Ozan TEKDEMİR, Gizem TİLKİ, Timuçin UĞURLU

Development of a multiple-unit system: Tablets containing amlodipine besylate which have different release kinetics

Multiple-unit systems may include tablets, capsules, pellets in a single administration. Once-a-dayadministration of Amlodipine Besylate (AML) accounts for fluctuation of plasma drug concentrations between dosingintervals. The aim of this study is to develop an extended-release (ER) and an immediate-release (IR) tablet to overcome the fluctuation of plasma drug concentrations. To achieve this purpose, 9 IR tablets and 6 ER tablet formulations were developed. The dissolution media for IR tablets was pH 2 for 1 hour and the dissolution media for ER tablets was pH 2 for 2 hours, and afterwards was pH 6.8 for 10 hours. The amount of AML released into the dissolution media was measured by Mettler Toledo UV 5 at a wavelength of 238 nm. The dissolution data of IR and ER tablets were statically evaluated. The highest dissolution rate for IR tablets (93%) was achieved with the IR-5 formulation. For ER tablets, a 50% drug release was achieved with the ER-1 and ER-4 formulation. The drug release kinetics of all ER tablets were calculated and subsequently the ER-1 formulation, which has Higuchi drug release kinetics, was chosen as the ER tablet.Lastly, a dissolution study of the selected formulations (IR-5 and ER-1) was conducted in the same vessel. After 12 hours of the dissolution study, drug release was found to be 79% ±0,92 (close to 75% which was targeted). Multiple-unit systems that have different tablet formulations in one administration could be used to enhance drug release kinetics that cannot be achieved with conventional tablets.

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[1] Li Y, Zhu J. Modulation of Combined-Release Behaviors From a Novel “Tablets-In-Capsule System”. J Controlled Release. 2004; 95(3): 381-389. [CrossRef]
[2] Comoglu T, Dilek Ozyilmaz E. Orally Disintegrating Tablets and Orally Disintegrating Mini Tablets – Novel Dosage Forms for Pediatric Use. Pharm Dev and Technol. 2019; 24(7): 902-914. [CrossRef]
[3] Jones RJ, Rajabi-Siahboomi A, Levina M, Perrie Y, Mohammed AR. The Influence of Formulation and Manufacturing Process Parameters on the Characteristics of Lyophilized Orally Disintegrating Tablets. Pharmaceutics. 2011; 3(3): 440-457. [CrossRef]
[4] Saharan VA. Current Advances in Drug Delivery Through Fast Dissolving/Disintegrating Dosage Forms, Bentham Books, India, 2017. [CrossRef]
[5] Chowdary KPR, Rao SS. Investigation of Dissolution Enhancement of Itraconazole by Solid Dispersion in Superdisintegrants. Drug Dev Ind Pharm. 2000; 26(11): 1207-1211. [CrossRef]
[6] Yen SY, Chen CR, Lee MT, Chen LC. Investigation of Dissolution Enhancement of Nifedipine by Deposition on Superdisintegrants. Drug Dev Ind Pharm. 1997; 23(3): 313-317. [CrossRef]
[7] Pahwa R, Gupta N. Superdisintegrants in the Development of Orally Disintegrating Tablets: a Review. Int J Pharm Sci Res. 2011; 2(11): 2767. [CrossRef]
[8] Desai PM, Liew CV, Heng PWS. Review of Disintegrants and the Disintegration Phenomena. J Pharm Sci. 2016; 105(9): 2545-2555. [CrossRef]
[9] Allen L, Ansel HC. Ansel's pharmaceutical dosage forms and drug delivery systems, Lippincott Williams & Wilkins, USA, 2013.
[10] Elliott WJ. Systemic hypertension. Curr Probl Cardiol. 2007; 32(4): 201-59. [CrossRef]
[11] Elliott WJ, Ram CVS. Calcium channel blockers. J Clin Hypertens (Greenwich). 2011; 13(9): 687-689. [CrossRef]
[12] Ananchenko G, Novakovic J, Lewis J. Amlodipine Besylate. In: Brittain HG (Eds). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press, USA, 2012. pp. 31-77. [CrossRef]
[13] Meredith PA, Elliott HL. Clinical Pharmacokinetics of Amlodipine. Clin. Pharmacokinet. 1992; 22(1): 22-31. [CrossRef]
[14] Abernethy DR. Pharmacokinetics and Pharmacodynamics of Amlodipine. Cardiology. 1992; 80(1): 31-36. [CrossRef]
[15] Battu SK, Repka MA, Majumdar S, Rao Y M. Formulation and Evaluation of Rapidly Disintegrating Fenoverine Tablets: Effect of Superdisintegrants. Drug Dev Ind Pharm. 2007; 33(11): 1225-1232. [CrossRef]
[16] Commission EP. Disintegration of Tablets and Capsules. Ph Eur 7: EU; 2009, pp. 253-56.
[17] Mohanachandran PS, Krishna Mohan PR, Saju F, Bini KB, Babu B, Shalina KK. Formulation and Evaluation of Mouth Dispersible Tablets of Amlodipine Besylate. Int J App Pharm. 2010; 2(3): 1-6.
[18] Raj BS, Punitha ISR, Dube S. Formulation and Characterization of Fast Disintegrating Tablets of Amlodipine Using Superdisintegrants. J Appl Pharm Sci. 2012; 2: 118-123. [CrossRef]
[19] Sheraz MA, Ahsan SF, Khan MF, Ahmed S, Ahmad I. Formulations of Amlodipine: A Review. J Pharm (Cairo). 2016;2016: 8961621.[CrossRef]
[20] Jaya S, Amala V. Formulation and In Vitro Evaluation of Oral Disintegrating Tablets of Amlodipine Besylate. Int J App Pharm. 2019; 11-49. [CrossRef]
[21] Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001; 13(2): 123-133.[CrossRef]
[22] Desai D, Rinaldi F, Kothari S, Paruchuri S, Li D, Lai M, et al. Effect of Hydroxypropyl Cellulose (HPC) on Dissolution Rate of Hydrochlorothiazide Tablets. Int J Pharm. 2006; 308(1): 40-45. [CrossRef]
[23] Qiu Y, Lee PI. Rational Design of Oral Modified-Release Drug Delivery Systems. In: Qiu Y, Chen Y, Zhang GGZ, Yu L, Mantri RV, (Eds). Developing Solid Oral Dosage Forms (Second Edition). Boston: Academic Press; 2017. pp. 519-54.
[24] Amlodipine Besylate dissolution medium. https://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_getallData.cfm. (accessed on 20 March 2020)
[25] Commission EP. Dissolution test for solid dosage forms. Ph Eur 7: EU; 2009, pp. 256-63.
[26] Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010; 12(3): 263-271. [CrossRef]