Abstract
Flurbiprofen (FB) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study was aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of FB were synthesized by amidation with ethyl esters of amino acids, namely, glycine, L-phenylalanine, L-tryptophan, L-valine, L-isoleucine, L-alanine, L-leucine, L-glutamic acid, L-aspartic acid and b alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for bioavailibility studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, anti-inflammatory activities were obtained in all cases as compared to FB. Among synthesized prodrugs AR-9, AR-10 and AR-2 showing excellent pharmacological response and encouraging hydrolysis rate both in (Simulated Intestinal Fluid) SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent resulted in enhanced partition coefficient but diminished dissolution and hydrolysis rate. Such prodrugs can be considered for sustained release purpose.
Highlights
Flurbiprofen (FB), a non-steroidal anti-inflammatory drug, could not be used as to its’ potentials because of adverse reactions offered due to presence of free carboxylic acid group
The non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for indications extending from inflammation and pain to cardiovascular and genitourinary diseases
The direct contact effect can be attributed to a combination of a local irritation produced by acidic group of NSAIDs and local inhibition of prostaglandin synthesis in the GIT
Summary
Flurbiprofen (FB), a non-steroidal anti-inflammatory drug, could not be used as to its’ potentials because of adverse reactions offered due to presence of free carboxylic acid group. Literature reveals that many efforts had been made to synthesize amino acid ester, glycolamide ester, and amide prodrugs using various amines but few attempts were made to develop amide prodrugs using amino acids.[2,3,4,5,6,7,8,9,10,11,12] The salient features of the usefulness of conjugation of amino acids with NSAIDs are as follows:13(i) Amino acids are normal dietary constituent and they are non-toxic in moderate doses as compared to other promoities; (ii) Amino acids have healing effect on gastric lesions produced by NSAIDs; (iii) A drug with free carboxyl group can be derivatized into corresponding esters or amide of amino acids, so as to alter the physical properties of a parent drug with one or more of the hydrolase enzymes serving as the in-vivo reconversion site(s); (iv) Being a nutritional substance, the use of amino acids as a derivatizing group might permit more specific targeting site for enzymes involved in the terminal phase of digestion; (v) Many amino acids possess marked anti-inflammatory activity against gelatin induced hind paw oedema in rats; (vi) By using different types of amino acids like non-polar, polar, acidic and basic, the drug molecule can be made more or less polar, or more or less soluble in given solvent. Bruker DRx300 1HNMR spectroscopy, Jeol SX102-FAB mass spectroscopy and Schimadzu 820 IPC IR spectrophotometer (CDRI, Lucknow, India), HPLC (Shimadzu liquid chromatograph-LC-10AT)
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