Modulating effect of Liv.100, an ayurvedic formulation on antituberculosis drug-induced alterations in rat liver microsomes

The influence of Liv.100 on the hepatotoxicity of antituberculosis drugs [isoniazid (INH), rifampicin (RMP) pyrazinamide (PZA)] was studied in male albino rats. INH, RMP, and PZA were proved to be the most hepatotoxic. Rats were treated with antituberculosis drugs daily for a period of 6 weeks by intragastric administration. The combined use of antituberculosis drugs elevated the levels of cytochrome P-450 and cytochrome-b5. A significant increase was observed in the levels of NADPH-cytochrome P-450 reductase and NADH-cytochrome-b5 reductases after antitubercular drug administration. During antitubercular drug treatment a significant decrease was also observed in the activity of glucose-6-phosphatase. The extent of NADPH-induced and ascorbic acid-induced lipid peroxides were marked in antitubercular drug treatment, when compared with normal control animals. Oral Liv.100 co-administration, for the same period, modulated the alterations in the xenobiotic metabolizing system and microsomal lipid peroxidation in experimental animals. The results are discussed with reference to drug metabolizing enzymes, lipid peroxidation and the hepatoprotective nature of Liv.100.     

Characterization of Murine Monoclonal Antibody to Tumor Necrosis Factor (TNF-MAb) Formulation for Freeze-Drying Cycle Development

Purpose. This study was designed to characterize the formulation of protein pharmaceuticals for freeze-drying cycle development. Thermal properties of a protein formulation in a freezing temperature range are important in the development of freezing and primary drying phases. Moisture sorption properties and the relationship between moisture and stability are the bases for the design of the secondary drying phase. Methods. We have characterized the formulation of TNF-MAb for the purpose of freeze-drying cycle development. The methods include: DTA with ER probes, freeze-drying microscopy, isothermal water adsorption, and moisture optimization.Results. The DTA/ER work demonstrated the tendency to noneutectic freezing for the TNF-MAb formulation at cooling rates of –1 to –3°C/min. The probability of glycine crystallization during freezing was quite low. A special treatment, either a high subzero temperature holding or annealing could promote the maximum crystallization of glycine, which could dramatically increase the T_g' of the remaining solution. The freeze-drying microscopy further indicated that, after the product was annealed, the cake structure was fully maintained at a T_p below –25°C during primary drying. The moisture optimization study demonstrated that a drier TNF-MAb product had better stability. Conclusions. An annealing treatment should be implemented in the freezing phase in order for TNF-MAb to be dried at a higher product temperature during primary drying. A secondary drying phase at an elevated temperature was necessary in order to achieve optimum moisture content in the final product.     

液相色谱-串联质谱法测定犬血浆中布地奈德

建立液相色谱-串联质谱法测定犬血浆中布地奈德。血浆样品碱化后，经乙酸乙酯液-液萃取，以乙腈-5 mmol·L^-1醋酸铵(60∶40，v/v)为流动相，Capcell Pak C₁₈ MG柱分离；采用电喷雾电离源，以多反应监测(MRM)方式进行负离子检测，用于定量分析的离子反应分别为m/z 489→m/z 357(布地奈德)和m/z 493→m/z 413(内标，曲安奈德)。测定血浆中布地奈德方法的线性范围为25.0～2 000 pg·mL^-1，定量下限为25.0 pg·mL^-1，日内、日间精密度(RSD)均小于15%，准确度(RE)在-8.1%～-1.7%。应用本法研究6只比格犬单次和多次给予布地奈德缓释胶囊9 mg后的药代动力学结果显示：单次给药后T_max为(3.5±3.3) h，C_max为(786±498) pg·mL^-1；多次给药后C_max为(2 142±1 515) pg·mL^-1。该法选择性强、灵敏度高、操作简便，适用于布地奈德缓释制剂的药代动力学研究。     

Evaluation of transdermal iontophoresis of enoxacin from polymer formulations: in vitro skin permeation and in vivo microdialysis using Wistar rat as an animal model

Polymers were used in vehicles to form hydrogel matrices in this study to evaluate the in vitro permeation and in vivo microdialysis of enoxacin. The highest transdermal delivery determined by area under flux-time curve (AUC) and intracutaneous enoxacin concentration were observed in methylcellulose (MC) and polyvinylpyrrolidone (PVP) hydrogels, respectively. To avoid the pH shift in vehicles during iontophoresis, buffer species were added to formulations to increase the buffer capacity. As expected, the permeability of enoxacin of anodal iontophoresis was larger than that of cathodal iontophoresis. Combination of benzalkonium chloride, a cationic surfactant as an enhancer, and iontophoresis exerted an enhancing effect for anionic enoxacin at pH 10.0. However, no effect or a negative effect was detected for cationic enoxacin in deionized water or pH 5.0 buffer, due to the shielding of the negative charge in the skin. The skin residue of enoxacin was slightly increased after the incorporation of Azone in PVP hydrogel. The result of in vivo microdialysis was in accordance with that of in vitro study. The effect of Azone on the intracutaneous enoxacin was more significant for in vivo microdialysis than in the in vitro study indicating the clinical feasibility of Azone for iontophoretic delivery. Microdialysis can be considered as a useful technique to investigate the pharmacokinetics of transdermal iontophoresis in vivo.     

Development of a membrane-controlled transdermal therapeutic system containing isosorbide dinitrate

The formulation of a transdermal delivery system for isosorbide dinitrate (ISDN) was examined. It was found that the target release rate should be 4.01 mg/h per 20 cm² for optimal dosing. In order to reach such this zero order release rate, a membrane permeation controlled transdermal therapeutic system (TTS) formulation was developed, with ethylene vinyl acetate copolymer (EVAC) and polyethylene (PE) membranes as rate controlling membranes; a carbomer gel was used as the drug reservoir. The release of ISDN from this drug delivery device was studied in vitro using FDA recommended method. PIB adhesive on the EVAC or PE membrane caused a decreased flux of ISDN; the release kinetics fitted Higuchi matrix kinetics. TTS with EVAC membrane release ISDN at a rate much lower than the calculated target release rate, but with PE membranes, the release rate was very close to the target. Release rate studies have revealed that, as the VA content in EVAC membrane increased, the flux of ISDN increased. All these results were compared with the commercial product Frandol^® Tape S from Japan. It was found that the release rate of Frandol was close to target release rate and fitted matrix kinetics. These results suggested that TTS that contain PE membrane as rate controlling membrane, polyisobutylene (PIB) adhesive and carbomer gel as a reservoir can be applicable as a TTS for ISDN.     

The Effect of Formulation Excipients on Protein Stability and Aerosol Performance of Spray-Dried Powders of a Recombinant Humanized Anti-IgE Monoclonal Antibody1

Purpose. To study the effect of trehalose, lactose, and mannitol on the biochemical stability and aerosol performance of spray-dried powders of an anti-IgE humanized monoclonal antibody. Methods. Protein aggregation of spray-dried powders stored at various temperature and relative humidity conditions was assayed by size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. Protein glycation was determined by isoelectric focusing and affinity chromatography. Crystallization was examined by X-ray powder diffraction. Aerosol performance was assessed as the fine particle fraction (FPF) of the powders blended with coarse carrier lactose, and was determined using a multiple stage liquid impinger. Results. Soluble protein aggregation consisting of non-covalent and disulfide-linked covalent dimers and trimers occurred during storage. Aggregate was minimized by formulation with trehalose at or above a molar ratio in the range of 300:1 to 500:1 (excipient:protein). However, the powders were excessively cohesive and unsuitable for aerosol administration. Lactose had a similar stabilizing effect, and the powders exhibited acceptable aerosol performance, but protein glycation was observed during storage. The addition of mannitol also reduced aggregation, while maintaining the FPF, but only up to a molar ratio of 200:1. Further increased mannitol resulted in crystallization, which had a detrimental effect on protein stability and aerosol performance. Conclusions. Protein stability was improved by formulation with carbohydrate. However, a balance must be achieved between the addition of enough stabilizer to improve protein biochemical stability without compromising blended powder aerosol performance.     

Molecular Mobility of Protein in Lyophilized Formulations Linked to the Molecular Mobility of Polymer Excipients,as Determined by High Resolution 13C Solid-State NMR

Purpose. The mobility of protein molecules in lyophilized protein formulations was compared with that of excipient molecules based on the spin-lattice relaxation time (T₁) of each molecule determined by high resolution ¹³C solid-state NMR. The relationship between molecular mobility and protein stability is discussed. Methods. Protein aggregation of lyophilized bovine serum --globulin (BGG) formulation containing dextran was measured by size exclusion chromatography. The T₁ of the BGG carbonyl carbon and dextran methin carbon in the formulation was determined by high resolution ¹³C NMR, and subsequently used to calculate the correlation time (_C) of each carbon. The spin-spin relaxation time (T₂) of BGG and dextran protons was measured by pulsed NMR spectrometry, and the critical temperature of appearance of Lorentzian relaxation due to liquid BGG and dextran protons (T_mc) was determined. Results. The _C of dextran methin carbon in BGG-dextran formulations exhibited a linear temperature dependence according to the Adam-Gibbs-Vogel equation at lower temperatures, and a nonlinear temperature dependence described by the Vogel-Tamman-Fulcher equation at higher temperatures. The temperature at which molecular motion of dextran changed was consistent with the T_mc. The _C of BGG carbonyl carbon exhibited a similar temperature dependence to the _C of the dextran methin carbon and substantially decreased at temperatures above T_mc in the presence of dextran. The temperature dependence of BGG aggregation could be described by the Williams-Landel-Ferry equation even at temperatures 20°C lower than T_mc. Conclusions. High resolution ¹³C solid-state NMR indicated that the molecular motion of BGG was enhanced above T_mc in association with the increased global segmental motion of dextran molecules.     

How actors,processes, context and evidence influenced the development of Malawi's Health Sector Strategic Plan II

Health sector strategic plans are health policies outlining health service delivery in low- and middle- income countries, guiding health sectors to meet health needs while maximizing resources. However, little research has explored the formulation of these plans. This study utilized qualitative methods to explore the formulation of Malawi's Health Sector Strategic Plan II, including processes utilized, actors involved, important contextual factors and the use of evidence-based decision-making. Thirteen semi-structured key informant interviews with health policy actors were conducted to explore perceptions and experiences of formulating the policy. Data analysis used an inductive-deductive approach and interpretation of the data was guided by an adapted version of the Walt and Gilson Health Policy Triangle. Our results indicate that HSSP II formulation was complex and inclusive but that the Ministry of Health may have given up ownership of the formulation process to development partners to ensure their continued involvement. Disagreements between actors centered around inclusion of critical services in the Essential Health Package and selection of performance-based financing as purchasing strategy. Resource constraints and the Cashgate Scandal are critical contextual elements influencing the formulation and content of the policy. Evidence-based decision-making contributed to the plan's development despite respondents' divergent opinions regarding evidence availability, quality and the weight that evidence carried. The study raises questions regarding the roles of policy actors during health policy formulation, the inclusivity of health policy processes and their potential influence on government ownership of health policy, as well as the use of evidence in developing health sector strategic plans.     

盐酸氟西汀微乳的制备及其离体大鼠透皮作用研究

目的:制备盐酸氟西汀(FLU)微乳并考察其对离体大鼠的透皮能力。方法:筛选空白微乳中表面活性剂、助表面活性剂、油相等的组成及质量比,制备FLU微乳并考察其粒径及分布等指标;用改进的Franz扩散池研究微乳的透皮速率,考察油相含量、混合表面活性剂含量及载药量对透皮吸收的影响以优化处方并进行验证试验。结果:空白微乳组成为肉豆蔻酸异丙酯(IPM)/聚乙二醇羟硬脂酸酯15(SolutolSH15)/聚乙二醇(PEG)400/水;样品平均粒径为44.6nm,呈正态分布,多分散系数为0.317;最优处方为FLU/IPM/SolutolSH15/PEG400/水(1∶9∶20∶20∶39),验证试验中3批样品稳态透皮速率平均值为(128.96±0.32)μg·cm-2·h-1。结论:所制FLU微乳有较强的透皮能力,可进一步开发为FLU的新型透皮给药制剂。     

我国钩端螺旋体疫苗的发展现状与挑战

目的：总结分析我国钩端螺旋体的发展现状以及面临的问题与挑战。方法：根据国内外文献材料进行整理、归纳和分析。结果与结论：应解决钩体疫苗发展中面临的一些困境,进一步优化我国钩体疫苗,从而保证国家扩大计划免疫规划成功实施。