Investigations of the assessment of bioequivalence of topical clotrimazole products using a dermatopharmacokinetic approach
- Authors: Parfitt, Natalie Rae
- Date: 2011 , 2010-07-05
- Subjects: Dermatopharmacology , Drugs -- Therapeutic equivalency , Antifungal agents , Therapeutics, Cutaneous and external
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3840 , http://hdl.handle.net/10962/d1007659 , Dermatopharmacology , Drugs -- Therapeutic equivalency , Antifungal agents , Therapeutics, Cutaneous and external
- Description: The specialised nature of the stratum corneum makes it an efficient barrier to foreign substances, including drug molecules. Therefore, cutaneous drug absorption is a slow and complex process of which stratum corneum penetration is the rate limiting step. The rate and extent of stratum corneum penetration by a drug compound depends greatly on the presence of penetration enhancing/retarding excipients and therefore the clinical outcomes of a product rely greatly on the components and quality of the formulation. Hence, establishing bioequivalence between topical products is crucial to ensure that patients receiving multisource drug products are assured of the same efficacy and safety as the brand product. Since locally acting topical formulations do not target the systemic circulation, conventional methods of assessing bioequivalence using plasma levels are not appropriate. Consequently, the current regulatory guidelines require comparative clinical trials to be carried out to show bioequivalence between topical products. As these studies are very expensive and time consuming, the development of a more direct and relatively rapid and inexpensive method for determining bioequivalence between topical products is required. Clotrimazole is an anti-fungal agent where the target site of action is in the stratum corneum. In this work, tape stripping, which involves the sampling of stratum corneum, was investigated as a tool for the determination of bioequivalence between topical clotrimazole products. The tape stripping method involved the analysis of each tape strip individually and standardization of stratum corneum thickness between subjects was carried out using TEWL measurements. This approach provided detailed information regarding the amount of clotrimazole present in the stratum corneum as well as the extent of drug penetration. Prior to the tape stripping studies an HPLC method was developed for the quantitative analysis of clotrimazole from the tape strip samples. This method was shown to be accurate and reproducible across the required range. It was also shown to be selective for clotrimazole in the presence of possible interfering substances such as those present in the tape adhesive and also skin components. The bioequivalence studies were conducted using a single “uptake” time point. In order to determine an appropriate dose duration for these studies a novel approach was employed, involving a preliminary dose duration study. For the bioequivalence investigations, Canesten® Topical cream was used as both test and reference products to determine if the method was capable of showing bioequivalence. Subsequently, Canesten® Topical cream was also compared to a 1% gel formulation to determine if the method could detect formulation differences. The conventional BE limits of 0.8 – 1.25 were used for the assessment of BE, however, the clinical relevance of using these limits for dermal studies is debatable since they are derived from oral pharmacokinetic studies. Therefore, the data from the tape stripping investigations were also assessed using more realistic limits of 0.75 – 1.33 and even 0.7 – 1.44. In addition to the tape stripping studies a novel method of determining the amount of drug present in the stratum corneum, the “Residual Method”, was investigated. This method involved assaying the amount of clotrimazole found in the residual formulation after a specified dose duration had elapsed and subtracting that amount from the amount of clotrimazole initially applied. The results of tape stripping investigations showed that, if the study is sufficiently powered, tape stripping may be used to determine bioequivalence according to the conventional limits, as well as possibly detect formulation differences between different clotrimazole products. Bioequivalence assessment using the widened intervals showed that fewer subjects were required to achieve a sufficient statistical power. The variability associated with this method was acceptable and tape stripping may therefore have the potential to be used as a BE tool in a regulatory setting for clotrimazole or other antifungal topical formulations. The “Residual Method” also showed promising results as a bioequivalence tool, but further investigation and extensive validation of this method is required before it can be suggested as a regulatory method. The results of these studies have clearly indicated that tape stripping has the potential to be used as an alternative to comparative clinical trails for the assessment of bioequivalence between clotrimazole formulations and also to assess bioequivalence between other antifungal products.
- Full Text:
- Date Issued: 2011
- Authors: Parfitt, Natalie Rae
- Date: 2011 , 2010-07-05
- Subjects: Dermatopharmacology , Drugs -- Therapeutic equivalency , Antifungal agents , Therapeutics, Cutaneous and external
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3840 , http://hdl.handle.net/10962/d1007659 , Dermatopharmacology , Drugs -- Therapeutic equivalency , Antifungal agents , Therapeutics, Cutaneous and external
- Description: The specialised nature of the stratum corneum makes it an efficient barrier to foreign substances, including drug molecules. Therefore, cutaneous drug absorption is a slow and complex process of which stratum corneum penetration is the rate limiting step. The rate and extent of stratum corneum penetration by a drug compound depends greatly on the presence of penetration enhancing/retarding excipients and therefore the clinical outcomes of a product rely greatly on the components and quality of the formulation. Hence, establishing bioequivalence between topical products is crucial to ensure that patients receiving multisource drug products are assured of the same efficacy and safety as the brand product. Since locally acting topical formulations do not target the systemic circulation, conventional methods of assessing bioequivalence using plasma levels are not appropriate. Consequently, the current regulatory guidelines require comparative clinical trials to be carried out to show bioequivalence between topical products. As these studies are very expensive and time consuming, the development of a more direct and relatively rapid and inexpensive method for determining bioequivalence between topical products is required. Clotrimazole is an anti-fungal agent where the target site of action is in the stratum corneum. In this work, tape stripping, which involves the sampling of stratum corneum, was investigated as a tool for the determination of bioequivalence between topical clotrimazole products. The tape stripping method involved the analysis of each tape strip individually and standardization of stratum corneum thickness between subjects was carried out using TEWL measurements. This approach provided detailed information regarding the amount of clotrimazole present in the stratum corneum as well as the extent of drug penetration. Prior to the tape stripping studies an HPLC method was developed for the quantitative analysis of clotrimazole from the tape strip samples. This method was shown to be accurate and reproducible across the required range. It was also shown to be selective for clotrimazole in the presence of possible interfering substances such as those present in the tape adhesive and also skin components. The bioequivalence studies were conducted using a single “uptake” time point. In order to determine an appropriate dose duration for these studies a novel approach was employed, involving a preliminary dose duration study. For the bioequivalence investigations, Canesten® Topical cream was used as both test and reference products to determine if the method was capable of showing bioequivalence. Subsequently, Canesten® Topical cream was also compared to a 1% gel formulation to determine if the method could detect formulation differences. The conventional BE limits of 0.8 – 1.25 were used for the assessment of BE, however, the clinical relevance of using these limits for dermal studies is debatable since they are derived from oral pharmacokinetic studies. Therefore, the data from the tape stripping investigations were also assessed using more realistic limits of 0.75 – 1.33 and even 0.7 – 1.44. In addition to the tape stripping studies a novel method of determining the amount of drug present in the stratum corneum, the “Residual Method”, was investigated. This method involved assaying the amount of clotrimazole found in the residual formulation after a specified dose duration had elapsed and subtracting that amount from the amount of clotrimazole initially applied. The results of tape stripping investigations showed that, if the study is sufficiently powered, tape stripping may be used to determine bioequivalence according to the conventional limits, as well as possibly detect formulation differences between different clotrimazole products. Bioequivalence assessment using the widened intervals showed that fewer subjects were required to achieve a sufficient statistical power. The variability associated with this method was acceptable and tape stripping may therefore have the potential to be used as a BE tool in a regulatory setting for clotrimazole or other antifungal topical formulations. The “Residual Method” also showed promising results as a bioequivalence tool, but further investigation and extensive validation of this method is required before it can be suggested as a regulatory method. The results of these studies have clearly indicated that tape stripping has the potential to be used as an alternative to comparative clinical trails for the assessment of bioequivalence between clotrimazole formulations and also to assess bioequivalence between other antifungal products.
- Full Text:
- Date Issued: 2011
Investigations of the bioavailability/bioequivalence of topical corticosteroid formulations containing clobetasol propionate using the human skin blanching assay, tape stripping and microdialysis
- Authors: Au, Wai Ling
- Date: 2010
- Subjects: Adrenocortical hormones -- Bioavailability , Drugs -- Therapeutic equivalency , Adrenocortical hormones -- Effectiveness , Adrenocortical hormones -- Testing , Adrenocortical hormones -- Side effects , Transdermal medication
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3743 , http://hdl.handle.net/10962/d1003221 , Adrenocortical hormones -- Bioavailability , Drugs -- Therapeutic equivalency , Adrenocortical hormones -- Effectiveness , Adrenocortical hormones -- Testing , Adrenocortical hormones -- Side effects , Transdermal medication
- Description: Currently, clinical trials in patients are required by most regulatory authorities for the assessment of bioequivalence of topical products where the drug is not intended for systemic absorption. Hence there is a dire need for suitable methods for the assessment of bioavailability and bioequivalence of such products since clinical safety and efficacy studies are expensive, time-consuming and require very large numbers of patients. Except for topical corticosteroid products where the human skin blanching assay/vasoconstrictor assay has been approved by the US FDA for bioequivalence assessment of those products, no other method has been “officially” approved for use in those investigations. However, a few alternative methods such as tape stripping and microdialysis have been pursued and considered to have the potential for use in ioequivalence/bioavailability studies. The human skin blanching assay was used to assess the bioequivalence of commercially available topical products containing 0.05% clobetasol propionate. Both visual and chromameter data were obtained and a commercially available topical corticosteroid product, Dermovate® cream was used as both the “Test” and the “Reference” product. The results indicated that both visual and chromametric assessments were comparable to each other and that either could be used for the assessment of the bioequivalence of topical products containing clobetasol propionate. The screening procedure was optimized to identify potential “detectors” for inclusion in the bioequivalence studies. This resulted in fewer subjects being required in a bioequivalence pivotal study, still having the necessary power to confirm bioequivalence using the human skin blanching assay. Another objective of this research was to re-visit tape stripping and other possible alternative methods such as dermal microdialysis and to optimize these procedures for bioequivalence assessment of topical formulations where the drug is not intended for systemic absorption. In the past few decades, tape stripping has been used to investigate bioavailability/bioequivalence of various topical formulations. This technique involves the removal of the stratum corneum to assess drug penetration through the skin. A draft FDA guidance for tape stripping was initially published but was subsequently withdrawn due to high variability and poor reproducibility. This research project used an optimized tape stripping procedure to determine bioavailability and establish bioequivalence between three commercially available formulations containing 0.05 % m/m clobetasol propionate. Furthermore, tape stripping was validated by undertaking a study to assess the bioequivalence of a 0.05% topical cream formulation (Dermovate® cream) using the same cream as both the “Test” and “Reference” product, in which bioequivalence was confirmed. The findings highlight the potential of tape stripping as an alternative method for the assessment of bioequivalence of clobetasol propionate formulations and may possibly be extended for use in other topical products. Microdialysis is another useful technique that can assess the penetration of topically applied substances which diffuses through the stratum corneum and into the dermis. Microdialysis has previously been successfully used for in vivo bioavailability and bioequivalence assessments of topical formulations. However, the drugs which were under investigation were all hydrophilic in nature. A major problem with the use of microdialysis for the assessment of lipophilic substances is the binding/adherence of the substance to the membrane and other components of the microdialysis system. As a result, this necessitates the development of a microdialysis system which can be used to assess lipophilic drugs. Intralipid® 20% was investigated and successfully utilized as a perfusate to recover a lipophilic topical corticosteroid, clobetasol propionate, in microdialysis studies. Hence, the bioavailability of clobetasol propionate from an extemporaneous preparation was determined in healthy human volunteers using microdialysis. These findings indicate that in vivo microdialysis can be used to assess lipophilic drug penetration through the skin. A novel approach to investigate drug release from topical formulations containing 0.05% clobetasol propionate using in vitro microdialysis was also undertaken. The in vitro findings were found to be in agreement with the results obtained using tape stripping to assess bioequivalence of the same commercially available products, namely Dermovate® cream, Dovate® Cream and Dermovate® ointment. These results indicate the potential to correlate in vitro with in vivo data for bioequivalence assessment of such topical dosage forms.
- Full Text:
- Date Issued: 2010
- Authors: Au, Wai Ling
- Date: 2010
- Subjects: Adrenocortical hormones -- Bioavailability , Drugs -- Therapeutic equivalency , Adrenocortical hormones -- Effectiveness , Adrenocortical hormones -- Testing , Adrenocortical hormones -- Side effects , Transdermal medication
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3743 , http://hdl.handle.net/10962/d1003221 , Adrenocortical hormones -- Bioavailability , Drugs -- Therapeutic equivalency , Adrenocortical hormones -- Effectiveness , Adrenocortical hormones -- Testing , Adrenocortical hormones -- Side effects , Transdermal medication
- Description: Currently, clinical trials in patients are required by most regulatory authorities for the assessment of bioequivalence of topical products where the drug is not intended for systemic absorption. Hence there is a dire need for suitable methods for the assessment of bioavailability and bioequivalence of such products since clinical safety and efficacy studies are expensive, time-consuming and require very large numbers of patients. Except for topical corticosteroid products where the human skin blanching assay/vasoconstrictor assay has been approved by the US FDA for bioequivalence assessment of those products, no other method has been “officially” approved for use in those investigations. However, a few alternative methods such as tape stripping and microdialysis have been pursued and considered to have the potential for use in ioequivalence/bioavailability studies. The human skin blanching assay was used to assess the bioequivalence of commercially available topical products containing 0.05% clobetasol propionate. Both visual and chromameter data were obtained and a commercially available topical corticosteroid product, Dermovate® cream was used as both the “Test” and the “Reference” product. The results indicated that both visual and chromametric assessments were comparable to each other and that either could be used for the assessment of the bioequivalence of topical products containing clobetasol propionate. The screening procedure was optimized to identify potential “detectors” for inclusion in the bioequivalence studies. This resulted in fewer subjects being required in a bioequivalence pivotal study, still having the necessary power to confirm bioequivalence using the human skin blanching assay. Another objective of this research was to re-visit tape stripping and other possible alternative methods such as dermal microdialysis and to optimize these procedures for bioequivalence assessment of topical formulations where the drug is not intended for systemic absorption. In the past few decades, tape stripping has been used to investigate bioavailability/bioequivalence of various topical formulations. This technique involves the removal of the stratum corneum to assess drug penetration through the skin. A draft FDA guidance for tape stripping was initially published but was subsequently withdrawn due to high variability and poor reproducibility. This research project used an optimized tape stripping procedure to determine bioavailability and establish bioequivalence between three commercially available formulations containing 0.05 % m/m clobetasol propionate. Furthermore, tape stripping was validated by undertaking a study to assess the bioequivalence of a 0.05% topical cream formulation (Dermovate® cream) using the same cream as both the “Test” and “Reference” product, in which bioequivalence was confirmed. The findings highlight the potential of tape stripping as an alternative method for the assessment of bioequivalence of clobetasol propionate formulations and may possibly be extended for use in other topical products. Microdialysis is another useful technique that can assess the penetration of topically applied substances which diffuses through the stratum corneum and into the dermis. Microdialysis has previously been successfully used for in vivo bioavailability and bioequivalence assessments of topical formulations. However, the drugs which were under investigation were all hydrophilic in nature. A major problem with the use of microdialysis for the assessment of lipophilic substances is the binding/adherence of the substance to the membrane and other components of the microdialysis system. As a result, this necessitates the development of a microdialysis system which can be used to assess lipophilic drugs. Intralipid® 20% was investigated and successfully utilized as a perfusate to recover a lipophilic topical corticosteroid, clobetasol propionate, in microdialysis studies. Hence, the bioavailability of clobetasol propionate from an extemporaneous preparation was determined in healthy human volunteers using microdialysis. These findings indicate that in vivo microdialysis can be used to assess lipophilic drug penetration through the skin. A novel approach to investigate drug release from topical formulations containing 0.05% clobetasol propionate using in vitro microdialysis was also undertaken. The in vitro findings were found to be in agreement with the results obtained using tape stripping to assess bioequivalence of the same commercially available products, namely Dermovate® cream, Dovate® Cream and Dermovate® ointment. These results indicate the potential to correlate in vitro with in vivo data for bioequivalence assessment of such topical dosage forms.
- Full Text:
- Date Issued: 2010
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