Bioequivalence testing of topical dermatological formulations, the gap between science and legislation
- Authors: Schwarb, Fabian P , Smith, Eric W , Haigh, John M , Surber, Christian
- Date: 1998
- Language: English
- Type: Conference paper
- Identifier: vital:6341 , http://hdl.handle.net/10962/d1006608
- Description: Bioavailability concerns for topical dermatological products are complex and it is especially difficult to determine the bioequivalence of similar topical formulations. Since only small amounts of drug dispersed in an appropriate vehicle are applied to the skin, the amount of drug that actually reaches the systemic circulation is often too small to be easily quantified. Additionally, it can be argued that the relevance of any serum/plasma concentration-time curve of a topical agent is questionable, since the curve reflects the amount of drug after the active moiety has left the site of action. For some topical drugs e.g., topical corticosteroids, it is possible to perform a pharmacodynamic bioassay to obtain acceptable bioequivalence data. In this case, the intensity of the side effect of blanching (vasoconstriction) in the skin caused by topical corticosteroids can be measured. The response is directly proportional to the clinical efficacy, and the skin blanching assay has proved to be a reliable procedure for the determination of topical corticosteroid bioavailability. Recently, we had sight of the results of a topical bioequivalence study, which was conducted for the registration of a new generic corticosteroid cream formulation. In this trial the new formulation was compared to two equivalent product from the local market and bioequivalence was demonstrated by the investigators for all three products. These results were examined with interest as the respective reference products have been used repeatedly as standard formulations in our laboratory. However, one of these reference formulations has consistently shown superior bioavailability in our trials, but was not demonstrated to be superior in the study results examined. In the present publication an overview of topical bioequivalence testing in general is given and the difficulties occurring in practice, for topical corticosteroid formulations in particular, are demonstrated.
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Chromametry: measuring precision of diurnal and local variation of human forearm skin colour
- Authors: Schwarb, Fabian P , Smith, Eric W , Haigh, John M , Surber, Christian
- Date: 1998
- Language: English
- Type: Conference paper
- Identifier: vital:6343 , http://hdl.handle.net/10962/d1006610
- Description: Chromameters are compact portable instruments used for the assessment of surface colour based on the tristimulus analysis of a reflected xenon light pulse, and have been used for the quantification of erythema in the study of irritant dermatitis, and corticosteroid-induced skin blanching in the vasoconstriction assay. The variability and the reproducibility of chromameter results were investigated since it is known that the location and application force of the measuring head on the skin and the orthostatic maneuver of the arms influence the colour measurement. Furthermore the diurnal variation and the homogeneity of forearm skin colour were investigated.
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Comparison of visual CR-200 and CR-300 chromameter data obtained from the corticosteroid-induced skin-blanching assay
- Authors: Schwarb, Fabian P , Smith, Eric W , Haigh, John M , Surber, Christian
- Date: 1998
- Language: English
- Type: Conference paper , text
- Identifier: vital:6344 , http://hdl.handle.net/10962/d1006611
- Description: In a recent Guidance document the American FDA recommended the use of a chromameterrather thanthe human eye for the assessment of the pharmacodynamic blanching response produced after topical application of corticosteroids. The purpose of this study was to investigate the appropriateness of the human eye and two types of chromameter for the estimation of skin blanching.
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Precision of tristimulus chromameter results from corticosteroid-induced skin blanching
- Authors: Smith, Eric W , Haigh, John M
- Date: 1998
- Language: English
- Type: Conference paper
- Identifier: vital:6342 , http://hdl.handle.net/10962/d1006609
- Description: The human skin blanching (vasoconstriction) assay has been in use for 3 decades as a tool for the assessment of the release of corticosteroids from topical dosage forms. Application of corticosteroids produces a whitening (blanching) of the skin, the intensity of which is directly related to the clinical efficacyof the formulation. Assessment of the intensity of the induced blanching has classically been, and continues to be, pe1fonned by visual grading, a method which has been criticised because of the subjectivenature of the assessment Recently there has been considerablediscussion in the literature regarding the use of the chromameter as an objective instrumental method of monitoring corticosteroid induced skin blanching for bioequivalence assessment purposes. The FDA has released a Guidance document recommending the use of the chromameter for this purpose. The chromameter measures colour in teims of three indices: the L-scale (light-dark), the a-scale (red-green) and the b-scale (yellow-blue).Any colour can be expressedabsolutelyin terms of these three values.The Guidance protocol suggests the use of only the a-scale values in quantifying the blanching response after correction of the data which includes subtraction of baseline and unmedicated site values. One of the unresolved issues in the FDA Guidance document is this method of data manipulation suggested since the instrument should be capable of assigning an absolute colour value to each site during the vasoconstriction period. The purpose of this study was to manipulate the instrumental data from a typical blanching study in a number of ways to investigate the appropriatenessof these suggested procedures.
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The use of supersaturated solutions for the percutaneous delivery of rooperol tetra-acetate
- Authors: Pefile, S C , Haigh, John M , Smith, Eric W
- Date: 1998
- Language: English
- Type: Conference paper , text
- Identifier: vital:6340 , http://hdl.handle.net/10962/d1006537
- Description: A major problem encountered in the transdermal delivery of drugs is the effectiveness of the barrier system imposed by the stratum corneum.To overcome tbe resistance of the skin to the ingress of exogenous chemicals, numerous innovative techniques requiring complex delivery systems have been studied. Many of these systems attempt to alter the barrier potential by the use of enhancer technology. Supersaturation, on the other hand, is a simple and economical technique which is not intended to modify the physical structure or the chemical composition of the stratum corneum, yet may effectively deliver a markedly greater mass of drug to the skin than that achieved by the use of conventional, saturated solutions. Supersaturated systems make use of the elevated thermodynamic activity of the permeant in the delivery vehicle, which results in higher flux rates across the contacting membrane by increasing the concentration gradient. The present study investigated the potential for using supersaturation techniques to transdermally deliver rooperol tetra-acetate (RTA), a lipophilic, cytotoxic agent with potential for use in the treatment of solar keratosis. The diffusion characteristics of the drug from a 60% propylene glycol/water supersaturated solution across silicone membrane and full thickness rat skin were studied using Franz diffusion cells. A comparison was made of the drug diffusion rates from a saturated system and from supersaturated systems prepared with and without an antinucleating agent.
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