Biowaiver monographs for immediate release solid oral dosage forms: acetazolamide

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing acetazolamide are reviewed. Acetazolamide's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.     

Effect of flavoring oils on preservative concentrations in oral liquid dosage forms.

The partitioning of methyl-, ethyl-, propyl-, and butylparabens into flavoring oils from aqueous systems was studied. The partitioning is dependent on the concentration of the flavoring oil, the pH of the aqueous medium, and the nature and concentration of additives to the aqueous medium.     

药物固体制剂的溶出度测定研讨会随笔

中国药学会《药物分析杂志》和德国法兰克福大学制药技术学院于2007年9月分别在北京和上海联合主办了药物固体制剂的溶出度测定研讨会。本文总结了研讨会有关专家对溶出度技术的研究、应用和发展演讲的内容。     

Research and development of oral controlled-release dosage forms

Important data concerning the gastrointestinal transit of oral solid dosage forms have been obtained recently by using the technique of gamma scintigraphy. It is now possible to put forward the principal limitations of the oral sustained release dosage forms actually available. The research and development of new controlled release products such as buoyant dosage forms and coevaporates with polymers should permit to decrease the large inter and intrasubject variations of drug plasma levels observed when the actual sustained release dosage forms are administered.     

缓释控释制剂的释放度测定方法的研究进展

目的　介绍缓、控释制剂的体外释放度测定方法 ,使其能更好地模拟体内状态。方法　综述最近的中外文献中有关缓释、控释制剂的体外释放度测定实验方法 ,实验条件的选择及影响因素。结果　体外释放度实验条件如释放介质的 pH值、离子强度、增溶剂、表面活性剂和释放仪器等可影响缓、控释制剂的体外释放度。结论　根据不同药物选择尽可能接近体内状态的方法     

缓释控释制剂的释放度测定方法的研究进展

目的介绍缓、控释制剂的体外释放度测定方法,使其能更好地模拟体内状态.方法综述最近的中外文献中有关缓释、控释制剂的体外释放度测定实验方法,实验条件的选择及影响因素.结果体外释放度实验条件如释放介质的pH值、离子强度、增溶剂、表面活性剂和释放仪器等可影响缓、控释制剂的体外释放度.结论根据不同药物选择尽可能接近体内状态的方法.     

Immediate drug release from solid oral dosage forms

Fast drug release from solid dosage forms requires a very fast contact of the vast majority of the drug particles with the solvent; this, however, is particularly delayed in tablets and granulations. Starch and cellulose substances favor the matrix disintegration during the starting phase and the generation of the effective dissolution surface of the drug substance, thereby. To investigate the very complex interrelation between the functionality of commonly used excipients and the structural effects of the production processes, wettability, porosity, water uptake, and drug release rates of several ketoprofen-excipient preparations (powder blends, granulations, tablets) were measured. Significant linear correlation between these parameters, however, was not achieved; only qualitative tendencies of the effects could be detected. In consequence, a general mathematical model describing the mechanistic steps of drug dissolution from solid dosage forms in a fully correct way was not realized. However, the time-dependent change of the effective dissolution surface follows stochastic models: a new dissolution equation is based on the differential Noyes-Whitney equation combined with a distribution function, e.g. the lognormal distribution, and numerically solved with the software system EASY-FIT by fitting to the observations. This new model coincides with the data to a considerably higher degree of accuracy than the Weibull function alone, particularly during the starting, matrix disintegration, and end phases. In combination with a procedure continuously quantifying the dissolved drug, this mathematical model is suitable for the characterization and optimization of immediate drug release by the choice and modification of excipients and unit operations. The interdependence of some characteristic effects of excipients and production methods is discussed.     

化学药物口服缓控释制剂体内外相关性研究

《口服缓控释制剂药学研究技术指导原则》中多处提到了体内外相关性,文中试图通过对体内外相关性(IVIVC)的定义、创建、评价和应用等方面的介绍,对IVIVC可行性的评估以及IVIVC与生物豁免和释放度质量标准的关系的讨论,帮助研发者理解该指导原则的相关内容。     

口服缓释制剂体内外相关性评价方法研究进展

对近年国内外文献中有关口服缓释制剂体外溶出度测定的试验方法和条件、体内评价的相关方法、体内外相关性研究进行了综述。根据药物的不同性质选择尽可能接近体内环境的试验方法,建立较好的体内外相关性,对口服缓释制剂的研究具有重要意义。     

Thein vitro development of extended-release solid oral dosage forms

A system is described for developing extended-release products, based upon predicting or simulating the entire plasma level-time curve to be expected from the administration of a controlled-release oral dosage form. Termed biorelevant dissolution, it employs the product's in vitrodissolution behavior and the drug's pharmacokinetic parameters in conjunction with a classical pharmacokinetic model. The basic system is described along with some pertinent examples.     

The relative bioavailability of paracetamol following administration of solid and liquid oral preparations and rectal dosage forms

Determination of the Relative Bioavailability of Paracetamol Following Administration of Solid and Liquid Oral Preparations and Rectal Dosage Forms. The relative bioavailability of paracetamol from two solid and two liquid oral preparations and two rectal dosage forms, each containing 500 mg of the active ingredient, was investigated in 12 healthy male individuals. The plasma concentration-time curves of paracetamol following administration of the oral formulations were very similar; consequently there were only minor differences of the AUC0-12h (21.4, 21.9; 23.0, 22.8 micrograms.h/ml), cmax (8.8, 9.1; 10.0, 10.7 micrograms/ml), tmax (35, 25; 20, 19 min), and the terminal plasma elimination half-life t1/2 beta (2.95, 2.85; 2.86, 2.99 h) for the solid and the liquid test and reference preparations, respectively. The suppositories (test and reference formulation) differed from the oral dosage forms, but were comparable to each other with respect to AUC0-12h (18.2, 18.8 micrograms.h/ml), cmax (3.3, 3.5 micrograms/ml), tmax (1.6, 2.45 h), and t1/2 beta (3.55, 3.54 h). In all test preparations the 95% confidence limits for AUC0-12h completely were enclosed in the range of 80-120% relative bioavailability (independently of whether parametric or non-parametric statistical methods were applied); the limits for the oral formulations were quite narrow, thus indicating a highly consistent release of the active compound from the tablets as well as from the liquid dosage form. A comparison of the mean values of cmax by analysis of variance at the 80% probability level did not reveal any significant differences between the test and the corresponding reference formulations; based on non-parametric statistical methods, the 95% confidence limits for cmax were enclosed in the range of 70-130%.(ABSTRACT TRUNCATED AT 250 WORDS)     

The automation of dissolution testing of solid oral dosage forms

Dissolution testing of solid oral dosage forms plays a very important part both in the development of new products and in quality control. A fully automated system for dissolution testing known as AUTO DISS is presented and its components are described. On-line determination of active ingredient concentration is possible with the aid of an integrated automatic sampler in combination with various measuring instruments (UV-vis spectrometry, liquid chromatography and flow injection analysis). The suitability of the system is demonstrated by determination of the dissolution of brotizolam from tablets by FIA and of bepafant from capsules by diode-array spectroscopy.     

The in vitro development of extended-release solid oral dosage forms

A system is described for developing extended-release products, based upon predicting or simulating the entire plasma level-time curve to be expected from the administration of a controlled-release oral dosage form. Termed "biorelevant dissolution," it employs the product's in vitro dissolution behavior and the drug's pharmacokinetic parameters in conjunction with a classical pharmacokinetic model. The basic system is described along with some pertinent examples.     

A comparative bioavailability of 2 oral solid phenytoin dosage forms

The comparative bioavailability of two phenytoin products, Phenytoin Sodium (CAPS (Pvt) Ltd) and Epanutin (Parke-Davis (Pty) Ltd) was studied. Single dose studies carried out in eight healthy volunteers showed that CAPS Phenytoin exhibited a small but significantly higher bioavailability (P less than 0.05). The AUC (0-72 hr) for CAPS Phenytoin was 50.61 microgram/ml/hr compared to 45.09 au/ml/hr for Epanutin. The time to peak concentrations, Tmax, was significantly longer in CAPS Phenytoin when compared to Epanutin being 3.75 hr and 3.25 hr respectively (P less than 0.05) and the peak concentrations Cmax, achieved after single dose administration showed that CAPS Phenytoin exhibited higher levels than Spanutin (1.76 au/ml and 1.58 au/ml respectively) although these differences were not statistically significant. Multiple dose studies carried out in four healthy volunteers and two epileptic patients showed that changes from one product to the other did not produce any significant differences in the steady state phenytoin levels.     

Methods of controlling drug release from solid oral dosage forms

Various possibilities of controlling drug release from solid oral dosage forms are discussed. Disintegration tests are usually not sufficiently representative and for this reason, dissolution rate, release tests under simulated physiological conditions andin-vitro simulated absorption tests will be the control methods of choice. In honour of Professor POLDERMAN on the occasion of his retirement.     

Imaging and behaviour of solid oral dosage forms in vivo

The kinetics of the hydrolysis of methyl, ethyl and n-propyl 4-hydroxybenzoate esters and a subsequent decarboxylation of 4-hydroxybenzoic acid have been studied at pH 1.26–10.59 and the sterilizing temperature of 130.5°C. Enthalpies (ΔH1) and entropies (ΔS1) of activation are reported for k_obs and the derived rate constants. The decarboxylation reaction showed a maximum rate near the mid-pH region where the esters were more susceptible to hydrolysis. The overall pathway for the degradation of the esters was accounted for by a consecutive reaction sequence:

where A represents ester, B, 4-hydroxybenzoic acid and C, phenol. Interference with the spectrophotometric assay by the subsequent oxidation of phenol, made necessary the exhaustive de-oxygenation of solutions for the kinetic runs where phenol was formed. The esters were found to be sufficiently stable to withstand a heat sterilization process within the pH range 3–6. The rate of phenol formation by decarboxylation of the acid was greater in the pH range where the esters are frequently used commercially, as preservatives.