冷冻干燥法制备阿糖胞苷冻干脂质体粉针研究

本文采用冷冻干燥法制备阿糖胞苷冻干脂质体粉针，并建立了质量控制标准。在扫描电镜和透射电镜观察下，将此脂质体冻干品加注射用水溶解后，能很快重新形成脂质体。算术平均粒径为０．４７５６±０．０８３３μｍ，包封率约３０％。     

药品冷冻干燥过程中的玻璃化作用

叙述了玻璃化药品的特点、玻璃化转变温度以及实现药品玻璃化的方法;分析了玻璃化对冷冻干燥过程中药品质量及稳定性的影响。     

Preparation,Characterization, and Pharmaceutical Application of Linear Dextrins. II. Complexation and Dispersion of Drugs with Amylodextrin by Freeze-Drying and Kneading

The ability of amylodextrin (a linear dextrin) to act as a complexing agent or as a carrier for solid dispersion was evaluated. Blends of amylodextrin with diazepam or prednisolone were freeze-dried and kneaded at elevated temperatures, respectively. The products were analyzed by DSC, X-ray diffractometry, and FTIR spectroscopy. Complex formation with amylodextrin by freeze-drying was found not to occur for diazepam but for prednisolone at a molar ratio of 1 to 1. The freeze-dried product of diazepam with amylodextrin proved to be a solid dispersion. Solid dispersions were formed by both wet (with ethanol) and dry kneading at elevated temperatures of low-melting drugs such as lidocain, diazepam, and methyl-PABA with amylodextrin. No solid dispersions were obtained for high-melting drugs such as prednisolone and salicylic acid. The results point to the formation of solid dispersions by a melting mechanism during the process of kneading at elevated temperatures of low-melting drugs with amylodextrin.     

注射用琥珀酰明胶的制备

目的制备注射用琥珀酰明胶,以提高其稳定性及运输贮藏的便易性。方法合成琥珀酰明胶,并用IR、1H-NMR及UV光谱方法对其进行表征,采用喷雾干燥和冷冻干燥工艺制备注射用琥珀酰明胶,同时对所制备产品的再分散性质进行了初步考察。结果合成条件为:明胶质量浓度为200 mg.L-1,琥珀酸酐质量浓度为10 mg.L-1,pH值为10,温度90℃,时间2 h。冷冻干燥法制备的注射用琥珀酰明胶与琥珀酰明胶对照品的1H-NMR、IR及UV谱图均相符。以质量浓度50 mg.L-1的甘露醇为冻干保护剂制备的产品外观蓬松饱满,复溶时间短。配成输液后渗透压为288 mmol.L-1,pH值为7.19。结论运用丁二酰化法合成琥珀酰明胶,以质量浓度50 mg.L-1甘露醇为冻干保护剂,利用冷冻干燥法可相对较稳定地制备拥有较好外观及溶解度的注射用琥珀酰明胶,且配制成输液后渗透压及pH值符合静脉用药要求。     

Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L-lactic acid) nanoparticles prepared by an emulsion-diffusion technique

Abstract

In this study, the purification by cross-flow filtration (CFF) and freeze drying of poly(D, L-lactic acid) (PLA) nanoparticles prepared by an emulsion-diffusion technique using poly(vinyl alcohol) (PVAL) or poloxamer 188 (P-188) were investigated. The stability of the suspensions was correlated to the affinity of the stabilizers for the nanoparticle surface, the resistance of the coating layer to continuous filtration and to freeze—thawing procedures. The results indicated a clear difference between the two stabilizers, suggesting that the nature of the coating layer has a very important role during CFF and freeze-drying. Nanoparticles prepared with PVAL were filtered and freeze-dried without nanoparticle fusion. This behaviour was attributed to the formation of a stable thick layer (similar to that found for polystyrene latex). In contrast, aggregation of nanoparticles was observed during CFF for the batches prepared with P-188, indicating that the polypropylene oxide blocks present in the copolymer have little affinity for the PLA surface. However, these suspensions were successfully recovered when using stabilizer solutions as diafiltration media, suggesting a dynamic exchange between the P-188–adsorbed chains and those of the identical polymer remaining in the bulk solution. The presence of P-188 did not prevent nanoparticle aggregation after freeze-drying. Therefore, the use of cryoprotectants was necessary. Aggregation may have been due to an increase in the solubility of P-188 in the bulk solution, which provokes a destabilization of the suspension by desorption and partial coverage of the surface. The best cryoprotectants were found to be sugars containing glucose units. The cryoprotective effect was related to the hydrogen bonding capability of these sugars, which prevented aggregation by dehydration of P-188 forcing it to the PLA surface.     

Testosterone solid lipid microparticles for transdermal drug delivery. Formulation and physicochemical characterization

Purpose: The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system.

Methods: Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5?mg TS?g^?1. Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24?h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated.

Results: The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7–95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM?<?5% GD?<?5% SA?<?5% GB?<?2.5% GM?<?2.5% SA?<?10% GD?<?10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB–2.5?mg TS?g^?1 SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB–2.5?mg TS?g^?1 stored at 5°C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation.

Conclusions: The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.     

Dexamethasone sodium phosphate-loaded Chitosan based delivery systems for buccal application

Chitosan (CH) was used as a biocompatible and bioadhesive polymer material to prepare solid dispersions as well as hydrogels loaded with dexamethasone sodium phosphate (DSP), a steroidal anti-inflammatory agent clinically used for treatment of different mouth diseases.

Binary solid dispersions at various drug-to-polymer weight ratios were prepared by freeze-drying; their direct compression gave tablets which were characterized for the swelling behaviour and drug release in vitro. Similarly, DSP-loaded hydrogels composed of CH and glycerine were prepared and characterized.

CH and DSP showed a good physical compatibility. A slow and prolonged release of the drug was observed in vitro from both kinds of systems. The swelling properties of the polymer seemed to be the main parameter affecting the drug release profile from both tablets and hydrogels at the pH value of mouth.

In vivo buccal application of both the systems allowed to obtain a prolonged release of DSP, as compared with a glycerine solution of the drug. From the in vitro swelling studies and in vivo test, the 2:1 CH-DSP solid dispersion in particular can be designated for further investigation.     

聚乳酸多孔支架制备及细胞实验

以冰粒子作为致孔剂，采用冷冻干燥-粒子滤出复合法制备了块状聚乳酸多孔支架。将聚乳酸溶于氯仿溶液后加入冰粒子，在液氮中冷冻后冷冻干燥获得多孔支架。对支架孔隙结构分析表明，该工艺制备的多孔支架无致孔剂残留，其孔隙大小由加入的冰粒子大小决定。细胞实验表明该多孔支架具有较好的生物相容性并且无细胞毒性。     

槲皮素-PLGA嵌段共聚物纳米粒冻干粉的制备及体外释放性能考察

目的:制备槲皮素-(聚乳酸-羟基乙酸共聚物)嵌段共聚物(QC-PLGA)纳米粒冻干粉并考察其体外释放规律。方法:采用乳化溶剂挥发法制备QC-PLGA纳米粒,通过正交试验确定最优处方工艺,通过单因素试验筛选冻干保护剂,通过动态透析技术考察QC-PLGA纳米粒冻干粉的体外释药规律。结果:最佳制备工艺为0.2%聚乙烯醇,PLGA质量浓度10 g·L~(-1),油/水相体积比1∶35,槲皮素用量5 mg,冻干保护剂为2%乳糖。QC-PLGA纳米粒冻干粉的外表光滑,形态无皱缩塌陷、结构致密且加入注射用水振摇后再分散性良好,体外释放规律基本符合Weibull方程的释药模型,释药动力学方程ln[ln(1/1-Q)]=0.399lnt-1.503(R~2=0.973)。结论:QC-PLGA纳米粒冻干粉制备工艺简单可行、性质稳定、易储存,相比槲皮素原料药具有明显的缓释作用。     

Freeze-drying of itraconazole-loaded nanosphere suspensions: a feasibility study

The present study concerns the stabilization of the association of the new hydrophobic triazole derivative itraconazole within poly-ϵ-caprolactone-nanospheres by means of freeze-drying. We have investigated the freeze-drying of nanospheres, and especially the cryopreservation conditions, with the help of differential scanning calorimetry and zeta potential measurements. Five commonly used cryoprotective agents were evaluated (glucose, sucrose, trehalose, dextran, mannitol at 0, 5, 10, 20, and 30% [w/v]) after freeze-thawing and freeze-drying. The addition of carbohydrates led to a partial protection of the colloidal suspension, with leakage of 30% of itraconazole under the best cryopreservation conditions (10% of glucose or sucrose). Zeta potential measurements revealed that the main destabilization mechanism during freeze-drying was surface modifications of the nanospheres, and particularly drug desorption. Therefore, the hydrophilic surfactant adsorbed at the surface of the nanospheres played an important role in the cryopreservation. Replacing the commonly used non ionic surfactant PLURONIC®PE F68 by the anionic surfactant sodium deoxycholate resulted in a complete stabilization of itraconazole-loaded nanospheres after freeze-drying, with no drug desorption, in the presence of 10% sucrose, but not in the presence of glucose. As shown by thermal analysis, PLURONIC®PE F68 may crystallize during freezing, which could lead to surface modifications and drug desorption, whereas sodium deoxycholate may not. Moreover, the Tg′ of glucose-containing suspensions is 10°C lower than Tg′ of sucrose-containing suspensions, which may explain the shrinkage of the cake observed in the case of glucose and the homogeneous appearance of the dried product in the case of sucrose. © 1996 Wiley-Liss, Inc.