Bioequivalence of ximelagatran,an oral direct thrombin inhibitor,as whole or crushed tablets or dissolved formulation

SUMMARY

Objective: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.

Research design and methods: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20–33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.

Results: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6μmol-h/l_ (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (Cmax) was 0.3μmol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t1/2) was 2.8?h for all treatments. The time to Cmax (tmax) was 2.2?h for the whole tablet and approximately 0.5?h earlier when the tablet was crushed or dissolved (1.7–1.8?h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported.

Conclusion: The present study showed that the pharmacokinetics (AUC and Cmax) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.     

Preformulation development of recombinant pegylated staphylokinase SY161 using statistical design

The goal of this study was to perform preformulation development of SY161 by using statistical design methods to understand the effects of buffer strength, NaCl concentration, and pH on conformation and stability of the protein. It was also important to elucidate interactions between these factors. A central composite design using a 2-level full-factorial study was performed. Secondary structure was evaluated using circular dichroism. Stability toward unfolding was investigated using high-sensitivity differential scanning calorimetry. Depegylation, aggregation, and protein loss were evaluated using SEC-HPLC with on-line light scattering, at time zero and after a 2-week stability study. Response surface plots clearly show optimal pH, NaCl, and buffer conditions. Interactions between pH and NaCl as well as pH and buffer concentration are observed. T_m is seen to be predictive of SY161 stability. Secondary structure changes were minimal and did not influence stability. Statistical design was very effective in providing an understanding of the effects of the formulation components on SY161 stability.     

Nuclear medicine techniques in the evaluation of pharmaceutical formulations

Nuclear medicine imaging techniques have great potential in the study of the behaviour of drug formulations and drug delivery systems in human subjects. No other technique can locate so precisely the site of disintegration of a tablet in the Gl tract, the depth of penetration of a nebulised solution into the lung, or the residence time of a drug on the cornea. Using the gamma camera to image the in vivo distribution of pharmaceutical formulations radiolabelled with a suitable gamma emitting radionuclide, images may be used to quantify the biodistribution, release and kinetics of drug formulations and delivery from novel carrier systems and devices. Radionuclide tracer techniques allow correlation between the observed pharmacological effects and the precise site of delivery. The strength of the technique lies in the quantitative nature of radionuclide images. Such studies not only provide data on the nature and characteristics of a product, such as reliability and reproducibility but, may also be used in submission to Regulatory Authorities in product registration dossiers.     

不同剂型的清开灵药物研究

本文探讨了清开灵药物的临床应用和不良反应以及不同剂型的清开灵药物的使用方法,为临床医生用药提供参考。     

清肺利湿解毒方药治疗痤疮的临床观察及对血清相关性激素水平的影响

目的评价清肺利湿解毒方药治疗寻常性痤疮的疗效及安全性,并观察其对痤疮患者性激素的调节作用。方法 100例寻常性痤疮患者内服本科自拟清肺利湿解毒中药方治疗8周,评价其临床疗效及安全性,并观察50例患者治疗前后外周血中睾酮(T)、雌二醇(E2)、黄体生成素(LH)、促卵泡素(FSH)、催乳素(PRL)、孕酮(PRG)的变化。结果临床治愈38例(38.0%),显效47例(47.0%),有效率为85.0%,无不良反应。其中女性痤疮患者的T及PRL水平治疗前后有显著变化(P0.05),男性患者激素水平治疗前后均无明显变化(P0.05)。结论清肺利湿解毒方治疗寻常性痤疮具有明显的临床疗效,且无不良反应,其可能通过调节机体性激素水平达到治疗寻常痤疮的目的 。     

明胶微球乙肝疫苗动物免疫效果研究

目的 研究并优化微球乙型肝炎疫苗的配方,观察微球乙肝疫苗对温度的稳定性。方法 用明胶包裹ＨＢｓ制备微球,设计不同配方及不同粒径微球乙肝疫苗、冻干微球乙肝疫苗于不同温度放置一定时间,免疫动物观察免疫效果。结果 微球疫苗ＨＢｓ包裹率〉９０％,微球疫苗的免疫效果受佐剂配方及制备程序等因素影响,〈１０μｍ的微球（５．６μｍ）免疫效果明显优于〉１０μｍ的微球（２５．４μｍ）（Ｐ〈０．０２）及铝佐剂组（Ｐ〈０     

Novel Vaginal Controlled-Delivery Systems Incorporating Coprecipitates of Nonoxynol-9

The purpose of this study was to formulate Nonoxynol-9 (N-9) into a solid coprecipitate form which can be used in preparing pharmaceutically attractive and nonirritating vaginal controlled-release delivery systems (DDSs) such as gelatin capsules (HGC) and tablets. N-9 was coprecipitated with polyvinylpyrrolidone (PVP) with or without iodine to produce solid powders which were incorporated into either (a) bilayer tablet DDSs which possess a fast- (outer) and slow- (inner core) releasing compartment, and (b) HGC DDSs (named Triad HGC) composed of fast- (outer), intermediate- (granules), and slow- (pellets) releasing compartments. The rates of release of iodine and/or [¹⁴C]N-9 from the two DDSs were studied in vitro in phosphate buffer at pH 5.0, in human seminal plasma and in vivo after intravaginal administration in rabbits. In all of the above-described release studies, the DDSs were shown to release their N-9 or iodine content rapidly, reaching spermicidal levels within 3 min. This was further substantiated by experiments in which the DDSs were introduced in whole human semen containing live spermatozoa. Complete spermicidal kill was obtained in less than 1 min and in less than 3 min from the bilayer tablet and the Triad HGC, respectively. Furthermore, the release of N-9 from the two DDSs was shown to continue for at least 4 hr in buffers (pH 5.0), human seminal fluid, and after intravaginal administration in rabbits. The resulting powder from the coprecipitation of N-9 and PVP (K-30) can be appropriately formulated into a controlled-released HGC or bilayer tablet to produce vaginal controlled-release DDSs which are nonirritating and have the potential to become effective spermicidal products.     

复方鱼腥草分散片的制备及其溶出度测定

目的:制备复方鱼腥草分散片,以黄芩苷为指标考察体外溶出度。方法:以分散均匀性为考察指标,采用正交设计试验对分散片的处方工艺进行筛选和优化。结果:优化处方的崩解剂组成为CMS-Na5%,MCC20%,L-HPC10%,制备的分散片分散均匀性符合中国药典规定,3min累积溶出百分数达95%以上。结论:试验研制的复方鱼腥草分散片处方工艺简单可行。     

Four simple procedures for the assay of methdilazine in bulk drug and in tablets and syrup using potassium iodate

Four simple, selective, accurate and reproducible procedures are described for the assay of methdilazine in bulk form and in formulations. One titrimetric and three spectrophotometric methods are based on the oxidation of the drug with potassium iodate, and determination of either excess iodate or iodine released in the reaction. In the titrimetric method (Method A) the drug is reacted with a known excess of iodate in sulphuric acid medium followed by the iodometric determination of residual oxidant. The residual oxidant is determined by reacting it with variamine blue and measuring the absorbance of the oxidised dye at 540 nm (Method B). The second spectrophotometric method (Method C) is based on the oxidation of the drug in sulphuric acid medium in the presence of chloride ions by a large excess of iodate and the iodate being reduced to iodine. The ICl(2)(-) generated in this reaction is used to iodinate 2',7'-dichlorofluorescein dye, and the red colour of the iodinated dye is measured at 525 nm. The other spectrophotometric method (Method D) also involves the oxidation of the drug in acid medium by a large excess of iodate with the liberation of iodine and its subsequent extraction with carbon tetrachloride followed by measuring the absorbance 520 nm. The methods were successfully applied to the determination of methdilazine in tablets and syrup and the results obtained in agreement with the label claim.