Pharmacokinetics of papaverine hydrochloride and the biopharmaceutics of its oral dosage forms

The pharmacokinetics of completely metabolized papaverine hydrochloride were characterized by a linear sum of three exponentials on intravenous administration with respective 1.5, 19 and 107 min apparent half lives. There was a time-dependent partition from plasma water into red blood cells with an apparent half life of 1.5--3 min. The partition coefficient normally ranged between 8 and 15 at therapeutic levels but approached unity at high plasma concentrations to indicate a saturable partition. Apparent compartmental volumes of distribution referenced to total concentrations in the plasma were 4.3--4.8, 11--13 and 20--25 liters. Protein binding was 91--95%. The hepatic clearance of blood was 960 ml/min, corresponding to a hepatic efficiency of 69%, and indicated that the clearance of protein-bound drug was consistent with the observed first pass metabolism of 70% for oral solutions. No dose dependency was observed on intravenous administration or on oral administration of solutions and tablets. Tablets with release lag times of 10--15 min showed relative bioavailabilities of 52%. Two different lots of sustained release capsules showed 68 and 89% relative bioavailabilities. Release lag times among capsules ranged between 0 and 170 min. Loo-Riegelman calculations and analog computer fittings were consistent with a half life of absorption from oral solutions of 19 min and zero order release rates from tablets and sustained release capsules. Chronic studies of tablets q.i.d. and capsules b.i.d. confirmed lack of accumulation. An appropriately designed 300 mg sustained release capsule, b.i.d., for an arbitrary plasma level of 0.200 microgram/ml should have one tenth the release rate of the studied capsules.     

基于生物药剂分类系统对普通口服固体制剂免除生物等效性研究的考虑

仿制药上市的根本条件是与原研药保持生物学等效;但是自从生物药剂分类系统(BCS)的概念提出以来,各国药品管理当局及工业界都在进行基于BCS信息免除普通口服固体制剂生物等效性研究的探索。文中介绍了不同管理当局目前所持态度,并给出具体实例,说明如何基于药物的溶解性、渗透性以及体外溶出特点,来分析是否有免除生物等效性研究的可能。     

The effect of modification of excipients for the bioavailability of vinburnine

Biopharmaceutic comparison is achieved between commercialized capsules of vinburnine and a new dosage form. The difference between the two drug products concerns only the quality of excipients. Drug bioavailability decreases of about 10%, in despite of the very important, and well known, interindividual variations of vincamine drug products. Only the absorption rate seems statistically lightly decreased by the new formulation.     

A validated stability-indicating liquid-chromatographic method for ranitidine hydrochloride in liquid oral dosage form

A selective, specific and stability-indicating gradient reverse phase high-performance liquid chromatographic (HPLC) method was developed for the determination of Ranitidine in presence of its impurities, forced degradation products and placebo substances such as saccharide and parabens. Ultraviolet detection was performed at 230 nm. Separate portions of the drug product and ingredients were exposed to stress conditions to induce oxidative, acidic, basic, hydrolytic, thermal and photolytic degradation. Ranitidine was found to degrade significantly at acidic, basic and oxidative stress conditions but was stable at heat and humidity. The developed method was validated as per International Conference on Harmonization (ICH) guidelines. The method was validated over this range for (i) system suitability (ii) specificity, (iii) precision, (iv) limit of detection and limit of quantification, (v) linearity, (vi) accuracy, (vii) robustness. The method was found to be precise, accurate, linear and robust. The proposed method was successfully employed for estimation of Ranitidine impurities in pharmaceutical preparations.     

Implication of biopharmaceutics and pharmacokinetics of rifampicin in variable bioavailability from solid oral dosage forms

Rifampicin is one of the oldest and most effective chemotherapeutic agents available for the treatment of tuberculosis but exhibits variable bioavailability from separate and fixed dose combination formulations, which has been identified as a major bottleneck in the effective treatment of tuberculosis. In this investigation, physico-chemical characterization, single dose pharmacokinetic studies and the permeability of rifampicin under physiological conditions in the rat were studied to trace the possible reasons for its variable absorption. Rifampicin exhibits very high solubility in acidic and basic pH, corresponding to the pH of the stomach and distal intestine, respectively, whereas it is moderately soluble at the jejunal pH. From single-dose pharmacokinetic studies and permeability characterization, rifampicin is a highly permeable molecule and thus according to BCS, it is a borderline class II drug. This investigation has ruled out the possibility of intrinsic solubility, effective permeability, drug decomposition, presystemic metabolism and interaction with other antituberculosis drugs as direct factors responsible for the variable bioavailability of rifampicin. However, it was found that the rate of dissolution in association with pH and the concentration-dependent absorption of rifampicin affects the in vivo performance of the dosage forms. In addition, this is the first report of methodology for correcting inlet concentration for permeability calculations of a chemically unstable molecule.     

肺炎喘嗽液质量控制方法的研究

目的：为肺炎喘嗽液提供质量控制方法。方法：采用正丁醇乙酸乙酯（１∶３）萃取净化样品，薄层色谱法鉴别制剂中黄芩、射干、化橘红、甘草；反相高效液相色谱法测定黄芩苷、柚皮苷和射干苷３种黄酮苷含量，固定相为十八烷基键合硅胶烷，流动相为甲醇水溶液（３０％～５０％）。结果：薄层色谱斑点清晰、集中；三组分的加样回收率在９３．９％～１０１．９％之间，制剂中各组分含量测定结果详见表２。结论：本文为肺炎喘嗽液提供了一种简便、快速、准确、实用的质量控制方法     

The preservation of some oral liquid preparations

Chloroform should be considered as an obsolete preservative for pharmaceutical preparations, because of its toxicological implications and its physical instability. The effectiveness of possible alternatives for chloroform in three oral liquid pharmaceutical preparations was investigated, using a microbiological challenge test. Magnesium trisilicate mixture (British Pharmacopoeia) can be adequately preserved with methylparaben (2 g/l). Only insignificant amounts of methylparaben were absorbed by the solids present in the magnesium trisilicate mixture. Ferrous sulfate mixture (British Pharmacopoeia) can be preserved with a mixture of methylparaben (1.8 g/l) and propylparaben (0.2 g/l). Sorbic acid (1 g/l) is a suitable preservative for promethazine hydrochloride syrup.     

Interplay of biopharmaceutics,biopharmaceutics drug disposition and salivary excretion classification systems

The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS.

Conclusion

The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding.     

Applying the biopharmaceutics classification system to veterinary pharmaceutical products. Part I: biopharmaceutics and formulation considerations

The complexity of multiple species approvals continues throughout the life of a product as post-approval manufacturing changes, as well as all generic versions of approved products, are evaluated for each of the approved target animal species. In comparing product bioavailability across animal species, it is not unusual to observe marked interspecies differences. For many compounds, these differences reflect species-specific presystemic metabolism. However, a host of other variables must also be considered, including in vivo drug solubility, gastric transit time, intestinal permeability, diet, and species-by-formulation interactions. To predict potential species-by-formulation interactions, one must consider the solubility and intestinal permeability of the drug entity, the type of formulation, nature of the excipients, and the physiological characteristics of the animal recipient. In this paper, we examine manufacturing and formulation variables that can affect drug bioavailability, and the potential for species-specific differences in the responses to these formulations.     

扶正口服液的药理学研究

扶正口服液是由中药组成的复方制剂。经药效学实验表明，该制剂具有调整因放疗、化疗后引起的茵群失调和免疫功能低下的作用。为了进一步考察该制剂对其它系统的影响，我们用扶正口服液对小鼠神经系统、心血管系统、呼吸系统、急性毒性试验做了研究。结果表明，该制剂对其均无明显性影响，且ＬＤ５０为１１４．９０ｇ／ｋｇ，说明该制剂无毒副作用，是一安全有效的微生态调整制剂。     

New oral solid dosage form for furosemide oral administration

Furosemide (FURO) is a drug labeled in class IV of the Biopharmaceutics Classification System (BCS) as it is both poor soluble and poor permeable. The aim of this work was to improve FURO biopharmaceutical properties by its formulation in a new solid oral dosage form. It consists in the realization of the composite MgAl-HTlc-FURO, obtained by FURO intercalation into the inorganic matrix hydrotalcite (MgAl-HTlc), and its successive formulation in tablets intended to be swallowed whole and to disintegrate rapidly in the stomach. These formulations were prepared by direct compression of a simple powder mixture constituted by MgAl-HTlc-FURO, a super disintegrant (Explotab, PolyplasdoneXL, PolyplasdoneXL-10, PolyplasdoneINF 10 or L-HPCLH-21) and a filler. The prepared formulations were submitted to disintegration time tests, and only those displaying the lowest disintegration time in gastric medium were submitted to in vitro release studies. Drug dissolution profiles from MgAl-HTlc-FURO tablets were compared with those containing crystalline FURO alone or physically mixed to MgAl-HTlc instead of MgAl-HTlc-FURO. The results revealed that tablets containing MgAl-HTlc-FURO give the best dissolution profile and that L-HPCLH-21 is able to promote the highest drug release in gastric medium, resulting in the most suitable super disintegrant in comparison with the other tested.     

A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: A cross-sectional survey with 500 bioequivalence studies

Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism.     

退黄灵口服液的制备及临床应用

目的对：退黄灵口服液处方工艺进行研究并观察其临床疗效。方法完善退黄灵口服液的制备工艺,制定临床使用方法。结果本制剂制备工艺可行,性质稳定,对脐血胆红素高值新生儿早期喂服退黄灵口服液,可减轻新生儿黄疸。结论退黄灵口服液是治疗新生儿黄疸的一种有效制剂。