Site-Specific Immunosuppression using a New Formulation of Topical Cyclosporine A with Polyethylene Glycol-8 Glyceryl Caprylate/Caprate

• Published in: The Journal of surgical research Vol. 83; no. 2; pp. 136 - 140
• Main Authors: Tran, Hoang S., Malli, Dipak, Chrzanowski, Francis A., Puc, Matthew M., Matthews, Martha S., Hewitt, Charles W.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 15-05-1999; Elsevier
• Subjects: Administration, Topical; Animals; Biological and medical sciences; Burns - surgery; Caprylates; Cyclosporine - administration & dosage; Cyclosporine - pharmacokinetics; Cyclosporine - therapeutic use; dual skin allografts; Graft Rejection - immunology; Graft Survival - drug effects; Immunosuppression; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Medical sciences; penetration enhancer; Pharmacology. Drug treatments; polyethylene glycol-8 glyceryl caprylate/caprate; Polyethylene Glycols; Rats; Rats, Inbred BN; Rats, Inbred Lew; site-specific immunosuppression (SITE); Skin Diseases - immunology; Skin Diseases - surgery; Skin Transplantation - immunology; Skin, nail, hair, dermoskeleton; Transplantation, Homologous; dual skin allografts; penetration enhancer; site-specific immunosuppression (SITE); polyethylene glycol-8 glyceryl caprylate/caprate; Skin disease; Rat; Treatment efficiency; Rodentia; Homograft; Percutaneous route; Immunomodulator; Ethylene oxide polymer; Site specificity; Vertebrata; Mammalia; Animal; Graft; Skin; Immunosuppressive agent; Therapeutic protocol; Double wall
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1999.5582

Purpose.Dermal application of immunosuppressants can be an effective means of achieving site-specific immunosuppression (SITE) on skin allografts in burn wound management and in the treatment of various immune skin disorders. We have previously reported success with topical cyclosporine A (tCsA) in the treatment of skin allograft rejection in rats. Using a new tCsA formulation with a penetration enhancer (PE), polyethylene glycol-8 (PEG-8) glyceryl caprylate/caprate (Labrasol, Gattefossé, St. Priest, France), in a trinary drug delivery system, we hypothesized that we would induce SITE and significantly delay rejection of dual skin allografts in rats.
Methods.Dual rat skin allografts from Lewis × Brown–Norway (LBN) donors were grafted to Lewis (Lew) recipients. Experimental animals (EXP,n= 7) received a 10-day course of systemic cyclosporine (sCsA, 8 mg/kg/day) followed by topical application. One of the two allografts on each experimental animal received tCsA/PE application (5 mg/kg/day) until sacrifice (tCsA/PE-treated). The other allograft received vehicle only (vehicle-treated). Allogeneic controls (ALLO-CON,n= 9) received no sCsA or tCsA. First signs of rejection were determined based on the initial observation of erythema, hair loss, flakiness, and/or scabs.
Results.The mean time to rejection for ALLO-CON allografts was 6.3 ± 0.7 days (ttest,P= 0.0013); for vehicle-treated allografts, 12.3 ± 3.8 days (pairedttest,P= 0.0146); and for tCsA/PE-treated allografts, 25.6 ± 5.4 days. The disparity of days to rejection between dual allografts in the ALLO-CON group was 0.0 ± 0.0 day and that between the tCsA/PE- and vehicle-treated dual allografts was 13.3 ± 3.9 days (ttest,P= 0.0016).
Conclusions.A new formulation of tCsA in a trinary drug delivery system is successful at delaying the onset of rejection in dual skin allografts in rats by SITE, and PEG-8 glyceryl caprylate/caprate may represent a potentially effective transdermal penetration enhancer.