DEVELOPMENT AND CHARACTERIZATION OF TACROLIMUS TABLET FORMULATIONS FOR SUBLINGUAL ADMINISTRATION

JISHA MOHANAN; SEENIVASAN PALANICHAMY; ARUL KUTTALINGAM; DAMODHARAN NARAYANASAMY

doi:10.22159/ijap.2021v13i6.42429

Authors

JISHA MOHANAN College of Pharmaceutical Sciences, Government Medical College, Kozhikode 673008, Kerala, India
SEENIVASAN PALANICHAMY Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai 600116, Tamil Nadu, India
ARUL KUTTALINGAM College of Pharmaceutical Sciences, Government Medical College, Kottayam 686008, Kerala, India
DAMODHARAN NARAYANASAMY SRM College of Pharmacy, SRM University, Kattankulathur 603203, Tamil Nadu, India

DOI:

https://doi.org/10.22159/ijap.2021v13i6.42429

Keywords:

Tacrolimus, β-Cyclodextrin, Inclusion complex, Kneading, Solubility, Sublingual tablet, Fast disintegrating

Abstract

Objective: The study aimed to prepare and characterize inclusion complexes of tacrolimus with β-cyclodextrin to improve its solubility and to formulate them into sublingual fast disintegrating tablets with a view to bypass the first-pass metabolism.

Methods: Tacrolimus: β-cyclodextrin inclusion complexes (1:1 and 1:2 molar proportions) were prepared using the kneading method. Their characterization was accomplished by determining the drug content, solubility, Attenuated Total Reflection-Infrared Spectroscopy (ATR-IR), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction analysis (pXRD). These were then formulated to fast disintegrating tablets and evaluated for precompression as well as post compressional characteristics.

Results: SEM analysis showed the inclusion complexes as rough, non-porous, irregular surfaced aggregate particles. DSC and pXRD analyses confirm the crystallinity change and partial conversion to the amorphous form of the drug in the inclusion complexes. From the solubility studies, it was observed that both the inclusion complexes of 1:2 molar ratio (14.82±0.889 µg/ml) and 1:1 molar ratio (12.72±0.1004 µg/ml) improved the aqueous solubility to greater extents in comparison to that of the pure drug (3.05±0.121 µg/ml). All the tablet formulations showed good precompression and mechanical properties. The inclusion complex loaded tablets exhibited a superior drug release pattern when compared to tablets prepared with tacrolimus alone. The optimized formulation (TT3) showed an in vitro disintegration time of 34.33 s and a percent drug release of 97.87.

Conclusion: The inclusion complex formulation combined with the sublingual route of administration can be expected to result in an improved bioavailability of tacrolimus by increasing its solubility and bypassing first-pass metabolism.

Downloads

Download data is not yet available.

References

Park YJ, Ryu DS, Li DX, Quan QZ, Oh DH, Kim JO, Seo YG, Lee YI, Yong CS, Woo JS, Choi HG. Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate. Arch Pharm Res. 2009;32(6):893-8. doi: 10.1007/s12272-009-1611-5, PMID 19557367.

Tamura S, Ohike A, Ibuki R, Amidon GL, Yamashita S. Tacrolimus is a class II low-solubility high-permeability drug: the effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats. J Pharm Sci. 2002;91(3):719-29. doi: 10.1002/jps.10041, PMID 11920757.

Joint formulary committee. British National Formulary. BMJ 2008;56:483.

Van Duijnhoven E, Christiaans M, Undre N, Stevenson P, Van Hooff J. The effect of breakfast on the oral bioavailability of tacrolimus in diabetic and nondiabetic patients before transplantation. Transplant Proc. 1998;30(4):1268-70. doi: 10.1016/s0041-1345(98)00237-1, PMID 9636515.

Patel P, Patel H, Panchal S, Mehta T. Formulation strategies for drug delivery of tacrolimus: an overview. Int J Pharm Investig. 2012;2(4):169-75. doi: 10.4103/2230-973X.106981, PMID 23580932.

Srinarong P, Pham BT, Holen M, Van Der Plas A, Schellekens RCA, Hinrichs WLJ, Frijlink HW. Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration. Drug Dev Ind Pharm. 2012;38(4):490-500. doi: 10.3109/03639045.2011.613075, PMID 21961909.

Zidan AS. Taste-masked tacrolimus-phospholipid nanodispersions: dissolution enhancement, taste masking and reduced gastric complications. Pharm Dev Technol. 2017;22(2):173-83. doi: 10.3109/10837450.2016.1138131, PMID 26811031.

Chung Y, Cho H. Preparation of highly water soluble tacrolimus derivatives: poly(ethylene glycol) esters as potential prodrugs. Arch Pharm Res. 2004;27(8):878-83. doi: 10.1007/BF02980183, PMID 15460452.

Yamashita K, Nakate T, Okimoto K, Ohike A, Tokunaga Y, Ibuki R, Higaki K, Kimura T. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm. 2003;267(1-2):79-91. doi: 10.1016/j.ijpharm.2003.07.010, PMID 14602386.

Yoshida T, Kurimoto I, Yoshihara K, Umejima H, Ito N, Watanabe S. Aminoalkyl methacrylate copolymers for improving the solubility of tacrolimus. I: Evaluation of solid dispersion formulations. Int J Pharm. 2012;428(1-2):18-24. doi: 10.1016/j.ijpharm.2012.02.041, PMID 22405967.

Kovvasu SP, Kunamaneni P, Kunderu RS. Cyclodextrins and their application in enhancing the solubility, dissolution rate and bioavailability. Innoriginal Int J Sci 2018;5:25-34.

Al Sagheer T, Enderby CY. Determining the conversion ratios for oral versus sublingual administration of tacrolimus in solid organ transplant recipients. Clin Transplant. 2019;33(10):e13727. doi: 10.1111/ctr.13727, PMID 31587353.

Solari S, Cancino A, Wolff R, Norero B, Vargas JI, Barrera F, Guerra JF, Martínez J, Jarufe N, Soza A, Arrese M, Benitez C. Sublingual tacrolimus administration provides similar drug exposure to per-oral route employing lower doses in liver transplantation: a pilot study. Aliment Pharmacol Ther. 2017;45(9):1225-31. doi: 10.1111/apt.14022, PMID 28261844.

Watkins KD, Boettger RF, Hanger KM, Leard LE, Golden JA, Hoopes CW. Use of sublingual tacrolimus in lung transplant recipients. J Heart Lung Transplant. 2012;31(2):127-32. doi: 10.1016/j.healun.2011.10.015, PMID 22177691.

Nasiri-Toosi Z, Dashti-Khavidaki S, Nasiri-Toosi M, Khalili H, Jafarian A, Irajian H, Abdollahi A, Sadrai S. Clinical pharmacokinetics of oral versus sublingual administration of tacrolimus in adult liver transplant recipients. Exp Clin Transplant. 2012;10(6):586-91. doi: 10.6002/ect.2012.0032, PMID 22770208.

Arima H, Yunomae K, Miyake K, Irie T, Hirayama F, Uekama K. Comparative studies of the enhancing effects of cyclodextrins on the solubility and oral bioavailability of tacrolimus in rats. J Pharm Sci. 2001;90(6):690-701. doi: 10.1002/jps.1025, PMID 11357172.

Tacrolimus Revision bulletin. The United States Pharmacopoeia. The United States Pharmacopoeial Convention; 2013. p. 3-5.

Joe JH, Lee WM, Park YJ, Joe KH, Oh DH, Seo YG, Woo JS, Yong CS, Choi HG. Effect of the solid-dispersion method on the solubility and crystalline property of tacrolimus. Int J Pharm. 2010;395(1-2):161-6. doi: 10.1016/j.ijpharm.2010.05.023, PMID 20580799.

Shinkar DM, Aher PS, Kothawade PD, Maru AD. Formulation and in vitro evaluation of fast dissolving tablet of verapamil hydrochloride. Int J Pharm Pharm Sci. 2018;10(10):93-9. doi: 10.22159/ijpps.2018v10i10.28714.

Purkayastha HD, Nath B. Formulation and evaluation of oral fast disintegrating tablet of ibuprofen using two super disintegrants. Int J Curr Pharm Sci. 2017;9(4):92-5. doi: 10.22159/20966.

Choudhury P, Deb P, Dash S. Formulation and statistical optimization of bilayer sublingual tablets of levocetirizine hydrochloride and ambroxol hydrochloride. Asian J Pharm Clin Res. 2016;9(5):228-34. doi: 10.22159/ajpcr.2016.v9i5.13343.

Lachman L, Lieberman HA Kanig JL. The theory and practice of industrial pharmacy. Lea & Febiger; 1987. p. 296-301.

Tashan E, Karakucuk A, Celebi N. Development of nanocrystal ziprasidone orally disintegrating tablets: optimization by using design of experiment and in vitro evaluation. AAPS PharmSciTech. 2020;21(3):115. doi: 10.1208/s12249-020-01653-9, PMID 32296987.

Prajapati ST, Patel PB, Patel CN. Formulation and evaluation of sublingual tablets containing sumatriptan succinate. Int J Pharm Investig. 2012;2(3):162-8. doi: 10.4103/2230-973X.104400, PMID 23373008.

Rawas-Qalaji MM, Simons FE, Simons KJ. Fast-disintegrating sublingual epinephrine tablets: effect of tablet dimensions on tablet characteristics. Drug Dev Ind Pharm. 2007;33(5):523-30. doi: 10.1080/03639040600897150, PMID 17520443.

Jaya S, Amala V. Formulation and in vitro evaluation of oral disintegrating tablets of amlodipine besylate. Int J App Pharm. 2019;11(1):49-54. doi: 10.22159/ijap.2019v11i1.28457.

Ponnammal P, Kanaujia P, Yani Y, Ng WK, Tan RBH. Orally disintegrating tablets containing melt extruded amorphous solid dispersion of tacrolimus for dissolution enhancement. Pharmaceutics. 2018;10(1):35. doi: 10.3390/pharmaceutics10010035, PMID 29547585.

Kassem AA, Labib GS. Flash dissolving sublingual almotriptan malate for management of migraine. Int J Pharm Pharm Sci. 2017;9:125-31.

Indian pharmacopoeia. Volume II. Government of India, Ministry of Health and Family Welfare. The Indian pharmacopoeia commission. Ghaziabad; 2014.

Rojas J, Guisao S, Ruge V. Functional assessment of four types of disintegrants and their effect on the spironolactone release properties. AAPS PharmSciTech. 2012;13(4):1054-62. doi: 10.1208/s12249-012-9835-y, PMID 22899380.

Tacrolimus capsules revision [bulletin]. The United States pharmacopoeia. The United States pharmacopoeial convention; 2018. p. 1-7.