A COMPREHENSIVE REVIEW ON DOSAGE FORM FOR ANTICOAGULANT DRUG
DOI:
https://doi.org/10.22159/ijcpr.2025v17i6.7068Keywords:
NOAC (Non-vitamin k oral anticoagulant), Thrombin, Microbubbles, Acute coronary syndrome (ACS)Abstract
Thromboembolic disorders are a major global health issue, requiring effective therapies rooted in understanding thrombophilia and the coagulation cascade. Warfarin, though widely used, presents challenges like dietary restrictions, narrow therapeutic index, and constant monitoring. New generation oral anticoagulant like hirudin, bivalirudin, argatroban, apixaban, and rivaroxaban offer improved safety and pharmacokinetic profiles. To further optimize their clinical use, advanced drug delivery systems have been developed. Formulations like hydrogels, microspheres, micellar nanocomplexes, nanoparticles, and fast-dissolving oral films enhance bioavailability and therapeutic efficacy. These systems also provide targeted or sustained drug release and reduce systemic side effects. Hirudin-based hydrogels and microspheres maintain prolonged thrombin inhibition. Bivalirudin micelles and hydrogels offer localized anticoagulation with minimal bleeding. Rivaroxaban and apixaban in film and nanoparticle forms ensure rapid absorption and patient-friendly administration. Such innovations improve both clinical outcomes and patient compliance in anticoagulant therapy.
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References
1. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965 Jun;13(2):516-30. doi: 10.1160/TH15-02-0141, PMID 14347873.
2. Marder VJ, Aird WC, Bennett JS, Schulman S, White GC. Hemostasis and thrombosis: basic principles and clinical practice. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2012.
3. Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med. 1984 Dec 13;311(24):1525-8. doi: 10.1056/NEJM198412133112401, PMID 6239102.
4. Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost. 2015 Nov;114(5):885-9. doi: 10.1160/TH15-02-0141, PMID 26018405.
5. Muszbek L, Bereczky Z, Kovacs B, Komaromi I. Antithrombin deficiency and its laboratory diagnosis. Clin Chem Lab Med. 2010 Dec;48 Suppl 1:S67-78. doi: 10.1515/CCLM.2010.368, PMID 21062218.
6. Moll S. Thrombophilia: clinical practical aspects. J Thromb Thrombolysis. 2015 Apr;39(3):367-78. doi: 10.1007/s11239-015-1197-3, PMID 25724822.
7. Messerschmidt C, Friedman RJ. Clinical experience with novel oral anticoagulants for thromboprophylaxis after elective hip and knee arthroplasty. Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):771-8. doi: 10.1161/ATVBAHA.114.303400, PMID 25767271.
8. Bacchus F, Schulman S. Clinical experience with the new oral anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):513-9. doi: 10.1161/ATVBAHA.114.303396, PMID 25717178.
9. Carreras ET, Mega JL. Role of oral anticoagulants in patients after an acute coronary syndrome. Arterioscler Thromb Vasc Biol. 2015;35(3):520-4. doi: 10.1161/ATVBAHA.114.303401, PMID 25614282.
10. Ieko M, Naitoh S, Yoshida M, Takahashi N. Profiles of direct oral anticoagulants and clinical usage dosage and dose regimen differences. J Intensive Care. 2016;4:19. doi: 10.1186/s40560-016-0144-5, PMID 26966542.
11. Panova Noeva M, Eggebrecht L, Prochaska JH, Wild PS. Potential of multidimensional large scale biodatabases to elucidate coagulation and platelet pathways as an approach towards precision medicine in thrombotic disease. Hamostaseologie. 2019 Jun;39(2):152-63. doi: 10.1055/s-0038-1677520, PMID 30722070.
12. Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(3):331-8. doi: 10.1161/ATVBAHA.118.312130, PMID 30700128.
13. Chaudhry R, Usama SM, Babiker HM. Physiology coagulation pathways. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2018 Mar 1. PMID 29489185.
14. Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW II. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry. 1990 Jul 1;29(30):7095-101. doi: 10.1021/bi00482a021, PMID 2223763.
15. Fitzgerald D, Murphy N. Argatroban: a synthetic thrombin inhibitor of low relative molecular mass. Coron Artery Dis. 1996 Jun;7(6):455-8. doi: 10.1097/00019501-199606000-00008, PMID 8889361.
16. Perzborn E, Kubitza D, Misselwitz F. A novel oral direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Hamostaseologie. 2007 Sep;27(4):282-9. doi: 10.1055/s-0037-1617095, PMID 17938768.
17. Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of Rivaroxaban. Clin Pharmacokinet. 2014 Jan;53(1):1-16. doi: 10.1007/s40262-013-0100-7, PMID 23999929.
18. Alburyhi MM, Hamidaddin MA, Saif AA, Noman MA. Formulation and evaluation of rivaroxabanorodispersible tablets. World J Pharm Pharm Sci. 2024;13(2):2066-92.
19. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. 2019 Oct;58(10):1265-79. doi: 10.1007/s40262-019-00775-z, PMID 31089975.
20. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807-15. doi: 10.1016/S0140-6736(09)62125-5, PMID 20206776.
21. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98. doi: 10.1056/NEJMoa1006885, PMID 21175312.
22. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604. doi: 10.1056/NEJMoa0810773, PMID 19657123.
23. Bao Z, Qi X, Zhu S, Zhang M, Liu X, Chen P. Recent progress on formulations of hirudin. Pharmaceutical Science Advances. 2025 May 21;3:100078. doi: 10.1016/j.pscia.2025.100078.
24. Wei D, Lyu J, Wang B, He Y, Bi L. Hirudin enhances perforator flap survival: clinical application report and mechanistic exploration. J Stomatol Oral Maxillofac Surg. 2024 Jun 1;125(3S):101868. doi: 10.1016/j.jormas.2024.101868, PMID 38588856.
25. Zhao YZ, Liang HD, Mei XG, Halliwell M. Preparation, characterization and in vivo observation of phospholipid-based gas-filled microbubbles containing hirudin. Ultrasound Med Biol. 2005;31(9):1237-43. doi: 10.1016/j.ultrasmedbio.2005.05.007, PMID 16176790.
26. Liu Y, Lu WL, Wang JC, Zhang X, Zhang H, Wang XQ. Controlled delivery of recombinant hirudin based on thermo-sensitive Pluronic F127 hydrogel for subcutaneous administration: in vitro and in vivo characterization. J Control Release. 2007;117(3):387-95. doi: 10.1016/j.jconrel.2006.11.024, PMID 17207884.
27. Sellers DL, Kim TH, Mount CW, Pun SH, Horner PJ. Poly(lactic-co-glycolic) acid microspheres encapsulated in Pluronic F-127 prolong hirudin delivery and improve functional recovery from a demyelination lesion. Biomaterials. 2014;35(31):8895-902. doi: 10.1016/j.biomaterials.2014.06.051, PMID 25064804.
28. Warkentin TE, Koster A. Bivalirudin: a review. Expert Opin Pharmacother. 2005 Jul;6(8):1349-71. doi: 10.1517/14656566.6.8.1349, PMID 16013985.
29. She ZG, Liu X, Kotamraju VR, Ruoslahti E. Clot-targeted micellar formulation improves anticoagulation efficacy of bivalirudin. ACS Nano. 2014;8(10):10139-49. doi: 10.1021/nn502947b, PMID 25270510.
30. Gao W, Shen H, Chang Y, Tang Q, Li T, Sun D. Bivalirudin hydrogel coatings of polyvinyl chloride on extracorporeal membrane oxygenation for anticoagulation. Front Cardiovasc Med. 2023 Dec 15;10:1301507. doi: 10.3389/fcvm.2023.1301507, PMID 38162136.
31. Lin S, Li X, Wang K, Shang T, Zhou L, Zhang L. An albumin biopassive polyallylamine film with improved blood compatibility for metal devices. Polymers (Basel). 2019 Apr 23;11(4):734. doi: 10.3390/polym11040734, PMID 31018520.
32. Mochizuki A, Niikawa T, Omura I, Yamashita S. Controlled release of argatroban from PLA film effect of hydroxylesters as additives on enhancement of drug release. J Appl Polym Sci. 2008 Jun 5;108(5):3353-60. doi: 10.1002/app.27970.
33. Imanishi T, Arita M, Hamada M, Tomobuchi Y, Hano T, Nishio I. Effects of locally administration of argatroban using a hydrogel coated balloon catheter on intimal thickening induced by balloon injury. Japan Circ J. 1997;61(3):256-62. doi: 10.1253/jcj.61.256, PMID 9152775.
34. Ganesh M. Design and optimization of Rivaroxaban lipid solid dispersion for dissolution enhancement using statistical experimental design. Asian J Pharm. 2016 Feb 26;10(1):59-64.
35. Elsayad MK, Mowafy HA, Zaky AA, Samy AM. Chitosan caged liposomes for improving oral bioavailability of rivaroxaban: in vitro and in vivo evaluation. Pharm Dev Technol. 2021 Mar 16;26(3):316-27. doi: 10.1080/10837450.2020.1870237, PMID 33356742.
36. Patra RK, Sahu SK, Mahapatra AK, Das R. Enhancement of solubility of Rivaroxaban and formulation of its fast-disintegrating tablets: using design of experiments. Res J Pharm Life Sci. 2023 May;4:40-55.
37. Khan WH, Asghar S, Khan IU, Irfan M, Alshammari A, Riaz Rajoka MS. Effect of hydrophilic polymers on the solubility and dissolution enhancement of Rivaroxaban/beta-cyclodextrin inclusion complexes. Heliyon. 2023 Sep;9(9):e19658. doi: 10.1016/j.heliyon.2023.e19658, PMID 37809727.
38. Choi MJ, Woo MR, Baek K, Kim JS, Kim JO, Choi YS. Novel Rivaroxaban-loaded microsphere systems with different surface microstructure for enhanced oral bioavailability. Drug Deliv Transl Res. 2024 Mar;14(3):655-64. doi: 10.1007/s13346-023-01420-w, PMID 37667087.
39. Kanna S, Nadendla RR, Satyanarayana J, Karthikeya V, Sonu MV, Bhargavi PN. Formulation and evaluation of fast-dissolving oral film of Rivaroxaban. J Young Pharm. 2023 Oct 1;15(4):687-95. doi: 10.5530/jyp.2023.15.94.
40. Askarizadeh M, Esfandiari N, Honarvar B, Ali Sajadian SA, Azdarpour A. Binary and ternary approach of solubility of Rivaroxaban for preparation of developed nano drug using supercritical fluid. Arab J Chem. 2024 Apr 1;17(4):105707. doi: 10.1016/j.arabjc.2024.105707.
41. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010 Apr 6;121(13):1523-32. doi: 10.1161/circulationaha.109.853119, PMID 20368532.
42. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604. doi: 10.1056/NEJMoa0810773, PMID 19657123.
43. Shireesha M, Reddy VP. Formulation and evaluation of apixaban orodispersible fast-dissolving tablets. Indo Am J Pharm Biosci. 2022 Dec 25;20(4):83-96.
44. Wang CC, Chen YL, Lu TC, Lee C, Chang YC, Chan YF. Design and evaluation of oral formulation for apixaban. Heliyon. 2023 Aug 1;9(8):e18422. doi: 10.1016/j.heliyon.2023.e18422, PMID 37534003.
45. Sagili SP, Deepika PP, Pavuluri E, Bai NJ, Priyadarshini KS, Kumar MS. Design and characterization of fast-dissolving oral film of apixaban. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2024;40:e20240022. doi: 10.62958/j.cjap.2024.022, PMID 39191637.
46. Mulay L, Hegde N, Kanugo A. Formulation optimization and characterization of solid lipid nanoparticles of apixaban. Recent Pat Nanotechnol. 2025 Jun;19(2):270-81. doi: 10.2174/0118722105284862240506045944, PMID 39099216.
47. Parveen S, Singh RP, Rathore G. Formulation evaluation and bioequivalence studies of apixaban tablet. AP. 2024;13(1):896-906. doi: 10.54085/ap.2024.13.1.96.
48. Mulay L, Hegde N, Kanugo A. Formulation optimization and characterization of solid lipid nanoparticles of apixaban. Recent Pat Nanotechnol. 2025 Jun;19(2):270-81. doi: 10.2174/0118722105284862240506045944, PMID 39099216.
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