In-vitro and in-vivo evaluation of oligoethylene esters as dermal prodrugs of 18beta-glycyrrhetic acid

J Pharm Pharmacol. 2006 Mar;58(3):311-9. doi: 10.1211/jpp.58.3.0004.

Abstract

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.

MeSH terms

  • Administration, Cutaneous
  • Adult
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / therapeutic use
  • Chromatography, High Pressure Liquid
  • Dermatologic Agents / administration & dosage*
  • Dermatologic Agents / therapeutic use
  • Drug Stability
  • Erythema / chemically induced
  • Erythema / drug therapy
  • Esters
  • Female
  • Gels
  • Glycyrrhetinic Acid / administration & dosage*
  • Glycyrrhetinic Acid / chemistry
  • Glycyrrhetinic Acid / therapeutic use
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Male
  • Nicotinic Acids
  • Permeability
  • Polyethylene Glycols / chemistry*
  • Prodrugs / administration & dosage*
  • Prodrugs / chemistry
  • Prodrugs / therapeutic use
  • Skin / metabolism
  • Skin Absorption

Substances

  • Anti-Inflammatory Agents
  • Dermatologic Agents
  • Esters
  • Gels
  • Nicotinic Acids
  • Prodrugs
  • Polyethylene Glycols
  • methyl nicotinate
  • Glycyrrhetinic Acid