Study of Effect of Variables on Particle Size of Telmisartan Nanosuspensions Using Box-Behnken Design

Abstract

Telmisartan, an orally active nonpeptide angiotensin II receptor antagonist is a BCS Class II drug having aqueous solubility of 9.9 µg/ml and hence oral bioavailability of 40%. The present study involved preparation of nanosuspensions by evaporative antisolvent precipitation technique to improve the saturation solubility and dissolution rate of telmisartan. Various stabilizers such as TPGS, PVPK 30, PEG 6000 were investigated of which TPGS was found to provide maximum decrease in particle size and accord greater stability to the nanosuspensions. Box-Behnken design was used to investigate the effect of independent variables like stabilizer concentration, time and speed of stirring on particle size of nanosuspensions. Pharmacodynamic studies using Goldblatt technique were undertaken to evaluate the effect of nano-sizing on the hypotensive effect of the drug. Concentration of TPGS and speed of rotation were found to play an important role in particle size of the nanosuspensions whereas time of stirring displayed an exponential relationship with particle size. Freeze dried nanocrystals obtained from nanosuspension of least particle size were found to have increased saturation solubility of telmisartan in different dissolution media. The reconstituted nanosuspension was found to reduce both systolic and diastolic blood pressure without affecting pulse pressure and heart rate. Statistical tools can be used to identify key process and formulation parameters which play a significant role in controlling the particle size in nanosuspensions.

Key words

telmisartan - nanosuspensions - Box-Behnken design - Goldblatt technique

• References

• 1 Jochem A, Kansy M. High Throughput Solubility Measurement in Drug Discovery and Development. Adv Drug Del Rev 2007; 59: 546-567
• 2 Blagden N, De Matas M, Pt Gavan et al. Crystal Engineering Of Active Pharmaceutical Ingredients To Improve Solubility And Dissolution Rates. Adv Drug Del Rev 2007; 59: 617-630
• 3 Kim C, Park J. Solubility Enhancement For Oral Drug Delivery: Can Chemical Structure Modification Be Avoided. Am J Drug Deliv 2004; 2: 113-130
• 4 Merisko-Liversidge E, Liversidge G, Cooper E. Nanosizing: A Formulation Approach for Poorly Water Soluble Compounds. Eur J Pharm Sci 2003; 18: 113-120
• 5 Forster A, Rades T, Hempenstall J. Selection Of Suitable Drug And Excipient Candidates To Prepare Glass Solutions By Melt Extrusion For Immediate Release Oral Formulations. Pharm Tech Eur 2001; 14: 27-37
• 6 Amin K, Dannenfesler R, Zielinski J et al. Lyophilization of Polyethylene Glycol Mixtures. J Pharm Sci 2004; 93: 2244-2249
• 7 Davis M, Brewster M. Cyclodextrin Based Pharmaceutics: Past, Present, Future. Nat Rev Drug Discov 2004; 3: 1023-1035
• 8 Humberstone A, Charman W. Lipid-Based Vehicles For The Oral Delivery Of Poorly Water Soluble Drugs. Adv Drug Del Rev 1997; 25: 103-128
• 9 Torchillin V. Micellar Nanocarriers: Pharmaceutical Perspectives. Pharm Res 2007; 24: 1-16
• 10 Dressman J, Amidon G, Reppas C et al. Dissolution Testing as a Prognostic Tool for Oral Drug Absorption- Immediate Release Dosage Forms. Pharm Res 1988; 15: 11-22
• 11 Goldblatt P. The Goldblatt Experiment: A Conceptual Paradigm. In: Laragh JH, Brenner BM. (eds.). Hypertension: Pathophysiology, Diagnosis And Management. 2^nd ed. New York: Raven Press; 1995
• 12 Keck C, Müller R. Drug Nanocrystals of Poorly Soluble Drugs Produced by High Pressure Homogenization. Eur J Pharm Biopharm 2006; 62: 3-16
• 13 Matteucci M, Hotze M, Johnston K et al. Drug Nanocrystals By Antisolvent Precipitation: Mixing Energy Vs. Surfactant Stabilization. Langmuir 2006; 22: 8951-8959
• 14 Eerdenbrugh B. Top-Down Production Of Drug Nanocrystals: Nanosuspension Stabilization, Miniaturization and Transformation into Solid Products. Int J Pharm 2008; 364: 64-75
• 15 Rao Monica RP, Amrita B, Amol P. Nanocrystallization by Evaporative Antisolvent Precipitation for Enhancement of Solubility and Bioavailability of Telmisartan. AAPS Pharmscitech 2012; 13: 1331-1340