-25.3±0.7）mV,（92.64±5.12）%和（18.45±1.34）%。药物在制剂的过程中稳定性良好。体外释放表明吡喹酮-硬脂酸固体脂质纳米粒在生理盐水中具有一定程度的突释和显著的缓释效果。结论：本试验制备的吡喹酮-硬脂酸固体脂质纳米粒具有较好的均匀度和高载药量,并具有良好的缓释性能。     

湿法研磨结合挤出滚圆法制备非诺贝特缓释微丸及工艺考察

目的湿法研磨结合挤出滚圆法制备稳定性良好的非诺贝特骨架型缓释微丸。方法将微粉化非诺贝特与亲水性载体共研磨,研磨液用固体辅料吸收,通过挤出滚圆法制备缓释微丸。以制剂体外释放度及加速试验中制剂稳定性为指标,筛选了研磨混悬液中亲水性载体的种类,考察了微晶纤维素用量、乳糖用量、挤出次数、滚圆时间等对药物释放的影响。结果以质量浓度为0.1 kg.L-1聚维酮(K30)为亲水载体溶液,药物与载体质量之比为10∶1时,制备微丸的释放度符合中国卫生部颁发标准(1 h释放10%~30%;4 h释放50%~75%;7 h释放75%以上),体外释药过程符合Higuchi方程。结论成功地制备了非诺贝特骨架型缓释微丸,该制备工艺重现性好,具有理想的缓释效果,加速试验稳定性良好。     

地塞米松眼部植入剂的制备

以生物可降解的乙交酯-丙交酯共聚物(PLGA)为载体,用溶剂法制备了地塞米松眼部植入剂。考察了处方中PLGA的构成和重均分子量、药物含量及释放调节剂对植入剂体外释放的影响。结果表明用分子量较小、乙交酯和丙交酯的摩尔比为50:50的PLGA制备的植入剂体外释药较快;提高药物含量、选用亲水性调节剂或乳酸也能加快体外释放。     

法罗培南钠缓释微丸的制备及体外释放特性考察

目的制备法罗培南钠缓释微丸,并对其体外释药特性进行研究。方法挤出滚圆法制备载药丸芯;以乙基纤维素N-100为包衣材料,以聚维酮k30为致孔剂,流化床包衣制备法罗培南钠缓释微丸;考察包衣增重、致孔剂用量等因素对缓释微丸释放度的影响,并考察其体外释药特征及释药机制。结果所制备的微丸有明显的缓释特征,体外释放符合Higuchi释药动力学方程。结论制备的法罗培南钠缓释微丸具有较理想的体外缓释效果。     

利培酮生物可降解注射型植入剂的制备及体外释放特性的研究

目的:制备利培酮生物可降解注射型植入剂并考察其体外释放特性。方法:选用聚乳酸乙醇酸共聚物(PLGA)为载体和N-甲基吡咯烷酮(NMP)为溶剂,制备利培酮生物可降解注射型植入剂。考察制剂在30d内累积释药率、PLGA在降解过程中分子量的变化情况以及固体聚合物在降解过程表面孔径的变化情况。结果:所制制剂30d内释药曲线平稳,累积释药率为89.01%,前24h突释量较小,为13.8%。聚合物降解30d后分子量从43000减少到10000左右,表面孔径逐渐变大。结论:利培酮生物可降解注射型植入剂可在体外30d持续稳定释药。     

罗替戈汀植入剂的制备及体外释放介质的研究

目的:制备可持续缓慢释药的罗替戈汀植入剂,并进行罗替戈汀植入剂体外释放介质的筛选。方法:采用热熔挤出法制备罗替戈汀植入剂,考察其在5种释放介质中的体外释药行为,通过体内外相关性拟合筛选最优释放介质,并用于各处方植入剂的体外释放评价,进行处方筛选。结果:以PLGA 8515 5A和5050 2A混合高分子为载体材料制备的罗替戈汀植入剂可持续平稳释药达40 d。罗替戈汀植入剂体外评价的最优释放介质为p H 4.5醋酸盐缓冲液,体内外拟合相关系数r为0.997,药物释放符合扩散-溶蚀模型。结论:罗替戈汀植入剂可实现长期缓慢释药,p H 4.5醋酸盐缓冲液作为释放介质用于罗替戈汀植入剂的体外释放评价,可预测体内的释药行为,从而可用于指导制剂处方筛选及质量评价。     

盐酸普拉克索缓释微丸的制备及体外释放度考察

目的:制备盐酸普拉克索缓释微丸。方法:采用挤出-滚圆法制备盐酸普拉克索微丸,再用EudragitRL30D和EudragitRS30D进行包衣,最终制成盐酸普拉克索缓释微丸,并用高效液相色谱法测定药物含量。结果:体外释放度实验显示,制备的盐酸普拉克索缓释微丸在24 h内平稳释放且释药完全。结论:用本方法制备的盐酸普拉克索缓释微丸体外释药平稳,释药规律符合一级释放模型。     

左旋氧氟沙星聚乳酸眼内缓释植片研制及其体外释药实验

目的:研制左旋氧氟沙星眼内缓释植片并观察其体外缓释效果。方法:以重均分子量为50000g.moL-1的DL-聚乳酸(PDLLA)为载体,通过溶液分散法制备载药量分别为5,10,20%的PDLLA-盐酸左旋氧氟沙星眼内缓释植片。利用紫外分光光度法检测3种缓释植片30d内在体外介质中释药含量,并将释放曲线进行Higuchi模型拟合,缓释植片进行IR谱图分析比较。结果:3种缓释植片30d内累积释放量为28.6%～71.4%,在8～30d释药后期药物释放平稳且缓慢;载药量较大的缓释片,释药早期突释现象较显著。3种缓释片的体外释放曲线均能较好的符合Higuchi模型,IR谱图显示缓释片中药物分散均匀。结论:研制的聚乳酸左旋氧氟沙星眼内缓释植片在体外释药研究中表现出良好的药物缓释行为和表征,符合临床治疗时间需要。     

盐酸普罗帕酮缓释片的制备及体外释放度考察

目的:盐酸普罗帕酮缓释片的研制并对其体外释放度进行评价。方法:羟丙基甲基纤维素为骨架材料,乳糖为致孔剂制备盐酸普罗帕酮缓释片。采用转篮法,以pH6.8的磷酸盐缓冲液为溶出介质,转速50r·min-1,高效液相色谱法测定盐酸普罗帕酮的体外释放度,并进行批间重现性和批内均一性考察。结果:3批样品在12h内完全释放,批间重现性良好;批内样品在1、4、8、12h取样点,释放度RSD分别为1.78%、1.12%、1.01%、0.95%,差异小。结论:盐酸普罗帕酮缓释片制备工艺简单、质量稳定,体外释放度考察表明达到了预期的缓释效果。     

Changes in morphology of in situ forming PLGA implant prepared by different polymer molecular weight and its effect on release behavior

The effects of polymer molecular weight on drug release behavior would be more complicated from in situ forming implants (ISFIs) that change gradually from liquid to semi-solid or solid after injection. To investigate this phenomenon, three commercially available D,L-lactic acid-co-glycolic acid (PLGA) polymers with molecular weights of 12, 34, and 48 kDa were used to prepare ISFIs containing leuprolide acetate (LA) as a model peptide. The influence of polymer molecular weight on the membrane formation, morphology, and also on their in vitro drug release behavior over a period of 28 days was investigated. Results showed that the amount of drug released over the first 24 h (36% +/- 0.34%) (burst release), for formulation prepared with polymer RG 503H (medium molecular weight, M(w) 34 kDa), was significantly higher than others (p < 0.05). Surface and cross-section morphology of ISFI prepared with medium molecular weight polymer to cellular and spongy-like structure which was in good agreement with the release behavior of LA from it.     

复方红霉素延迟起释型缓释片的研制及其体外释放

以重均分子量50 000聚乳酸(polylactic acid,PLA)为载体,与一定比例的红霉素(erythromycin,EM)和醋酸泼尼松(prednisone acetate,PNA)混合制备复方红霉素延迟起释型缓释片。利用紫外分光光度法检测EM和高效液相法检测PNA在体外介质中的释药量。缓释片持续释放时间约为21天,EM平均含量为99.7 mg/片,RSD为0.82%;PNA平均含量为10.03 mg/片,RSD为0.93%。缓释片从第5天开始缓慢而平稳地释放,在初期的突释现象尤为显著。在21天内EM累积释放量为86.1%,PNA累积释放量为78.3%。结果表明:缓释片制备方法可行,释药性能良好,临床疗效显著。     

In vivo-in vitro study of biodegradable and osteointegrable gentamicin bone implants.

Three implants composed of phosphate (25% hydroxyapatite, 75% tricalcium phosphate), 20% poly(DL-lactide) (DL-PLA; weight-average molecular weight (Mw), 30 kD) and 3% gentamicin sulphate (GS) were assayed in vitro and in vivo to study their release profiles as potential drug delivery systems to prevent or treat osteomyelitis. To prolong GS release, some implants were coated with poly(lactide-co-glycolide) (PLGA; Mw, 100 kD; I-PLGA) or DL-PLA (Mw, 200 kD; I-PLA). GS levels were measured in bone, kidney and blood after implantation into the femur of rats. The release profiles show a burst in the first few days, followed by a slower release rate. After I-PLA implantation, bone antibiotic concentrations higher than the minimum bactericidal concentration were maintained for 4 weeks. A linear correlation between in vitro and in vivo GS release was found to continue until complete drug release. Histological and radiological analysis showed that the implants were well tolerated and gradual new bone formation was observed.     

Effect of formulation parameters on 2-methoxyestradiol release from injectable cylindrical poly(dl-lactide-co-glycolide) implants.

The objective of this study was to investigate the potential of various formulation strategies to achieve 1-month continuous (improved) release of the novel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindrical poly(dl-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by a solvent extrusion method. PLGA 50:50 (M(w)=51kDa, end group=lauryl ester) (PLGA-lauryl ester) implants loaded with 3-30wt% 2-ME exhibited a pronounced lag phase (i.e., corresponding to induction time to polymer mass loss) and triphasic release profile. Incorporation of 5wt% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) ( approximately 57% release after 28days) or Pluronic((R)) F127 ( approximately 42% release after 28days) in PLGA-lauryl ester implants reduced the lag-phase and improved the drug release moderately over a period of 28days. The formation and the incorporation of a 2-ME/polyethylene glycol (PEG) 8000 solid dispersion in PLGA-lauryl ester implants further increased drug release ( approximately 21% and 73% release after 1 and 28days, respectively), attributable to improved drug solubility/dissolution, higher matrix porosity, and accelerated polymer degradation. Blending of PLGA 50:50 (M(w)=24kDa, end group=COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderate enhancement of 2-ME release over a period of 28days. PLGA-COOH (M(w)=24kDa) implants with 3-5% w/w pore-forming MgCO(3) exhibited the most desirable drug release among all the formulations tested, and, demonstrated 1-month slow and continuous in vitro release of approximately 80% 2-ME after a minimal initial burst. Hence, these formulation approaches provide several possible avenues to improve release rates of the hydrophobic drug, 2-ME, from PLGA for future application in regional anti-cancer therapy.     

Injection-molding versus extrusion as manufacturing technique for the preparation of biodegradable implants.

Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled-release systems for pharmaceutical agents. The factors determining the degradation kinetics of these systems include the composition and the molecular mass of the polymer, the morphology and the structure of the device, and the influence of thermal processes. The processing of the polymer determines the structure and design of the device, and influences to a high degree its morphology, namely its microporous structure, polymeric chain orientation and crystallinity.In this work, we aimed to compare the influence of two different implant manufacturing techniques, extrusion and injection-molding, on the in vitro degradation of the polymeric matrix. Both kinds of implants were loaded with a somatostatin analogue. Decrease in molecular weight, and polydispersity evolution during an accelerated in vitro degradation test were studied by size exclusion chromatography. Morphological changes in the polymeric matrix during degradation were followed after defined time intervals by means of scanning electron microscopy. Crystallinity studies were performed by differential scanning calorimetry and by X-ray analysis. Peptide stability in the polymeric matrix after both manufacturing methods was evaluated. Peptide release profiles, obtained in vitro during a week dissolution test, from both implant samples, were studied.It was shown that both molecular weight and polydispersity decreased after extrusion or injection-molding. This decrease was more pronounced with the latter technique. Crystallinity studies demonstrated that the crystalline network was not destroyed after both manufacturing methods. Peptide release profiles obtained in vitro were in good accordance with scanning electron microscopy. It was found that both manufacturing techniques had to be considered, although the extruded implants degraded more rapidly in vitro than the injection-molded ones.     

Controlled systemic delivery by polymeric implants enhances tissue and plasma curcumin levels compared with oral administration

Curcumin possesses potent anti-inflammatory and anti-proliferative activities but with poor biopharmaceutical attributes. To overcome these limitations, curcumin implants were developed and tissue (plasma, brain and liver) curcumin concentrations were measured in female ACI rats for 3 months. Biological efficacy of tissue levels achieved was analyzed by modulation of hepatic cytochromes. Curcumin implants exhibited diffusion-mediated biphasic release pattern with ～2-fold higher in vivo release as compared to in vitro. Plasma curcumin concentration from implants was ～3.3 ng/ml on day 1, which dropped to ～0.2 ng/ml after 3 months, whereas only 0.2-0.3 ng/ml concentration was observed from 4-12 days with diet and was undetected subsequently. Almost 10-fold higher curcumin levels were observed in brain on day 1 from implants compared with diet (30.1 ± 7.3 vs 2.7 ± 0.8 ng/g) and were still significant even after 90 days (7.7 ± 3.8 vs 2.2 ± 0.8 ng/g). Although curcumin levels were similar in liver from both the routes (～25-30 ng/g from day 1-4 and ～10-15 ng/g at 90 days), implants were more efficacious in altering hepatic CYP1A1 levels and CYP3A4 activity at ～28-fold lower doses at 90 days. Curcumin implants provided much higher plasma and tissue concentrations and are a viable alternative for delivery of curcumin to various organs like brain.     

Polyanhydride implant for antibiotic delivery--from the bench to the clinic

A polyanhydride implant (Septacin) containing gentamicin sulfate was developed for sustained local delivery of the drug to the site of infection in the treatment of osteomyelitis. Laboratory-scale injection molding equipment was utilized to fabricate the implant for in vitro characterization. Molding conditions were optimized to produce implants with a skin-core structure which was found to be critical in preventing the initial cracking of the implant during in vitro drug release test in water. A manufacturing process consisting of twin-screw extrusion, pelletizing, and injection molding was developed. Polymer-drug pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The implants were terminally sterilized by gamma-radiation which was found to cause increase in copolymer molecular weight as a result of polymer chain extension. The stability of Septacin was evaluated as a function of storage temperature and time. A marked decline in copolymer molecular weight occurred in samples stored above freezing temperatures and significantly slower drug-release profiles were also exhibited by these samples. In vivo drug release from Septacin in rats showed that the gentamicin plasma levels were extremely low, indicating the low systemic exposure to gentamicin. Furthermore, Septacin samples have demonstrated efficacy in the rat skin-abscess and horse-joint infection models. Results from a human in vivo study also showed high local drug concentrations at implantation sites while systemic exposure to the drug was minimal.     

去甲斑蝥素肝动脉栓塞缓释微球的制备及其体外释放性评价

目的:制备去甲斑蝥素肝动脉栓塞缓释微球(NCTD-MS),并考察其体外释放特性。方法:以NCTD为主药,海藻酸钠ALG)/壳聚糖(CS)为复合载体,采用内部凝胶化法制备NCTD-MS;选取ALG浓度、凝胶化反应剂冰醋酸的用量、药物-载体重量比(简称药载比)为因素,以粒径偏差、载药量及包封率为指标进行正交设计优化最佳处方并进行验证;动态透析法考察微球在不同介质(磷酸盐缓冲液和生理盐水)中的体外释放特性,并与NCTD原料药的释放性进行比较。结果:最佳处方为ALG浓度2.0%、冰醋酸1.0mL、药-载重量比0.8∶1,以该处方制备的微球平均粒径为(309.75±2.19)μm、载药量为(12.65±0.87)%、包封率为(68.66±0.38)%;NCTD-MS在2种介质中24h释放可达80%,释放行为均遵循Weibull方程,而NCTD原料药在3h内即释放完毕。结论:NCTD-MS制备工艺简单,缓释效果明显。     

曲尼司特巴布剂的研制及释放度测定

目的:制备曲尼司特巴布剂并研究其体外释药性能.方法:以水溶性高分子材料为主要基质,以巴布剂基质的成型时间为指标,考察影响巴布剂物理性状和影响因素;进行体外释放度的测定,研究巴布剂的透皮释放行为.结果:巴布剂最佳处方为:曲尼司特 0.5 g,聚乙烯醇 6 g,水溶性高分子材料 25 g,甘油 5 g,丙二醇 5 g,氮酮 5 g,蒸馏水加至 150 g;4天药物释放率大于80%.结论:曲尼司特巴布剂含水量高,皮肤水合效果好,无刺激性;符合皮肤缓释型透皮给药系统的要求.