| The aim is to develop a novel low-molecule-organogel system with good biocompatibilityand steady drug release profile, avoiding the existing issues including high cost, complextechnology and solvent biotoxicity of marketed long-acting products. In this paper,injectable soybean oil for medicinal use was employed as gel medium, biocompatible fattyacids and fatty acid esters were employed as gelators, paliperidone for the treatment ofschizophrenia was employed as model drug, to develop a novel injectable in situ formingorganogel system, which was syringable solution before injection, once administrated itformed a semi-solid drug depot immediately, and the properties and drug release behaviorwere investigated.Four commercial long chain fatty acids with different alkane chain length (MyristicAcid, Palmitic Acid, Stearic Acid, Arachidic Acid), and two kind of stearates (GlycerinMonostearate, Glyceryl Tristearate) were chosen as organogelators, and the gelling abilityto soybean oil was studied. Inverse flow method was applied to determine Sol-Gel phasetransition temperature (Tsg) and time (tsg) of gel formulations; DSC was applied todetermine the thermal properties of the gels; viscosity was determined to evaluate themechanicalproperties of gel system. Results indicated that the gelling ability to soybeanoil increase with the growth of alkane chain length. Meanwhile, the properties offormulations prepared with different content of gelators were investigated, and the gelsystem prepared with7.5%stearic acid and with5.0%arachidic acid showed propergelling temperature, higher gelation efficiency and larger mechanical strength. Whileformulations prepared with stearates were unableto generate a homogeneous gel system.Microstructure of the organogel was observed to be a tight reticular structure under opticalmicroscope. The preliminary stability studies of the optimizing gel formulation revealed that this gel system remained stable under ambient temperature condition and repeatedlyheating and cooling conditions.Drug loading organogel were prepared with optimizing gel formulation, and the drugrelease behavior was investigated. Drug concentration determination method in vitro wasestablished. Tsg and tsg of drug loading organogels were measured. Results suggested thataddition of drug particle could increase the phase inversion rate, but not change the phaseinversion temperature. Drug release behavior of the gel system prepared7.5%stearic acidand with5.0%arachidic acid was further researched, revealing that both of theformulations process sustained-release effect on the model drug paliperidone, and the invitro drug release period was one to three weeks; gel system prepared with arachidic acidgenerate a more sustained drug release profile than that with stearic acid.In vivo evaluation of paliperidone organogel was researched about the in vivo drugrelease, morphological changes and biocompatibility. In vivo drug release behavior wasinvestigated by subcutaneously injection of paliperidone loaded in situ forming gelformulation in rats. Results suggested that a one-week uniform drug release formulationwas reached without burst release, well fitted to the drug release mechanism ofRitger-Peppas model comprised of both drug diffusion and frame erosion. In vivo imagingsystem was applied to monitor the morphological changes of the formulation at theinjection site, which was proved to be consistent with the drug release mechanism. Tissueirritant experiment was performed on the back of mice with local hair removal, and itshowed no obvious inflammation reaction of this gel system with surrounding tissues aftersix days, revealing good biocompatibility.This in situ organogel long-acting injection showed good biocompatibility andone-week steady drug release profile with simple preparation technology, indicating goodpractical value and application prospect, and provide theory support for the developmentof long-term controlled-release formulation. |
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