皮下埋植避孕剂左旋18甲基炔诺酮Ⅰ型体内释药速率及其影响…

采用紫外分光光度法测定了左旋１８甲基块诺酮皮下埋植避孕剂Ⅰ型埋植３－１１１个月体内药物释放速率，其结果与美国人口理事会报道相近，并考察 体重，年龄因素对释药速率的影响。实验表明，此长效 埋植剂的释药速率不受体重、年龄因素影响。     

阿魏酸钠双层片的制备及体外释放特性

目的:制备阿魏酸钠双层片并考察其体外释放特性.方法:采用粉末直接压片法,以羟丙基甲基纤维素(HPMC)为骨架材料制备阿魏酸钠双层片,通过紫外分光光度法,按照<中国药典>的转篮法测定体外释放度,并对体外药物释放的影响因素进行考察.结果:HPMC的规格和用量是影响药物释放的主要因素,填充剂不同对药物的释放也产生一定影响.结论:以HPMC K15M为骨架材料,微晶纤维素为填充剂制备的阿魏酸钠双层片具有良好的缓释和速释特性.     

皮下埋植避孕剂左旋18甲基炔诺酮Ⅰ型体内释药速率及其影响因素

采用紫外分光光度法测定了左旋１８甲基炔诺酮皮下埋植避孕剂Ⅰ型（Ｎｏｒｐｌａｎｔ○ＲⅠ）埋植３～１１１个月体内药物释放速率，其结果与美国人口理事会报道相近，并考察了体重、年龄因素对释药速率的影响。实验表明，此长效埋植剂的释药速率不受体重、年龄因素影响。     

盐酸索他洛尔爆破型脉冲片的制备及释放度研究

目的:以盐酸索他洛尔为模型药物,研制爆破型脉冲片并考察其体外释药特性.方法:通过体外释放实验,考察片芯崩解剂种类、包衣组成与厚度、增塑剂种类与用量、致孔剂种类与用量等处方因素对脉冲片体外释放的影响;并通过吸水实验分析脉冲片的释药机制.结果:以乙基纤维素(EC)为包衣材料,邻苯二甲酸二乙酯(DEP)为增塑剂,聚乙二醇6000(PEG6000)为致孔剂,采用薄膜包衣法,制备含盐酸索他洛尔30 mg 的脉冲片.该制剂在体外延迟释放时间为4 h～6 h,时滞后1.5 h累积释药达90%.结论:盐酸索他洛尔爆破型脉冲片在体外具有脉冲释放特性.     

Implanon单根皮下埋植避孕法在江苏省可接受性研究

Implanon单根皮下埋植剂除具有埋植避孕法的高效、长效、可逆、简单、安全五大优点外，还具有较强的抗雄激素活性，对脂蛋白影响小的优点。1989年经卫生部批准，在北京、上海、浙江、江苏进行多中心临床研究，以观察中国妇女对该避孕剂的可接受性。兹将江苏的研究结果报告如下。材料与方法一、材料Implanon皮下埋植剂系荷兰Organon公司研制。是以一根4cm硅橡胶细软管为载体，内置60mg3一酮地索高诺酮的缓释装置。置入皮下，每日释放60ug的药物。二、方法l．对象：35岁以下生育过一个孩子，对笛体激素无禁忌的非哺乳期健康妇女。在接受前进…     

聚三亚甲基碳酸酯对孕二烯酮透过性的影响

目的考察聚三亚甲基碳酸酯对孕二烯酮的透过性,以期为避孕及其他埋植剂、透皮制剂的制备提供一定的参考依据。方法采用溶剂自然挥散法制备薄膜,双隔室静态小室法进行透过实验,紫外-可见分光光度法测定孕二烯酮的透过量。结果聚三亚甲基碳酸酯成膜性能良好,24 h孕二烯酮的透过量接近或大于4.425×10-6 g.cm-2。结论通过控制分子质量、剂型和载药面积,聚三亚甲基碳酸酯可作为降解型避孕药物控释系统的载体。     

硫普罗宁缓释片的制备及体外释放度考察

目的制备硫普罗宁缓释片并对其体外释放度进行考察。方法以HPLC法为分析方法,采用相似因子法评价硫普罗宁缓释片体外释放行为。结果硫普罗宁缓释片的体外释放行为符合Highuchi方程。KollidonSR用量、填充剂的种类与用量及种类对药物的释放速度有较大影响,而硬度和释放介质的离子强度对药物的释放速度无显著影响。结论体外释放度符合缓释制剂要求,可进一步进行体内释药行为考察。     

米非司酮皮下埋植剂抑制大鼠异位子宫内膜的效果观察

目的:观察米非司酮埋植剂抑制大鼠异位子宫内膜的效果。方法:分别在子宫内膜异位症模型大鼠皮下埋植单根0.75、1.5、3.0cm长和2根、3根、4根3cm长规格米非司酮埋植剂,3个月后测定并计算异位子宫内膜抑制率,并与不含药对照组进行比较。结果:1根3cm长埋植剂在前15d米非司酮释放速度约为9μg.d-1,30d后约为5μg.d-1,并可维持6个月以上。皮下植入1根1.5、3.0cm长或2根3.0cm长埋植剂1个月时,异位内膜抑制率分别为(18.6±17.3)%、(31.5±12.7)%、(72.2±12.3)%,与对照组比较具有显著性差异(P<0.05)。结论:米非司酮皮下埋植剂作为治疗子宫内膜异位症的长效制剂是可行的。     

磷酸川芎嗪脉冲释放片的研制

目的:以磷酸川芎嗪为模型药物制备了脉冲释放片,并考察其体外释放的影响因素.方法:以十八醇、聚乙二醇和乙基纤维素等为包衣材料,采用干压包衣法制备脉冲释放片,采用紫外分光光度法测定脉冲片的体外释放度.结果:崩解剂的用量和包衣材料中致孔剂的用量为影响药物体外释放的主要因素,可以根据需要调节药物的释放时滞.结论:磷酸川芎嗪脉冲释放片在体外具有脉冲释放特性.     

采用相似因子法评价不同因素对复方二甲双胍格列吡嗪双层缓释片体外释放的影响

目的考察不同因素对复方二甲双胍格列吡嗪双层缓释片(BT)体外释放的影响。方法采用相似因子法进行考察。结果各种因素对二甲双胍释放速率影响不大;HPMC的黏度、用量、填充剂的种类和搅拌速度对格列吡嗪释放速率有明显影响,填充剂的用量对格列吡嗪释放速率影响较小。结论相似因子法适合于缓控释制剂体外释放的评价。     

Permeation measurement of gestodene for some biodegradable materials using Franz diffusion cells

Biodegradable poly(d,l-lactide) (PDLLA), Poly(trimethylene carbonate) (PTMC), polycaprolactone (PCL), poly(caprolactone-co-d,l-lactide) (PCDLLA) and poly(trimethylene carbonate-co-caprolactone) (PTCL) are recently used for clinical drug delivery system such as subcutaneous contraceptive implant capsule due to their biodegradable properties that they could possess long-term stable performance in vivo without removal, however their permeation rate is unknown. In the work, biodegradable material membranes were prepared by solvent evaporation using chloroform, and commercial silicone rubber membrane served as a control. Gestodene was used as a model drug. Gestodene has high biologic progestational activity which allows for high contraceptive reliability at very low-dose levels. The permeation rate of gestodene for several biodegradable materials was evaluated. In vitro diffusion studies were done using Franz diffusion cells with a diffusion area of 1.33 cm². Phosphate buffer solution (PBS, pH 7.4), 10% methanol solution and distilled water were taken in donor and receiver chambers at temperature of 37 °C respectively. The in vitro experiments were conducted over a period of 24 h during which samples were collected at regular intervals. The withdrawn samples were appropriately diluted and measured on UV–vis spectrophotometer at 247 nm. Conclusion data from our study showed that permeation rate of PCDLLA with CL ratio more than 70% could be more excellent than commercial silicone rubber membrane. They may be suitable as a candidate carrier for gestodene subcutaneous contraceptive implants in contraceptive fields.     

Development of an aciclovir implant for the effective long-term control of herpes simplex virus type-1 infection in Vero cells and in experimentally infected SKH-1 mice

Human herpes simplex virus type-1 (HSV-1) is treatable with oral doses of an antiviral agent such as aciclovir (ACV), a drug that has poor bioavailability. An alternative for delivering ACV would employ a long-lived subcutaneous implant that would allow for near zero-order drug delivery kinetics. This study aimed to develop an implant composed of a matrix of silicone and ACV that is capable of sustained long-term release of ACV. Once the implants had been created, release of ACV from the implants was determined and quantified in vitro using a spectrophotometric assay for the drug. Solvent-exposed surface area of the implant (2.86 mm(2), 6.28 mm(2), 34.62 mm(2) and 100.48 mm(2)) had a significant effect on release kinetics, whereas temperature (37 degrees C, 25 degrees C and 4 degrees C) and pH (6.0, 7.0 and 8.0) did not. The implants were also used successfully to suppress HSV-1 (KOS)-induced cytopathic effect in cultured Vero cells. The implants protected HSV-1-infected SKH-1 mice from viral reactivation (n = 37; P = 0.0367) via ultraviolet light compared with mice that were untreated (n = 37). Furthermore, mice that received silicone-only implants had no lowered risk of reactivation (n = 34; P = 0.7268), demonstrating the antiviral efficacy of the ACV implants.     

Comparison of the biological effectiveness of injected testosterone propionate and testosterone released from silastic capsules

The in vitro release and biological effectiveness of silicone rubber implants containing testosterone in orchidectomized male rats was investigated over a period of 20 weeks. A marked reduction in release in 0.9% saline solution could be observed in vitro relative to the incubation time in the medium. The reduction in release was greatest during the first few weeks of the experiment. Rat seminal vesicles and prostates, which were greatly stimulated at the start of the experiment, lost weight corresponding to the release rate in vitro. The implants containing testosterone used here were 4 to 26 times more effective than testosterone propionate injected s.c.     

Dexamethasone-loaded poly(epsilon-caprolactone) intravitreal implants: a pilot study.

PURPOSE: Poly(epsilon-caprolactone) (PCL) is a biodegradable and biocompatible polymer that presents a very low degradation rate, making it suitable for the development of long-term drug delivery systems. The objective of this pilot study is to evaluate the feasibility and characteristics of PCL devices in the prolonged and controlled intravitreous release of dexamethasone. METHODS: The in vitro release of dexamethasone was investigated and the implant degradation was monitored by the percent of mass loss and by changes in the surface morphology. Differential scanning calorimetry was used to evaluate stability and interaction of the implant and the drug. The short-term tolerance of the implants was studied after intravitreous implantation in rabbit eye. Results: PCL implant allows for a controlled and prolonged delivery of dexamethasone since it releases 25% of the drug in 21 weeks. Its low degradation rate was confirmed by the mass loss and scanning electron microscopy studies. Preliminary observations show that PCL intravitreous implants are very well tolerated in the rabbit eye. CONCLUSION: This study demonstrates the PCL drug delivery systems allowed to a prolonged release of dexamethasone in vitro. The implants demonstrated a strikingly good intraocular short-term tolerance in rabbits eyes. The in vitro and preliminary in vivo studies tend to show that PCL implants could be of interest when long-term sustained intraocular delivery of corticosteroids is required.     

Exploration and Preparation of Patient-specific Ciprofloxacin Implants Drug Delivery System Via 3D Printing Technologies

A suitable drug-loaded implant delivery system that can effectively release antibacterial drug in the postoperative lesion area and help repair bone infection is very significant in the clinical treatment of bone defect. The work was aimed to investigate the feasibility of applying three-dimensional (3D) printing technology to prepare drug-loaded implants for bone repair. Semi-solid extrusion (SSE) and Fuse deposition modeling® (FDM) technologies were implemented and ciprofloxacin (CIP) was chosen as the model drug. All of the implants exhibited a smooth surface, good mechanical properties and satisfactory structural integrity as well as accurate dimensional size. In vitro drug release showed that the implants made by 3D printing technologies slowed down the initial drug burst effect and expressed a long-term sustained release behavior, compared with the implants prepared with traditional method. In addition, the patient-specific macrostructure implants, consisting of interconnected and different shapes pores, were created using unique lay down patterns. As a result, the weakest burst release effect and the sustained drug release were achieved in the patient-specific implants with linear pattern. These results clearly stated that 3D printing technology offers a viable approach to prepare control-releasing implants with patient-specific macro-porosity and presents novel strategies for treating bone infections.     

Microencapsulation of gentamicin in biodegradable PLA and/or PLA/PEG copolymer

Biodegradable carriers containing gentamicin for local treatment of bone infection were developed. This paper describes the preparation and in vitro evaluation of these biodegradable implants. Poly-l-lactic acid (PLA) and polyl-lactic acid/polyethylene glycol (PLA/PEG) disk implants containing gentamicin sulphate were obtained by compression of microspheres prepared by a double emulsion process. The mean particle size distribution of the microspheres, based on volume, ranged from 95-270 µm. The gentamicin sulphate loading of the microspheres, after a methylene chloride-water extraction procedure, exceeded 90% of the theoretical value. In vitro dissolution studies on the microspheres and implants with drug loadings 10-40% w/w indicated that the rate of drug release from both PLA and PLA/PEG implants increased, with an increase in drug loading. The release of gentamicin from microspheres was dependent on the properties of PLA and/or PLA/PEG. The PLA/PEG copolymer was more hydrophilic than the PLA homopolymer, and with a smaller pH change in the microenvironment with polymer being degraded. In comparison, the PLA/PEG implant released antibiotic faster and had a larger inhibitory zone based on the Bauer-Kirby experiments used to test the inhibitory activity of antimicrobial devices. Experimental results showed that the biodegradable PLA/PEG gentamicin delivery system had a potential for prophylaxis of post-operative infection.     

Microencapsulation of gentamicin in biodegradable PLA and/or PLA/PEG copolymer.

Biodegradable carriers containing gentamicin for local treatment of bone infection were developed. This paper describes the preparation and in vitro evaluation of these biodegradable implants. Poly-L-lactic acid (PLA) and poly-L-lactic acid:polyethylene glycol (PLA/PEG) disk implants containing gentamicin sulphate were obtained by compression of microspheres prepared by a double emulsion process. The mean particle size distribution of the microspheres, based on volume, ranged from 95-270 microm. The gentamicin sulphate loading of the microspheres, after a methylene chloride-water extraction procedure, exceeded 90% of the theoretical value. In vitro dissolution studies on the microspheres and implants with drug loadings 10-40% w/w indicated that the rate of drug release from both PLA and PLA/PEG implants increased, with an increase in drug loading. The release of gentamicin from microspheres was dependent on the properties of PLA and/or PLA/PEG. The PLA/PEG copolymer was more hydrophilic than the PLA homopolymer, and with a smaller pH change in the microenvironment with polymer being degraded. In comparison, the PLA/PEG implant released antibiotic faster and had a larger inhibitory zone based on the Bauer-Kirby experiments used to test the inhibitory activity of antimicrobial devices. Experimental results showed that the biodegradable PLA/PEG gentamicin delivery system had a potential for prophylaxis of post-operative infection.     

硅橡胶质量参数与氟尿嘧啶植入剂释放度的相关性研究

目的 分析硅橡胶分子量及黏度特性对氟尿嘧啶植入剂释放度的影响。方法 依据GN/T21863-2008标准和《中国药典》对不同批号硅橡胶的分子量分布和黏度进行检测,记录数均分子量、分子量分布和黏度,采用相同制剂工艺制备20份不同硅橡胶的小试样品,依据国家药品标准WS1-（X-103）-2005Z对小试样品的释放度进行检测,以数均分子量（X₁）、分子量分布（X₂）和黏度（X₃）作为X变量,以120 h释放度结果作为Y变量,使用Minitab 16.0软件进行多元回归分析,确定硅橡胶关键质量参数。结果 多元回归分析表明,数均分子量和黏度参数是关键质量参数（P<0.05）,分子量分布为非关键质量参数（P>0.05）;120 h释放度的线性回归方程：Y=-0.3+3.76 X₁+0.267X₃。结论 硅橡胶数均分子量和黏度是影响氟尿嘧啶植入剂释放度的关键质量参数,产品生产过程中应依据制剂工艺参数对硅橡胶的制备进行严格控制,从而最大程度降低硅橡胶对产品质量稳定性造成的影响。     

PLA/PEG-PPG-PEG/Dexamethasone implant prepared by hot-melt extrusion for controlled release of immunosuppressive drug to implantable medical devices,part 2: in vivo evaluation

Abstract

Hot-melt extrusion (HME) plays an important role in preparing implants as local drug delivery systems in pharmaceutical fields. Here, a new PLA/PEG-PPG-PEG/Dexamethasone (PLA/F68/Dex) implant prepared by HME has been developed. Importantly, the implant was successfully achieved to control release of immunosuppressive drug to an implanted device. In particular, this implant has not been reported previously in pharmaceutical fields. FTIR and XRD were adopted to investigate the properties of the samples. The in vivo release study showed that the maximum value of Dex release from the implants was approximately 50% at 1 month. The in vivo degradation behavior was determined by UV spectrophotometer and scanning electron microscopy studies, and the weight loss rate of the implants were up to 25% at 1 month. Furthermore, complete blood count (CBC) test, serum chemistry and major organs were performed, and there is no significant lesion and side effects observed in these results. Therefore, the results elucidated that the new PLA/F68/Dex implant prepared by HME could deliver an immunosuppressive drug to control the inflammatory reaction at the implant site.     

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.