Design and in vivo evaluation of entecavir-3-palmitate microcrystals for subcutaneous sustained delivery

Ho, Myoung Jin; Lee, Dae Ro; Im, Sung Hyun; Yoon, Ji‐Young; Shin, Chang Yong; Kim, Hyun Jung; Jang, Sun Woo; Choi, Young Wook; Han, Young Taek; Kang, Myung Joo

doi:10.1016/j.ejpb.2018.06.024

Cited by 12 publications

(7 citation statements)

References 32 publications

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“…Being unable to phagocytose the EV‐P drug aggregates over 500 μm due to its increased particle size, macrophages and proteins such as derived from extravasated blood, such as albumin and fibrinogen, would become nonspecifically adsorbed to the surface of the drug clusters, forming macrophage layer around the drug aggregates. This granulomatous inflammatory reaction against drug particles is consistent with previous reports 18,54,55 . In our previous study, the SC injection of EV‐P AS (6.3 μm, 30–150 mg/kg) caused inflammatory responses in a dose‐dependent manner, which is characterized by the drug aggregates covered with thickened fibroblastic bands, extensive infiltration of inflammatory cells, necrosis, and angiogenesis around the injection site 54 .…”

Section: Resultssupporting

confidence: 92%

Tricaprylin‐based drug crystalline suspension for intramuscular long‐acting delivery of entecavir with alleviated local inflammation

Jeong,

Ho,

Park

et al. 2024

Bioengineering & Transla Med

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In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin‐based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3‐palmitate (EV‐P), an ester lipidic prodrug for entecavir (EV), was employed. The EV‐P‐loaded TS was prepared by ultra‐sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 μm), crystallinity (melting point of 160–165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS‐injected site, drug aggregates of up to 500 μm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS‐injected site, with >4 weeks remaining of the oily vehicle in micro‐computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long‐acting delivery, with improved local tolerability.

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Section: Resultssupporting

confidence: 92%

Tricaprylin‐based drug crystalline suspension for intramuscular long‐acting delivery of entecavir with alleviated local inflammation

Jeong,

Ho,

Park

et al. 2024

Bioengineering & Transla Med

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“…The development of LAI for chronic viral infections beyond HIV, including HBV, is gaining traction due to its potential to simplify regimens and treatment outcomes. Encouraging preclinical research has been conducted on LAI formulations of emtricitabine, lamivudine, tenofovir, and entecavir [ 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. LAI anti-HBV agents can be particularly beneficial for high-risk patients facing treatment adherence and stigma challenges.…”

Section: Long-acting Therapeuticsmentioning

confidence: 99%

“…In vivo, pharmacokinetic evaluations in rats showed sustained plasma ETV concentrations for up to four weeks following a single subcutaneous injection of 1.44mg/kg of ETV. The microparticles were well tolerated at higher doses [ 94 ]. In a separate study by Zhang et al, ETV was formulated as an extended-release poly (lactic-co-glycolic acid) microsphere and exhibited plasma ETV levels for 42 days in rats following a single intramuscular injection at 1.5 mg/kg.…”

Section: Long-acting Therapeuticsmentioning

confidence: 99%

Chronic Hepatitis B Infection: New Approaches towards Cure

Ogunnaike,

Das,

Raut

et al. 2023

Biomolecules

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Chronic hepatitis B virus (HBV) infection leads to the development of cirrhosis and hepatocellular carcinoma. Lifelong treatment with nucleotides/nucleoside antiviral agents is effective at suppressing HBV replication, however, adherence to daily therapy can be challenging. This review discusses recent advances in the development of long-acting formulations for HBV treatment and prevention, which could potentially improve adherence. Promising new compounds that target distinct steps of the virus life cycle are summarized. In addition to treatments that suppress viral replication, curative strategies are focused on the elimination of covalently closed circular DNA and the inactivation of the integrated viral DNA from infected hepatocytes. We highlight promising long-acting antivirals and genome editing strategies for the elimination or deactivation of persistent viral DNA products in development.

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“…The effect of formulation variables, such as sonication powder and the number of sonication cycles, the drug and the PVP polymer concentrations in the preparation process, on crystal size and homogeneity is presented in Figure 1. Four formulation variables were set from the previous report [38] and our preliminary experiment. As expected [38], as the sonication intensity increased from 13-33 Watts, the drug crystal size markedly decreased, providing nano-sized drug crystals below 150 nm with a sonication power of 33 Watts (Figure 1a).…”

Section: Effect Of Process Parameters On Size and Homogeneity Of Mtk mentioning

confidence: 99%

“…Four formulation variables were set from the previous report [38] and our preliminary experiment. As expected [38], as the sonication intensity increased from 13-33 Watts, the drug crystal size markedly decreased, providing nano-sized drug crystals below 150 nm with a sonication power of 33 Watts (Figure 1a). Drug nanocrystal size was also decreased as the number of sonication cycles were increased, and they reached a plateau with three cycles (total 6 min), with a particle size below 150 nm (Figure 1b).…”

Section: Effect Of Process Parameters On Size and Homogeneity Of Mtk mentioning

confidence: 99%

Montelukast Nanocrystals for Transdermal Delivery with Improved Chemical Stability

Jung

et al. 2019

Pharmaceutics

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A novel nanocrystal system of montelukast (MTK) was designed to improve the transdermal delivery, while ensuring chemical stability of the labile compound. MTK nanocrystal suspension was fabricated using acid-base neutralization and ultra-sonication technique and was characterized as follows: approximately 100 nm in size, globular shape, and amorphous state. The embedding of MTK nanocrystals into xanthan gum-based hydrogel caused little changes in the size, shape, and crystalline state of the nanocrystal. The in vitro drug release profile from the nanocrystal hydrogel was comparable to that of the conventional hydrogel because of the rapid dissolution pattern of the drug nanocrystals. The drug degradation under visible exposure (400–800 nm, 600,000 lux·h) was markedly reduced in case of nanocrystal hydrogel, yielding only 30% and 50% amount of cis-isomer and sulfoxide as the major degradation products, as compared to those of drug alkaline solution. Moreover, there was no marked pharmacokinetic difference between the nanocrystal and the conventional hydrogels, exhibiting equivalent extent and rate of drug absorption after topical administration in rats. Therefore, this novel nanocrystal system can be a potent tool for transdermal delivery of MTK in the treatment of chronic asthma or seasonal allergies, with better patient compliance, especially in children and elderly.

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Design and in vivo evaluation of entecavir-3-palmitate microcrystals for subcutaneous sustained delivery

Cited by 12 publications

References 32 publications

Tricaprylin‐based drug crystalline suspension for intramuscular long‐acting delivery of entecavir with alleviated local inflammation

Tricaprylin‐based drug crystalline suspension for intramuscular long‐acting delivery of entecavir with alleviated local inflammation

Chronic Hepatitis B Infection: New Approaches towards Cure

Montelukast Nanocrystals for Transdermal Delivery with Improved Chemical Stability

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