Entecavir
stability and drug-excipient compatibility
DOI:
https://doi.org/10.1590/Keywords:
Entecavir, Stability, Drug-excipient compatibility, Thermal analysis, HPLCAbstract
Entecavir is an inhibitor of hepatitis B virus (HBV) DNA synthesis that has been widely prescribed in the treatment of chronic infections caused by the virus. Production of generic ETV drugs is an ongoing global endeavor, with particular significance for developing countries that rely on importing the expensive reference drug. ETV-excipient compatibility studies were conducted with the declared inputs in solid pharmaceutical formulations on the market through thermal analysis and HPLC techniques. Thermal analyses by TGA and DTA indicated compatibility of entecavir with the excipients microcrystalline cellulose, crospovidone, titanium dioxide, magnesium stearate, hypromellose, polyethylene glycol and povidone; this was confirmed via HPLC. Lactose monohydrate proved to be incompatible with ETV in thermal and chromatographic assays. The thermal analysis of marketed solid dosage forms revealed a predominance of the lactose monohydrate profile at the expense of ETV and other inputs in the TGA and DTA curves, due to its high content in the formulations; this makes the evidence of ETV-lactose chemical interaction even more important. Compatibility tests by HPLC showed no chemical interaction of ETV with the excipient mannitol, a soluble diluent proposed as a replacement for lactose monohydrate, with the same function in the formulation.
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Amidon GL, Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, et al. Molecular Properties of WHO Essential Drugs and Provisional Biopharmaceutical Classification. Mol Pharm. 2004; 1(1): 85-96.
Barathe SS, Barathe SB, Bajaj AN. Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J Excip Food Chem. 2010; 1: 3-26.
Bertol CD, Cruz AP, Stulzer HK, Murakami FS. Thermal decomposition kinetics and compatibility studies of primaquine under isothermal and non-isothermal conditions. J Therm Anal Calorim. 2010; 102(1): 187-192.
BMS - Bristol-Myers Squibb. 2018. Leaflet for the healthcare professional: Baraclude® coated tablets. Available at: https://www.bms.com/assets/bms/brazil/documents/hcp/bulas-profissionais-otimizadas/BARACLUDE_COMP_VPS_Rev0918.pdf >. Accessed: 15 dec. 2022.
Brazil. Ministry of Health. 2011. Law No. 12,401, of April 28, 2011. Official Gazette, Brasilia.
Brazil. Ministry of Health. 2012. Ordinance No. 837, of April 18, 2012. Official Gazette, Brasilia.
Brazil. Ministry of Health. 2013. Ordinance No. 3,089, of December 11, 2013. Official Gazette, Brasilia.
Brazil. National Health Surveillance Agency. 2017. Resolution RDC No. 166, of July 24, 2017. Official Gazette, Brasilia.
Brazil. National Health Surveillance Agency. 2018. Resolution RDC No. 1465, of June 7, 2018. Official Gazette, Brasilia.
Brazil. Ministry of Health. Secretariat of Science, Technology and Strategic Inputs. Department of Pharmaceutical Services and Strategic Inputs. 2019a. National List of Essential Medicines: RENAME 2020. Brasilia: Ministry of Health.
Brazil. Ministry of Economy. Council for Monitoring and Evaluation of Public Policies. Evaluation Report of the Specialized Component of Pharmaceutical Services (CEAF). Cycle 2019. Brasilia: Ministry of Economy. 2019b.
Christopher KO, William ML, Kirkpatrick P. Entecavir Nat Rev Drug Discov. 2005; 4(7): 535-539.
EASL (European Association for the Study of the Liver) Clinical Practice Guidelines: Management of chronic hepatitis B J Hepatol. 2009; 50(2): 227-242.
EMA - European Medicine Agency. Committee for Medicinal Products for Human Use (CHMP). Entecavir film-coated tablets 0.5 and 1 mg, oral solution 0.05mg/ml product-specific bioequivalence guidance. London: European Medicines Agency. 2015.
EMA - European Medicine Agency. Committee for Medicinal Products for Human Use (CHMP). Assessment report: Entecavir Accord European Medicines Agency: London. 2018.
FDA - Food and Drug Administration. Center for Drug Evaluation and Research. Drug Approval Package: Baraclude (Entecavir) Film Coated Tablets & Oral Solution. 2005. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21797_21798_BaracludeTOC.cfm >. Accessed: 07 may 2022.
» https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21797_21798_BaracludeTOC.cfm
FDA - Food and Drug Administration. Center for Drug Evaluation and Research. Baraclude (entecavir) oral solution label. 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021797s011lbl.pdf >. Accessed: 18 mar. 2022.
» https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021797s011lbl.pdf
FUNED - Fundação Ezequiel Dias. Entecavir. 2018. Available at: http://www.funed.mg.gov.br/2018/10/parque-industrial/entecavir/ >. Accessed: 26 apr. 2021.
» http://www.funed.mg.gov.br/2018/10/parque-industrial/entecavir/
FUNED - Fundação Ezequiel Dias. Package leaflet for the health professional: entecavir monohydrate (Generic Drug, Law No. 9,787/1999) 0.5 mg. 2019. Available at: http://www.funed.mg.gov.br/wp-content/uploads/2019/10/Bula-entecavir-monoidratado-para-o-profissional-de-sa%C3%BAde.pdf >. Accessed: 15 dec. 2021.
FUNED - Fundação Ezequiel Dias. Funed makes the first delivery of entecavir to the Ministry of Health. 2020. Available at: http://www.funed.mg.gov.br/2020/05/geral/funed-realiza-primeira-entrega-do-entecavir-ao-ministerio-da-Lsaude/#:~:text=Funed%20realiza%20primeira%20entrega%20do%20Entecavir%20ao%20Minist%C3%A9rio%20da%20Sa%C3%BAde,-Funed%20desenvolve%2C%20registra&text=A%20Funda%C3%A7%C3%A3o%20Ezequiel%20Dias%20(Funed,da%20Hepatite%20B%20(VHB) >. Accessed: 14 july 2021.
Gabbott P. Principles and applications of thermal analysis. Oxford: Blackwell Publishing. 2008. 464 p.
Gautier JC, Abramovici B, Boulenc X, Vilain P. Pharmaceutical formulation, and process for their preparation. Depositor: Sanofi-Synthelabo. Attorney: Momsen, Leonardos & Cia. FR n. PI 9807406-7A2. Deposit: 17 fev. 1998. Publication: 14 mar. 2000.
ICH Q2 (R1) - International Conference on Harmonization of Technical Requirements for the Registration of Drugs for Human Use. 2005. Validation of analytical procedures: text and methodology Q2(R1). Available at: http://www.ich.org/LOB/media/MEDIA417.pdf >. Accessed: 05 may 2019.
» http://www.ich.org/LOB/media/MEDIA417.pdf
Kang Y, Shao Z, Wang Q, Hu X, Yu D. Quantitation of polymorphic impurity in entecavir polymorphic mixtures using powder X-ray diffractometry and Raman spectroscopy. J Pharm Biomed Anal. 2018; 158: 28-37.
Keating GM. Entecavir: A review of its use in the treatment of chronic hepatitis B in patients with decompensated liver disease. Drugs, Springer International Publishing, 2011; 71(18): 2511-29.
Lima NGPB, Lima IPB, Barros DMC, Oliveira TS, Raffin FN, Moura TFAL et al. Compatibility studies of trioxsalen with excipients by DSC, DTA, and FTIR. J Therm Anal Calorim. 2014; 115(3): 2311-2318.
Listiohadi Y, Hourigan JA, Sleigh RW, Steele RJ. Thermal analysis of amorphous lactose and α-lactose monohydrate. Dairy SciTechnol. 2009; 89(1): 43-67.
Liu M, Shi P, Wang G, Wang G, Song P, Liu Y, et al. Quantitative analysis of binary mixtures of entecavir using solid-state analytical techniques with chemometric methods. Arab J Chem. 2021; 14(10): 103360.
Oliveira MA, Yoshida MI, Lima Gomes EL. Thermal analysis applied to drugs and pharmaceutical formulations in the pharmaceutical industry. Quim Nova. 2011; 34(7): 1224-1230.
Oliveira MA, Silva GD, Campos MST. Chemical degradation kinetics of fibrates: bezafibrate, ciprofibrate and fenofibrate. Braz J Pharm Sci. 2016; 52(3): 545-553.
Pereira MAV, Fonsêca GD, Silva Júnior AA, Pedrosa MFF, Moura MFV, Barbosa EG, et al. Compatibility study between chitosan and pharmaceutical excipients used in solid dosage forms. J Therm Anal Calorim. 2014; 116(2): 1091-1100.
Ph. Eur. (European Pharmacopoeia). 9. ed. Strasbourg: European Department for Quality of Medicines. 2016.
Pires SA. 2016. Compatibility studies of the drugs fenofibrate, ciprofibrate and citalopram with some excipients. Tese (PhD in Sciences - Chemistry) - Federal University of Minas Gerais.
Ramesh T, Rao PN, Rao RN. LC-MS/MS method for the characterization of the forced degradation products of Entecavir. J Sep Sci. 2014; 37(4): 368-375.
Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 2020. 9. ed. Pharmaceutical Press: London.
Sandes T. Fiocruz produces the country’s first generic for hepatitis B. Portal Fiocruz. 2020. Available at: https://portal.fiocruz.br/noticia/fiocruz-produz-primeiro-generico-do-pais-para-hepatite-b >. Accessed: 15 dec. 2022.
» https://portal.fiocruz.br/noticia/fiocruz-produz-primeiro-generico-do-pais-para-hepatite-b
Satyanaryana L, Naidu SV, Rao MN, Priya LR, Suresh K. The estimation of entecavir in tablet dosage form by RP-HPLC. Res J Pharm Technol. 2011; 4(11): 1699-1701.
Sena LCS, Santos JLA, Andrade PHS, Brito GC, Lira AAM, Lobo IMF. Pharmaceutical excipients and their health risks: a literature review. Rev Bras Farm Hosp Serv Saúde. 2014; 5(4): 25-34.
Silveira LM, Fiorot AB, Xavier TP, Yoshida MI, Oliveira MA. Drug-excipient compatibility assessment of solid formulations containing meloxicam. Eur J Pharm Sci. 2018; 112: 146-151.
Solomons TWG, Fryhle CB, Snyder SA. 2017. Organic Chemistry. 12 ed. 1208 p. Nova Iorque: Softcover Wiley & Sons Ltda.
USP (United States Pharmacopoeia). 2017. 40. ed. Rockville: United States Pharmacopeial Convention.
WHO - Worlds Health Organization. WHO Model Lists of Essential Medicines. 2017. Available at: https://www.who.int/medicines/publications/essentialmedicines/en/ >. Accessed: 05 may 2022.
» https://www.who.int/medicines/publications/essentialmedicines/en/
WHO - Worlds Health Organization. Hepatitis B. 2018. Available at: https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-b >. Accessed: 05 may 2022.
» https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-b
Yousaf AM, Jee JP, Hwang SR, Maeng HJ, Park YJ, Kim JO, et al. Development of direct compression entecavir 0.5 mg-loaded tablet exhibiting enhanced content uniformity. Powder Technol. 2014; 267: 302-308.
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