正交实验优化川陈皮素微乳凝胶剂促渗剂及体外释药评价

本文筛选了川陈皮素微乳凝胶剂的最佳透皮促渗剂并考察了其体外释药机制。采用正交实验设计,对离体家兔鼻粘膜进行体外渗透实验,以川陈皮素的累积渗透量及渗透速率常数为指标,优选最佳处方;采用扩散池法对川陈皮素微乳凝胶剂进行体外释药研究,并用无膜溶出法考察其释药机制。结果表明,不同促渗剂对川陈皮素的累积渗透量及渗透速率常数影响大小为:氮酮冰片丙二醇,且氮酮具有显著性差异(P0.05),微乳凝胶剂12 h的累积释药率为86%,符合Higuchi方程,其溶蚀量较少且与释药率无明显线性相关(r=0.9387)。可见,2%氮酮、2%冰片和1%丙二醇可作为最佳促渗剂处方在川陈皮素微乳凝胶剂中使用,且该制剂体外释药性能良好,有一定的缓释特性。     

壳聚糖-海藻酸钠靛玉红自微乳缓释微囊制备、评价及体外释放的研究

以靛玉红自微乳为囊心物,壳聚糖和海藻酸钠为囊材,采用复凝聚法制备壳聚糖-海藻酸钠靛玉红自乳化缓释微囊,通过正交实验和单因素考察确定壳聚糖-海藻酸钠靛玉红缓释微囊的最佳制备工艺。并以载药量、包封率为评价指标对其进行质量评价,同时以体外释放度评价其释药性能。壳聚糖-海藻酸钠靛玉红缓释微囊的最佳工艺是海藻酸钠的浓度为1.5%,靛玉红自微乳体积、海藻酸钠体积、壳聚糖质量三者比例为1∶1∶0.5,氯化钙浓度的最佳浓度为2.0%。采用该工艺制备的微囊载药量为0.0416%、包封率为79.2%,体外释放24 h累积释放率为(97.1±2.68)%。该微囊的释放符合Higuchi方程和一级释药模型,具有较好的缓释作用。     

改善蛋白质药物PELA控释微球释放性能的研究

开展了以乙酸乙酯(EA)与二氯甲烷(MC)的混合溶液为有机溶剂、以单甲氧基聚乙二醇-聚-DL-乳酸(PELA)为膜材的W／O／W复乳-分步固化法制备蛋白质药物控释微球的研究。为解决微球突释率高、且突释后的释药速度缓慢的问题,实现后期快速释放,以溶菌酶为模型蛋白,重点考察了膜材组成、内水相体积以及外水相盐浓度对微球释药速率的影响。结果表明,当外水相盐浓度增大至1.5％时可将释放率由22％提升至45％,是一种较好的加快微球释药速率的途径,因此可通过选择适当的外水相盐浓度,达到所期望的药物释药速率。     

载阿霉素PLGA纳米微球的制备及性质研究

目的:制备新型癌症化疗制剂载阿霉素(Adriamycin)、聚乳酸-羟基乙酸共聚物(PLGA)纳米微球(ADM-PLGA-NP),研究其性质及体外释药特点。方法:以聚乳酸-羟基乙酸共聚物为包封材料,阿霉素为模型药物,采用复乳蒸发法制备ADM-PLGA-NP,扫描电镜观察微球形态,激光粒度分析仪检测粒径分布,紫外分光光度法计算载药率及包封率,体外药物释放实验考察微球对ADM的缓释作用。结果:ADM-PLGA-NP外观呈球形,平均粒径约(237±12.7)nm,载药量及包封率分别为(6.42±1.67)%和(53.82±8.34)%,药物在体外缓慢释放,5 d累积释放量达85%。结论:通过复乳蒸发法制备的ADM-PLGA-NP性质稳定,具有药物缓释性,有望成为一种新型的药物化疗载体。     

叶酸介导的普鲁兰多糖-阿霉素聚合物前药的制备及生物学性能初探

目的：制备叶酸介导的普兰多糖-阿霉素聚合物前药（FA-MP-DOX）,实现阿霉素药物的靶向控制释放。方法：将普鲁兰多糖用马来酸酐进行修饰后,通过酰胺键键合阿霉素制备得到普鲁兰多糖-阿霉素（MP-DOX）,继而酯键键合叶酸制备得到叶酸介导的普鲁兰多糖-阿霉素聚合物前药（FA-MP-DOX）。红外光谱、核磁共振光谱表征聚合物药物的结构,动态透析法模拟体外释药特性,监测不同pH值聚合物药物中阿霉素的释药特性,同时采用人口腔表皮样癌细胞（KB细胞）测定聚合物药物体系的细胞毒性。结果：①经核磁共振表征FA-MP-DOX聚合物合成完成。②在pH2.5、pH5.0及pH7.4的PBS缓冲体系16h中,阿霉素药物累积释放率分别为49.1%,30.3%和15.3%,证实FA-MP-DOX中阿霉素的释放具有pH依赖性。③细胞实验证实FA-MP-DOX的细胞毒性高于阿霉素和MP-DOX。结论：FA-MP-DOX聚合物药物有望成为阿霉素智能型控释和靶向性药物载体。     

叶酸介导的普鲁兰多糖- 阿霉素聚合物前药的制备及生物学性能初探

目的:制备叶酸介导的普兰多糖-阿霉素聚合物前药(FA-MP-DOX),实现阿霉素药物的靶向控制释放。方法:将普鲁兰多糖用马来酸酐进行修饰后,通过酰胺键键合阿霉素制备得到普鲁兰多糖-阿霉素(MP-DOX),继而酯键键合叶酸制备得到叶酸介导的普鲁兰多糖-阿霉素聚合物前药(FA-MP-DOX)。红外光谱、核磁共振光谱表征聚合物药物的结构,动态透析法模拟体外释药特性,监测不同pH值聚合物药物中阿霉素的释药特性,同时采用人口腔表皮样癌细胞(KB细胞)测定聚合物药物体系的细胞毒性。结果:①经核磁共振表征FA-MP-DOX聚合物合成完成。②在pH2.5、pH5.0及pH7.4的PBS缓冲体系16h中,阿霉素药物累积释放率分别为49.1%,30.3%和15.3%,证实FA-MP-DOX中阿霉素的释放具有pH依赖性。③细胞实验证实FA-MP-DOX的细胞毒性高于阿霉素和MP-DOX。结论:FA-MP-DOX聚合物药物有望成为阿霉素智能型控释和靶向性药物载体。     

尺寸均一的壳聚糖微球的制备及其作为胰岛素控释载体的研究

采用新型微孔膜乳化技术制备了载胰岛素的壳聚糖微球。研究表明,要制备粒径均一的壳聚糖微球,必须将亲水性膜修饰成疏水性;制得的微球粒径和所采用的膜孔径之间存在很好的线性关系,使得微球粒径可控;以胰岛素为模型药物,主要考察了交联剂用量和交联时间对微球表面形态、药物包埋率和微球体外释药特性的影响。结果表明当氨基与醛基的摩尔比为1∶0.7、交联时间为1h时,所得载药微球的包埋率最高,随着戊二醛用量的增加和交联时间的延长,药物体外释放速率减慢。     

包封不对称膜高分子囊泡对PLGA微球中蛋白释放行为的改善作用

目的:研究含蛋白的不对称膜高分子囊泡包封进PLGA微球后对其体外释放动力学的改善作用.方法:将包封有BSA蛋白的不对称膜高分子囊泡采用S/O/W法包裹进PLGA微球中,制备复合微球,对微球表征后,以包封葡聚糖颗粒的微球做对照品,于37℃测定微球的体外释放,比较两者的释放曲线,考察不对称膜高分子囊泡时微球中蛋白释放的改善作用.结果:①经扫描电镜(SEM)观察,包裹高分子囊泡的复合微球形态圆整,表面光滑,平均粒径为75.20μm,粒径较为均匀,复合微球制备成功.②比较复合微球和对照微球的释放曲线,发现对照微球有较小的突释,而复合微球的几乎没有突释效应.结论:不对称膜高分子囊泡包封进PLGA微球后可以很好的改善蛋白的释放行为,获得更为理想的释放曲线.     

一种体内恒速持续给药的方法—微量渗透泵

利用微量渗透泵给药是一种崭新的动物实验性持续给药方法。泵体由３个同心层（由内向外）—贮药池、渗透性套筒及控制渗透泵药物释放速度的半透膜组成。泵在被水激活后,因水可按渗透梯度渗入渗透性套筒部分,压迫泵体以恒定速度持续释放药物几天至若干星期,其渗透速度与被释放药物的理化性质无关,因而适用于多种药物     

多糖颗粒复合PLGA微球用于脉冲式释药系统的研究

目的:考察多糖颗粒复合PLGA微球用作脉冲式释药系统的可行性.方法:用水相-水相乳化法将模型蛋白BSA包裹于多糖颗粒中,再用S/O/W法制备多糖颗粒复合PLGA微球.采用microBCA法测定该微球体外释放行为,并与W/O/W复乳法制备的BSA微球相对照.结果:用W/O/W复乳法制备的BSA微球的体外释放曲线显示,该微球在开始释放第一天起就出现一个平台期,之后则产生一个持续高释放量的行为.而多糖颗粒复合PLGA微球的体外释放曲线显示,其在释放第一天和一个较长平台期之后都出现峰形释放,相对于前者微球与脉冲释药模式更为相近.平台期时长与高分子性质有关,PLGA结构中乳酸相对于乙醇酸比例越高则平台期越长.结论:多糖颗粒复合PLGA微球具有良好的脉冲式释药效果,是一种较有前景的脉冲释药系统.     

Osmotically Regulated Floating Asymmetric Membrane Capsule for Controlled Site-Specific Delivery of Ranitidine Hydrochloride: Optimization by Central Composite Design

A nondisintegrating, floating asymmetric membrane capsule (FAMC) was developed to achieve site-specific osmotic flow of a highly water-soluble drug, ranitidine hydrochloride (RHCl), in a controlled manner. Solubility suppression of RHCl was achieved by the common ion effect, using optimized coated sodium chloride as a formulation component. The capsular wall of FAMC was prepared by the phase inversion process wherein the polymeric membrane was precipitated on glass pins by dipping them in a solution of cellulose acetate followed by quenching. Central composite design was utilized to investigate the influence of independent variables, namely, level(s) of membrane former, pore former, and osmogen, on percent cumulative drug release (response). The release mechanism of RHCl through FAMC was confirmed as osmotic pumping. The asymmetry of the membrane was characterized by scanning electron microscopy that revealed a dense nonporous outer region of membrane supported by an inner porous region. Differential scanning calorimetry indicated no incompatibility between the drug and excipients. In vitro drug release in three biorelevant media, pH 2.5 (low fed), pH 4.5 (intermediate fed), and pH 6.5 (high fed), demonstrated pH-independent release of RHCl (P > 0.05). Floating ability for 12 h of the optimized FAMC9 was visually examined during the in vitro release studies that showed maximal drug release with zero-order kinetics (r² = 0.9991). Thus, a novel osmotically regulated floating capsular system was developed for site-specific delivery of RHCl.

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-012-9870-8) contains supplementary material, which is available to authorized users.KEY WORDS: asymmetric membrane capsule, central composite design, floating system, osmotic delivery, ranitidine hydrochloride     

Osmotic flow through asymmetric membrane: A means for controlled delivery of drugs with varying solubility

A nondisintegrating, controlled release, asymmetric membrane capsular system of flurbiprofen was developed and evaluated for controlled release of the drug to overcome some of its side effects. Asymmetric membrane capsules were prepared using fabricated glass mold pins by phase inversion process. The effect of different formulation variables was studied based on 2³ factorial design; namely, level of osmogen, membrane thickness, and level of pore former. Effects of polymer diffusibility and varying osmotic pressure on drug release were also studied. Membrane characterization by scanning electron microscopy showed an outer dense region with less pores and an inner porous region for the prepared asymmetric membrane. Differential scanning calorimetry studies showed no incompatibility between the drug and the excipients used in the study. In vitro release studies for all the prepared formulations were done (n=6). Statistical test (Dunnett multiple comparison test) was applied for in vitro drug release atP>.05. The best formulation closely corresponded to the extra design checkpoint formulation by a similarity (f2) value of 92.94. The drug release was independent of pH but dependent on the osmotic pressure of the dissolution medium. The release kinetics followed the Higuchi model and the mechanism of release was Fickian diffusion. Published: July 7, 2006     

Solubility-modulated asymmetric membrane tablets of triprolidine hydrochloride: statistical optimization and evaluation

The aim of the present study was to develop asymmetric membrane (AM) tablets for controlled delivery of highly water-soluble antihistaminic drug triprolidine hydrochloride. The solubility of triprolidine hydrochloride was modulated through the incorporation of coated sodium chloride crystals encapsulated with asymmetric membrane coating polymer, cellulose acetate butyrate. Formulation of AM tablets was based on a 2³ factorial design to study the effect of formulation variables, namely, polymer concentration, level of pore former, and amount of osmogen on the in vitro release. Core tablets prepared by wet granulation and coated with asymmetric membrane by a dip coating method were evaluated. Statistical analysis was done with the Design Expert Software 8.0.2 (USA), and the polynomial equation generated by Pareto charts was used for validation of the experimental design. The interaction chart and response surface plots deduced the simultaneous effect of independent variables on in vitro drug release. The in vitro drug release was inversely proportional and directly related to the level(s) of polymer and pore former in the membrane, respectively. The level of osmogen not only increased the osmotic pressure but also controlled the drug release due to a common ion effect. The drug release of the optimized formulation (F6) followed zero-order kinetics, which would be capable of reducing the administration, and was stable over 3 months. SEM photographs revealed asymmetry in membrane structure.     

A Novel Injection-Molded Capsular Device for Oral Pulsatile Delivery Based on Swellable/Erodible Polymers

The feasibility of injection molding was explored in the preparation of a novel capsular device for oral pulsatile/delayed delivery based on swellable/erodible polymers. For this purpose, a mold intended to be coupled with a bench-top injection-molding press was designed. This was expected to enable the preparation of matching capsule cap and body items within a single manufacturing cycle and the selection of differing shell thicknesses (300, 600, and 900 μm). Hydroxypropylcellulose (Klucel^® EF, LF, and GF) was employed as the release-controlling polymer in admixture with polyethylene glycol 1500 (10%, w/w) as the plasticizer. After preliminary trials aimed at the setup of operating conditions, Klucel^® EF and LF capsule shells with satisfactory technological properties were manufactured. The performance of capsular devices filled with a tracer drug powder was studied by means of a modified USP31 disintegration apparatus. Typical in vitro delayed release patterns were thereby obtained, with lag time increasing as a function of the wall thickness. A good correlation was found between the latter parameter and t _10%, i.e., the time to 10% release, for both polymer grades employed. On the basis of the overall results, the investigated technique was proven suitable for the manufacturing of an innovative pulsatile release platform.     

Formulation and optimization of porous osmotic pump-based controlled release system of oxybutynin

The aim of the current study was to design a porous osmotic pump-based drug delivery system for controlled release of oxybutynin. The porous osmotic pump contains pore-forming water-soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a microporous structure. The dosage regimen of oxybutynin is one 5-mg tablet 2 to 3 times a day. The plasma half-life ranges from ∼2 to 3 hours. Hence, oxybutynin was chosen as a model drug with an aim to develop a controlled release system for a period of 24 hours. Linear and reproducible release similar to that of Ditropan XL was achieved for optimized formulation (f2>50) independent of hydrodynamic conditions. The effect of different formulation variables, namely, ratio of drug to osmogent, membrane weight gain, and level of pore former on the in vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. It was found that drug release rate increased with the amount of osmogent because of the increased water uptake, and hence increased driving force for drug release. Oxybutynin release was inversely proportional to the membrane weight gain; however, directly related to the level of pore former, sorbitol, in the membrane. This system was found to deliver oxybutynin at a zero-order rate for 20 hours. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per International Conference on Harmonisation (ICH) guidelines and formulations were stable after a 3 month study. Published: July 13, 2007     

Development and Optimization of Micro/Nanoporous Osmotic Pump Tablets

Micro/nanoporous osmotic pump tablets coated with cellulose acetate containing polyvinylpyrolidone (PVP) as pore formers were fabricated. Propranolol hydrochloride was used as a model drug in this study. Formulation optimization based on USP 31 requirements was conducted following a central composite design using a two-level factorial plan involving two membrane variables (pore former and coating levels). Effect of molecular weight of pore former (PVP K30 and PVP K90) was also evaluated. Responses of drug release to the variables were analyzed using statistical software (MINITAB 14). Scanning electron microscopy and atomic force microscopy showed that the pores formed by PVP. The drug release was dependent on the molecular weight and concentration of PVP and the level of coating. The results showed that acceptable 12-h profile could be achieved with only specific range of PVP K30-containing membrane at the defined membrane thickness. However, satisfactory 24-h profile could be accomplished by both PVP K30 and PVP K90-containing membrane at the range and membrane thickness tested. Preparation and testing of the optimized formulation showed a good correlation between predicted and observed values.     

Comparative in vitro and in vivo evaluation of matrix,osmotic matrix,and osmotic pump tablets for controlled delivery of diclofenac sodium

The aim of this investigation was preparation and comparative evaluation of fabricated matrix (FM), osmotic matrix (OM), and osmotic pump (OP) tablets for controlled delivery of diclofenac sodium (DS). All formulations were evaluated for various physical parameters, and in vitro studies were performed on USP 24 dissolution apparatus II in pH 7.4 buffer and distilled water. In vivo studies were performed in 6 healthy human volunteers; the drug was assayed in plasma using HPLC, and results were compared with the performance of 2 commercial tablets of DS. Various pharmacokinetic parameters (ie, C_max, T_max, area under the curve [AUC_0–24], and mean residence time) and relative bioavailability were compared. All fabricated formulations showed more prolonged and controlled DS release compared with commercial tablets studied. The OM and OP tablets, however, performed better than the matrix tablets. The rate and extent of drug release from FM1 matrix tablets (single polymer) was significantly different from that of FM2 (admixed polymers). Type of porosigenic agents and osmogens also influenced the drug release. Analysis of in vitro data by regression coefficient analysis revealed zero-order release kinetics for OM and OP tablets, while FM tablets exhibited Higuchi kinetics. In vivo results indicated prolonged blood levels with delayed peak and improved bioavailability for fabricated tablets compared to commercial tablets. It was concluded that the osmotic matrix and osmotic pump tablets could provide more prolonged, controlled, and gastrointestinal environmental-independent DS release that may result in an improved therapeutic efficacy and patient compliance.     

Cellulose Acetate Butyrate: Ammonio Methacrylate Copolymer Blends as a Novel Coating in Osmotic Tablets

The objective of this work was the preparation of osmotic tablets using polymer blends of cellulose acetate butyrate (CAB) or ethylcellulose with ammonio methacrylate copolymer (Eudragit® RL). The advantage of these coatings in comparison to the traditionally used cellulose acetate is their solubility in safer organic solvents like ethanol. Polymer films were characterized with respect to their water uptake, dry mass loss, and mechanical properties. The effect of the polymer blend ratio on drug release and on the rupture force of the coating was investigated. In addition, the effect of drug solubility and content, pH and agitation rate of the release medium, and coating level and plasticizer content on the release were studied. With increased Eudragit® RL content in the coating blends, higher medium uptake of the film was observed, resulting in shorter lag times and faster drug release from the osmotic tablets. Replacing ethylcellulose with cellulose acetate butyrate as a coating material led to shorter lag times and faster drug release due to increased film permeability. In addition, CAB-based films had a higher strength and flexibility. The drug release was osmotically controlled and decreased with increasing coating level. It increased with increased drug solubility, plasticizer content, change of buffer species (acetate > phosphate), and decreased coating level. Agitation rate and drug content had no effect on the drug release. A 20% w/w coating level was sufficient for the tablet to tolerate forces of more than five times of the gastric destructive force reported in literature.     

Ketal cross-linked poly(ethylene glycol)-poly(amino acid)s copolymer micelles for efficient intracellular delivery of doxorubicin

A biocompatible, robust polymer micelle bearing pH-hydrolyzable shell cross-links was developed for efficient intracellular delivery of doxorubicin (DOX). The rationally designed triblock copolymer of poly(ethylene glycol)-poly(L-aspartic acid)-poly(L-phenylalanine) (PEG-PAsp-PPhe) self-assembled to form polymer micelles with three distinct domains of the PEG outer corona, the PAsp middle shell, and the PPhe inner core. Shell cross-linking was performed by the reaction of ketal-containing cross-linkers with Asp moieties in the middle shells. The shell cross-linking did not change the micelle size and the spherical morphology. Fluorescence quenching experiments confirmed the formation of shell cross-linked diffusion barrier, as judged by the reduced Stern-Volmer quenching constant (K(SV)). Dynamic light scattering and fluorescence spectroscopy experiments showed that shell cross-linking improved the micellar physical stability even in the presence of micelle disrupting surfactants, sodium dodecyl sulfate (SDS). The hydrolysis kinetics study showed that the hydrolysis half-life (t(1/2)) of ketal cross-links was estimated to be 52 h at pH 7.4, whereas 0.7 h at pH 5.0, indicating the 74-fold faster hydrolysis at endosomal pH. Ketal cross-linked micelles showed the rapid DOX release at endosomal pH, compared to physiological pH. Confocal laser scanning microscopy (CLSM) showed that ketal cross-linked micelles were taken up by the MCF-7 breast cancer cells via endocytosis and transferred into endosomes to hydrolyze the cross-links by lowered pH and finally facilitate the DOX release to inhibit proliferation of cancer cells. This ketal cross-linked polymer micelle is promising for enhanced intracellular delivery efficiency of many hydrophobic anticancer drugs.     

Development of Silymarin Self-Microemulsifying Drug Delivery System with Enhanced Oral Bioavailability

The objective of this work was to develop a self-microemulsifying drug delivery system (SMEDDS) for improving oral absorption of poorly water-soluble drug, silymarin. The pseudo-ternary phase diagrams were constructed using ethyl linoleate, Cremophor EL, ethyl alcohol, and normal saline to identify the efficient self-microemulsification region. The particle size and its distribution of the resultant microemulsions were determined using dynamic light scattering. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 10% (w/w) of ethyl linoleate, 30% of Cremophor EL, and 60% of ethyl alcohol. The release of silymarin from SMEDDS was significantly faster than that from the commercial silymarin preparation hard capsule (Legalon®). The bioavailability results indicated that the oral absorption of silymarin SMEDDS was enhanced about 2.2-fold compared with the hard capsule in fasted dogs. It could be concluded that SMEDDS would be a promising drug delivery system for poorly water-soluble drugs by the oral route.