Optimization and Biopharmaceutical Evaluation of Sustained-Release Macitentan Pellets Using Polymeric Coating and Box–Behnken Design

Authors

  • Abhay Kumar Mishra
  • Rajasekaran S

Keywords:

Macitentan, Sustained-release pellets, Controlled drug delivery, Extrusion–spheronization, Ethyl cellulose, Hydroxypropyl methylcellulose, Box–Behnken Design (BBD)

Abstract


Macitentan, an endothelin receptor antagonist widely used for the long-term management of pulmonary arterial hypertension (PAH), exhibits poor aqueous solubility, extensive first-pass metabolism, and variable plasma concentrations when delivered through conventional immediate-release formulations. These limitations justify the development of a sustained-release (SR) multiarticulate delivery system to achieve prolonged therapeutic exposure, reduced dosing frequency, and improved patient adherence. This study aimed to formulate, optimize, and evaluate sustained-release Macitentan pellets using a polymeric coating system and a Quality by Design (QbD) approach employing the Box–Behnken Design (BBD). Preformulation studies including solubility profiling, FTIR, DSC, and PXRD confirmed the physicochemical integrity of Macitentan and its compatibility with selected excipients such as microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), and ethyl cellulose (EC). Pellets were prepared through extrusion–spherization and coated with EC–HPMC blends to modulate drug release kinetics. A three-factor, three-level BBD—evaluating polymer ratio (X1), coating level (X2), and spherization time (X3)—was applied to study their effect on % drug release at 12 h (Y1), sphericity index (Y2), and friability (Y3). Statistical modelling demonstrated significant contributions of all variables (p < 0.05), with strong predictive power (R² > 0.98). The optimized formulation containing an EC:HPMC ratio of 3:1, coating level of 10%, and spheronization time of 12 min achieved a controlled release of ~78% at 12 h and >95% at 24 h, following zero-order kinetics and anomalous (non-Fickian) diffusion. In-silico pharmacokinetic simulation revealed reduced Cmax, prolonged Tmax, and increased mean residence time compared with immediate-release formulations, indicating improved plasma stability and suitability for once-daily administration. Accelerated stability studies performed as per ICH Q1A(R2) confirmed the formulation’s robustness with no significant change in assay, dissolution, or physical properties. Overall, the optimized sustained-release Macitentan pellets demonstrate strong potential as an improved therapeutic delivery system for chronic PAH management, with advantages in biopharmaceutical performance, dosing convenience, and patient compliance.

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References

1. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2022;60(4):2101544.

2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336(2):111–117.

3. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Circulation. 2008;117:3010–3019.

4. Sidharta PN, van Giersbergen PL, Dingemanse J. Macitentan: Entry-into-humans study of a novel endothelin receptor antagonist. Br J Clin Pharmacol. 2011;71(6):833–841.

5. Alderman DA. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int J Pharm Tech Prod Mfr. 1984;5:1–9.

6. Ghebre-Selassie I. Pellets and pelletization techniques. Pharm Tech. 1989;13(10):68–80.

7. Shah RB, Tawakkul MA, Khan MZ. Comparative evaluation of flow for pharmaceutical powders and granules. AAPS PharmSciTech. 2008;9(1):250–258.

8. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–133.

9. United States Pharmacopeia USP-43–NF-38, Rockville, MD; U.S. Pharmacopeial Convention; 2020.

10. Guideline ICH Q1A(R2): Stability testing of new drug substances and products. 2003.

11. Crouter A, Briens L. The effect of moisture on the flowability of pharmaceutical excipients. AAPS PharmSciTech. 2014;15(1):65–74.

12. Roberts M, Rowe RC. The effect of spheronization time on the physical characteristics of pellets. Int J Pharm. 1985;24:89–95.

13. Jain SK, Ahuja M, Jain S, Agrawal GP. Development of controlled-release pellets using extrusion–spheronization technique. Drug Dev Ind Pharm. 2001;27(4):419–426.

14. Bodmeier R, Paeratakul O. Spherical agglomerates: formation and characterization. Eur J Pharm Biopharm. 1994;40:305–312.

15. Colombo P, Bettini R, Santi P, et al. Swelling and drug release: the role of the polymeric film. J Control Release. 1996;39(2–3):231–237.

16. Sinha VR, Wadhawan S, Singh S, et al. Biodegradable polymers in drug delivery. Indian J Pharm Sci. 2004;66(3):338–351.

17. Agrawal AM, Neau SH, Bonate PL. Wetting, swelling and erosion behavior of HPMC and EC matrices. Drug Dev Ind Pharm. 2003;29(10):1031–1045.

18. Montgomery DC. Design and Analysis of Experiments. 8th ed. John Wiley & Sons; 2012.

19. Siepmann J, Peppas NA. Higuchi equation: Derivation, applications, use and misuse. Int J Pharm. 2011;418(1):6–12.

20. Colombo P. Swellable matrices for controlled drug delivery: gel-layer behavior. J Control Release. 1993;24(1–3):43–51.

21. Efentakis M, Buckton G. Influence of HPMC on drug release. STP Pharma Sci. 2002;12:263–269.

22. Mandal UK, Chatterjee B, Senjoti FG. Gastroretentive drug delivery systems: a review. Asian J Pharm Sci. 2016;11(5):575–589.

23. Varshosaz J, Khoshayand MR, Jafarabadi M, et al. Optimization of sustained-release pellets using RSM. DARU J Pharm Sci. 2012;20(1):7.

24. Khan GM, Zhu JB. Controlled-release drug delivery systems: Optimization and kinetics. Drug Dev Ind Pharm. 1998;24(6):455–460.

25. Pillai O, Panchagnula R. Polymers in controlled drug delivery: An overview. Curr Opin Chem Biol. 2001;5:447–451.

26. Dixit N, Sheth A. Controlled-release drug delivery system for prolonged therapeutic effect. J Pharm Sci. 2003;92(11):231–239.

27. ICH Q1A(R2): Stability testing of new drug substances and products. ICH Harmonized Tripartite Guideline. 2003.

28. Waterman KC, Adami RC. Accelerated aging: prediction of chemical stability in pharmaceuticals. Int J Pharm. 2005;293:101–125.

29. Guideline ICH Q1B: Photostability Testing of New Drug Substances and Products. 1996.

30. Blessy M, Patel RD, Prajapati PN, Agrawal YK. Development of forced degradation and stability-indicating methods. J Pharm Anal. 2014;4(3):159–165.

31. Baert L, Remon JP. Moisture and the stability of solid and semi-solid pharmaceuticals. Drug Dev Ind Pharm. 1998;24(11):1127–1135.

32. Singh S, Bakshi M. Guidance on stress testing to determine stability of drug substances. Pharm Technol. 2000;24(2):1–14..

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Published

2025-12-16

How to Cite

1.
Mishra AK, S R. Optimization and Biopharmaceutical Evaluation of Sustained-Release Macitentan Pellets Using Polymeric Coating and Box–Behnken Design. J Neonatal Surg [Internet]. 2025 Dec. 16 [cited 2026 Jan. 20];14(33S):38-5. Available from: https://jneonatalsurg.com/index.php/jns/article/view/9696

Issue

Vol. 14 No. 33S (2025): Journal of Neonatal Surgery

Section

Original Article

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