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The use of supersaturated solutions for the percutaneous delivery of rooperol tetra-acetate

- Pefile, S C, Haigh, John M, Smith, Eric W

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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Date Issued: 1998

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The registration of generic topical corticosteroid formulations in South Africa: a report

- Haigh, John M, Smith, Eric W

Authors: Haigh, John M , Smith, Eric W
Date: 2002
Language: English
Type: Article
Identifier: vital:6368 , http://hdl.handle.net/10962/d1006068
Description: [From the text]Topical corticosteroid formulations are used widely for a variety of skin conditions such as psoriasis and eczema. The most commonly used formulation types are cream, ointment, lotion and scalp application, with some mousse formulations being released recently onto the market for scalp application. The type of formulation used depends on the condition being treated. Dry lesions are normally treated with ointments and wet lesions with creams. Cosmetically, cream formulations are more acceptable as they can be rubbed in, thus leaving no residual oiliness. Scalp applications have to be less viscous to allow the formulation to pass through the hair and contact the scalp. Occlusion with plastic wrapping hydrates the stratum corneum and facilitates the passage of the corticosteroid through this barrier to the basal layer where the therapeutic effect is required.
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Date Issued: 2002

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The human skin-blanching assay for in vitro topical corticosteroid assessment. I. Reproducibility of the assay

- Haigh, John M, Meyer, Eric, Smith, Eric W, Kanfer, Isadore

Authors: Haigh, John M , Meyer, Eric , Smith, Eric W , Kanfer, Isadore
Date: 1997
Language: English
Type: text , Article
Identifier: vital:6381 , http://hdl.handle.net/10962/d1006299
Description: The human skin blanching (vasoconstriction) assay for the assessment of topical corticosteroids has been in use for over 30 years, the intensity of the drug-induced blanching being assessed subjectively by eye. Both arms of several male and female volunteers are used for product application and more than one observer is used to estimate the degree of induced blanching. There are, therefore, numerous variables which are inherent in the assay procedure. This investigation consisted of three identical trials performed at 8-week intervals, utilising the same 18 volunteers and the same three observers in an attempt to address the question of reproducibility of the assay. From the results obtained it is clear that the assay methodology is capable of consistently distinguishing, on a rank order basis, between preparations which show similar blanching (chemically-equivalent formulations). The similarity of the results for the three individual trials gives considerable confidence to results produced using this methodology. An experiment designed to test the reproducibility of the blanching scores showed that the observers are capable of producing identical results even though visual observation is highly subjective.
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Date Issued: 1997

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The human skin-blanching assay for comparing topical corticosteroid availability

- Smith, Eric W, Meyer, Eric, Haigh, John M, Maibach, Harold I

Authors: Smith, Eric W , Meyer, Eric , Haigh, John M , Maibach, Harold I
Date: 1991
Language: English
Type: Article
Identifier: vital:6433 , http://hdl.handle.net/10962/d1006604
Description: The human skin blanching assay remains in widespread use as a reliable, qualitative, comparative indicator of topical corticosteroid availability and potency. The experimental refinements promulgated by certain researchers in this field have yielded a versatile bioassay for the accurate assessment of new drugs or delivery vehicles. With the increasing appearance of generic topical corticosteroid formulations which compete with trade-name equivalents, the vital importance of this assay in regulatory affairs and assessing bioequivalence has been re-emphasized. It is stressed that if the blanching assay is to be used in this sphere, then multiple-reading trials must be conducted; important registration or clinical decisions cannot be made with any validity from short-term assessments.
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Date Issued: 1991

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The human skin-blanching assay as an indicator of topical corticosteroid bioavailability and potency: an update

- Smith, Eric W, Meyer, Eric, Haigh, John M, Maibach, Harold I

Authors: Smith, Eric W , Meyer, Eric , Haigh, John M , Maibach, Harold I
Date: 1989
Language: English
Type: Book chapter
Identifier: vital:6440 , http://hdl.handle.net/10962/d1006627 , ISBN 0824780361
Description: The human skin-blanching (or vasoconstrictor) assay has evolved from initial observations that corticosteroids induce a pallor or whitening of the skin to which they are applied. McKenzie and Stoughton (1962) are generally recognized as having developed the first scientific bioassay for comparing corticosteroid potency. The extensive use of this bioassay to compare drug release from topical delivery systems has demonstrated numerous instances in which the topical bioavailability may vary greatly, dependent on the character of the delivery vehicle. It has become evident that simply incorporating an intrinsically potent drug into a formulation does not necessarily produce a clinically efficacious product.
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Date Issued: 1989

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The human skin blanching assay for in vivo topical corticosteroid assessment. II. Subject- and observer-dependent variation in blanching responses

- Haigh, John M, Meyer, Eric, Smith, Eric W, Kanfer, Isadore

Authors: Haigh, John M , Meyer, Eric , Smith, Eric W , Kanfer, Isadore
Date: 1997
Language: English
Type: text , Article
Identifier: vital:6382 , http://hdl.handle.net/10962/d1006300
Description: The human skin blanching (vasoconstriction) assay for the assessment of topical corticosteroids has been in use for over 30 years, the intensity of the drug-induced blanching being assessed subjectively by eye. Both arms of several male and female volunteers are used for product application and more than one observer is used to estimate the degree of induced blanching. There are, therefore, numerous variables which are inherent in the assay procedure. This investigation consisted of three identical trials performed at 8-week intervals, utilising the same 18 volunteers and the same three observers in an attempt to address the question of reproducibility of the assay. From the results obtained it is clear that the assay methodology is capable of consistently distinguishing, on a rank order basis, between preparations which show similar blanching (chemically-equivalent formulations). The similarity of the results for the three individual trials gives considerable confidence to results produced using this methodology. An experiment designed to test the reproducibility of the blanching scores showed that the observers are capable of producing identical results even though visual observation is highly subjective.
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Date Issued: 1997

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The effects of elevated and ambient temperature conditions on dilutions of fluocinolone acetonide ointment assessed using the human skin-blanching assay

- Haigh, John M, Smith, Eric W

Authors: Haigh, John M , Smith, Eric W
Date: 1995
Language: English
Type: text , Article
Identifier: vital:6380 , http://hdl.handle.net/10962/d1006298
Description: Topical corticosteroid formulations have been in use now for some 30 years and many methods are available for the in vivo assessment of these preparations. Of all the assays described in the literature, the one first advocated by McKenzie and Stoughton, the so-called vasoconstrictor assay, is one of the most reliable if performed by experienced researchers using - the optimised methodology. Topical application of corticosteroids produces a whitening (blanching) of the skin, the intensity of which is directly proportional to the clinical efficacy of the formulation. Assessment of the degree of blanching produced is therefore of use in determining the rate and extent of corticosteroid release' from the semi-solid base through the stratum corneum. Since it is the degree of blanching which is measured, we prefer to call this test the human skin blanching assay. Some of the main advantages of this assay technique are that normal healthy skin is used therefore persons with dermatological complaints are not compromised, it is not painful for the volunteers, it is non-invasive and several formulations can be evaluated simultaneously. Most commercially available topical corticosteroid preparations have been formulated in such a way as to provide optimum release of the active ingredient from the base through the stratum corneum. Despite this fact, many practitioners often prescribe dilutions of topical corticosteroid formulations, presumably in an effort to reduce the unwanted side effects. This could be problematic; dilution with an incompatible base could destroy the delivery environment thus considerably reducing the efficacy of the formulation. The method of dilution could also play a role in the suitability of the final preparation. The objective of this work was to determine the effects of two different dilutions of fluocinolone ointment at both ambient and elevated temperature on the blanching produced by the dilutions and, by inference, the relative clinical efficacies of these dilutions compared to the full strength product.
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Date Issued: 1995

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Sensitivity of different areas of the flexor aspect of the human forearm to corticosteroid-induced skin blanching

- Meyer, Eric, Smith, Eric W, Haigh, John M

Authors: Meyer, Eric , Smith, Eric W , Haigh, John M
Date: 1992
Language: English
Type: Article
Identifier: vital:6394 , http://hdl.handle.net/10962/d1006317
Description: The intensity of corticosteroid-induced blanching has been found to vary at different areas of the flexor aspect of the human forearm. A retrospective analysis of 38,880 observations of skin blanching in 56 volunteers was conducted to assess the sensitivity of forearm skin to betamethasone 17-valerate. The mid-forearm appears to be more sensitive to the blanching response than do the areas close to the wrist or elbow. These results indicate that each preparation under evaluation should be applied to several sites along the forearm when using the human skin blanching assay in order to obtain an accurate comparative assessment of corticosteroid release from topical delivery vehicles.
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Date Issued: 1992

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Role of percutaneous penetration enhancers

- Walker, Roderick B, Smith, Eric W

Authors: Walker, Roderick B , Smith, Eric W
Date: 1996
Language: English
Type: text , Article
Identifier: vital:6446 , http://hdl.handle.net/10962/d1006633
Description: It is clear that scientists are now only beginning to comprehend the complexity of transdermal drug delivery. Elucidation of the biochemical composition and functioning of the intrinsic diffusional barrier of the stratum corneum has prompted investigation of chemical and physical means of enhancing the percutaneous penetration of poorly absorbed drugs. Chemical enhancers that aid absorption of co-administered moieties are currently believed to improve solubility within the stratum corneum or increase lipid fluidity of the intracellular bilayers. Alternatively,the use of ionto- or phonophoresis may facilitate the absorption of some drug molecules by physical alteration of the barrier. The role of penetration enhancer inclusion in topical formulations has been well documented and will undoubtedly, in the future, permit the delivery of broader classes of drugs through the stratum corneum.
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Date Issued: 1996

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Reply to correspondence: P.M. Gaylarde (1986) The human skin blanching assay—use and abuse

- Haigh, John M, Kanfer, Isadore, Meyer, Eric, Smith, Eric W

Authors: Haigh, John M , Kanfer, Isadore , Meyer, Eric , Smith, Eric W
Date: 1986
Language: English
Type: Article
Identifier: vital:6376 , http://hdl.handle.net/10962/d1006293
Description: Finally, we would like to assure Dr Gaylarde that we do not advocate the use of the human skin blanching assay. There are several other in vivo methods for determining corticosteroid activity which will provide equally meaningful results. What we are advocating is that if the human skin blanching assay is going to be used, then it should be used properly.
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Date Issued: 1986

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Relative potencies of topical corticosteroid formulations

- Haigh, John M, Kanfer, Isadore, Meyer, Eric, Smith, Eric W

Authors: Haigh, John M , Kanfer, Isadore , Meyer, Eric , Smith, Eric W
Date: 1985
Language: English
Type: Article
Identifier: vital:6375 , http://hdl.handle.net/10962/d1006291
Description: It seems to us, and others (Burdick, 1974), that multiple reading times are essential to produce the response-time profile. Comparisons of potencies of topical corticosteroid formulations should only be made on the basis of area under the curve measurements and statistical treatment of all values obtained at each reading time throughout the course of the experiment.
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Date Issued: 1985

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Ranking of topical corticosteroids: principles and results

- Smith, Eric W, Haigh, John M

Authors: Smith, Eric W , Haigh, John M
Date: 1993
Language: English
Type: text , Article
Identifier: vital:6434 , http://hdl.handle.net/10962/d1006607
Description: The increasing synthesis and use of topical corticosteroid products over the past 30 years has necessitated the development of suitable methods for evaluating the efficacy and potency of new drug entities. Several in vivo models have been developed in this regard using laboratory animals and human subjects. Generally, these tests measure the difference in the non-immunological inflammatory response to an exogenous inflammatory mediator in the presence and absence of the corticosteroid under test. There are also immunologically based assays and several tests which assess the anti proliferative effects of the drug. Several comparative disease model evaluations have also been developed using human subjects. Most of these assays are non-ideal from one point of view or another: most are invasive methods which require some form of trauma to be induced in the skin and therefore problematic to perform and monitor.
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Date Issued: 1993

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Quantification of corticosteroid-induced skin vasoconstriction: visual ranking, chromameter measurement or digital image analysis

- Smith, Eric W, Haigh, John M, Surber, Christian

Authors: Smith, Eric W , Haigh, John M , Surber, Christian
Date: 2002
Language: English
Type: text , Article
Identifier: vital:6427 , http://hdl.handle.net/10962/d1006564
Description: Topical corticosteroid formulations have been evaluated by visual grading protocols for many years. Toward a more objective methodology, several instrumental methods have been evaluated for applicability in quantifying the vasoconstriction side-effect that follows corticosteroid application to the skin. Although the chromameter has been adopted by regulatory bodies throughout the world as the current standard for topical bioequivalence determinations, there is considerable criticism of this instrument from several quarters. A preliminary comparison reported here indicates that digital image analysis provides statistically significant results that are similar to those obtained by visual assessment techniques, and shows considerably greater precision than that obtained by the chromameter. Continued evaluation of objective assessment techniques, such as digital imaging, and continued modernisation of regulatory bioequivalence requirements will assist in protecting patients and optimising clinical results.
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Date Issued: 2002

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Precision of tristimulus chromameter results from corticosteroid-induced skin blanching

- Smith, Eric W, Haigh, John M

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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Date Issued: 1998

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Potency ranking of two new topical corticosteroid creams containing 0.1% desonide or 0.05% halometasone utilizing the human skin-blanching assay

- Meyer, Eric, Smith, Eric W, Haigh, John M, Kanfer, Isadore

Authors: Meyer, Eric , Smith, Eric W , Haigh, John M , Kanfer, Isadore
Date: 1988
Language: English
Type: Article
Identifier: vital:6400 , http://hdl.handle.net/10962/d1006327
Description: The human blanching assay was used to assess the potency of two new proprietary corticosteroid creams. The blanching abilities of 0.1% desonide cream and 0.05% halometasone cream were evaluated relative to the blanching elicited by 0.05% clobetasol 17-propionate cream, 0.1% betamethasone 17-valerate cream and 0.05% clobetasone 17-butyrate cream. The results of the trial indicated that the 0.1% desonide cream falls into the potent group of topical corticosteroid preparations and the 0.05% halomethasone cream falls into the moderately potent group.
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Date Issued: 1988

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New developments in the methodology available for the assessment of topical corticosteroid-induced skin blanching

- Haigh, John M, Smith, Eric W, Maibach, Howard I

Authors: Haigh, John M , Smith, Eric W , Maibach, Howard I
Date: 1998
Language: English
Type: text , Article
Identifier: vital:6384 , http://hdl.handle.net/10962/d1006305
Description: Since the publication of the previous edition of this book there have been considerable developments and controversy in the field of topical corticosteroid bioequivalence assessment. There has been considerable discussion in the literature concerning the use of the Minolta chromameter for the measurement of corticosteroid-induced skin blanching, as it is believed this instrument would produce more objective results than the visual grading procedure. These efforts culminated in the release of a guidance document from the Food and Drug Administration (FDA) detailing the procedures to be followed for the determination of topical corticosteroid bioequivalence using the chromameter. Since the promulgation of this document there have been challenges on the validity and scientific merit of the documented procedures, and recently the FDA itself conceded that it may be necessary to redefine some of the protocol evaluations. This chapter attempts to redefine the current standing of the two methods of response assessment.
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Date Issued: 1998

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In vivo/in vitro assessments of topical hydrocortisone availability: correlation between blanching assay and laboratory cell experiments

- Smith, Eric W, Haigh, John M

Authors: Smith, Eric W , Haigh, John M
Date: 1995
Language: English
Type: Book chapter
Identifier: vital:6438 , http://hdl.handle.net/10962/d1006624
Description: From introduction: Topical corticosteroids are still the most widely used drugs in the treatment of dermatological conditions. Early corticosteroid dosage forms consisted of simple creams or ointments where more emphasis was placed on the potency of the drug molecule than on the intrinsic delivery potential of the vehicle. More recently, the effect that the composition of the semisolid base has on the extent of drug delivery has been researched to a much greater extent. These advances in the science of dosage form design have necessitated the refinement of precise and accurate methods for testing the drug delivery efficacies of the developed products. Obviously, the best method for the assessment of the effectiveness of corticosteroid formulations is in a therapeutic situation. Clinical trials, however, are fraught with methodological problems that make duplication of a trial impossible. Alternatively, a number of pharmacological models4 exist for this type of assessment, but it is often problematic to obtain correlation with the true dermatological conditions. The human skin blanching assay is one of the most reliable and reproducible of the ill vivo methods available for the assessment of topical corticosteroid formulations. The skin whitening (blanching or vasoconstriction) side-effect that follows corticosteroid application was first utilized in 1962 as a measure of the percutaneous absorption of corticosteroids from topical formulations. Optimization of this initial procedure7.s has produced a reliable and precise bioassay methodology for the assessment of the efficacy of topical corticosteroid formulations. One criticism of this assay has been the subjective nature of the observation procedure. Although these points have repeatedly been addressed in the literature, it has been suggested that it would be beneficial to have some ill vitro penetration data to supplement ill vivo observations, as this would strengthen the assessment of the topical equivalence of similar delivery formulations. With this objective in mind, a comparison of hydrocortisone release from two proprietary cream formulations was compared by in vivo and ill vitro techniques to determine if any correlation could be established between the methodologies.
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Date Issued: 1995

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