title: Development and in vivo/in vitro evaluation of novel herpetrione nanosuspension.
abstract: Herpetrione (HPE), is a new compound extracted from Herpetospermum caudigerum, which is proved to be a novel and potent antiviral agent. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To improve the dissolution and absorption of the drug, formulation of HPE as nanosuspension has been performed in this study. HPE nanosuspension were produced by high pressure homogenization and transformed into dry powder by lyophilization. The nanosuspension was then investigated using photon correlation spectroscopy (PCS), zeta potential measurement, SEM and PXRD. To verify the theoretical hypothesis on the benefit of decreased particle size and increased surface area, in vitro dissolution characterization and in vivo pharmacokinetics were investigated. The inhibitory effect on HBsAg, HBeAg, and HBV-DNA of HPE nanosuspension in 2.2.15 cells was studied. Results showed that a narrow size distributed nanosuspension with a mean particle size of 286±1.3 nm, a polydispersity index of 0.18±0.06 and a zeta potential of -26.9±2.4 mV was obtained. The result of PXRD showed that HPE was amorphous state in both coarse powder and nanosuspension. In the in vitro dissolution test, HPE nanosuspension showed an increased dissolution velocity markedly. In the in vivo evaluation, compared to coarse HPE, nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. The inhibitory effect of HBsAg, HBeAg, and HBV-DNA of 2.2.15 cells treated by HPE nanosuspension were stronger than those of the HPE. The in vitro activity experiments provided evidence for an enhanced efficacy of the HPE nanosuspension formulation compared to HPE coarse suspension. These results revealed that particle size reduction could enhance HPE dissolution rate and absorption in gastrointestinal tract, and nanosuspension might be a good choice for oral delivery of poor bioavailability drug like HPE.
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China.
authors.forename: Jing-jing
authors.initials: JJ
authors.lastname: Guo
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Yue
authors.forename: Jun-lan
authors.initials: JL
authors.lastname: Lv
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Shan-shan
authors.initials: SS
authors.lastname: Fu
authors.forename: Shi-xiao
authors.initials: SX
authors.lastname: Jin
authors.forename: Shi-ying
authors.initials: SY
authors.lastname: Jin
authors.forename: Hai-Long
authors.initials: HL
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D019662:Cucurbitaceae / Q000737:chemistry*; D004279:DNA, Viral / Q000187:drug effects; D004339:Drug Compounding; D005612:Freeze Drying; D005663:Furans / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006514:Hepatitis B Surface Antigens / Q000187:drug effects; D006513:Hepatitis B e Antigens / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013535:Suspensions; D014961:X-Ray Diffraction
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D005663:Furans; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D013535:Suspensions; C582460:herpetrione