Synthesis and transdermal penetration of NSAID glycoside esters
Introduction
The benefits associated with the topical route of drug administration have been well documented. The greatest advantages include a non-invasive treatment regimen, bypassing of first pass metabolism and quick interruption of treatment (Naik et al., 2000, Flynn, 1993, Beckett, 1982). These reasons have led to the recent upsurge in research in the transdermal delivery of drugs. The skin is an efficient barrier between the internal plasma and the harsh exterior, providing a great challenge to the scientist in the quest for transdermal drug delivery (Pefile and Smith, 1997). Much research has been conducted to improve the flux of drugs through the skin, concentrating primarily on decreasing the barrier function of this complex membrane system. Another feasible option is the synthesis of derivatives with improved transdermal flux, but which do not compromise the drug's efficacy (Bonina et al., 2001). A further approach is to use enhancers with optimum permeation properties that can be delivered concurrently with the drug.
NSAIDs possess anti-pyretic, analgesic and anti-inflammatory activity. Their primary use is as anti-inflammatory agents for the treatment of musculoskeletal disorders, including rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Their use is limited to the relief from pain and inflammation, as they do not halt the progression of the pathological injury caused to the tissue. They are also used in the treatment of inflammation, fever, primary dysmenorrhoea and in the management of mild pain (Insel, 1996).
Transdermal drug delivery offers a number of advantages over the traditional NSAID formulations, namely oral delivery and injection. It includes the elimination of first pass metabolism, minimisation of pain and discomfort, possible sustained drug release over a specific period of time and vastly improved patient compliance (Mitragotri, 2000). There is much concern regarding the scale of morbidity associated with gastric complications resulting from NSAIDs used by the elderly in the treatment musculoskeletal and joint pain associated with rheumatoid and osteoarthritis (Grahame, 1995).
Optimal transport through the skin requires a drug to possess lipophilic as well as hydrophilic properties (Sloan and Wasdo, 2003, Guy and Hadgraft, 1992). Previous research indicated the ideal log P value for optimal transdermal permeation of non-steroidal anti-inflammatory drugs (NSAIDs) to be between 2 and 3 (Hadgraft and Wolff, 1993, Hadgraft et al., 2000). In this investigation NSAIDs, all having log P values higher than 2, were selected for the preparation of their glycosides with the objective of determining the skin penetration properties of these compounds as a function of their structure and stereochemistry. This information will enhance our database on the relationship between physical properties and the transdermal penetration of compounds.
In this study, the glucose and mannose esters of flurbiprofen (1), ibuprofen (2), ketoprofen (3) and naproxen (4) were successfully prepared from glucose and mannose, respectively, in an enzyme catalysed reaction.
Section snippets
Chemicals
Ibuprofen, ketoprofen and naproxen were generously donated by Lennon (South Africa) and flurbiprofen was generously donated by Abbott Laboratories (South Africa) and BASF (Germany). The Candida antarctica lipase B (SP 435) was generously donated by the Department of Microbiology and Biochemistry, University of the Free State, South Africa. Reagent grade glucose, mannose, t-butanol, o-phosphoric acid and 4 Å molecular sieves were purchased from Sigma–Aldrich (South Africa). Reagent grade
Synthesis
The products obtained were 6′-glucopyranosyl-2-(3-fluoro-4-biphenyl) propanoate (flurbiprofen glucoside) (5), 6′-glucopyranosyl-2-(4-isobutyl-phenyl) propanoate (ibuprofen glucoside) (6), 6′-glucopyranosyl-2-(3-benzoylphenyl) propanoate (ketoprofen glucoside) (7), 6′-glucopyranosyl-2-(6-methoxy-2-naphthyl) propanoate (naproxen glucoside) (8), 6′-mannopyranosyl-2-(3-fluoro-4-biphenyl) propanoate (flurbiprofen mannoside) (9), 6′-mannopyranosyl-2-(4-isobutyl-phenyl) propanoate (ibuprofen
Aqueous solubility
The aqueous solubility (in phosphate buffer, Table 3) of all compounds increased with increasing pH from 4.0 to 7.0 (although some had a lower solubility at pH 5.5). This phenomenon may be explained by an increase in the ionisation of the compounds with an increase in pH to 7.0 and a subsequent higher aqueous solubility. Whereas the solubility of the parent NSAIDs increased substantially (up to 100 times) through the pH range, that of the glycosides only increased marginally (at most three
Conclusion
These results confirm that transdermal flux is greatly determined by partition coefficient and aqueous solubility as the parent NSAIDS with log P values closer to 2–3 and higher aqueous solubility at pH 7 than that of the glycoside derivatives presented with higher transdermal flux.
Acknowledgements
We thank the South African National Research Foundation for financial support, Prof. MS Smit from the Department Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa for C. antarctica Lipase B, Abbott Laboratories and BASF for a generous gift of flurbiprofen and Novo Nordisk for a generous gift of Novazym SP 435 enzyme.
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