Enhanced percutaneous absorption of a novel topical cyclosporin A formulation and assessment of its immunosuppressive activity

J I Duncan, S N Payne, A J Winfield, Anthony Ormerod, A W Thomson

Research output: Contribution to journalArticle

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Abstract

No clinically successful topical cyclosporin A (CyA) formulation has been produced, mainly due to the apparent lack of drug penetration. This study has produced the first in vitro kinetic data on CyA penetration across human cadaver stratum corneum and has shown that addition of the penetration enhancers (PE) Azone and propylene glycol to the CyA vehicle significantly enhanced drug permeation across the skin barrier. Using flow-through permeability cells with 5% w/v CyA (Sandimmun) alone (CyA) or with PE (CyA + PE) in olive oil in the donor chamber, the penetration rate (mean +/- SD microgram/cm2/h) into receptor fluid was 53 +/- 43 (n = 13) for CyA and 660 +/- 175 (n = 7) for CyA + PE. The in vivo efficacy of this formulation was assessed in guinea-pigs undergoing delayed-type hypersensitivity (DTH) reactions to dinitrofluorobenzene (DNFB). CyA was applied topically at the time of challenge and twice daily thereafter. At 24 h, skin reactions revealed that compared with appropriate drug vehicles, concentrations of 0.25, 0.5 and 5% CyA +/- PE had a significant inhibitory effect upon the erythema response and this corresponded with significant reductions in T-cell infiltrates (0.5 and 5% CyA). No statistically significant reductions in erythema were demonstrated with 0.05% CyA +/- PE, but there was a reduction in the number of infiltrating lymphocytes in sites receiving 0.05% CyA + PE compared with vehicle-treated sites (P less than 0.01). This suggests that PE permitted some penetration of an otherwise non-immunosuppressive concentration of CyA through the skin.
Original languageEnglish
Pages (from-to)631-640
Number of pages10
JournalBritish Journal of Dermatology
Volume123
Issue number5
DOIs
Publication statusPublished - 1 Nov 1990

Fingerprint

Skin Absorption
Immunosuppressive Agents
Cyclosporine
Erythema
Skin
Pharmaceutical Preparations
Dinitrofluorobenzene
Propylene Glycol
Delayed Hypersensitivity
Lymphocyte Count

Keywords

  • Animals
  • Azepines
  • Cyclosporins
  • Guinea Pigs
  • Humans
  • Hypersensitivity, Delayed
  • Leukocyte Count
  • Male
  • Propylene Glycols
  • Skin
  • Skin Absorption
  • T-Lymphocytes, Cytotoxic
  • T-Lymphocytes, Regulatory
  • Time Factors
  • Vehicles

Cite this

Enhanced percutaneous absorption of a novel topical cyclosporin A formulation and assessment of its immunosuppressive activity. / Duncan, J I; Payne, S N; Winfield, A J; Ormerod, Anthony; Thomson, A W.

In: British Journal of Dermatology, Vol. 123, No. 5, 01.11.1990, p. 631-640.

Research output: Contribution to journalArticle

Duncan, J I ; Payne, S N ; Winfield, A J ; Ormerod, Anthony ; Thomson, A W. / Enhanced percutaneous absorption of a novel topical cyclosporin A formulation and assessment of its immunosuppressive activity. In: British Journal of Dermatology. 1990 ; Vol. 123, No. 5. pp. 631-640.
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abstract = "No clinically successful topical cyclosporin A (CyA) formulation has been produced, mainly due to the apparent lack of drug penetration. This study has produced the first in vitro kinetic data on CyA penetration across human cadaver stratum corneum and has shown that addition of the penetration enhancers (PE) Azone and propylene glycol to the CyA vehicle significantly enhanced drug permeation across the skin barrier. Using flow-through permeability cells with 5{\%} w/v CyA (Sandimmun) alone (CyA) or with PE (CyA + PE) in olive oil in the donor chamber, the penetration rate (mean +/- SD microgram/cm2/h) into receptor fluid was 53 +/- 43 (n = 13) for CyA and 660 +/- 175 (n = 7) for CyA + PE. The in vivo efficacy of this formulation was assessed in guinea-pigs undergoing delayed-type hypersensitivity (DTH) reactions to dinitrofluorobenzene (DNFB). CyA was applied topically at the time of challenge and twice daily thereafter. At 24 h, skin reactions revealed that compared with appropriate drug vehicles, concentrations of 0.25, 0.5 and 5{\%} CyA +/- PE had a significant inhibitory effect upon the erythema response and this corresponded with significant reductions in T-cell infiltrates (0.5 and 5{\%} CyA). No statistically significant reductions in erythema were demonstrated with 0.05{\%} CyA +/- PE, but there was a reduction in the number of infiltrating lymphocytes in sites receiving 0.05{\%} CyA + PE compared with vehicle-treated sites (P less than 0.01). This suggests that PE permitted some penetration of an otherwise non-immunosuppressive concentration of CyA through the skin.",
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N2 - No clinically successful topical cyclosporin A (CyA) formulation has been produced, mainly due to the apparent lack of drug penetration. This study has produced the first in vitro kinetic data on CyA penetration across human cadaver stratum corneum and has shown that addition of the penetration enhancers (PE) Azone and propylene glycol to the CyA vehicle significantly enhanced drug permeation across the skin barrier. Using flow-through permeability cells with 5% w/v CyA (Sandimmun) alone (CyA) or with PE (CyA + PE) in olive oil in the donor chamber, the penetration rate (mean +/- SD microgram/cm2/h) into receptor fluid was 53 +/- 43 (n = 13) for CyA and 660 +/- 175 (n = 7) for CyA + PE. The in vivo efficacy of this formulation was assessed in guinea-pigs undergoing delayed-type hypersensitivity (DTH) reactions to dinitrofluorobenzene (DNFB). CyA was applied topically at the time of challenge and twice daily thereafter. At 24 h, skin reactions revealed that compared with appropriate drug vehicles, concentrations of 0.25, 0.5 and 5% CyA +/- PE had a significant inhibitory effect upon the erythema response and this corresponded with significant reductions in T-cell infiltrates (0.5 and 5% CyA). No statistically significant reductions in erythema were demonstrated with 0.05% CyA +/- PE, but there was a reduction in the number of infiltrating lymphocytes in sites receiving 0.05% CyA + PE compared with vehicle-treated sites (P less than 0.01). This suggests that PE permitted some penetration of an otherwise non-immunosuppressive concentration of CyA through the skin.

AB - No clinically successful topical cyclosporin A (CyA) formulation has been produced, mainly due to the apparent lack of drug penetration. This study has produced the first in vitro kinetic data on CyA penetration across human cadaver stratum corneum and has shown that addition of the penetration enhancers (PE) Azone and propylene glycol to the CyA vehicle significantly enhanced drug permeation across the skin barrier. Using flow-through permeability cells with 5% w/v CyA (Sandimmun) alone (CyA) or with PE (CyA + PE) in olive oil in the donor chamber, the penetration rate (mean +/- SD microgram/cm2/h) into receptor fluid was 53 +/- 43 (n = 13) for CyA and 660 +/- 175 (n = 7) for CyA + PE. The in vivo efficacy of this formulation was assessed in guinea-pigs undergoing delayed-type hypersensitivity (DTH) reactions to dinitrofluorobenzene (DNFB). CyA was applied topically at the time of challenge and twice daily thereafter. At 24 h, skin reactions revealed that compared with appropriate drug vehicles, concentrations of 0.25, 0.5 and 5% CyA +/- PE had a significant inhibitory effect upon the erythema response and this corresponded with significant reductions in T-cell infiltrates (0.5 and 5% CyA). No statistically significant reductions in erythema were demonstrated with 0.05% CyA +/- PE, but there was a reduction in the number of infiltrating lymphocytes in sites receiving 0.05% CyA + PE compared with vehicle-treated sites (P less than 0.01). This suggests that PE permitted some penetration of an otherwise non-immunosuppressive concentration of CyA through the skin.

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KW - Propylene Glycols

KW - Skin

KW - Skin Absorption

KW - T-Lymphocytes, Cytotoxic

KW - T-Lymphocytes, Regulatory

KW - Time Factors

KW - Vehicles

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VL - 123

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EP - 640

JO - British Journal of Dermatology

JF - British Journal of Dermatology

SN - 0007-0963

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