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Novel Thioester Prodrug of N-acetylcysteine for Odor Masking and Bioavailability Enhancement

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Background: The mucolytic N-acetylcysteine (NAC) is used to control the excessive mucus secretion if mucus is the underlying cause of broncho-constriction. Its major drawbacks are poor bioavailability due to extensive first pass effect, poor lipophilicity, high protein binding and offensive odor.

Methods: For minimizing above shortcomings of NAC, in present study thioester (A1) prodrug of NAC was synthesized by conventional as well as microwave-assisted methods. Release studies of A-1 were carried out using HPLC and pharmacological evaluation was performed in ovalbumin-induced model of pulmonary inflammation in Sprague dawley rats.

Results: A-1 was found to be stable in HCl buffer, phosphate buffer, stomach homogenates but furnished 30% NAC in 6h and 1.7% of NAC in 4h when incubated with small intestinal and liver homogenates respectively. Upon oral administration of A-1 to rats, 4.85% NAC was detected in blood at 8h. Urine samples pooled over a period of 24h exhibited 0.75% NAC while negligible concentration was found in 24 h pooled samples of feces.

Conclusion: The findings of this preliminary investigation demonstrated significant effects of thioester prodrug A-1 as compared to NAC through reduction of lung inflammation, airway eosinophilia and reversal of lung function parameters in ovalbumin- challenged rats at half the equimolar dose of NAC. Interestingly masking thiol group through thioester formation resulted in odorless prodrug. We propose that thioester prodrug using palmitic acid as a carrier is a promising strategy to enhance bioavailability of NAC by increasing its lipophilicity/ absorption and minimizing its first pass metabolism.
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Keywords: N-acetylcysteine; odor masking; ovalbumin; palmitic acid; poor bioavailability; thioester prodrug; thiol

Document Type: Research Article

Publication date: 01 June 2016

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  • The aim of Current Drug Delivery is to publish peer-reviewed articles, short communications, short and in-depth reviews in the rapidly developing field of drug delivery. Modern drug research aims to build in delivery properties of a drug at the design phase, however in many cases this ideal cannot be met and the development of delivery systems becomes as important as the development as the drugs themselves.

    The journal aims to cover the latest outstanding developments in drug and vaccine delivery employing physical, physico-chemical and chemical methods. The drugs include a wide range of bioactive compounds from simple pharmaceuticals to peptides, proteins, nucleotides, nucleosides and sugars. The journal will also report progress in the fields of transport routes and mechanisms including efflux proteins and multi-drug resistance.

    The journal is essential for all pharmaceutical scientists involved in drug design, development and delivery.
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