The comparative bioavailability and in vitro assessment of solid oral dosage forms of paracetamol
- Authors: Braae, Karen
- Date: 1981 , 2013-04-02
- Subjects: Acetaminophen , Bioavailability , Drugs -- Bioavailability , Drugs -- Dosage forms , Analysis of variance
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3827 , http://hdl.handle.net/10962/d1006288 , Acetaminophen , Bioavailability , Drugs -- Bioavailability , Drugs -- Dosage forms , Analysis of variance
- Description: The dissolution profiles of eight lots of paracetamol tablets representing seven different tablet brands are determined in a USP rotating basket assembly and a stationary basket-rotating paddle apparatus. The in vitro data are expressed in terms of dissolution parameters and inter-tablet differences are assessed statistically using analysis of variance (ANOVA) and the Scheffe test. Highly significant differences are observed between a number of the tablets at the 95% confidence level. Representative tablets from the dissolution rate study and a control dose of paracetamol dissolved in water are subsequently investigated in a 4 x 4 latin square design bioavailability trial. Serum and urine samples are collected and assayed for paracetamol alone (serum) and together with its metabolites (urine) by means of high pressure liquid chromatography. The in vivo data are expressed in terms of bioavailability parameters and differences between the test doses are assessed by means of ANOVA. No significant differences are observed between the dosage forms at the 95% confidence level.
- Full Text:
- Date Issued: 1981
In vitro passage of ibuprofen through synthetic and biological membranes
- Authors: Purdon, Carryn Hamilton
- Date: 2001
- Subjects: Ibuprofen , Diffusion processes
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3786 , http://hdl.handle.net/10962/d1003264 , Ibuprofen , Diffusion processes
- Description: Ibuprofen is a non-steroidal anti-inflammatory drug with three major types of effect: anti-inflammatory, analgesic and antipyretic. Ibuprofen may be administered in a number of different forms via the oral as well as the topical route. Published evidence suggests that topical, unlike oral, non-steroidal anti-inflammatory drugs are associated with few systemic side effects as plasma concentrations are low compared to oral therapy. In some countries it is particularly difficult to obtain human skin for in vitro experimentation and it is therefore important to have alternate biological or synthetic membranes which mimic human skin for diffusion experiments. Synthetic membranes serve as predictive models for topical drug release and in South Africa, shed snake skin is easily obtainable from the many snake parks present in the country. The FDA guidelines were considered when choosing the apparatus to be used in the comparative diffusion study on proprietary ibuprofen-containing topical preparations from three countries and the verification of the usefulness, or otherwise, of shed snake skin as a biological membrane for the assessment of the permeation of ibuprofen. Two diffusion techniques were considered appropriate for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing. One was the Franz diffusion cell, as modified by Keshary and Chien (88,169) and the other was the European Pharmacopoeia diffusion cell (187). High performance liquid chromatography was used as the analytical technique for the analysis of ibuprofen in aqueous solution using ultraviolet detection at 222 nm. The validated method was applied to the determination of the diffusion of ibuprofen from topical ibuprofen-containing formulations (gels, creams and mousse) through synthetic silicone membrane and shed snake skin biological membrane from four different species. In a study of fifteen topical ibuprofen-containing formulations (gels, creams and mousse) from three countries (South Africa, United Kingdom and France) it was found that there was a trend of products from two countries consistently exhibiting superior diffusion characteristics as well as products from the same two countries consistently exhibiting the lowest diffusion of ibuprofen. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses and peak integration values when drawing conclusions regarding comparative diffusion characteristics. Shed snake skin has been described as a 'model' membrane, i.e. a membrane which shows similar permeability to human stratum corneum. The results reported here show clearly that, for ibuprofen, the four species of snake produce shed skin with completely different diffusion characteristics when all other conditions are identical. It may well be that there is one particular species of snake which produces shed skin of identical permeability to human stratum corneum, but to describe shed snake skin in general as a model membrane seems incorrect. It is therefore important that if shed snake skin is used as a membrane, the species, skin site and orientation should be reported. The European Pharmacopoeia diffusion apparatus was judged to be the better of the two diffusion techniques assessed for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing using silicone membranes and for the measurement of the amount of ibuprofen diffusing across the ventral outside orientation of shed skin during in vitro testing, whereas the Franz diffusion apparatus was judged to be better for the measurement of the amount of ibuprofen diffusing across the dorsal outside orientation of shed skin during in vitro testing. However, the choice of this diffusion apparatus must be weighed against the relatively poor reproducibility as compared with the European Pharmacopoeia diffusion apparatus.
- Full Text:
- Date Issued: 2001
Development of a high pressure liquid chromatographic method for the simultaneous analysis of sulphamethoxazole and trimethoprim and its application to biological fluids and dissolution rate studies on solid oral dosage forms
- Authors: Gochin, Rosa
- Date: 1980
- Subjects: High performance liquid chromatography , Body fluids -- Analysis , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3735 , http://hdl.handle.net/10962/d1001524
- Description: Co-trimoxazole, a combination of a 5-to-l ratio of Sulphamethoxazole (SMZ) and Trimethoprim (TMP) , is a highly effective, broad-spectrum antibacterial agent. Since its introduction in 1968, it has been extensively used in infections of the respiratory and urinary tracts. Co-trimoxazole was developed by the systematic investigation of a series of compounds whose mechanism of action was already known. As early as 1950 synergy between sulphonamides and 2,4-diaminopyrimidines was reported. This was to be expected as both groups of drugs exert their antibacterial activity by interfering with the same biochemical pathway in bacteria. TMP was chosen from among many 2,4-diaminopyrimidines tested because of its good antibacterial activity and low toxicity. SMZ was chosen from the sulphonamides available for combination with TMP because of similarity of their biological half-lives. The widespread use of the combination coupled with the fact that monitoring of the levels of all drugs in the body is becoming increasingly important has stimulated research into rapid and efficient methods for the analysis of TMP and SMZ in biological fluids. Another consequence of the immense popularity of the combination is the appearance on the market of several generic preparations of Co-trimoxazole. It is now generally recognized that drug products from different manufacturers which are chemically equivalent may not be therapeutically equivalent. This is due to the fact that the absorption rate and/or bioavailability (extent of absorption) of a poorly soluble drug may be markedly affected by its release rate from the product and by its subsequent dissolution rate in gastrointestinal fluids. Hence bioequivalence of these various products should be established
- Full Text:
- Date Issued: 1980
Comparative bioavailability and ranking of topical corticosteroid formulations
- Authors: Meyer, Eric
- Date: 1985
- Subjects: Adrenocortical hormones -- Therapeutic use Drugs -- Bioavailability Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3732 , http://hdl.handle.net/10962/d1001471
- Description: Numerous experiments in recent years have indicated differences in the bioavailability of corticosteroids from seemingly identical topical dosage forms. The human blanching assay was utilized in this study to assess the comparative blanching activities of various locally manufactured proprietary corticosteroid preparations. The first experiment was performed to assess the relative blanching activities of six semi - solid preparations containing the same concentration of betamethasone 17-valerate. The preparations used were Betnovate cream and ointment, Persivate cream and ointment and Celestoderm-V cream and ointment. This was followed, in the second experiment, by the investigation of the blanching activities of two lotions containing betamethasone 17-valerate (Betnovate and Celestoderm-V) and a lotion containing betamethasone 17,21- dipropionate (Diprosone). The third experiment involved a study of six semi-solid proprietary corticosteroid-containing formulations, viz. Dermovate (clobetasol propionate) cream and ointment, Betnovate (betamethasone 17-valerate) cream and ointment and Eumovate (clobetasone butyrate) cream and ointment. This investigation was prompted by claims in advertisements in the medical media that Dermovate is therapeutically more efficacious than Betnovate which is more efficacious than Eumovate. The penultimate experiment in this study served the purpose of finding a corticosteroid-containing preparation that falls into the moderately potent group of corticosteroid formulations, as described in the United Kingdom MIMS. This preparation was used in the final experiment which was undertaken to ascertain the potency category of Florone (diflorasone diacetate) cream and ointment.
- Full Text:
- Date Issued: 1985
Biopharmaceutics of phenylpropanolamine
- Authors: Dowse, Roslind
- Date: 1984
- Subjects: Biopharmaceutics Pharmacokinetics Phenylpropanolamine Pharmacology High performance liquid chromatography
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3818 , http://hdl.handle.net/10962/d1004915
- Description: Phenylpropanolamine (PPA), a sympathomimetic amine, has been widely used over the past 40 years as a decongestant and, in much larger dosages, as an appetite suppressant. Considerable interest has recently been shown in this drug due to its increasing popularity as an over-the-counter anorectic agent. Much controversy exists concerning the unfavourable side-effects of PPA resulting from the higher doses required for appetite suppression and the potential of this drug for abuse. A literature search revealed a paucity of information concerning the determination of PPA in biological fluids and, most noticeably, on the pharmacokinetics of this drug. An original method for determining PPA in serum and urine using high performance liquid chromatography (HPLC) which has increased sensitivity over other published HPLC methods is presented here. The simplicity of the extraction from biological fluids and subsequent determination by HPLC, enables concentrations of PPA to be monitored after a single dose of the drug. This method is therefore readily applicable to bioavailability and pharmacokinetic studies. The dissolution profiles of 4 sustained-release formulations of PPA were determined in a modified USP rotating paddle apparatus and the samples analysed using HPLC. A mathematical equation was applied to these data which are expressed in terms of dissolution parameters. Oral test dosage forms and solutions of PPA were investigated in bioavailability trials using the developed HPLC method to analyse the urine and serum samples. Linear one body compartment kinetics were assumed and the WagnerNelson method used to transform in vivo serum data to absorption plots which were then fitted to the well known Weibull equation. In order to more appropriately characterize the kinetic processes of absorption, distribution and elimination, a more complex model was utilized which involved numerical integration of a series of differential equations. The data were fitted to these models using nonlinear regression techniques. The pharmacokinetics of PPA are shown to exhibit some evidence of nonlinearity. The absorption of the drug appears to be di scontinuous and PPA seems to favour a two body compartment model.
- Full Text:
- Date Issued: 1984
Aspects of the transdermal permeation and analysis of betamethasone 17-valerate
- Authors: Smith, Eric W
- Date: 1988
- Subjects: Transdermal medication Skin absorption Dermatologic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3815 , http://hdl.handle.net/10962/d1004741
- Description: The current world-wide interest in transdermal drug delivery makes the prospect of valid in vitro diffusion cell methodology highly attractive. A new laboratory diffusion cell has been designed and constructed based on theoretical principles and practical permeation reports surveyed in recent literature, and has been applied to the monitoring of betamethasone 17-valerate permeation. The cell performance has been validated with respect to hydrodynamic mixing efficiency and temperature of the receptor phase. The steady-state permeation of this corticosteroid has been monitored through various synthetic and animal membranes in order to select the most appropriate media for in vitro study. The permeation of betamethasone 17-valerate has been monitored from various types of commercial and extemporaneously prepared semisolid topical formulation (cream, lotion, ointment and scalp application), through silicone membrane, human and weanling pig stratum corneum, and full thickness hairless mouse skin, and these in vitro results have been compared to data from in vivo blanching assays, using the same formulations, in an attempt to correlate the findings. This experimental methodology has necessitated the development of ancillary analytical techniques. A column-switching high-performance liquid chromatographic method has been developed for the rapid on-line clean-up and analysis of betamethasone 17-valerate contained in the various topical formulations, which minimizes sample handling and extraction procedures. The method has been modified for the analysis of this corticosteroid in the isopropyl myristate receptor phase used in the in vitro permeation experiments, and scintillation counting of tritium-labelled water has been used to verify the integrity of the animal membranes. The comparison of in vitro permeation and in vivo blanching results indicate good correlation of the data in certain instances. The closest correlations have been observed when the human stratum corneum has been used in vitro and these results are compared to data from the occluded mode of the blanching assay. The results of the porcine and murine media have also correlated with the human in vivo data, whereas the silicone membrane appears applicable only in certain in vitro experiments. The results indicate that valid, comparative percutaneous absorption data may be obtained in vitro by using a well designed, validated diffusion cell system.
- Full Text:
- Date Issued: 1988
A critical evaluation of the human skin blanching assay and comparative bioavailability studies on topical corticosteroid preparations
- Authors: Meyer, Eric
- Date: 1989
- Subjects: Dermatopharmacology Skin, Effect of drugs on Adrenocortical hormones
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3727 , http://hdl.handle.net/10962/d1001464
- Description: Several aspects of the human skin blanching assay were evaluated in an attempt to suggest improvements in the methodology of this assay. Three trials were performed in the unoccluded application mode, using two proprietary creams containing 0,1% betamethasone (as the 17-valerate). Preliminary observations of the influence of ambient temperature and relative humidity on the blanching response did not allow definite conclusions to be drawn. Studies on the number of observers required for reliable results of comparative blanching indicated that at least two trained observers should be employed. Analyses of the results of individual volunteers demonstrated the expected biological variability, and suggest that subjects selected for trials should represent a range of blanching responses. No sex-related differences in blanching responses were found, and both arms exhibited similar sensitivity to corticosteroids. Retrospective analysis of 95 040 observations of blanching responses showed that in the unoccluded application mode blanching is lowest close to the wrist, and in the occluded mode blanching is lowest close to the elbow. Studies on the method of transportation of Betnovate preparations suggest that topical formulations should not be exposed to temperature extremes during transportation. It is proposed that patients should not transport topical formulations in the holds of ships or aircraft, and that exporters and manufacturers should make use of special transportation and storage conditions. In a study of ten topical formulations from three countries it was found that there was no trend of products from one country consistently exhibiting superior blanching to products from the other two countries, or products from one country consistently exhibiting the lowest degree of blanching, although considerable differences in blanching responses were found in some cases. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses, blanching profiles and AUC values when drawing conclusions regarding comparative bioavailability. A study of the blanching profiles of Betnovate cream included in all 16 trials performed during this work indicated that this preparation behaved in a similar fashion during all trials, thereby giving credence to the results of the trials
- Full Text:
- Date Issued: 1989