Microsuspension of fatty acid esters of entecavir for parenteral sustained delivery
- Authors
- Ho, Myoung Jin; Lee, Dae Ro; Im, Sung Hyun; Yoon, Jeong A.; Shin, Chang Yong; Kim, Hyun Jung; Jang, Sun Woo; Choi, Young Wook; Han, Young Taek; Kang, Myung Joo
- Issue Date
- May-2018
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Entecavir; Lipidic prodrug; Injectable suspension; Sustained release; Pharmacokinetics
- Citation
- INTERNATIONAL JOURNAL OF PHARMACEUTICS, v.543, no.1-2, pp 52 - 59
- Pages
- 8
- Journal Title
- INTERNATIONAL JOURNAL OF PHARMACEUTICS
- Volume
- 543
- Number
- 1-2
- Start Page
- 52
- End Page
- 59
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/2157
- DOI
- 10.1016/j.ijpharm.2018.03.042
- ISSN
- 0378-5173
1873-3476
- Abstract
- Entecavir (EV), an anti-viral agent for hepatitis B infection, should be administered under fasted state, as intestinal absorption of this hydrophilic compound is markedly decreased under post-prandial conditions. Herein, in order to improve therapeutic adherence, a parenteral sustained delivery system was constructed, by synthesizing water-insoluble ester prodrugs of the nucleotide analogous with fatty acids. EV-3-palmitate (named EVP), exhibited the lowest solubility in phosphate buffered saline (pH 7.4, 1.1 mu g/ml), with extended release profile compared with EV, EV-3-myristate, and EV-3-stearate, was selected as a candidate to formulate drug suspension. The crystalline suspension was fabricated using anti-solvent crystallization technique, with a mean particle size of 7.7 mu m. After subcutaneous (SC) injection in beagle dogs (0.43 mg/kg as EV), the plasma concentrations of EV were markedly protracted with lowered maximum plasma concentration (C-max, 4.7 ng/ml), extended time required to reach C-max (T-max, 9.0 days), and lengthened elimination half-life (T-1/2,T- 129.3 h) compared with those after oral administration (0.0154 mg/kg, C-max, 15.4 ng/ml; T-max, 0.01 days; T-1/2, 4.1 h). The systemic exposure of the lipidic prodrug was below 0.1% compared with that of EV following SC injection, denoting that EV-P was rapidly converted into the parent compound in blood. Therefore, SC delivery of EV-P microsuspension can be an alternative to oral EV therapy, offering prolonged pharmacokinetic profile after single injection.
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