依托泊苷微乳相图的研究

目的确定o／w型依托泊苷微乳处方。方法选用油酸、十四酸异丙酯和十六酸异丙酯作为油相，Tween80、Cremophor EL和Cremophor RH40作为表面活性剂，乙醇、1，2-丙二醇、异丙醇、甘油和PEG400为助表面活性剂，通过滴定法绘制伪三元相图，以o／w型微乳区大小为指标筛选处方。结果确定了最终空白微乳处方为Cremophor RH40：乙醇：PEG 400：水：十四酸异丙酯=19．0：19．0：19．0：38．2：4．8（w／w）。结论所选择的微乳处方可以满足依托泊苷载药量的要求。     

注射用葫芦素B自微乳化药物传递系统的处方优化

目的对注射用葫芦素B自微乳化药物传递系统进行处方优化。方法在注射级辅料中筛选油相、乳化剂和助乳化剂,根据空白假三元相图和粒径分析进一步优化处方。结果最佳处方组成为m(油酸乙酯)∶m(Cremophor RH)∶m(乙醇)=30∶55∶15,其中药物含量的质量分数为1%。结论可按照最佳处方组成制备注射用葫芦素B自微乳化药物传递系统。     

氯己定碘溶液剂的初步毒理学评价

摘要：目的:检测氯己定碘溶液剂的安全性。方法:通过急性经口毒性实验、皮肤刺激实验、急性眼刺激性实验、小鼠骨髓嗜多染红细胞微核实验4个实验对氯己定碘溶液剂进行初步毒理学评价。结果:氯己定碘水溶液制剂对皮肤、眼睛均无刺激性对骨髓嗜多染红微核细胞及红细胞也无抑制作用。结论:氯己定碘水溶液制剂属于低毒性消毒剂。     

姜黄素自微乳化释药系统的制备与评价

目的研制姜黄素自微乳化释药系统(Cur-SMEDDS)并对其理化性能、稳定性等进行评价。方法通过溶解度实验和伪三元相图筛选SMEDDS组分;采用星点设计和效应面法优化处方研制Cur-SMEDDS,并对其形态、粒径、理化参数及稳定性进行考察。结果优化后Cur-SMEDDS的处方为油相MCT∶乳化剂Cremophor RH40∶助乳化剂甘油=22.5∶49.3∶28.2,其平均载药量为1.0%,澄清度好,微乳粒子形态主要为圆球形,平均粒径为40.83 nm,稳定性良好。结论所制制剂理化性质稳定,制备工艺简单,质量稳定,容易控制。     

氯己定碘消毒剂的研究与临床应用进展

通过文献检索,对氯己定碘的消毒机制、合成方法、剂型制备及其应用进行了总结归纳,综述氯己定碘消毒剂的特点和临床优势. 氯己定碘消毒剂对病原菌有显著的杀灭和抑制作用,可广泛应用于临床,在消毒领域具有广阔的应用前景.     

依托泊苷口服微乳的制备及质量评价

目的 研制O/W型依托泊苷口服微乳制剂并评价其质量.方法 通过相图筛选处方,并考察最大载药量及所制微乳的性质.结果 空白微乳最终处方为;Cremophor RH40-乙醇-PEG 400-水-十四酸异丙酯(19.0;19.0;19.0;38.2;4.8),依托泊苷的含量为10 mg·ml-1,平均粒径为34.6 nm.结论 所制备的O/W型微乳能显著提高依托泊苷的溶解度,且制备简单,质量稳定.     

正交试验优选浓碘酊处方

目的优选浓碘酊的最佳处方.方法采用L9（34）正交设计,以碘和碘化钾含量变化为考察指标,考察碘与碘化钾比例、乙醇浓度两个因素对浓碘酊稳定性的影响.结果最优处方为碘与碘化钾比例1：0.6,乙醇浓度76%.结论按优化处方制备的制剂稳定性较好.     

氟康唑眼用剂型凝胶的制备及质量控制

目的制备氟康唑眼用即型凝胶并建立其质量控制方法。方法以泊洛沙姆407为基质制备凝胶,并采用高效液相色谱法对氟康唑与氯己定进行含量测定。结果 15.5%浓度的泊洛沙姆407在温度达到32℃即成凝胶状态。氟康唑、氯己定在100～600μg·mL-1和10～60μg·mL-1(r=0.9999、0.999)范围内线笥关系良好,平均回收率为102.78%、101.52%,精密度RSD为1.45%、2.70%。结论本实验成功完成氟康唑眼用即型凝胶的制备,处方设计合理,制备方法简便,质量控制方法可靠。     

醋酸氯己定的临床观察

目的评价醋酸氯己定溶液不同含量治疗口腔炎、泌尿系统感染,及其它致病菌引起的各种阴道炎、宫颈炎、白带增多症及性病等的治疗效果。方法不同剂量的醋酸氯己定溶液,用多中心随机双盲实验法。结果醋酸氯己定溶液治疗口腔炎、皮肤粘膜和泌尿系统感染的临床痊愈率和有效率分别为95.04%、98.7%,细菌阴转率为95.65%,无药物不良反应。结论醋酸氯己定溶液治疗临床常见致病菌引起的口腔炎、皮肤黏膜发炎,泌尿系统感染临床疗效较好,无药物不良反应。     

醋酸氯己定凝胶剂的制备与质量控制

目的:制备醋酸氯己定凝胶剂并建立质量控制方法.方法:以卡波姆940为基质制备醋酸氯己定凝胶剂,采用紫外分光光度法测定凝胶剂中醋酸氯己定的含量.结果:醋酸氯己定在6～13μg·mL-1浓度范围内线性关系良好(r=0.999 9),平均回收率99.51%,RSD=0.42% (n=6).结论:醋酸氯己定凝胶剂制备工艺可行,含量测定方法简便、准确.     

Preparation and evaluation of microemulsion of vinpocetine for transdermal delivery

Poorly soluble vinpocetine was selected as the model drug to prepare a microemulsion in order to increase solubility and in vitro transdermal delivery of the drug. Oleic acid was chosen as the oil phase due to its excellent solubilizing capacity. PEG-40 hydrogenated castor oil (Cremophor RH40) was employed as a surfactant (S) and purified diethylene glycol monoethyl ether (Transcutol P) was used as a cosurfactant (CoS). The effects of diverse types of oil, different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. The optimized microemulsion consisted of 1% vinpocetine, 4% oleic acid, 20% Cremophor RH40, 10% Transcutol P and 65% distilled water (w/w), in which drug solubility was about 2,100 fold compared to that in water and the apparent permeation rate across the excised rat skin was 15.0 +/- 2.5 microg/cm2/h. Finally the physicochemical properties of the optimized microemulsion including pH, viscosity, refractive index, conductivity and particle size distribution were examined, which showed stable behavior after more than 12 months at ambient temperature. The irritation study showed that optimized microemulsion was a safe transdermal delivery system.     

Self-nanoemulsifying drug delivery systems of tamoxifen citrate: Design and optimization

Tamoxifen citrate is an antiestrogen for peroral breast cancer treatment. The drug delivery encounters problems of poor water solubility and vulnerability to enzymatic degradation in both intestine and liver. In the current study, tamoxifen citrate self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent such obstacles. Preliminary screening was carried out to select proper ingredient combinations. All surfactants screened were recognized for their bioactive aspects. Ternary phase diagrams were then constructed and an optimum system was designated. Three tamoxifen SNEDDS were then compared for optimization. The systems were assessed for robustness to dilution, globule size, cloud point, surface morphology and drug release. An optimum system composed of tamoxifen citrate (1.6%), Maisine 35-1 (16.4%), Caproyl 90 (32.8%), Cremophor RH40 (32.8%) and propylene glycol (16.4%) was selected. The system was robust to different dilution volumes and types. It possessed a mean globule size of 150 nm and a cloud point of 80 °C. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension, as well. Realizing drug incorporation into an optimized nano-sized SNEDD system that encompasses a bioactive surfactant, our results proposed that the prepared system could be promising to improve oral efficacy of the tamoxifen citrate.     

Preparation and evaluation of dl-praeruptorin A microemulsion based hydrogel for dermal delivery

Abstract

The purpose of the present investigation was to develop and optimize the microemulsion (ME) as a transdermal system for Pd-Ia, a poor water soluble and low bioavailable drug. The pseudo-ternary phase diagrams were constructed for various ME formulations including oleic acid as the oil phase, Cremophor RH40 as the surfactant, ethanol as the cosurfactant, and water. The maximum cumulative amount permeated through rat abdominal skins per unit area in 32?h (Q₃₂), and the maximum flux were evaluated using the Franz diffusion cell in order to optimize the ME formulation. The results indicated that the optimized ME formulation was composed of oleic acid (5%, W/W), Cremophor RH40 (13.33%, W/W), ethanol (26.67%, W/W), and water (55%, W/W); the maximum cumulative amount of Pd-Ia was 354.330?±?12.006?μg?cm^?2, the maximum flux was 11.467?±?0.500?μg?cm^?2?h^?1. ME-gel was administered transdermally to rats. The mean plasma concentration of Pd-Ia following transdermal application of ME-gel could be maintained for 32?h at least and the half-life was evidently prolonged. It shows that the ME-gel could be a promising vehicle for dermal delivery of Pd-Ia.     

Solubilization of the lichen metabolite (+)-usnic acid for testing in tissue culture

The pharmacological testing of natural products can often be hampered by the poor solubility of such compounds in non-toxic solvents. There is thus a need for a suitable agent for solubilization of natural substances to allow testing on a variety of cell lines in-vitro. Such an agent should ideally have no direct effects on any of the commonly used cell lines from a variety of tissues and mammalian species to allow proper comparison. In this study, the lichen metabolite (+)-usnic acid, a dibenzofuran derivative, was used as a prototype for an insoluble natural product with the aim of finding a solvent that was both capable of solubilizing usnic acid and was free of direct activity against a test cell line. Solubilization was measured at different pH values in various concentrations of co-solvents (glycofurol 75, propylene glycol, polyethylene glycol 400), surfactants (polysorbate 20 and Cremophor RH40), and the complexing agent 2-hydroxypropyl-beta-cyclodextrin. The solubility achieved in a 20% aqueous solution was 0.11 mg mL(-1) for propylene glycol, 0.19 for PEG 400, 0.27 for glycofurol 75, 0.57 for Cremophor RH40, 0.68 for 2-hydroxypropyl-beta-cyclodextrin and 0.84 for polysorbate 20. The direct effects of the various solvent systems were tested on the human leukaemia cell line K-562 in a standard proliferation assay. Most of the solvents proved toxic with the exception of propylene glycol, PEG 400 and 2-hydroxypropyl-beta-cyclodextrin. Anti-proliferative activity of usnic acid could be demonstrated with an ED50 (amount of substance required to reduce thymidine uptake to 50% of uptake by untreated control culture) of 4.7 microg mL(-1) using PEG 400 and 2-hydroxypropyl-beta-cyclodextrin but only the latter gave satisfactory solubility. 2-Hydroxypropyl-beta-cyclodextrin was thus identified as a solubilizing agent that fulfilled both set criteria of solubility and lack of toxicity against the test cells.     

Characterization of prototype self-nanoemulsifying formulations of lipophilic compounds

This study describes the evaluation and characterization of a self-nanoemulsifying drug delivery system (SNEDDS) consisting of a nonionic surfactant (Cremophor RH40), a mixture of long chain mono-, di-, and triacylglycerides (Maisine 35-1 and Sesame oil) and ethanol. Compositions containing 10% (w/w) ethanol, 40%-60% (w/w) lipid content, and 30%-50% (w/w) Cremophor RH40 were identified as pharmaceutically relevant, robust, and self-nanoemulsifying when dispersed in aqueous media. The influence of adding three different lipophilic model drug compounds (danazol, halofantrine, and probucol) to the SNEDDS was evaluated. While danazol precipitated from the SNEDDS after dispersion in aqueous media, halofantrine and procubol remained solubilized. Halofantrine- and procubol-loaded SNEDDS were evaluated in both saline and in media simulating fasted and fed-state intestinal fluid (FaSSIF and FeSSIF) using dynamic light scattering and small-angle X-ray scattering (SAXS) techniques. Stable nanoemulsions with droplet sizes in the range of 20-50 nm were formed in all media and with and without drugs. The mean size of the droplets was neither affected significantly by being dispersed into the media simulating gastro intestinal fluid, nor by addition of the drug.     

Understanding the Freezing of Biopharmaceuticals: First-Principle Modeling of the Process and Evaluation of Its Effect on Product Quality

Freezing and thawing are important process steps in the manufacture of numerous biopharmaceuticals. It is well established that these process steps can significantly influence product quality attributes (PQA). Herein, we describe a physico-mathematical model to predict product temperature profiles based on the freezing program as input parameter in a commercial freeze–thaw module. Applying this model, the time from first nucleation until the last point to freeze (LPF) reaching ? 5°C and the time from ? 5°C at LPF to ? 30°C at LPF was varied to study the effect on PQA in a full factorial design. Effects of process parameter settings on a typical fully formulated, highly concentrated monoclonal antibody (mAb) solution as well as highly concentrated mAb solution formulated with buffer only were investigated. We found that both process phases affected PQA, such as aggregates by size-exclusion chromatography, polydispersity index by dynamic light scattering, and number of subvisible particles and turbidity in a complex way. In general, intermediate cooling and freezing times resulted in overall optimized PQA. Fully formulated mAb solution containing cryoprotectant and nonionic surfactant was significantly less affected by freezing–thawing than mAb solution formulated in buffer only.     

Phase behavior of TPGS-PEG400/1450 systems and their application to liquid formulation: a formulation platform approach

Vitamin E D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and polyethylene glycol are common excipients used in both preclinical and commercial formulations. In this paper, the phase diagrams of TPGS and polyethylene glycol 400 (PEG 400) in the presence of either water or ethanol were constructed. The effect of water and ethanol on the cloud point temperature of TPGS-PEG 400 mixtures was investigated. In general, the cloud point temperature was reduced by the presence of either water or ethanol in the formulation. However, water was more effective in lowering the cloud point temperature than ethanol. Similarly, the phase diagram of TPGS-PEG 1450 was constructed. The cloud point temperature was observed to decrease with increasing TPGS concentration. It was found that TPGS and PEG 1450 could form a single phase when TPGS concentration was above 75%, based on differential scanning calorimetry, and FT-Raman analysis indicated that a vibration at 1330 cm(-1) disappeared in the melted single phase. In addition, a systematic melting point depression was observed for the mixtures of TPGS-PEG 1450. In the presence of Ibuprofen, a model compound, the cloud point temperature was also reduced. Finally, the extended Flory-Huggins theory for polymer solution was used to analyze the entropic and enthalpic contributions of water and ethanol to the free energy of mixing.     

Paclitaxel/beta-cyclodextrin complexes for hyperthermic peritoneal perfusion - formulation and stability.

Due to its low aqueous solubility paclitaxel is currently formulated in a Cremophor EL/ethanol mixture. However, the vehicle of this formulation causes several side-effects. Our objective was to formulate a tensioactive-free and solvent-free paclitaxel solution, which can be used for a hyperthermic intraperitoneal chemoperfusion procedure (HIPEC). The potential of chemically modified beta-cyclodextrins to form complexes with paclitaxel was investigated as a means to increase the aqueous solubility of paclitaxel. Methylated beta-CDs (randomly methylated and 2,6-dimethylated) showed the best ability to solubilise paclitaxel compared to sulfobutyl-ether- and hydroxypropyl-beta-CD. The minimal ratio of paclitaxel versus randomly methylated-beta-cyclodextrin (RAME-beta-CD) yielding 100% inclusion efficiency was 1/20 (mol/mol). Paclitaxel/RAME-beta-CD inclusion complexes prepared via freeze drying were stable for at least 6 months when stored at 4 degrees C. A 5mg/ml paclitaxel solution was formulated using paclitaxel/RAME-beta-CD-complexes. Upon dilution of these solutions, no precipitation was seen. After 24h storage at room temperature or 2h at HIPEC conditions (41.5 degrees C) the 1/40 (mol/mol) ratio showed the highest stability at paclitaxel concentrations of 0.1 and 0.5mg/ml. When hydroxypropyl methylcellulose (HPMC) was added to the reconstitution medium, the stability significantly increased, offering the opportunity to reduce the amount of RAME-beta-CDs in the formulation.     

Kinetic Analysis of the Toxicity of Pharmaceutical Excipients Cremophor EL and RH40 on Endothelial and Epithelial Cells

Cremophor EL and RH40 are widely used excipients in oral and intravenous drug formulations such as Taxol infusion to improve drug dissolution and absorption. Studies indicate that Cremophors, especially EL, have toxic side effects, but few data are available on endothelial and epithelial cells, which form biological barriers and are directly exposed to these molecules. Human hCMEC/D3 brain endothelial and Caco-2 epithelial cells were treated with Cremophor EL and RH40 in the 0.1–50 mg/mL concentration range. Cell toxicity was monitored by real-time cell microelectronic sensing and verified by lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and morphological methods. Cremophors caused dose- and time-dependent damage in both cell types. In endothelial cells, 0.1 mg/mL and higher concentrations, in epithelial cells, concentrations of 5 mg/mL and above were toxic, especially at longer incubations. Cell death was also proven by double fluorescent staining of cell nuclei. Immunostaining for tight junction proteins claudin-4 and -5 showed barrier disruption in cells treated by surfactants at 24 h. In conclusion, Cremophor EL and RH40 in concentrations corresponding to clinical doses caused endothelial and epithelial toxicity. Endothelial cells were more sensitive to surfactant treatment than epithelial cells, and Cremophor EL was more toxic than RH40 in both cell types.