Foam drug delivery in dermatology: beyond the scalp
- Authors: Purdon, Carryn H , Haigh, John M , Surber, Christian , Smith, Eric W
- Date: 2003
- Subjects: Adis International Limited , Drug delivery systems , Skin disorders
- Language: English
- Type: text , Article
- Identifier: vital:6418 , http://hdl.handle.net/10962/d1006541
- Description: Consumers of topical formulations apply a wide spectrum of preparations, both cosmetic and dermatological, to their healthy or diseased skin. These formulations range in physicochemical nature from solid through semisolid to liquid. Pharmaceutical foams are pressurized dosage forms containing one or more active ingredients that, upon valve actuation, emit a fine dispersion of liquid and/or solid materials in a gaseous medium. Foam formulations are generally easier to apply, are less dense, and spread more easily than other topical dosage forms. Foams may be formulated in various ways to provide emollient or drying functions to the skin, depending on the formulation constituents. Therefore, this delivery technology should be a useful addition to the spectrum of formulations available for topical use; however, as yet, only a few are commercially available. Probably the most convincing argument for the use of foams is ease of use by the patient, and consumer acceptance. Most foam dosage forms used in dermatology to date have incorporated corticosteroids, although some products have also been used to deliver antiseptics, antifungal agents, anti-inflammatory agents, local anesthetic agents, skin emollients, and protectants. Although there is no clinical evidence that foam formulations are currently superior to other conventional delivery vehicles, these formulations have a clear application advantage and with continued developments in the science of supersaturation technology, it seems certain that foam delivery systems will retain their place in the dermatological and cosmetic armamentarium.
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Quantification of corticosteroid-induced skin vasoconstriction: visual ranking, chromameter measurement or digital image analysis
- 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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The registration of generic topical corticosteroid formulations in South Africa: a report
- 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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Analysis of chromameter results obtained from corticosteroid-induced skin blanching assay: comparison of visual and chromameter data
- Authors: Schwarb, Fabian P , Smith, Eric W , Haigh, John M , Surber, Christian
- Date: 1999
- Language: English
- Type: text , Article
- Identifier: vital:6426 , http://hdl.handle.net/10962/d1006562
- Description: In a Guidance document, the American FDA recommends the use of a Minolta chromameter rather than the human eye for the quantitative assessment of the pharmacodynamic blanching response produced by topical application of corticosteroids. The purpose of this study was to compare the appropriateness of the human eye and two models of chromameter for the estimation of skin blanching, in terms of the quality of the data generated by each method. The corticosteroid-induced skin blanching from four different betamethasone 17-valerate cream formulations was compared in a typical human skin blanching trial. The optimized assay methodology routinely practised in our laboratories was utilized. The blanching responses were assessed visually by three trained, independent observers and recorded by two chromameters (Minolta model CR-200 and model CR-300). The topical availability of the four creams was determined using visual scoring and chromameter measurements. All data were manipulated in such a manner as to produce a blanching response versus time profile from which AUBC analysis could be performed. Good correlation was observed between the visual assessments made by three independent observers. In contrast, moderate correlation was determined between visual, CR-200 and CR-300 measurements. Surprisingly, no direct linear relationship between the AUBCs produced by the two chromameters was observed indicating that the quality of the data obtained from the two instruments may not be equal. This investigation also indicated that the use of the chromameter is not completely objective. Visual scoring and chromameter measurement produce data sets that differ in quality. Each procedure needs to be validated and investigators have to be trained for both visual assessment and the operation of the chromameter, particularly with regard to the manipulation of the measuring head of the instrument.
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Effect of concentration and degree of saturation of topical fluocinonide formulations on in vitro membrane transport and in vivo availability on human skin
- Authors: Schwarb, Fabian P , Imanidis, Georgios , Smith, Eric W , Haigh, John M , Surber, Christian
- Date: 1999
- Language: English
- Type: text , Article
- Identifier: vital:6425 , http://hdl.handle.net/10962/d1006560
- Description: Purpose. The thermodynamic acitvity of drugs in topical vehicles is considered to significantly influence topical delivery. In vitro diffusion across a synthetic membrane was shown to be correlated to the degree of saturation of the drug in the applied vehicle and therefore offers a potential for increased topical drug delivery. Fluocinonide a topical corticosteroid, was chosen as a model compound to investigate in vitro and in vivo availability from formulations with different degrees of saturation. Methods. Sub-, as well as, supersaturated drug solutions were prepared using PVP as an antinucleant agent. In vitro membrane diffusion experiments across silicone membrane and in vivo pharmacodynamic activity assessments, using the human skin blanching assay, were carried out. Results. Over the concentration range studied, the in vitro membrane transport of fluocinonide was proportional to the degree of saturation of the respective formulations. The in vivo pharmacodynamic response in the human skin blanching assay was related to the concentration of the drug in the vehicle irrespective of the degree of saturation. Conclusions. From the membrane permeation experiment it can be concluded, that the drug flux might be increased supra-proportionally with increasing donor concentration, drug (super-)saturation (proportional), beyond what would be anticipated based on ideal donor concentration and partition coefficient considerations only. These findings could not be confirmed in the in vivo investigation, probably due to additional vehicle effects (e.g., enhancement, irritation, drug binding) which have to be expected and could have altered the integrity of the stratum corneum and therewith topical bioavailability of the drug.
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Analysis of chromameter results obtained from corticosteroid-induced skin blanching. I. Manipulation of data
- Authors: Smith, Eric W , Haigh, John M , Walker, Roderick B
- Date: 1998
- Language: English
- Type: text , Article
- Identifier: vital:6424 , http://hdl.handle.net/10962/d1006559
- Description: Purpose. One of the unresolved issues in the FDA Guidance document for topical corticosteroid bioequivalence testing is the method of manipulation suggested for the chromameter data. The purpose of this study was to manipulate the instrumental data from a typical blanching study in a number of ways to investigate the appropriateness of these procedures for comparison with the subjective visually-assessed results. Methods. The human skin blanching assay methodology routinely practiced in our laboratories was utilised and the vasoconstriction produced by two corticosteroid formulations of different potency was assessed visually and instrumentally by use of a Minolta chromameter. The instrumental data were corrected for zero-time and unmedicated site readings. In addition, Euclidean distances were calculated using all data generated by the instrument. Results. Individually the a-, b- and L-scale chromameter values are imprecise and there is negligible vasoconstriction response recorded for the moderately potent formulation. Arithmetical manipulation of the data as suggested by the FDA does not appear to improve the quality of the data in any way. Euclidean distance analysis more closely resembles the visual data and appears to have better precision. Conclusions. It is clear that mathematical correction of chromameter data is unnecessary, especially since the instrumental data are extremely imprecise. Furthermore, the assessment of each individual chromameter index does not adequately characterise the blanching response profile. It is therefore suggested that Euclidean distance may be a better measure on which to base an analysis of bioequivalence than the truncated data set methodology currently suggested by the FDA.
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Evaluation of the proposed FDA pilot-dose response methodology for topical corticosteroid bioeqivalence testing [authors' reply in Letters to the Editor]
- Authors: Smith, Eric W , Walker, Roderick B , Haigh, John M , Kanfer, Isadore
- Date: 1998
- Language: English
- Type: text , Article
- Identifier: vital:6423 , http://hdl.handle.net/10962/d1006558
- Description: Reply to: Letter to the Editor by Singh GJ; Fleischer N; Lesko L; Williams R - relating to original article in Pharmaceutical Research (USA), Mar 1997, vol. 14, pp. 303-308.
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New developments in the methodology available for the assessment of topical corticosteroid-induced skin blanching
- 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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The requirements for accurate analysis of pharmaceutical research at South African Universities
- Authors: Haigh, John M , Smith, Eric W
- Date: 1998
- Language: English
- Type: text , Article
- Identifier: vital:6367 , http://hdl.handle.net/10962/d1006067
- Description: International Pharmaceutical Abstracts is a valuable database for pharmaceutical research, although the multisiciplinary nature of this field implies that the database should only be the starting point of a search. This database is totally inappropriate for comparing outputs of individual pharmacy teaching institutions.
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Evaluation of the proposed FDA pilot-dose response methodology for topical corticosteroid bioequivalence testing
- Authors: Demana, Patrick H , Smith, Eric W , Walker, Roderick B , Haigh, John M , Kanfer, Isadore
- Date: 1997
- Language: English
- Type: Article
- Identifier: vital:6356 , http://hdl.handle.net/10962/d1006047
- Description: The American FDA has recently released a Guidance document for topical corticosteroid bioequivalence testing. The purpose of this study was to evaluate the recommendations of this document for appropriateness. The new specifications require a dose-vasoconstriction response estimation by the use of a Minolta chromameter in a preliminary pilot study to determine the parameters for use in a pivotal bioequivalence study. Methods. The visually-assessed human skin blanching assay methodology routinely practiced in our laboratories was modified to comply with the requirements of the pilot study so that visual and chromameter data could be compared. Two different cream formulations, each containing 0.12% betamethasone 17-valerate, were used for this comparison. Results. Visual data showed the expected rank order of AUC values for most dose durations whereas the chromameter data did not show similar results. The expected rank order of AUC values for both chromameter and visual data was not observed at very short dose durations. In fitting the data to pharmacodynamic models, equivalent goodness of fit criteria were obtained when several different parameter estimates were used in the model definition, however the visual data were best described by the sigmoid E[subscript max] model while the chromameter data were best described by the simple E[subscript max] model. Conclusions. The E[subscript max] values predicted by the models were close to the observed values for both data sets and, in addition, excellent correlation between the AUC values and the maximum blanching response (R[subscript max]) (r > 0.95) was noted for both methods of assessment. The chromameter ED[subscript 50] values determined in this study were approximately 2 hours for both preparations. At this dose duration the instrument would not be sensitive enough to distinguish between weak blanching responses and normal skin for bioequivalence assessment purposes.
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The human skin blanching assay for in vivo topical corticosteroid assessment. II. Subject- and observer-dependent variation in blanching responses
- 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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The human skin-blanching assay for in vitro topical corticosteroid assessment. I. Reproducibility of the assay
- 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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Role of percutaneous penetration enhancers
- 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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The effects of elevated and ambient temperature conditions on dilutions of fluocinolone acetonide ointment assessed using the human skin-blanching assay
- 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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In vitro release of propranolol hydrochloride from topical vehicles
- Authors: Smith, Eric W , Haigh, John M
- Date: 1994
- Language: English
- Type: text , Article
- Identifier: vital:6435 , http://hdl.handle.net/10962/d1006612
- Description: Transdermal drug delivery is becoming increasingly important and for this reason it is clear that academia must ensure that current graduates are knowledgeable in all facets of topical drug administration. An in vitro diffusion cell experiment was designed to demonstrate the rate of release of propranolol hydrochloride (PHC) from three different topical vehicles: (i) an oil-in-water cream; (ii) a gel; and (iii) anointment. This experiment was performed by final-year students enroled in an undergraduate course on percutaneous absorption. In vitro release of PHC from the three bases to an aqueous receptor phase through silicone membrane was monitored spectrophotometrically at a wavelength of 290 nm. By monitoring and attempting to explain the numerous possible reasons for the different rates of drug release from the three vehicles, it was hoped that the students would gain a better understanding of the complexities of transdermal drug administration. Overall, the experiment would appear to be a good model for student investigation into factors affecting the release of drugs from topical formulations.
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The selection and use of natural and synthetic membranes for in vitro diffusion experiments
- Authors: Haigh, John M , Smith, Eric W
- Date: 1994
- Language: English
- Type: text , Article
- Identifier: vital:6379 , http://hdl.handle.net/10962/d1006297
- Description: The following membranes are discussed: human skin; animal models (including mouse, hairless mouse, rat, guinea pig, rabbit, monkey, pig, shed snake skin, egg-shell membrane, and synthetic stratum corneum); and synthetic membranes (including cellulose media, filter membranes, and synthetic polymers). Membrane integrity and diffusive characteristics are also considered.
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Ranking of topical corticosteroids: principles and results
- 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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In vitro diffusion cell design and validation. II. Temperature, agitation and membrane effects on betamethasone 17-valerate permeation
- Authors: Smith, Eric W , Haigh, John M
- Date: 1992
- Language: English
- Type: text , Article
- Identifier: vital:6422 , http://hdl.handle.net/10962/d1006557
- Description: An in vitro permeation cell has been designed and validated for use in monitoring the transmembrane permeation of betamethasone 17-valerate. The design utilizes common laboratory equipment and incorporates as many beneficial features as possible from other designs. The importance of fully validating the hydrodynamic performance of the cell prior to experimentation is stressed. The cell was validated by monitoring the diffusion of betamethasone 17-valerate in isopropyl myristate solution into purified isopropyl myristate receptor phase at different temperatures, different agitation rates and through different synthetic and biological membranes. The results of the hydrodynamic validation agree with data from other researchers and show that the permeation cell is adequately sensitive to these experimental parameters. The results of the membrane evaluation allow appropriate selection of the barrier material for representative transdermal experiments to be conducted. While human and porcine stratum corneum/epidermis are similar in diffusive properties, hairless mouse skin appears to be the most convenient animal membrane for these studies. Although silicone and cellulose membranes appear to be useful in this application, porous filter membranes and egg-shell membranes are insufficiently discriminatory to betamethasone 17-valerate diffusion to provide useful in vitro permeation data.
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Sensitivity of different areas of the flexor aspect of the human forearm to corticosteroid-induced skin blanching
- 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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The human skin-blanching assay for comparing topical corticosteroid availability
- 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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