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Impact of vehicle on clobetasol propionate skin permeation and drug distribution in vitro 1
P693
P695
ASSESSING THE BURDEN OF PSORIASIS Stefan C. Weiss, MD; Stanford University, Stanford, CA; Alexa Kimball, MD, MPH; Stanford University, Stanford, CA Psoriasis affects 7 million people in the United States at an estimated cost of $3.2 billon annually. The mainstay of therapy continues to be a combination of topical formulations despite limited efficacy and difficulty of use, especially in patients with moderate to severe disease. Systemic and biologic therapies are available but are probably underutilized. Indeed, approximately 10% of dermatologists are responsible for more than half of all prescriptions written for systemic therapy. Additionally, fewer physicians are even offering phototherapy for their patients. The purpose of this investigation is to assess therapeutic modalities actually utilized in the treatment of psoriasis. Using a database of pharmaceutical prescriptions, we will examine both patterns of use and cost, including single and combination therapy. Independent variables including sociodemographics, extent of disease, location of disease, and board specialty of prescribing physician will additionally be explored for their impact on prescribing.
IMPACT OF VEHICLE ON CLOBETASOL PROPIONATE SKIN PERMEATION AND DRUG DISTRIBUTION IN VITRO X. Huang, MD; Center For Skin Biology, Connetics Corporation, Stanford, CA; H. Tanojo, PhD; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; J. Lenn, MS; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; C. Cuesico, BA; Center for Skin Biology, Connetics Corporation, Palo Alto, CA Topical glucocorticosteroids are among some of the most frequently used medications in dermatological practice. Over the years, research has focused on strategies to optimize potency and, in particular, the anti-inflammatory and immunosuppressive capacity of these drugs, while also minimizing adverse effects. Commonly the delivery vehicle is modified to achieve these purposes. Clobetasol propionate, a fifth generation corticosteroid, is a typical example of a potent molecule for dermatoses, which is available in various formulations and delivery vehicles (such as foam, lotion, cream, ointment, spray, and shampoo) that have been employed in clinical practice. Objective: To compare the impact of vehicles on clobetasol propionate skin permeation and distribution profile in vitro. Methods: Products containing clobetasol propionate 0.05% were tested for in vitro skin permeation and drug distribution in human split-thickness skin (⬃0.25mm) using flow-through diffusion cells. Receptor fluid was collected at 4-hour intervals. Each formulation was tested on three replicate skin sections from at least three donors. At 24 hours after application, the surface of the skin membrane was washed and split into epidermis and dermis to measure the drug content within these layers. Results and Conclusions: Immediately after application the foam vehicle delivers clobetasol propionate faster than the other formulations tested. The distribution profile results demonstrated that, compared to other commercially available clobetasol propionate vehicles, foam is the most efficient vehicle to deliver clobetasol propionate following a vehicle-skin non-interactive pathway.
Disclosure not available at press time. Centocor will be providing access to the database
Disclosure not available at press time. 100 percent sponsored by Connetics Corporation
P696
IN VITRO HUMAN SKIN STUDY OF COMBINED APPLICATION OF PIMECROLIMUS CREAM AND BETAMETHASONE 17-VALERATE H. Deng, MD, PhD; Department of Dermatology, Stanford University School of Medicine, Stanford, CA; H. Tanojo, PhD; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; J. Lenn, MS; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; C. Cuesico, BA; Center for Skin Biology, Connetics Corporation, Palo Alto, CA Topical calcineurin inhibitors are becoming common therapies for various dermatoses. Combining topical steroids with topical calcineurin inhibitors could potentially accelerate the onset of action, enhance permeation through thicker skin, and reduce the amount of each active medication applied, due to synergistic effects of topical steroids and calcineurin inhibitors. Objective: To investigate the feasibility of co-applying pimecrolimus cream and betamethasone 17-valerate (BMV) in various vehicles. Methods: Five microliters of BMV 0.12% in either foam, ointment, cream, or lotion vehicle was added to a series of glass vials containing 5 mL of pimecrolimus cream 1%. Formulations alone were used individually as controls. Samples were incubated for 0, 2, 4, 6, 8 and 24 hours at either 32°C or 37°C. Drug content was analyzed with HPLC. Permeation through splitthickness human skin (⬃0.25 mm) was measured using flow-through diffusion cells. Five microliters of Pimecrolimus cream 1% was applied on the skin membranes, followed 5 minutes later by 5 mL BMV 0.12% either in foam, ointment, or cream vehicle. BMV and pimecrolimus were applied individually as controls. Each combination was tested on three replicate skin sections of at least three human donors. Receptor fluid was collected at 4-hour intervals. At 24 hours after application, the skin was washed and split into epidermis and dermis to measure drug content within these layers. The drug content in samples was measured by HPLC. Results: Pimecrolimus and BMV contents in combination did not show apparent degradation when mixed in different vehicles in vitro after various periods of co-incubation. Permeation of pimecrolimus and BMV will be tested by analyzing the drugs content in the receptor fluid following co-application of pimecrolimus cream and BMV in either foam, ointment, or cream vehicle. Conclusions: Our data show that pimecrolimus and BMV were stable over a period of 24 hours when mixed in various vehicles at either 32°C or 37°C. We will study the permeability of pimecrolimus and BMV when co-applied to skin in various vehicles. The potential synergistic effects of combined application will also be studied.
DIRECTIONAL ASSOCIATION OF PRECLINICAL, VASOCONSTRICTOR ASSAY AND CLINICAL RESULTS OF TOPICAL CLOBETASOL FORMULATIONS X. Huang, MD; Center For Skin Biology, Connetics Corporation, Stanford, CA; H. Tanojo, PhD; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; J. A. Myers, MS; Center for Skin Biology, Connetics Corporation, Palo Alto, CA Currently, topical glucocorticosteroids are the most frequently used class of drugs in dermatological practice. Over the years, research has focused on strategies to optimize the delivery vehicle to maximize clinical efficacy while minimizing any associated adverse effects. Recently, a novel topical delivery vehicle, thermolabile foam, has been developed. Two foam-based topical corticosteroid products (betamethasone 17-valerate foam and clobetasol propionate foam) have been approved by FDA for treatment of dermatoses. During the development of these two products, in vitro skin penetration, a vasoconstrictor assay and randomized clinical efficacy study were conducted. Objectives: To compare results of the foam-based clobetasol propionate (0.05%) and another commercially available clobetasol product (clobetasol propionate solution, 0.05%) in the in vitro assay, vasoconstrictor assay and clinical efficacy, and to define the correlation of three commonly used assays. Methods: During the development process, three sets of results were collected. (1) Preclinically, an in vitro flow through system was used to profile the rate of drug penetrating into skin membrane (expressed as peak flux, ng/cm2/hr). (2) A vasoconstrictor assay to determine steroid potency was conducted in 24 healthy subjects in a randomized fashion at a single center. The blanching effects of steroid were monitored by using a chromameter at various timepoints post-application and the maximum skin color change from the baseline was presented as Emax. (3) Clinical efficacy was evaluated in a randomized trial of 188 adult patients with moderate to severe scalp psoriasis treated with a clobetasol product (foam or solution) for 14 days. Investigator’s Global Assessment (IGA) was used, and the percentage of patients to attain completely clear or almost clear (IGA 0 or 1) was presented. Results: Clobetasol Propionate Foam: Preclinical Peak Flux (ng/cm2/hr) ⫽ 16.90, Vasoconstrictor Assay (Emax) ⫽ ⫺1.15, Clinical Efficacy (% Patients*) ⫽ 74%. Clobetasol Propionate Solution: Preclinical Peak Flux (ng/cm2/hr) ⫽ 8.56, Vasoconstrictor Assay (Emax) ⫽ ⫺.71, Clinical Efficacy (% Patients*) ⫽ 63%. *With completely clear or almost clear. Conclusion: The results showed that foam-based clobetasol has higher skin penetration, more potent vasoconstriction and higher clinical efficacy response rate when compared to clobetasol solution. Thus, it suggests that in vitro skin penetration could be a very useful assay for evaluating novel formulations of topical corticosteroids.
Disclosure not available at press time. 100 percent sponsored by Connetics Corporation
Disclosure not available at press time. 100 percent sponsored by Connetics Corporation
P694
P178
J AM ACAD DERMATOL
MARCH 2004
P695
ASSESSING THE BURDEN OF PSORIASIS Stefan C. Weiss, MD; Stanford University, Stanford, CA; Alexa Kimball, MD, MPH; Stanford University, Stanford, CA Psoriasis affects 7 million people in the United States at an estimated cost of $3.2 billon annually. The mainstay of therapy continues to be a combination of topical formulations despite limited efficacy and difficulty of use, especially in patients with moderate to severe disease. Systemic and biologic therapies are available but are probably underutilized. Indeed, approximately 10% of dermatologists are responsible for more than half of all prescriptions written for systemic therapy. Additionally, fewer physicians are even offering phototherapy for their patients. The purpose of this investigation is to assess therapeutic modalities actually utilized in the treatment of psoriasis. Using a database of pharmaceutical prescriptions, we will examine both patterns of use and cost, including single and combination therapy. Independent variables including sociodemographics, extent of disease, location of disease, and board specialty of prescribing physician will additionally be explored for their impact on prescribing.
IMPACT OF VEHICLE ON CLOBETASOL PROPIONATE SKIN PERMEATION AND DRUG DISTRIBUTION IN VITRO X. Huang, MD; Center For Skin Biology, Connetics Corporation, Stanford, CA; H. Tanojo, PhD; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; J. Lenn, MS; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; C. Cuesico, BA; Center for Skin Biology, Connetics Corporation, Palo Alto, CA Topical glucocorticosteroids are among some of the most frequently used medications in dermatological practice. Over the years, research has focused on strategies to optimize potency and, in particular, the anti-inflammatory and immunosuppressive capacity of these drugs, while also minimizing adverse effects. Commonly the delivery vehicle is modified to achieve these purposes. Clobetasol propionate, a fifth generation corticosteroid, is a typical example of a potent molecule for dermatoses, which is available in various formulations and delivery vehicles (such as foam, lotion, cream, ointment, spray, and shampoo) that have been employed in clinical practice. Objective: To compare the impact of vehicles on clobetasol propionate skin permeation and distribution profile in vitro. Methods: Products containing clobetasol propionate 0.05% were tested for in vitro skin permeation and drug distribution in human split-thickness skin (⬃0.25mm) using flow-through diffusion cells. Receptor fluid was collected at 4-hour intervals. Each formulation was tested on three replicate skin sections from at least three donors. At 24 hours after application, the surface of the skin membrane was washed and split into epidermis and dermis to measure the drug content within these layers. Results and Conclusions: Immediately after application the foam vehicle delivers clobetasol propionate faster than the other formulations tested. The distribution profile results demonstrated that, compared to other commercially available clobetasol propionate vehicles, foam is the most efficient vehicle to deliver clobetasol propionate following a vehicle-skin non-interactive pathway.
Disclosure not available at press time. Centocor will be providing access to the database
Disclosure not available at press time. 100 percent sponsored by Connetics Corporation
P696
IN VITRO HUMAN SKIN STUDY OF COMBINED APPLICATION OF PIMECROLIMUS CREAM AND BETAMETHASONE 17-VALERATE H. Deng, MD, PhD; Department of Dermatology, Stanford University School of Medicine, Stanford, CA; H. Tanojo, PhD; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; J. Lenn, MS; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; C. Cuesico, BA; Center for Skin Biology, Connetics Corporation, Palo Alto, CA Topical calcineurin inhibitors are becoming common therapies for various dermatoses. Combining topical steroids with topical calcineurin inhibitors could potentially accelerate the onset of action, enhance permeation through thicker skin, and reduce the amount of each active medication applied, due to synergistic effects of topical steroids and calcineurin inhibitors. Objective: To investigate the feasibility of co-applying pimecrolimus cream and betamethasone 17-valerate (BMV) in various vehicles. Methods: Five microliters of BMV 0.12% in either foam, ointment, cream, or lotion vehicle was added to a series of glass vials containing 5 mL of pimecrolimus cream 1%. Formulations alone were used individually as controls. Samples were incubated for 0, 2, 4, 6, 8 and 24 hours at either 32°C or 37°C. Drug content was analyzed with HPLC. Permeation through splitthickness human skin (⬃0.25 mm) was measured using flow-through diffusion cells. Five microliters of Pimecrolimus cream 1% was applied on the skin membranes, followed 5 minutes later by 5 mL BMV 0.12% either in foam, ointment, or cream vehicle. BMV and pimecrolimus were applied individually as controls. Each combination was tested on three replicate skin sections of at least three human donors. Receptor fluid was collected at 4-hour intervals. At 24 hours after application, the skin was washed and split into epidermis and dermis to measure drug content within these layers. The drug content in samples was measured by HPLC. Results: Pimecrolimus and BMV contents in combination did not show apparent degradation when mixed in different vehicles in vitro after various periods of co-incubation. Permeation of pimecrolimus and BMV will be tested by analyzing the drugs content in the receptor fluid following co-application of pimecrolimus cream and BMV in either foam, ointment, or cream vehicle. Conclusions: Our data show that pimecrolimus and BMV were stable over a period of 24 hours when mixed in various vehicles at either 32°C or 37°C. We will study the permeability of pimecrolimus and BMV when co-applied to skin in various vehicles. The potential synergistic effects of combined application will also be studied.
DIRECTIONAL ASSOCIATION OF PRECLINICAL, VASOCONSTRICTOR ASSAY AND CLINICAL RESULTS OF TOPICAL CLOBETASOL FORMULATIONS X. Huang, MD; Center For Skin Biology, Connetics Corporation, Stanford, CA; H. Tanojo, PhD; Center for Skin Biology, Connetics Corporation, Palo Alto, CA; J. A. Myers, MS; Center for Skin Biology, Connetics Corporation, Palo Alto, CA Currently, topical glucocorticosteroids are the most frequently used class of drugs in dermatological practice. Over the years, research has focused on strategies to optimize the delivery vehicle to maximize clinical efficacy while minimizing any associated adverse effects. Recently, a novel topical delivery vehicle, thermolabile foam, has been developed. Two foam-based topical corticosteroid products (betamethasone 17-valerate foam and clobetasol propionate foam) have been approved by FDA for treatment of dermatoses. During the development of these two products, in vitro skin penetration, a vasoconstrictor assay and randomized clinical efficacy study were conducted. Objectives: To compare results of the foam-based clobetasol propionate (0.05%) and another commercially available clobetasol product (clobetasol propionate solution, 0.05%) in the in vitro assay, vasoconstrictor assay and clinical efficacy, and to define the correlation of three commonly used assays. Methods: During the development process, three sets of results were collected. (1) Preclinically, an in vitro flow through system was used to profile the rate of drug penetrating into skin membrane (expressed as peak flux, ng/cm2/hr). (2) A vasoconstrictor assay to determine steroid potency was conducted in 24 healthy subjects in a randomized fashion at a single center. The blanching effects of steroid were monitored by using a chromameter at various timepoints post-application and the maximum skin color change from the baseline was presented as Emax. (3) Clinical efficacy was evaluated in a randomized trial of 188 adult patients with moderate to severe scalp psoriasis treated with a clobetasol product (foam or solution) for 14 days. Investigator’s Global Assessment (IGA) was used, and the percentage of patients to attain completely clear or almost clear (IGA 0 or 1) was presented. Results: Clobetasol Propionate Foam: Preclinical Peak Flux (ng/cm2/hr) ⫽ 16.90, Vasoconstrictor Assay (Emax) ⫽ ⫺1.15, Clinical Efficacy (% Patients*) ⫽ 74%. Clobetasol Propionate Solution: Preclinical Peak Flux (ng/cm2/hr) ⫽ 8.56, Vasoconstrictor Assay (Emax) ⫽ ⫺.71, Clinical Efficacy (% Patients*) ⫽ 63%. *With completely clear or almost clear. Conclusion: The results showed that foam-based clobetasol has higher skin penetration, more potent vasoconstriction and higher clinical efficacy response rate when compared to clobetasol solution. Thus, it suggests that in vitro skin penetration could be a very useful assay for evaluating novel formulations of topical corticosteroids.
Disclosure not available at press time. 100 percent sponsored by Connetics Corporation
Disclosure not available at press time. 100 percent sponsored by Connetics Corporation
P694
P178
J AM ACAD DERMATOL
MARCH 2004