牙周缓释凝胶的体外释放度研究

目的:探讨各因素对牙周缓释凝胶体外释放度的影响。方法:制备不同的聚乳酸-乙醇酸共聚物(PLGA)浓度,不同溶剂配比和不同多西环素浓度的凝胶,用紫外分光法测定多西环素浓度,对各制剂进行体外释放试验,绘制其释放曲线。结果:凝胶在水中初期呈突然释放,然后缓慢、持续地释放,PLGA浓度越高,混合溶剂中三乙酸甘油酯(GTA)比例越高,释放就越缓慢,多西环素浓度对凝胶的药物释放影响不大。结论:凝胶在水中的释放速度与PLGA浓度和GTA比例成反比。     

多西环素牙周缓释凝胶的配方筛选研究

目的探索一种牙周缓释凝胶的最佳配方。方法将聚乳酸-乙醇酸共聚物(PLGA)浓度、溶剂配比和多西环素浓度按三个水平作正交设计,进行体外释放度试验,以第6天的释放百分率和凝结时间的综合分为指标,计算极差。结果按极差大小,PLGA浓度>溶剂配比>多西环素浓度,最佳配方为PLGA浓度15%,1MP:GTA=7:3,多西环素浓度为6%。结论用正交设计进行配方筛选是一种较好的试验方法。     

盐酸多西环素注射用缓释凝胶的体内释药研究

目的考察盐酸多西环素注射用缓释凝胶的体内释放特性及体内外相关性。方法将含药凝胶注射到家兔牙龈内 ,用HPLC法测定不同时间凝胶中的残余药量 ,从而计算药物的释放量。结果 7d盐酸多西环素的释放度达 99 7%。结论药物可缓释 7d ,体内外相关。     

复方多西环素缓释凝胶的体内释放度测定

目的：观察复方多西环素缓释凝胶的体内缓释性能。方法将11名患者的26颗患牙随机分为实验组和对照组,于基础治疗1周后,分别在牙周袋内置入复方多西环素缓释凝胶和复方多西环素凝胶,并于置药后每天定时用滤纸条法采集龈沟液样本,高效液相色谱法测定龈沟液内多西环素的浓度。结果复方多西环素凝胶在用药后第3天,龈沟液内多西环素浓度已降至6．82μg/ml;复方多西环素缓释凝胶在用药7 d后龈沟液内多西环素浓度仍可达到60．46μg/ml。结论复方多西环素缓释凝胶在牙周袋内可缓慢释放,较长时间维持有效浓度。     

盐酸多西环素羧甲基壳聚糖微球的体外释放研究

目的:探讨各因素对盐酸多西环素羧甲基壳聚糖微球体外释放度的影响。方法:采用乳化-交联固化法制备盐酸多西环素羧甲基壳聚糖微球(doxycycline hydrochloride-carboxymethyl chitosan-microspheres,DXY-CMCTS-MS),采用动态透析法测定体外释药性能,用紫外分光法测定盐酸多西环素浓度,绘制其释放曲线。结果:释放介质pH越大,交联剂量越大,固化时间越长,药物/载体比例越小,药物的释放则越慢。结论:该制剂制备工艺切实可行,所得DXY-CMCTS-MS具有明显的缓释效果。     

卡莫氟-聚乳酸纳米纤维缓释体系的制备及体外缓释性能

目的：以聚乳酸纳米纤维为载体,制备卡莫氟-聚乳酸纳米纤维药物缓释体系,研究其体外药物释放性能.方法：用静电纺丝制备卡莫氟-聚乳酸纳米纤维药物缓释体系,用紫外分光光度法研究药物的在37℃模拟体液中的释放性能.结果：溶剂不同,纤维的形貌有很大差别;纳米纤维体外药物释放速度也大不相同,缓释曲线符合Higuchi方程.结论：随着溶液的导电性和介电常数的增加,静电纺丝纤维的直径明显变小,纤维表面也逐渐光滑;纳米纤维的形貌对体外药物释放速度有较大影响.     

辛伐他汀聚乳酸微球的体外加速释放研究

目的：考察聚乳酸微球体外长期释放和加速释放的相关性，建立辛伐他汀聚乳酸微球的体外加速释放方法。方法：用紫外分光光度法测定微球中辛伐他汀的含量。采用改良的摇瓶培养法分别在不同温度的介质中进行体外加速释放试验和长期释放试验。用点点相关法考察两者的相关性。结果：PLA10000和PLA20000制备的微球在37℃放置30d内的释放分别达到92．68％和84．07％，微球在44℃，48℃和50℃下的释放均明显加速，释放动力学分别符合一级释药方程及Higuchi方程。辛伐他汀聚乳酸微球在48℃条件下的加速释放与在37℃的长期释放有良好的相关性。结论：辛伐他汀聚乳酸微球具有很好的缓释能力，采用体外加速试验的方法可以快速考察辛伐他汀聚乳酸微球的体外释药行为。     

盐酸丁卡因脂质体凝胶剂的制备与释放度的测定

目的：研究盐酸丁卡因脂质体以及脂质体凝胶的制备方法，并考察脂质体及脂质体凝胶对药物释放的影响。方法：乙醇注入法制备盐酸丁卡因脂质体，研和法制备脂质体凝胶，透析法测定盐酸丁卡因脂质体以及脂质体凝胶中药物的释放。结果：采用乙醇注入法制备盐酸丁卡因脂质体，包封率大于80％，脂质体及脂质体凝胶中药物释放均符合Hguchi方程，分别为Qt= -0.7662 7.588t^1/2和Qt=-4.4081 5.059t^1/2，游离药物凝胶中药物释放符合一级方程，为Ln(Q∞-Qt)=18.53-4.899t。结论：盐酸丁卡因脂质体凝胶剂对药物有缓释作用，延长药物的作用时间。     

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。     

挤出滚圆法制备盐酸多西环素肠溶微丸

目的应用挤出滚圆法及包衣锅包衣制备盐酸多西环素肠溶微丸,并对其性质进行考察。方法用挤出滚圆法制备了盐酸多西环素微丸,采用单因素考察和L9（34）正交设计筛选最优处方和工艺条件,再用包衣锅将微丸包肠溶衣,考察了微丸的粉体学性质及不同包衣增重微丸的体外释放情况。结果制得的盐酸多西环素肠溶微丸圆整度好,大小均匀,收率高。15%包衣增重的微丸在0.1 mol•L 1盐酸释放度＜10%,在pH6.8的缓冲液中释放度＞80%,体外释放较理想。结论该法制备工艺简单易行,重复性好,采用适当的包衣工艺,制得的盐酸多西环素肠溶微丸具备较理想的肠溶特征。     

注射型原位凝胶植入剂的研究进展

综述以聚乳酸，聚乳酸-乙醇酸共聚物（PLA/PLGA）、醋酸-异丁酸蔗糖酯（SAIB）、有机凝胶和PLA／PLGA与PEG的三嵌段共聚物为载体的注射型原位凝胶植入剂的研究进展，包括其特性、释药机制、制备和应用。这种新型给药系统已成为近年来非胃肠给药研究的热点之一。     

Controlling the in vitro release profiles for a system of haloperidol-loaded PLGA nanoparticles

We have used a systematic methodology to tailor the in vitro drug release profiles for a system of PLGA/PLA nanoparticles encapsulating a hydrophobic drug, haloperidol. We applied our previously developed sonication and homogenization methods to produce haloperidol-loaded PLGA/PLA nanoparticles with 200-1000 nm diameters and 0.2-2.5% drug content. The three important properties affecting release behavior were identified as: polymer hydrophobicity, particle size and particle coating. Increasing the polymer hydrophobicity reduces the initial burst and extends the period of release. Increasing the particle size reduces the initial burst and increases the rate of release. It was also shown that coating the particles with chitosan significantly reduces the initial burst without affecting other parts of the release profile. Various combinations of the above three properties were used to achieve in vitro release of drug over a period of 8, 25 and >40 days, with initial burst <25% and a steady release rate over the entire period of release. Polymer molecular weight and particle drug content were inconsequential for drug release in this system. Experimental in vitro drug release data were fitted with available mathematical models in literature to establish that the mechanism of drug release is predominantly diffusion controlled. The average value of drug diffusivities for PLGA and PLA nanoparticles was calculated and its variation with particle size was established.     

Preparation,Characterization, and In Vitro Evaluation of 1- and 4-Month Controlled Release Orntide PLA and PLGA Microspheres

Purpose. To prepare, characterize and evaluate in vitro sustained delivery formulations for a novel LHRH antagonist, Orntide acetate, using biodegradable microspheres (ms). Methods. Poly(d,l-lactide) (PLA) and poly(d,l-lactide-co-glycolide) (PLGA) were characterized for molecular weight (M_w, M_n) using gel permeation chromatography (GPC) and content of free end carboxyl groups (acid number, AN) by a titration method. 1- and 4-month Orntide ms were prepared by a dispersion / solvent extraction / evaporation process and characterized for drug content (HPLC), bulk density (tapping method), particle size (laser diffraction method), surface morphology (scanning electron microscopy, SEM), and structural integrity of encapsulated peptide by Fourier Transform Matrix Assisted Laser Desorption mass spectrometry (FT-MALDI). Peptide binding to PLA and PLGA and non-specific adsorption to blank ms was studied in 0.1 M phosphate buffer pH 7.4 (PB) and 0.1 M acetate buffer pH 4.0 (AB). In vitro release of peptide was assessed in PB and AB. Results. M_w for the PLGA copolymers varied from 10,777 to 31,281 Da and was 9,489 Da for PLA. AN was between 4.60 and 15.1 for the hydrophilic resomers and 0.72 for the hydrophobic 50:50 PLGA copolymer. Spherical ms (3.9 μ to 14 μ in diameter) with mostly non-porous surface and varying degree of internal porosity were prepared. FT-MALDI mass spectra of the extracted peptide showed that the encapsulation process did not alter its chemical structure. Peptide binding to PLGA and PLA and non-specific adsorption to blank PLGA ms were dependent upon pH and were markedly higher in PB than in AB. The initial in vitro release in PB varied from 0.5 to 26%/24 h but due to substantial binding of the peptide to the polymeric matrix the long-term release in PB could not be determined. Application of a dialysis method allowed for a more accurate determination of in vitro release and a good total drug recovery. Conclusions. Orntide acetate was successfully incorporated into PLA and PLGA ms and the 1- and 4-month in vitro release profiles were achieved by polymer selection and optimization of the manufacturing parameters.     

Controlled DNA Delivery Systems

Purpose. Genes are of increasing interest as pharmaceuticals, but current methods for long-term gene delivery are inadequate. Controlled release systems using biocompatible and/or biodegradable polymers offer many advantages over conventional gene delivery approaches. We have characterized systems for controlled delivery of DNA from implantable polymer matrices (EVAc: poly (ethylene-co-vinyl acetate)) and injectable microspheres (PLGA and PLA: poly (D, L-lactide-co-glycolide) copolymer and poly (L-lactide), respectively). Methods. Herring sperm DNA and bacteria phage DNA were encapsulated as a model system. Released DNA concentration was determined by fluoroassays. Agarose electrophoresis was used to determine the dependence of release rate on DNA size. The Green Fluorescent Protein (GFP) gene was used to determine the integrity and functionality of released DNA. Results. Both small and large DNA molecules (herring sperm DNA, 0.1–0.6 kb; GFP, 1.9 kb; DNA, 48.5 kb) were successfully encapsulated and released from EVAc matrices, and PLGA or PLA microspheres. The release from DNA-EVAc systems was diffusion-controlled. When co-encapsulated in the same matrix, the larger DNA was released more slowly than herring sperm; the rate of release scaled with the DNA diffusion coefficient in water. The chemical and biological integrity of released DNA was not changed. Conclusions. These low cost, and adjustable, controlled DNA delivery systems, using FDA-approved biocompatible/biodegradable and implantable/injectable materials, could be useful for in vivo gene delivery, such as DNA vaccination and gene therapy.     

Preparation, characterization, and in vitro evaluation of 1- and 4-month controlled release orntide PLA and PLGA microspheres

PURPOSE: To prepare, characterize and evaluate in vitro sustained delivery formulations for a novel LHRH antagonist, Orntide acetate, using biodegradable microspheres (ms). METHODS: Poly(d,l-lactide) (PLA) and poly(d,l-lactide-co-glycolide) (PLGA) were characterized for molecular weight (Mw, Mn) using gel permeation chromatography (GPC) and content of free end carboxyl groups (acid number, AN) by a titration method. 1- and 4-month Orntide ms were prepared by a dispersion/solvent extraction/evaporation process and characterized for drug content (HPLC), bulk density (tapping method), particle size (laser diffraction method), surface morphology (scanning electron microscopy, SEM), and structural integrity of encapsulated peptide by Fourier Transform Matrix Assisted Laser Desorption mass spectrometry (FT-MALDI). Peptide binding to PLA and PLGA and non-specific adsorption to blank ms was studied in 0.1 M phosphate buffer pH 7.4 (PB) and 0.1 M acetate buffer pH 4.0 (AB). In vitro release of peptide was assessed in PB and AB. RESULTS: Mw for the PLGA copolymers varied from 10,777 to 31,281 Da and was 9,489 Da for PLA. AN was between 4.60 and 15.1 for the hydrophilic resomers and 0.72 for the hydrophobic 50:50 PLGA copolymer. Spherical ms (3.9 mu to 14 mu in diameter) with mostly nonporous surface and varying degree of internal porosity were prepared. FT-MALDI mass spectra of the extracted peptide showed that the encapsulation process did not alter its chemical structure. Peptide binding to PLGA and PLA and non-specific adsorption to blank PLGA ms were dependent upon pH and were markedly higher in PB than in AB. The initial in vitro release in PB varied from 0.5 to 26%/24 h but due to substantial binding of the peptide to the polymeric matrix the long-term release in PB could not be determined. Application of a dialysis method allowed for a more accurate determination of in vitro release and a good total drug recovery. CONCLUSIONS: Orntide acetate was successfully incorporated into PLA and PLGA ms and the 1- and 4-month in vitro release profiles were achieved by polymer selection and optimization of the manufacturing parameters.     

Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation

The objective of this research is to develop injectable polymers solution based controlled release delivery systems for testosterone (TSN), using phase sensitive and thermosensitive polymers. A combination of poly(lactide) (PLA) and solvents mixture of benzyl benzoate (BB) and benzyl alcohol (BA) was used in the phase sensitive polymer delivery system. The effects of solvents system and drug loading on the in vitro TSN release were evaluated. In the case of thermosensitive polymer delivery systems, a series of low-molecular-weight poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with varying ratio of lactide/glycolide (LA/GA, 2.0-3.5) were studied to control the release of TSN. The effects of varying block length of copolymers 1-4 on the in vitro TSN release were evaluated. Phosphate buffer saline (pH 7.4) containing 0.5% (w/v) Tween-80 was used as in vitro release medium. The amount of the released TSN was determined by an HPLC method. A controlled (zero-order) in vitro release of TSN was observed from both the phase sensitive and thermosensitive polymer delivery systems. Addition of BA (15%, v/v) in solvents system significantly (p<0.05) increased the release rate of TSN (0.33+/-0.01 mg/ml) from phase sensitive delivery system in comparison to solvent without BA (0.27+/-0.00 mg/day). Increasing drug loading also increased release rate. In the case of thermosensitive polymer delivery system, increasing the hydrophobic PLGA block length of copolymers significantly (p<0.05) decreased the release rate of TSN. It is evident from this study that the phase sensitive and thermosensitive polymers are suitable for developing prolong-release injectable implant delivery systems for TSN.     

注射用乳酸-羟基乙酸共聚物微球的体内外相关性研究进展

注射用乳酸-羟基乙酸共聚物(polylactide-polyglycolide,PLGA)微球作为一种储库型释药系统,自1989年第1个产品Lupron depot获准在美国上市起,已成功用于多种疾病的治疗,具备在体内几天到几个月长时间释药的能力,可显著改善用药安全性,提升患者顺应性。体内外相关性(in vitro-in vivo correlation,IVIVC)研究给微球制剂的发展带来更多可能。IVIVC可以通过微球的体外释放行为阐述体内释药的动态信息,在表征微球性能的同时减轻各阶段的工作量,对药物的研发、生产变更和监督管理等具有指导或支持作用。本文将注射用PLGA微球的释放机制、体内外释放测定涉及的常用方法和理论进行归纳总结,重点讨论了IVIVC尤其是A级IVIVC在微球制剂领域的建立及应用,为进一步的微球体内外相关性研究提供参考。     

可注射硫酸延胡索总碱温度敏感型原位凝胶的 制备及其体外释药评析

 目的：研究可注射硫酸延胡索总碱原位凝胶的制备方法及其体外释药特性。方法：以泊洛沙姆407为载体材料制备注射用硫酸延胡索总碱温敏型原位凝胶制剂;采用高效液相色谱法测定释放介质中药物含量,考察凝胶体外释放特性;并对制剂进行评价。结果：原位凝胶最佳配方为：16%泊洛沙姆407、11%泊洛沙姆188、0.2%壳聚糖、0.5%硫酸延胡索总碱,该原位凝胶在室温下为流体,在体温下发生相转变形成凝胶;药物在48 h释放了88.4%,无突释现象,释药规律符合Higuchi方程;凝胶属Ostwald流体。结论：可注射硫酸延胡索总碱原位凝胶制备工艺简便,有良好的缓释作用,为研究中药植入型给药系统提供了依据。     

Controlled delivery of aspirin: effect of aspirin on polymer degradation and in vitro release from PLGA based phase sensitive systems

The objective of this study was to develop poly (d,l-lactide-co-glycolide) (PLGA) based injectable phase sensitive in situ gel forming delivery system for controlled delivery of aspirin, and to characterize the effect of drug/polymer interaction on the in vitro release of aspirin and polymer degradation. Aspirin was dissolved into PLGA solution in 1-methyl-2-pyrrolidone. Poly(ethylene glycol)400 was used as plasticizer to reduce initial burst release. The solution formulation was injected into aqueous release medium to form a gel depot. Released samples were withdrawn periodically and assayed for aspirin content by high performance liquid chromatography. The effect of aspirin on the degradation of PLGA matrix was evaluated using Proton Nuclear Magnetic Resonance and Gel Permeation Chromatography. PLGA based in situ gel forming formulations controlled the in vitro release of aspirin for 7 days only. Analysis of PLGA matrix residuals revealed that PLGA in aspirin loaded formulations exhibited a significantly (p < 0.05) faster degradation compared to blank formulations. These findings suggest that aspirin causes an unusually faster degradation of PLGA. Such faster degradation of PLGA has not been noticed for any other drugs reported in the literature.