GASTRO-RETENTIVE SUSTAINED RELEASE MUPS (MULTI-UNIT PARTICULATE SYSTEM) OF RIVAROXABAN FOR ORAL ADMINISTRATION
DOI:
https://doi.org/10.22159/ijap.2026v18i1.56204Keywords:
Rivaroxaban, Gastro-retentive, Sustain release, Fluidized bed coater, Eudragit NM 30DAbstract
Objective: This study focuses on the development and evaluation of gastro-retentive multi-unit particulate systems (MUPS) by utilizing fluidized bed coater, for the oral delivery of rivaroxaban, a direct oral anticoagulant (DOAC).
Methods: The method involves coating of three layers comprising the drug layer, effervescent layer, and polymer layer, each layer containing specific ingredients. These solutions were magnetically stirred, filtered, and coated onto sugar spheres (sucrose) using a Fluidized bed coater (FBC) (P+AM Glatt). The coated pellets were evaluated for parameters like particle size, friability, buoyancy, in vitro drug release, differential scanning calorimetry (DSC) analysis, scanning electron microscopy (SEM), and capsule filling performance. The method is designed in order to optimize the coating process and to assess the quality of pellets and enhance the drug delivery of rivaroxaban.
Results: Batch N-IV (4% Eudragit NM 30D) achieved 84.8% sustained drug release over 24 h with minimal burst (20.85% at 1 h), fitting the Korsmeyer-Peppas model (R²=0.995, n=0.647). This formulation floated rapidly (2.15 min lag time) for >24 h, and exhibited excellent physical properties (friability: less than 1%; Carr’s index: 0.842%; Hausner ratio: 1.008), with high drug loading (17.11 mg/250 mg pellets), and high coating efficiency (98.6%).
Conclusion: Compared to immediate-release formulations, the MUPS-based approach improved gastric retention, provide sustain release and improve dissolution profile along with a reduction in dosing frequency.
References
1. Martin KA, Lee CR, Farrell TM, Moll S. Oral anticoagulant use after bariatric surgery: a literature review and clinical guidance. Am J Med. 2017;130(5):517-24
2. Ashton V, Kerolus-Georgi S, Moore KT. The Pharmacology, Efficacy, and Safety of Rivaroxaban in Renally Impaired Patient Populations. J Clin Pharmacol. 2021;61(8):1010-26
3. Mastenbroek TG, Karel MFA, Nagy M, Chayoua W, Korsten EIJ, Coenen DM, et al. Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery. Sci Rep. 2020;10(1):19360
4. Alalawneh M, Awaisu A, Abdallah I, Elewa H, Danjuma M, Matar KM, et al. Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK). Clin Transl Sci. 2024;17(6):e13853
5. Harder S. Pharmacokinetic and pharmacodynamic evaluation of rivaroxaban: considerations for the treatment of venous thromboembolism. Thromb J. 2014;12(1):22
6. Anwer MK, Mohammad M, Iqbal M, Ansari MN, Ezzeldin E, Fatima F, et al. Sustained release and enhanced oral bioavailability of rivaroxaban by PLGA nanoparticles with no food effect. J Thromb Thrombolysis. 2020;49(3):404-12
7. Puhr HC, Ilhan-Mutlu A, Preusser M, Quehenberger P, Kyrle PA, Eichinger S, Eischer L. Absorption of Direct Oral Anticoagulants in Cancer Patients after Gastrectomy. Pharmaceutics [Internet]. 2022; 14(3).
8. Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants-reasons, methods and current limitations. J Thromb Thrombolysis. 2013;36(2):187-94
9. Martin KA, Lee CR, Farrell TM, Moll S. Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance. Am J Med. 2017;130(5):517-24
10. Food and Drug Administration. Xarelto FDA Package Insert. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202439s017lbl.pdf. [Accessed on 2025 23/08].
11. Homayun B, Lin X, Choi HJ. Challenges and Recent Progress in Oral Drug Delivery Systems for Biopharmaceuticals. Pharmaceutics. 2019;11(3):129
12. Chaturvedi P, Soni PK, Paswan SK. Designing and Development of Gastroretentive Mucoadhesive Microspheres of Cefixime Trihydrate using Spray Dryer. Int J App Pharm. 2023;15(2):185-93
13. Mandal UK, Chatterjee B, Senjoti FG. Gastro-retentive drug delivery systems and their in vivo success: A recent update. Asian J Pharm Sci. 2016;11(5):575-84
14. Murphy CS, Pillay V, Choonara YE, Toit du LC. Gastroretentive drug delivery systems: current developments in novel system design and evaluation. Curr Drug Deliv. 2009;6(5):451-60
15. Vinchurkar K, Sainy J, Khan MA, Mane S, Mishra DK, Dixit P. Features and Facts of a Gastroretentive Drug Delivery System-A Review. Turk J Pharm Sci. 2022;19(4):476-87
16. Badoni A, Ojha A, Gnanarajan G, Kothiyal P. Review on gastro retentive drug delivery system. Pharma Innovation. 2012;1(8):32-42
17. Tomar A, Upadhyay A, Gupta S, Kumar S. An overview on gastroretentive drug delivery system: current approaches and advancements. Curr Res Pharm Sci. 2019;9(1):12-6
18. Tripathi J, Thapa P, Maharjan R, Jeong SH. Current State and Future Perspectives on Gastroretentive Drug Delivery Systems. Pharmaceutics. 2019;11(4):193
19. Aulton ME, Taylor K. Aulton's pharmaceutics: the design and manufacture of medicines: Elsevier Health Sciences; 2013.
20. Gandhi A, Verma S, Imam SS, Vyas M. A review on techniques for grafting of natural polymers and their applications. Plant Arch. 2019;19(2):972-8
21. Chudiwal V, Shahi S, Chudiwal S, Ahale D. Innovative technologies for gastro-retentive drug delivery systems. Glob J Pharm Pharm Sci. 2018;4(5):110-4
22. Wang LK, Heng PW, Liew CV. Classification of annular bed flow patterns and investigation on their influence on the bottom spray fluid bed coating process. Pharm Res. 2010;27(5):756-66
23. Dewettinck K, Huyghebaert A. Fluidized bed coating in food technology. Trends Food Sci Technol. 1999;10(4):163-8
24. Teunou E, Poncelet D. Batch and Continuous Fluid Bed Coating—Review and State of the Art. J Food Eng. 2002;53(4):325-40
25. Turk M, Šibanc R, Dreu R, Frankiewicz M, Sznitowska M. Assessment of Mini-Tablets Coating Uniformity as a Function of Fluid Bed Coater Inlet Conditions. Pharmaceutics. 2021;13(5):746
26. Foppoli A, Cerea M, Palugan L, Zema L, Melocchi A, Maroni A, Gazzaniga A. Evaluation of powder-layering vs. spray-coating techniques in the manufacturing of a swellable/erodible pulsatile delivery system. Drug Dev Ind Pharm. 2020;46(8):1230-7
27. Dewettinck K, Huyghebaert A. Top-Spray Fluidized Bed Coating: Effect of Process Variables on Coating Efficiency. LWT - Food Sci and Techol. 1998;31(6):568-75
28. Maniyar D, Kadu P, Baig MIR. Critical variables affecting the layering method of pelletization. Futur J Pharm Sci. 2023;9(1):68
29. Kim YI, Pradhan R, Paudel BK, Choi JY, Im HT, Kim JO. Preparation and evaluation of enteric-coated delayed-release pellets of duloxetine hydrochloride using a fluidized bed coater. Arch Pharm Res. 2015;38(12):2163-71
30. Arora U, Thakkar V, Baldaniya L, Gohel MC. Fabrication and evaluation of fast disintegrating pellets of cilostazol. Drug Dev Ind Pharm. 2020;46(12):1927-46
31. Kumari MH, Samatha K, Balaji A, Shankar MU. Recent novel advandcements in pellet formulation: a review. Int J Pharm Sci Res. 2013;4(10):3803
32. Gautam N. Wurster Based Pelletization Technique, a Qualitative Approach. Elixir Int J. 2014;74:27131-6
33. Battu S, Yalavarthi PR, Reddy GVS, Rao VUM, Devi KJ, Vadlamudi HC. Design and assessment of pulsatile technology based chronomodulated delivery systems of nifedipine. Beni-Suef Univ J Basic Appl Sci. 2018;7(4):441-5
34. Balagani PK, Chandiran I, Bhavya B, Sindhuri M. Microparticulate drug delivery system: a review. Indian J Pharm Sci. 2011;1(1):19-37
35. Mohylyuk V, Patel K, Scott N, Richardson C, Murnane D, Liu F. Wurster Fluidised Bed Coating of Microparticles: Towards Scalable Production of Oral Sustained-Release Liquid Medicines for Patients with Swallowing Difficulties. AAPS PharmSciTech. 2019;21(1):3
36. Xu M, Liew CV, Heng PWS. Evaluation of the coat quality of sustained release pellets by individual pellet dissolution methodology. Int J Pharm. 2015;478(1):318-27
37. Gryczova E, Dvorackova K, Rabiskova M. Evaluation of pellet friability. Čes Slov Farm. 2009;58(1):9-13
38. Shafer EGE, Wollish EG, Engel CE. The ”Roche” Friabilator. J Am Pharm Assoc (Sci Ed). 1956;45(2):114-6
39. Kaur V, Goyal AK, Ghosh G, Chandra Si S, Rath G. Development and characterization of pellets for targeted delivery of 5-fluorouracil and phytic acid for treatment of colon cancer in Wistar rat. Heliyon. 2020;6(1):e03125
40. Shah RB, Tawakkul MA, Khan MA. Comparative evaluation of flow for pharmaceutical powders and granules. AAPS PharmSciTech 2008;9(1):250–8
41. Sarraguça MC, Cruz AV, Soares SO, Amaral HR, Costa PC, Lopes JA. Determination of flow properties of pharmaceutical powders by near infrared spectroscopy. J Pharm Biomed Anal. 2010;52(4):484-92
42. Zhang P, Shadambikar G, Almutairi M, Bandari S, Repka MA. Approaches for developing acyclovir gastro-retentive formulations using hot melt extrusion technology. J Drug Deliv Sci Technol. 2020;60:102002
43. Mounika D, Reddy I, Chandralekha K, Harika K, Nadendla R, Gudipati M. Formulation and in-vitro evaluation of ciprofloxacin HCL floating matrix tablets. Int J Res Pharm Sci Technol. 2020;2(1):01-6
44. Clinical Pharmacology and Biopharmaceutics Review(s): Addendum to NDA 202-439 for Rivaroxaban (XARELTO®) U.S. Food and Drug Administration. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202439orig1s000clinpharmr.pdf. [Accessed on 2025 23/08].
45. Çelebier M, Kaynak M, Altinoz S, Sahin S. UV Spectrophotometric Method for Determination of the Dissolution Profile of Rivaroxaban. Dissolution Technol. 2014;21(4):56-9
46. Soni PK, Saini TR. Formulation design and optimization of cationic-charged liposomes of brimonidine tartrate for effective ocular drug delivery by design of experiment (DoE) approach. Drug Dev Ind Pharm. 2021;47(11):1847-66
47. Prakash A, Soni PK, Paswan SK, Saini TR. Formulation and optimization of mucoadhesive buccal film for nicotine replacement therapy. Int J App Pharm. 2023;15(3):100-12
48. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences. 2001;13(2):123-33
49. Chandwani S, Saini TR, Soni R, Paswan SK, Soni PK. Box-Behnken Design Optimization of Salicylic Acid Loaded Liposomal Gel Formulation for Treatment of Foot Corn. Int J App Pharm. 2023;15(3):220-33
50. Tiwari A, Sharma S, Soni PK, Paswan SK. Fabrication and development of dissolving microneedle patch of butorphanol tartrate. Int J App Pharm. 2023;15(3):261-71
51. Dehariya P, Soni R, Paswan SK, Soni PK. Design of experiment based formulation optimization of chitosan-coated nano-liposomes of progesterone for effective oral delivery. J Appl Pharm Sci. 2023;13(6):256-70
52. Sahoo S, Jena M, Dhala S, Barik BB. Formulation and Evaluation of Gelatin Micropellets of Aceclofenac: Effect of Process Variables on Encapsulation Efficiency, Particle Size and Drug Release. Indian J Pharm Sci. 2008;70(6):795-8
53. Kaffash E, Badiee A, Akhgari A, Rezayat NA, Abbaspour M, Saremnejad F. Development and characterization of a multiparticulate drug delivery system containing indomethacin-phospholipid complex to improve dissolution rate. J Drug Deliv Sci Technol. 2019;53:101177
54. Soni PK, Saini TR. Formulation design and optimization of cationic-charged liposomes of brimonidine tartrate for effective ocular drug delivery by design of experiment (DoE) approach. Drug Development and Industrial Pharmacy. 2021;47(11):1847-66
55. Chopra R, Podczeck F, Newton J, Alderborn G. The influence of pellet shape and film coating on the filling of pellets into hard shell capsules. Eur J Pharm Biopharm. 2002;53(3):327-33
56. Dumpala RL, Patil C. A Review on Pellets and Pelletization Techniques. Int J Res Pharm Sci Technol. 2020;2(4):13
57. Zeeshan F, Bukhari NI. Development and evaluation of a novel modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride as model drugs. AAPS PharmSciTech. 2010;11(2):910–6
58. Nagaraju N, Soni PK, Mukherji G. Water dispersible pharmaceutical formulation and process for preparing the same. Patent No. WO2008104996A2. 2009-01-29.
59. Baggi RB, Kilaru NB. Calculation of predominant drug release mechanism using Peppas-Sahlin model, Part-I (substitution method): A linear regression approach. Asian J Pharm Tech. 2016;6(4):223-30
60. Yang HS, Kim DW. Fabrication of Gastro-Floating Famotidine Tablets: Hydroxypropyl Methylcellulose-Based Semisolid Extrusion 3D Printing. Pharmaceutics. 2023;15(2)
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