In-vitro and in-vivo evaluation of oligoethylene esters as dermal prodrugs of 18beta-glycyrrhetic acid.
Novel polyoxyethylene esters of 18 beta-glycyrrhetic acid (GA) were synthesized and evaluated as potential dermal prodrugs. The permeation of these prodrugs (1a-e) was studied in-vitro, using excised human skin membranes (SCE; stratum corneum/epidermis) mounted in Franz type cells, and in-vivo, evaluating the ability of these compounds to inhibit methyl nicotinate (MN)-induced skin erythema in healthy human subjects. All the esters synthesized showed a good water stability, while the enzymatic hydrolysis rate was significantly affected by the length of the polyoxyethylenic chain used as promoiety. In in-vitro percutaneous absorption studies, only esters 1b and 1c (respectively triethylen- and tetraethylenglycol derivatives) showed an increased flux through SCE membranes compared with GA. Furthermore, we observed an appreciable and sustained in-vivo topical anti-inflammatory activity of esters 1b and 1c compared with the parent drug.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Catania, Italy. capuglia@unict.it
Carmelo
C
Puglia
Carmine
C
Ostacolo
Antonia
A
Sacchi
Sonia
S
Laneri
Francesco
F
Bonina
D000279:Administration, Cutaneous; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004355:Drug Stability; D004890:Erythema / Q000139:chemically induced / Q000188:drug therapy; D004952:Esters; D005260:Female; D005782:Gels; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D009539:Nicotinic Acids; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption
D000893:Anti-Inflammatory Agents; D003879:Dermatologic Agents; D004952:Esters; D005782:Gels; D009539:Nicotinic Acids; D011355:Prodrugs; D011092:Polyethylene Glycols; C008473:methyl nicotinate; D006034:Glycyrrhetinic Acid