FORMULATION DEVELOPMENT AND EVALUATION OF GASTRO-RETENTIVE DOSAGE FORM OF ATAZANAVIR SULPHATE
Objective: To improve dissolution properties of atazanavir sulphate by preparing gastro-retentive granules by solid dispersion method and development of RP-HPLC method for estimation of this drug.
Methods: Estimation of atazanavir sulphate was done using high performance liquid chromatography (HPLC) on inertsil column (5 Âµm, 250x4, 6 mm) with a mobile phase consists of methanol: water (91:9 v/v), at 0.5 ml/min flow rate and 249 nm UV detection. The method was validated as per ICH guidelines. Selection of the carrier for gastro-retentive formulation was based on phase solubility study of the drug. Solid dispersions of gastro-retentive granules of different composition of drug and carrier, were prepared by the kneading, heating and solvent evaporation. A 32factorial design was applied to optimize the gastro-retentive formulation. The amounts of polyethylene glycol 6000 (PEG 6000) (X1) and hydroxypropyl methyl cellulose (HPMC) (X2) were selected as independent variables and in vitro-release at 5, 9 h and total floating time was selected as dependent variables.
Results: HPLC method was found to be linear in a concentration range of 10-60 Î¼g/ml of the drug (r2= 0.999). The low value of % RSD in precision study indicates reproducibility of the method. The low value of LOD and LOQ suggests the sensitivity of the method. The solubility enhancement study of drug with various carriers followed descending order of solubility [Gelucire 44/14>PEG 6000>polyvinyl pyrrilidone (PVP)]. Highest % cumulative release was observed for the heating method at drug polymer (PEG 6000) ratio 1:5. Hence, this ratio has been selected for preparation of solid dispersion. From comparison of dissolution profile of formulated batches, formulation F4 [containing PEG6000 (1.6 g) and HPMC (200 mg)] showed promising dissolution parameters with desired floating properties.
Conclusion: Results obtained by validation studies suggested that the developed HPLC method is simple, accurate, precise and can be used for routine analysis of atazanavir sulphate formulation. Results of evaluation of prepared batches indicate that batch F4 is a promising formulation for gastro-retentive dosage form of drug.Â
2. Goldsmith D, Perry C. Atazanavir. Drugs 2003;16:1679-93.
3. Raja A, Lebbos J, Kirkpatrick P. Atazanavir sulphate nature reviews. News Anal 2003;2:857-8.
4. Kis O, Walmsley S, Bendayan R. In vitro and in situ evaluation of pH-dependence of atazanavir intestinal permeability and interactions with acid-reducing agents. Springer Sci Business Media New York 2014;31:2404-19.
5. Saxena A, Padmanabhan S, Gautam S, Chowan G, Desikan S. Prediction of pH dependent absorption using in vitro, in silico and in vivo rat models: early liability assessment during lead optimization. Eur J Pharm Sci 2015;76:173â€“80.
6. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B 2015;5:442-5.
7. Savjani K, Gajjar A, Savjani J. Drug solubility: importance and enhancement techniques. International Scholarly Research Network ISRN Pharmaceutics; 2012. p. 1-10.
8. Dey S, Patro S, Babu N, Murthy P, Panda S. Development and validation of a stability indicating RP-HPLC method for estimation of atazanavir sulphate in bulk. J Pharm Anal 2013;76:177-86.
9. Bhirud S, Hiremath S. Stability indicating RP-HPLC method for the determination of atazanavir sulphate in bulk and dosage form. Drug Invention Today 2013;5:81-6.
10. Seshachalam U, Rao N, Haribabu B, Chandrashekhar B. Determination of atazanavir in the presence of its degradation products by a stability indicating LC method. Chromatographia 2007;65:355-8.
11. Cattaneo D, Maggioalo M, Ripamonti D, Perico P. Determination of atazanavir in human plasma by HPLC with UV Detection. J Chromatographic Sci 2008;46:485-9.
12. Shrinivasu K, Rao J, Raju N, Mukkanti K. A validated RP-HPLC method for the determination of atazanavir in pharmaceutical dosage form. J Chem 2011;1:453-56.
13. Jain HK, Ranjale R. Development and validation of RP-HPLC method for simultaneous estimation of cefoperazone and tazobactam in marketed formulation. Int J Pharm Pharm Sci 2014;6:462-5.
14. Devkare PN, Jain HK. Development and validation of RP-HPLC method for simultaneous estimation of S(-) amlodipine besylate and clopidogrel bisulphate in tablet dosage form. Int J Pharm Pharm Sci 2013;5:770-5.
15. ICH Harmonized-tripartite guidelines, validation of analytical procedure: text and methodology Q2 (R1); 2005.
16. Sinha S, Ali M, Ali J. Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir. PharmSciTech 2010;2:518â€“27.
17. Yadav P, Kumar V, Singh U, Bhat H, Mazumder B. Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and D-mannitol. Saudi Pharm J 2013;21:77â€“84.
18. Balata G, Mahdi M, Bakera R. Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes. Indian J Pharm Sci 2011;5:517â€“26.
19. Hadiabdic J, Elezovic A, Rahic O, Mujezin I. Effect of cyclodextrin complexation on the aqueous solubility of diazepam and nitrazepam: phase-solubility analysis, thermodynamic properties. Am J Anal Chem 2012;3:811-20.
20. Nama M, Gonugunta C, Veerareddy P. Formulation and evaluation of gastroretentive dosage forms of clarithromycin. Pharm SciTech 2008;9:521-35.
21. Gambhire M, Ambade K, Kurmi K, Kadam V, Jadhav K. Development and in vitro evaluation of an oral floating matrix tablet formulation of diltiazem hydrochloride. PharmSciTech 2007;3:1-9.
22. Shimpi S, Chauhan B, Mahadik K, Paradkar A. Preparation and evaluation of diltiazem hydrochloride-gelucire 43/01 floating granules prepared by melt granulation. PharmSciTech 2004;3:1-6.
23. Patel D, Patel N, Patel V, Bhatt D. Floating granules of ranitidine hydrochloride-gelucire 43/01: formulation optimizat0ion using factorial design. PharmSciTech 2007;2:1-7.