In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl pro...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 1998-12, Vol.87 (12), p.1622-1628
Main Authors: Rautio, Jarkko, Taipale, Hannu, Gynther, Jukka, Vepsalainen, Jouko, Nevalainen, Tapio, Jarvinen, Tomi
Format: Article
Language:English
Subjects:
Acylation
Alkylation
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Chromatography, High Pressure Liquid
Esters - chemical synthesis
Esters - pharmacokinetics
Humans
In Vitro Techniques
Ketoprofen - analogs & derivatives
Ketoprofen - blood
Ketoprofen - pharmacokinetics
Medical sciences
Naproxen - analogs & derivatives
Naproxen - blood
Naproxen - pharmacokinetics
Pharmacology. Drug treatments
Prodrugs
Skin Physiological Phenomena
Solubility
Spectrometry, Mass, Secondary Ion
Time Factors
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Summary:A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.
ISSN:0022-3549
1520-6017
DOI:10.1021/js970465w