| In vitro and in vivo evaluation of polyoxyethylene esters as dermal prodrugs of ketoprofen, naproxen and diclofenac. | |
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MedLine Citation:
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PMID: 11500258 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Novel polyoxyethylene esters of ketoprofen (1(a-e)), naproxen (2(a-e)) and diclofenac (3(a-e)) were synthesized and evaluated as potential dermal prodrugs of naproxen, ketoprofen and diclofenac. These esters were obtained by coupling these drugs with polyoxyethylene glycols by a succinic acid spacer. The aqueous solubilities, lipophilicities and hydrolysis rates of esters 1(a-e), 2(a-e) and 3(a-e) were determined in a buffered solution and in porcine esterase. The permeation of these prodrugs through excised human skin was studied in vitro. Furthermore we investigated the in vivo topical anti-inflammatory activity of esters 1(d), 2(e) and 3(e), which showed the best in vitro profile, evaluating the ability of these compounds to inhibit methyl nicotinate (MN)-induced skin erythema on healthy human volunteers. Esters 1(a-e), 2(a-e) and 3(a-e) showed good water stability and rapid enzymatic cleavage and their hydrolysis rates, both chemical and enzymatic, were not significantly affected by the length of the polyoxyethylenic chain used as promoiety. Concerning in vitro percutaneous absorption studies, only esters 1(d-e), 2(d-e) and 3(c-e) showed an increased flux through stratum corneum and epidermis membranes compared to their respective parent drugs. In vivo results showed an interesting delayed and sustained activity of esters 1(d) and 3(e) compared to the parent drugs. In conclusion polyoxyethylene glycols could prove to be suitable promoieties for ketoprofen, naproxen and diclofenac design since esters 1(d-e), 2(d-e) and 3(c-e) showed some requirements (chemical stability, enzymatic lability and an increased skin permeation) needed to obtain successful dermal prodrugs. Furthermore, was observed an appreciable and sustained in vivo topical anti-inflammatory activity of esters 1(d) and 3(e), compared to the parent drugs, using MN-induced erythema in human volunteers as inflammation model. |
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Authors:
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F P Bonina; C Puglia; T Barbuzzi; P de Caprariis; F Palagiano; M G Rimoli; A Saija |
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Publication Detail:
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Type: Evaluation Studies; Journal Article |
Journal Detail:
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Title: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences Volume: 14 ISSN: 0928-0987 ISO Abbreviation: Eur J Pharm Sci Publication Date: 2001 Sep |
Date Detail:
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Created Date: 2001-08-13 Completed Date: 2001-12-04 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 9317982 Medline TA: Eur J Pharm Sci Country: Netherlands |
Other Details:
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Languages: eng Pagination: 123-34 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. boninaf@mbox.unict.it |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Cutaneous Adult Anti-Inflammatory Agents, Non-Steroidal / administration & dosage*, chemistry, metabolism Area Under Curve Diclofenac / administration & dosage, chemistry, metabolism Erythema / drug therapy Female Gels Humans Ketoprofen / administration & dosage, chemistry, metabolism Male Middle Aged Naproxen / administration & dosage, chemistry, metabolism Polyethylene Glycols / administration & dosage*, chemistry, metabolism Prodrugs / administration & dosage*, chemistry, metabolism Skin Absorption / drug effects*, physiology Solubility Solvents / administration & dosage, chemistry, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Gels; 0/Polyethylene Glycols; 0/Prodrugs; 0/Solvents; 15307-86-5/Diclofenac; 22071-15-4/Ketoprofen; 22204-53-1/Naproxen |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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