• SHAILESH SHARMA Department of Pharmaceutical Research, ASBASJSM College of Pharmacy, Bela, Punjab, India.
  • NIMRATA SETH Department of Pharmaceutics, Rayat Institute of Pharmacy, Railmajra, Punjab, India.


Objective: Blood pressure (BP) pursues circadian rhythms projecting its highest values during early morning and lowest during night. The aim of the present investigation was to design a newer programmable chronotherapy based capsule system containing delayed release microspheres of losartan potassium for effective management of hypertension.

Methods: First, the microspheres were prepared with Eudragit RS100 by optimization technique through the application of Design Expert® software. The optimized microsphere formulation was filled in a capsule shell, and these shells were coated with 10% w/v Eudragit L100:Eudragit S100 (in ratio 1:2), in isopropyl alcohol: water as solvent system, to provide the necessary delay in emptying of capsule content. The whole capsular system was evaluated by various characteristic formulation parameters. Validation of optimization model and statistical interpretation of results was done using analysis of variance.

Results: The results indicated that the optimized triple coated capsule shells showed an extended release of drug from microspheres after a lag time of 4 h.

Conclusion: Conclusively, the chronotherapeutic system of losartan potassium was successfully developed to be dosed at bedtime that could benefit from the known circadian rhythms of the disease to control the BP for once a day therapy

Keywords: Statistical design approach, Eudragit, Chronotherapy, Coated Capsule system, Losartan Potassium


1. Smith DH. Pharmacology of cardiovascular chronotherapeutic agents. Am J Hypertens 2001;14:296S-301S.
2. Prisant LM. Hypertension and chronotherapy: Shifting the treatment paradigm. Am J Hypertens 2001;14:277S-9S.
3. Hermida RC, Smolensky MH. Chronotherapy of hypertension. Curr Opin Nephrol Hypertens 2004;13:501-5.
4. Nayak UY, Shavi GV, Nayak Y, Averinen RK, Mutalik S, Reddy SM, et al. Chronotherapeutic drug delivery for early morning surge in blood pressure: A programmable delivery system. J Control Release 2009; 136:125-31.
5. Prisant LM, Weber M, Black HR. The role of circadian rhythm in cardiovascular function-efficacy of a chronotherapeutic approach to controlling hypertension with Verelan PM (verapamil HCL). Todays Ther Trend 2003;21:201-13.
6. Percel PJ, Vishnupad KS, Ventakesh GM. Timed Sustained Release Systems for Propranolol. Dublin, United States: Eurand Pharmaceuticals Limited; 2003.
7. Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL), a new chronotherapeutic formulation. Heart Dis 2003;5:176-81.
8. Wu PC, Huang YB, Chang JS, Tsai MJ, Tsai YH. Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit. Eur J Pharm Sci 2003;19:115-22.
9. Barzegar-Jalali M, Alaei-Beirami M, Javadzadeh Y. Comparison of physicochemical characteristics and drug release of diclofenac sodium Eudragit RS100 nanoparticles and solid dispersion. Powder Technol 2012;219:211-6.
10. Mehta KA, Kislaloglu MS, Phuapradit W. Release performance of poorly soluble drug from a novel Eudragit based multi-unit erosion matrix. Int J Pharm 2001;213:7-12.
11. Degussa Rohm Pharma Polymers, Enteric Coatings-pH control with Eudragit®. Available from: http://www.chemistry.mdma.ch/hiveboard/ picproxie_docs/000494861-xx4_1c_Enteric_Coatings_pH_control_ with_EUDRAGIT.pdf. [Last accessed on 2015 Dec 07].
12. Lee JH, Park TG, Choi HK. Effect of formulation and processing variables on the characteristics of microspheres for water soluble dugs prepared by w/o/o double emulsion solvent diffusion method. Int J Pharm 2000;196:75-83.
13. Phutane P, Shidhaye S, Lotlikar V, Ghule A, Sutar S, Kadam V, et al. In vitro evaluation of novel sustained release microspheres of glipizide prepared by the emulsion solvent diffusion-evaporation method. J Young Pharm 2010;2:35-41.
14. EL-Nahas HM. Optimization of Eudragit RS microspheres for controlled release of theophylline using response surface methodology. J Pharm Sci Res 2010;2 Suppl 10:663-71.
15. Das SK, Yuvaraj K, Khanam J. Formulation development and statistical optimization of ibuprofen-loaded polymethacrylate microspheres using response surface methodology. Chem Eng Res Design 2015;96:1-14.
16. Chopra S, Patil GV, Motwani SK. Release modulating hydrophilic matrix systems of losartan potassium: Optimization of formulation using statistical experimental design. Eur J Pharm Biopharm 2007;66:73-82.
17. Kehoe S, Kilcup N, Boyd D. Evaluation of cytotoxicity for novel composite microspheres: Material optimization by response surface methodology. Matter Lett 2012;86:13-7.
18. Martins SA, Prazerers DM, Fonseca LP. Application of central composite design for DNA hybridization onto magnetic micropsheres. Anal Biochem 2009;391:17-23.
19. Deshmukh RK, Naik JB. The impact of preparation parameters on sustained release aceclofenac microspheres: A design of experiments. Adv Powder Tech 2015;26:244-52.
20. Myers RH, Montgomery DC, Anderson-Cook CM. Response Surface Methodology: Process and Product Optimization Using Designed Experiments. New Jersey, USA: John Wiley and Sons; 2009.
21. Milling EL. Microencapsulation. In: Lachman L, Lieberman HA, Kanig JL, editors. The Theory and Practice of Industrial Pharmacy. Mumbai: Varghese Publishing House; 1991. p. 26-7.
22. Sinko PJ. Martin’s Physical Pharmacy & Pharmaceutical Sciences. New Delhi: BI Publications Pvt., Ltd.; 2006.
23. Trivedi P, Verma AM, Garud N. Preparation and characterization of aceclofenac microspheres. Asian J Pharm 2008;2:110-5.
24. Tanwar YS, Naruka P, Ojha GR. Development and evaluation of microspheres of verapamil hydrochloride. Braz J Pharm Sci 2006;43: 529-34.
25. Srivastava AK, Ridhurkar DN, Wadhwa S. Floating microspheres of cimetidine: Formulation, characterization and in vitro evaluation. Acta Pharm 2005;55:277-85.
26. Arindam H, Biswanath S. Preparation and in vitro evaluation of polystyrene coated microcapsule of drug-resin complex for achieving prolonged release of diltiazem hydrochloride. AAPS PharmSciTech 2006;7 Suppl 2:34-49.
27. Tayade PT, Kale RD. Encapsulation of water-insoluble drug by a cross-linking technique: Effect of process and formulation variables on encapsulation efficiency, particle size, and in vitro dissolution rate. AAPS PharmSci 2004;6:E12.
28. Raslan HK, Maswadeh H. In vitro dissolution kinetic study of theophyline from mixed controlled release matrix containing HPMC and glycerylbehenate. Indian J Pharm Sci 2006;68:308-12.
29. Augustijns P. In vitro dissolution models for prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci 2014;57:342-66.
30. Eudragit L100/L100-55 Technical Literature-Evonik Industries. Available from: http://www.eudragit.evonik.com/sites/dc/Downloadcenter/Evonik/ Product/Eudragit/Eudragit®%20Products.pdf. [Last accessed on 2010].
31. Missaghi S, Young C, Fegely K, Rajabi-Siahboomi AR. Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: Case studies. Drug Dev Ind Pharm 2010;36:180-9.
32. Swamykannu DM, Gupta VR, Yasam H. Nonaqueous enteric coating application of HPMC and Eudragit L100 on hard gelatin capsules: Designed to achieve intestinal delivery. J App Pharm Sci 2015;5:1-6.
33. EUDRAGIT® Acrylic Polymers for Solid Oral Dosage Forms. Available from: http://www.rofarma.com/allegati/97.pdf. [Last accessed on 2015 Feb 02].
34. Matteucci ME, Paguio JC, Miller MA, Williams RO 3rd, Johnston KP. Highly supersaturated solutions from dissolution of amorphous itraconazole microparticles at pH 6.8. Mol Pharm 2009;6: 375-85.
35. Kiliçarslan M, Baykara T. The effect of the drug/polymer ratio on the properties of the verapamil HCl loaded microspheres. Int J Pharm 2003;252:99-109.
36. Patwekar SL, Baramade MK. Controlled release approach to novel multiparticulate drug delivery system. Int J Pharm Pharm Sci 2012;4:757-63.
37. Redfern PH, Lemmer B. Physiology and Pharmacology of Biological Rhythms. New York: Springer Science & Business Media; 2014.
38. Malladi M, Jukanti R. Floating pulsatile drug delivery system of famotidine: Design, statistical optimization, and in vitro evaluation. Int J Pharm Pharm Sci 2016;8:169-81.
39. Singh S, Arora S, Neelam, Allawadi D. Formulation, optimization and evaluation of sustained release microspheres using Taguchi design. J Pharm Technol Res Manage 2014;2 Suppl 1:253-64.
40. Patil CC, Joshi AS, Shiralashetti SS. Design, characterization and evaluation of Eudragit microspheres containing glipizide. Drug Invent Today 2013;5:229-34.
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How to Cite
SHAILESH SHARMA, and NIMRATA SETH. “OPTIMIZATION OF COMPONENT VARIABLES BY STATISTICAL APPROACH FOR DESIGN OF CHRONOTHERAPEUTIC DOSAGE FORM FOR HYPERTENSION”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 4, Feb. 2019, pp. 64-72, https://innovareacademics.in/journals/index.php/ajpcr/article/view/31334.
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