DEVELOPMENT OF EXTENDED-RELEASE ANAGRELIDE TABLETS: A FORMULATION AND DISSOLUTION STUDY
Main Article Content
Keywords
Anagrelide, thrombocythemia, extended-release, wet granulation
Abstract
Anagrelide immediate release is commonly used multiple times a day for patients with thrombocythemia. However, frequent dosing can lead to potential dose-related side effects. The purpose of this study was to formulate an extended-release of anagrelide by the matrix manufacturing method to be compressed into tablets and compare its release profile with the reference patented formulation. The wet granulation method was utilized to produce the extended-release tablet. Different formulations of anagrelide tablets containing HPMC, ethyl cellulose, and other excipients were prepared. Flow characteristics and quality control tests including Carr’s index, Hausner's ratio, hardness, thickness, weight variation, content uniformity, as well as dissolution test were conducted using HPLC analysis. Finally, results were compared with the patent release profile as a reference. Through a series of pre-formulation studies and dissolution tests, it was determined that the F5 formulation, with an optimized balance of HPMC, ethyl cellulose, and other excipients, achieved a drug release profile similar to the reference patent formulation. The F5 formulation showed sustained release of anagrelide over the desired period, making it a promising candidate for further clinical evaluation. Further studies are needed to assess the pharmacokinetic profile and efficacy of the F5 formulation in patients with essential thrombocythemia.
References
1. Barbui T, Thiele J, Vannucchi A, Tefferi A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood cancer journal. 2015;5(8):e337-e337.
2. Al Dayyeni AM, Al-Gailani BT, Mahdi MG, Khazeem MM. Journal of Population Therapeutics & Clinical Pharmacology.
3. Gisslinger H, Buxhofer‐Ausch V, Hodisch J, et al. A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia–the TEAM‐ET 2· 0 trial. British Journal of Haematology. 2019;185(4):691-700.
4. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood. 2015;126(23):4055.
5. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood, The Journal of the American Society of Hematology. 2012;120(26):5128-5133.
6. Kanakura Y, Miyakawa Y, Wilde P, Smith J, Achenbach H, Okamoto S. Phase III, single-arm study investigating the efficacy, safety, and tolerability of anagrelide as a second-line treatment in high-risk Japanese patients with essential thrombocythemia. International journal of hematology. 2014;100:353-360.
7. Dombi P, Illés Á, Demeter J, et al. Anagrelide reduces thrombotic risk in essential thrombocythaemia vs. hydroxyurea plus aspirin. European Journal of Haematology. 2017;98(2):106-111.
8. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood, The Journal of the American Society of Hematology. 2013;121(10):1720-1728.
9. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. Journal of clinical oncology. 2011;29(6):761.
10. Andes WA, Noveck RJ, Fleming J. Inhibition of platelet production induced by an antiplatelet drug, anagrelide, in normal volunteers. Thrombosis and haemostasis. 1984;52(06):325-328.
11. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. New England Journal of Medicine. 2005;353(1):33-45.
12. Petrides PE. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opinion on Pharmacotherapy. 2004;5(8):1781-1798.
13. Besses C, Zeller W, Alvarez-Larrán A, et al. Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18-50 years) and elderly (≥ 65 years) patients with essential thrombocythemia. International Journal of Clinical Pharmacology and Therapeutics. 2012;50(11):787-796.
14. Martínez-Sellés M, Datino T, Figueiras-Graillet L, et al. Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions. Clinical Drug Investigation. 2013;33:45-54.
15. Petrides PE, Gisslinger H, Steurer M, et al. Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation. Clinical therapeutics. 2009;31(2):386-398.
16. Al-Zein H, Sakeer K, Alanazi FK. Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex. Saudi pharmaceutical journal. 2011;19(4):245-253.
17. Kaleem MA, Alam MZ, Khan M, Jaffery SHI, Rashid B. An experimental investigation on accuracy of Hausner Ratio and Carr Index of powders in additive manufacturing processes. Metal Powder Report. 2021;76:S50-S54.
18. Chao P-C. Easy Flow: Kontinuierliche Feuchtgranulation am Beispiel von Calciumcarbonat. Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Diss., 2013; 2013.
19. Zhao N, Zidan A, Tawakkul M, Sayeed VA, Khan M. Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. International journal of pharmaceutics. 2010;401(1-2):25-31.
20. Swain RP, Kumari TR, Panda S. Formulation development and evaluation of sustained release ibuprofen tablets with acrylic polymers (eudragit) and HPMC. Int J Pharm Pharmaceut Sci. 2016;8(2):131-135.
21. Krishanaiah Y, Latha K, Nageswara Rao L, Karthikeyan R, Bhaskar P, Satyanarayana V. Development of colon targeted oral guar gum matrix tablets of Albendazole for the treatment of helminthiasis. Indian journal of pharmaceutical sciences. 2003;65(4):378-385.
22. Apu AS, Pathan AH, Shrestha D, Kibria G, Jalil R-u. Investigation of in vitro release kinetics of carbamazepine from Eudragit® RS PO and RL PO matrix tablets. Tropical journal of pharmaceutical research. 2009;8(2)
23. Sinko PJ. Martin's physical pharmacy and pharmaceutical sciences. Lippincott Williams & Wilkins; 2023.
24. Moore J, Flanner H. Mathematical comparison of dissolution profiles. Pharmaceutical technology. 1996;20(6):64-74.
25. Spencer CM, Brogden RN. Anagrelide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia. Drugs. 1994;47:809-822.
26. Ummadi S, Shravani B, Rao N, Reddy MS, Sanjeev B. Overview on controlled release dosage form. System. 2013;7(8):51-60.
27. Schlick‐Hasper E, Bethke J, Vogler N, Goedecke T. Flow properties of powdery or granular filling substances of dangerous goods packagings—Comparison of the measurement of the angle of repose and the determination of the Hausner ratio. Packaging Technology and Science. 2022;35(10):765-782.
28. Jaimini M, Kothari AH. Sustained release matrix type drug deliery system: A review. Journal of drug delivery and therapeutics. 2012;2(6)
29. Abdel-Hamid S, Betz G. Radial die-wall pressure as a reliable tool for studying the effect of powder water activity on high speed tableting. International journal of pharmaceutics. 2011;411(1-2):152-161.
30. Steendam R, Frijlink HW, Lerk CF. Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties. European journal of pharmaceutical sciences. 2001;14(3):245-254.
31. Avis KA, Lieberman HA, Lachman L. Pharmaceutical dosage forms: Tablets. Marcel Dekker; 1990.
32. Li J, Wu Y. Lubricants in pharmaceutical solid dosage forms. Lubricants. 2014;2(1):21-43.
33. Conceição J, Estanqueiro M, Amaral M, Silva J, Lobo J. Technological excipients of tablets: Study of flow properties and compaction behavior. AJMSM. 2014;2:71-76.
34. Petrides PE, Schoergenhofer C, Widmann R, Jilma B, Klade CS. Pharmacokinetics of a novel anagrelide extended‐release formulation in healthy subjects: food intake and comparison with a reference product. Clinical Pharmacology in Drug Development. 2018;7(2):123-131.
35. Košir D, Ojsteršek T, Baumgartner S, Vrečer F. A study of critical functionality-related characteristics of HPMC for sustained-release tablets. Pharmaceutical Development and Technology. 2018;23(9):865-873.
36. Ayorinde JO, Odeniyi MA, Balogun-Agbaje O. Formulation and Evaluation of Oral Dissolving Films of Amlodipine Besylate Using Blends of Starches With Hydroxypropyl Methyl Cellulose. Polimery w Medycynie. 2016;46(1)
37. Ahmed SA, Panda N, Ansari M, Kauser A. DEVELOPMENT AND IN VITRO EVALUATION OF ACEBROPHYLLINE SUSTAINED RELEASE MATRIX TABLETS EMPLOYING DIFFERENT GRADE OF HPMC AND ETHYL CELLULOSE.
38. Yasmin R, Shoaib MH, Ahmed FR, Qazi F, Ali H, Zafar F. Aceclofenac fast dispersible tablet formulations: Effect of different concentration levels of Avicel PH102 on the compactional, mechanical and drug release characteristics. Plos one. 2020;15(2):e0223201.
2. Al Dayyeni AM, Al-Gailani BT, Mahdi MG, Khazeem MM. Journal of Population Therapeutics & Clinical Pharmacology.
3. Gisslinger H, Buxhofer‐Ausch V, Hodisch J, et al. A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia–the TEAM‐ET 2· 0 trial. British Journal of Haematology. 2019;185(4):691-700.
4. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood. 2015;126(23):4055.
5. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood, The Journal of the American Society of Hematology. 2012;120(26):5128-5133.
6. Kanakura Y, Miyakawa Y, Wilde P, Smith J, Achenbach H, Okamoto S. Phase III, single-arm study investigating the efficacy, safety, and tolerability of anagrelide as a second-line treatment in high-risk Japanese patients with essential thrombocythemia. International journal of hematology. 2014;100:353-360.
7. Dombi P, Illés Á, Demeter J, et al. Anagrelide reduces thrombotic risk in essential thrombocythaemia vs. hydroxyurea plus aspirin. European Journal of Haematology. 2017;98(2):106-111.
8. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood, The Journal of the American Society of Hematology. 2013;121(10):1720-1728.
9. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. Journal of clinical oncology. 2011;29(6):761.
10. Andes WA, Noveck RJ, Fleming J. Inhibition of platelet production induced by an antiplatelet drug, anagrelide, in normal volunteers. Thrombosis and haemostasis. 1984;52(06):325-328.
11. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. New England Journal of Medicine. 2005;353(1):33-45.
12. Petrides PE. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opinion on Pharmacotherapy. 2004;5(8):1781-1798.
13. Besses C, Zeller W, Alvarez-Larrán A, et al. Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18-50 years) and elderly (≥ 65 years) patients with essential thrombocythemia. International Journal of Clinical Pharmacology and Therapeutics. 2012;50(11):787-796.
14. Martínez-Sellés M, Datino T, Figueiras-Graillet L, et al. Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions. Clinical Drug Investigation. 2013;33:45-54.
15. Petrides PE, Gisslinger H, Steurer M, et al. Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation. Clinical therapeutics. 2009;31(2):386-398.
16. Al-Zein H, Sakeer K, Alanazi FK. Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex. Saudi pharmaceutical journal. 2011;19(4):245-253.
17. Kaleem MA, Alam MZ, Khan M, Jaffery SHI, Rashid B. An experimental investigation on accuracy of Hausner Ratio and Carr Index of powders in additive manufacturing processes. Metal Powder Report. 2021;76:S50-S54.
18. Chao P-C. Easy Flow: Kontinuierliche Feuchtgranulation am Beispiel von Calciumcarbonat. Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Diss., 2013; 2013.
19. Zhao N, Zidan A, Tawakkul M, Sayeed VA, Khan M. Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. International journal of pharmaceutics. 2010;401(1-2):25-31.
20. Swain RP, Kumari TR, Panda S. Formulation development and evaluation of sustained release ibuprofen tablets with acrylic polymers (eudragit) and HPMC. Int J Pharm Pharmaceut Sci. 2016;8(2):131-135.
21. Krishanaiah Y, Latha K, Nageswara Rao L, Karthikeyan R, Bhaskar P, Satyanarayana V. Development of colon targeted oral guar gum matrix tablets of Albendazole for the treatment of helminthiasis. Indian journal of pharmaceutical sciences. 2003;65(4):378-385.
22. Apu AS, Pathan AH, Shrestha D, Kibria G, Jalil R-u. Investigation of in vitro release kinetics of carbamazepine from Eudragit® RS PO and RL PO matrix tablets. Tropical journal of pharmaceutical research. 2009;8(2)
23. Sinko PJ. Martin's physical pharmacy and pharmaceutical sciences. Lippincott Williams & Wilkins; 2023.
24. Moore J, Flanner H. Mathematical comparison of dissolution profiles. Pharmaceutical technology. 1996;20(6):64-74.
25. Spencer CM, Brogden RN. Anagrelide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia. Drugs. 1994;47:809-822.
26. Ummadi S, Shravani B, Rao N, Reddy MS, Sanjeev B. Overview on controlled release dosage form. System. 2013;7(8):51-60.
27. Schlick‐Hasper E, Bethke J, Vogler N, Goedecke T. Flow properties of powdery or granular filling substances of dangerous goods packagings—Comparison of the measurement of the angle of repose and the determination of the Hausner ratio. Packaging Technology and Science. 2022;35(10):765-782.
28. Jaimini M, Kothari AH. Sustained release matrix type drug deliery system: A review. Journal of drug delivery and therapeutics. 2012;2(6)
29. Abdel-Hamid S, Betz G. Radial die-wall pressure as a reliable tool for studying the effect of powder water activity on high speed tableting. International journal of pharmaceutics. 2011;411(1-2):152-161.
30. Steendam R, Frijlink HW, Lerk CF. Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties. European journal of pharmaceutical sciences. 2001;14(3):245-254.
31. Avis KA, Lieberman HA, Lachman L. Pharmaceutical dosage forms: Tablets. Marcel Dekker; 1990.
32. Li J, Wu Y. Lubricants in pharmaceutical solid dosage forms. Lubricants. 2014;2(1):21-43.
33. Conceição J, Estanqueiro M, Amaral M, Silva J, Lobo J. Technological excipients of tablets: Study of flow properties and compaction behavior. AJMSM. 2014;2:71-76.
34. Petrides PE, Schoergenhofer C, Widmann R, Jilma B, Klade CS. Pharmacokinetics of a novel anagrelide extended‐release formulation in healthy subjects: food intake and comparison with a reference product. Clinical Pharmacology in Drug Development. 2018;7(2):123-131.
35. Košir D, Ojsteršek T, Baumgartner S, Vrečer F. A study of critical functionality-related characteristics of HPMC for sustained-release tablets. Pharmaceutical Development and Technology. 2018;23(9):865-873.
36. Ayorinde JO, Odeniyi MA, Balogun-Agbaje O. Formulation and Evaluation of Oral Dissolving Films of Amlodipine Besylate Using Blends of Starches With Hydroxypropyl Methyl Cellulose. Polimery w Medycynie. 2016;46(1)
37. Ahmed SA, Panda N, Ansari M, Kauser A. DEVELOPMENT AND IN VITRO EVALUATION OF ACEBROPHYLLINE SUSTAINED RELEASE MATRIX TABLETS EMPLOYING DIFFERENT GRADE OF HPMC AND ETHYL CELLULOSE.
38. Yasmin R, Shoaib MH, Ahmed FR, Qazi F, Ali H, Zafar F. Aceclofenac fast dispersible tablet formulations: Effect of different concentration levels of Avicel PH102 on the compactional, mechanical and drug release characteristics. Plos one. 2020;15(2):e0223201.
Article Sidebar
Published
Jun 16, 2025
Article Details
How to Cite
Seyedeh Shima Jalilimagham, & Alireza Dabirsiaghi. (2025). DEVELOPMENT OF EXTENDED-RELEASE ANAGRELIDE TABLETS: A FORMULATION AND DISSOLUTION STUDY. Journal of Population Therapeutics and Clinical Pharmacology, 32(5), 759-770. https://doi.org/10.53555/5j97p439
Section
Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Author Biographies
Seyedeh Shima Jalilimagham
Department of Pharmaceutics, Faculty of Pharmacy, Islamic Azad University, Tehran medical sciences, Tehran, Iran
Alireza Dabirsiaghi
Department of Pharmaceutics, Faculty of Pharmacy, Islamic Azad University, Tehran medical sciences, Tehran, Iran,
How to Cite
Seyedeh Shima Jalilimagham, & Alireza Dabirsiaghi. (2025). DEVELOPMENT OF EXTENDED-RELEASE ANAGRELIDE TABLETS: A FORMULATION AND DISSOLUTION STUDY. Journal of Population Therapeutics and Clinical Pharmacology, 32(5), 759-770. https://doi.org/10.53555/5j97p439