Steep improvement in dissolution profile of ezetimibe through co-inclusion in urea
Tóm tắt
The main objective of the present study was to simultaneously improve the dissolution profile and content uniformity of ezetimibe (EZ), a low dose poorly soluble drug, through co-inclusion in urea. EZ, a new category of cholesterol absorption inhibitor used in the treatment of primary hypercholesterolemia and sitosterolemia, reveals extremely poor solubility in water and dissolution rate limited absorption resulting in its low bioavailability. In the current study, EZ—a highly substituted potent compound which is normally non-complexing guest (NNCG) was successfully incorporated in urea lattice in the presence of readily complexing guest (RCG). The modified Zimmerschied calorimetric method was used for the estimation of the minimum amount of RCG required per unit weight of drug for co-inclusion in urea. Ezetimibe urea co-inclusion complexes (EZUCIC) containing varying proportions of RCG and NNCG were prepared and subjected to thermal analysis using DSC. The formation of EZUCIC was confirmed by FTIR, DSC, XRD and 1H-NMR studies. The thermal data was subjected to the regression studies to study the effect of the relative molar fraction of RCG on the heat of decomposition of EZUCIC. Study exhibited improved content uniformity of EZ in EZUCIC. In vitro dissolution rate studies exhibited steep improvement in the dissolution profile of EZ, a BCS class II drug. The dissolution data was subjected to various release kinetic models. Steep improvement in the dissolution profile offer urea co-inclusion technique a promising alternative for formulation of poorly soluble potent drug candidates into immediate release products with improved content uniformity.
Tài liệu tham khảo
Ajmera A, Deshpande S, Kharadi S, Rathod K, Patel K, Patel P (2012) Dissolution rate enhancement of atorvastatin, fenofibrate and ezetimibe by inclusion complex with Î2 cyclodextrin. Asian J Pharm Clin Res 5(4):73–78
Bengen MF (1940) Urea channel inclusion compounds. German Patent Application OZ123438
Bergum JS, Li H (2007) Acceptance Limits for the New ICH USP 29 content uniformity test. Pharm Tech 31(10):91–96
Brodman BW, Radell J (1967) X-ray powder diffraction patterns of some—alkanone urea inclusion compounds. Seperation Sci 2:139–142
Chaitanya P, Penta J, Devadasu VR, Venisetty RK, Vemula SK (2014) ezetimibe solid dispersions: formulation, development and in vitro evaluation. AJADD 2(1):090–103
Chimalakonda K, Kamani V, Gutta M, Polisetty S, Koduri SVS (2013) Isolation and characterization of r-enantiomer in ezetimibe. Am J Anal Chem 4:488–495
Clanton DC (1978) Non-protein nitrogen in range supplements. J Anim Sci 47:765–779
Davies JP, Levy B, Ioannou YA (2000) Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics 65(2):137–145
Dhall M, Madan AK (2015a) Studies on urea co-inclusion complexes of simvastatin for improvement of pharmaceutical characteristics. J Incl Phenom Macrocycl Chem 81(1–2):105–120
Dhall M, Madan AK (2015b) Simultaneous improvement in dissolution profile and content uniformity of lafutidine through co-inclusion in urea. J Incl Phenom Macrocycl Chem. doi:10.1007/s10847-015-0493-z
Drazen JM, Jarcho JA, Morrissey S, Curfman GD (2008) Cholesterol lowering and ezetimibe. N Eng J Med 358(14):1507–1508
Dujovne CA, Ettinger MP, McNeer JF (2002) Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J of Cardiol 90(10):1092–1097
Fischer PHH, McDowell CA (1960) The infrared absorption spectra of urea-hydrocarbon adduct. Can J Chem 38(187–1):93
Frank SG (1975) Inclusion compounds. J Pharm Sci 64:1585–1604
Galkina E, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Ann Rev Immun 27:165–197
Gulsun T, Gursoy RN, Oner L (2011) Design and characterization of nanocrystal formulations containing ezetimibe. Chem Pharm Bull 59(1):41–45
Harris KDM (1993) Solid state NMR. Nucl Mag Reson 22:230–260
Harris KDM (1997) Meldola Lecture: understanding properties of urea and thiourea inclusion compounds. Chem Soc Rev 26:279–289
Harris KDM (2007) Fundamental and applied aspects of urea and thiourea inclusion compounds. Supramol Chem. doi:10.1080/10610270600977706
Harris KDM, Thomas JM (1990) Structure aspects of urea inclusion compounds and their investigation by X-ray diffraction: a general discussion. J Chem Soc 86:2985–2996
Ijioma N, Robinson JG (2011) Lipid-lowering effects of ezetimibe and simvastatin in combination. Expert Rev Cardiovasc Ther 9(2):131–145
Kane RN, Kuchekar BS, Naik SR, Bumrela SB (2010) Physicochemical characterization, formulation, and dissolution studies of ezetimibe hydroxypropyl-beta-cyclodextrin inclusion complex. Int J Chem Ana Sci 1(2):65–70
Khanfar M, Salem MS, Hawari R (2012) Formulation factors affecting the release of ezetimibe from different liquisolid compacts. Pharm Dev Technol. doi:10.3109/10837450.2012.680594
Kumar YP, Sridhar C, Reddy AS, Reddy LS (2011) Development and validation of spectrophotometric method for estimation of ezetimibe in tablet formulation. J Glob Trend Pharm Sci. 2(2):118–130
Lee M, Lu K, Patel SB (2001) Genetic basis of sitosterolemia. Curr Opin Lipid 12(2):141–149
Madan AK (1994) Microencapsulation of low dose drugs. Ph.D. Thesis, IIT Delhi, Delhi
Madan AK, Bajaj V (1994) A process for preparation of urea based inclusion compounds of vitamin E and its esters. Indian Patent 182620
Madan AK, Grover PD (1993) A process for preparation of urea based inclusion compounds of vitamin A esters. Indian Patent 180627
Marsh KL, Sims GK, Mulvaney RL (2005) Availability of urea to autotrophic ammonia-oxidizing bacteria as related to the fate of 14C- and 15 N-labeled urea added to soil. Biol Fert Soil 42:137–145
Mauro VF, Tuckerman CE (2003) Ezetimibe for management of hypercholesterolemia. Downloads/Ez pharma 1.htm Ann Pharmcother 37(6):839–848
McAdie MG (1963) Thermal decomposition of molecular complexes. Can J Chem 41:2144–2153
Nutescu EA, Shapiro NL (2003) ezetimibe: a selective cholesterol absorption inhibitor. Pharmacother 23(11):1–6
Oner L, Gursoy RN, Gulsun T (2010) Methods for the preparation of ezetimibe nanacrystals. European Patent WO2010144066A1
Parmar KR, Shah SR, Sheth NR (2011a) Preparation, characterization and in vitro evaluation of ezetimibe binary solid dispersions with poloxamer 407 and PVP K30. J Pharm Innov 6(2):104–114
Parmar KR, Shah SR, Sheth NR (2011b) Studies in dissolution enhancement of ezetimibe by solid dispersions in combination with a surfactant. Dissolution Technol 18(3):55–61
Patel SB (2004) Ezetimibe: a novel cholesterol-lowering agent that highlights novel physiologic pathways. Curr Cardiol Rep 6(6):439–442
Patel R, Bhimanj D, Patel J, Patel D (2007) Solid state characterization and dissolution properties of ezetimibe cyclodextrins inclusion complexes. J Incl Phenom Macrocycl Chem 60(3–4):241–251
Sancheti PP, Karekar P, Vyas VM, Shah M, Pore YV (2009) Preparation and physicochemical characterization of surfactant based solid dispersions of ezetimibe. Pharmazie 64(4):227–231
Schiessler RW, Flitter D (1954) Urea and thiourea adduction of C5-C42- Hydrocarbons. J Am Chem Soc 74:1720–1723
Schlenk W (1949) Urea addition of aliphatic compounds. Justus Liebigs Ann Chem 565:204–240
Selic L, Ham Z (2008) Inclusion complex of ezetimibe and a cyclodextrin and processes in the preparation thereof. European Patent EP1939174A1
Smith AE (1952) The crystal structure of urea-hydrocarbon complexes. Acta Crystallogr 5:224–235
Son B, Tep S, Kulkin NA (2011) Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. J Lipid Res 52(4):679–687
Stella V, Haslam J, Yata N, Okada H, Lindenbaum S, Higuchi T (1978) Enhancement of bioavailability of a hydrophobic amine antimalarial by formulation with oleic acid in a soft gelatin capsule. J Pharm Sci 67:1375–1377
Takemoto K, Sonada N (1984) Inclusion compounds of urea, thiourea and selenourea. In: Atwood JL, Davis JED, MacNicol DD (eds) Inclusion compounds, vol 2. Academic Press, London, pp 47–67
Taylor F, Ward K, Moore T, Burke M, Smith GD, Casa JP, Ebrahim S (2011) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. doi:10.1002/14651858.CD004816.pub4
Thakral S, Madan AK (2007) Urea inclusion compounds of enalapril maleate for the improvement of pharmaceutical characteristics. J Pharm Pharmacol 59(11):1501–1507
Thakral S, Madan AK (2008a) Adduction of amiloride hydrochloride in urea through a modified technique for the dissolution enhancement. J Pharm Sci 97(3):1191–1201
Thakral S, Madan AK (2008b) Reduction in moisture sensitivity/uptake of moisture sensitive drugs through adduction in urea. J Pharm Innov. doi:10.1007/s12247-008-9045-z
Thakral S, Madan AK (2008c) Urea co-inclusion compounds of 13 cis-retinoic acid for simultaneous improvement of dissolution profile, photostability and safe handling characteristics. J Pharm Pharmacol 60(7):823–832
Thakral S, Madan AK (2008d) Urea co-inclusion compounds of glipizide for the improvement of dissolution profile. J Incl Phenom Macrocycl Chem. doi:10.1007/s10847-007-9368-2
Thakral S, Madan AK (2012) Topological models for prediction of heat of decomposition of urea inclusion compounds containing aliphatic endocytes. J Incl Phenom Macrocycl Chem 60(1):187–192
Zimmerschied WJ, Dinnerstein RA, Weitkamp AW, Marschner RF (1950) Crystalline adducts of urea with linear aliphatic compounds. Ind Eng Chem 42:1300–1306