Development and In Vitro/In Vivo Evaluation of Berberine and Liraglutide-Loaded SNEDDS Formulations for the Treatment of Diabetes

Project no. 29612 · Status: Kapanmış (Yayın bekleniyor) · 2023

Summary

<p>In&nbsp;this&nbsp;thesis,&nbsp;the&nbsp;co-delivery&nbsp;feasibility&nbsp;and&nbsp;bioavailability&nbsp;potential&nbsp;of&nbsp;two&nbsp;structurally&nbsp;distinct&nbsp;active&nbsp;pharmaceutical&nbsp;ingredients&nbsp;with&nbsp;limited&nbsp;oral&nbsp;bioavailability&nbsp;—&nbsp;the&nbsp;lipophilic&nbsp;small&nbsp;molecule&nbsp;Berberine&nbsp;and&nbsp;the&nbsp;peptide-based&nbsp;drug&nbsp;Liraglutide&nbsp;—&nbsp;were&nbsp;investigated&nbsp;within&nbsp;a&nbsp;single&nbsp;lipid-based&nbsp;drug&nbsp;delivery&nbsp;system.&nbsp;Both&nbsp;actives&nbsp;exhibit&nbsp;restricted&nbsp;oral&nbsp;bioavailability&nbsp;in&nbsp;conventional&nbsp;formulations&nbsp;due&nbsp;to&nbsp;poor&nbsp;solubility&nbsp;and/or&nbsp;gastrointestinal&nbsp;degradation.&nbsp;Therefore,&nbsp;a&nbsp;self-nanoemulsifying&nbsp;drug&nbsp;delivery&nbsp;system&nbsp;(SNEDDS)&nbsp;capable&nbsp;of&nbsp;enhancing&nbsp;solubility&nbsp;while&nbsp;providing&nbsp;controlled&nbsp;release&nbsp;was&nbsp;designed.</p><p>During&nbsp;formulation&nbsp;development,&nbsp;appropriate&nbsp;ratios&nbsp;of&nbsp;the&nbsp;oil&nbsp;phase,&nbsp;surfactant,&nbsp;and&nbsp;co-surfactant&nbsp;were&nbsp;determined,&nbsp;and&nbsp;seven&nbsp;candidate&nbsp;formulations&nbsp;were&nbsp;prepared.&nbsp;These&nbsp;formulations&nbsp;were&nbsp;evaluated&nbsp;in&nbsp;terms&nbsp;of&nbsp;self-emulsification&nbsp;time,&nbsp;physical&nbsp;appearance,&nbsp;phase&nbsp;separation,&nbsp;thermodynamic&nbsp;and&nbsp;long-term&nbsp;stability,&nbsp;droplet&nbsp;size,&nbsp;polydispersity&nbsp;index&nbsp;(PDI),&nbsp;zeta&nbsp;potential,&nbsp;and&nbsp;pH.&nbsp;Based&nbsp;on&nbsp;the&nbsp;overall&nbsp;performance&nbsp;across&nbsp;these&nbsp;parameters,&nbsp;the&nbsp;most&nbsp;suitable&nbsp;formulation&nbsp;was&nbsp;selected.&nbsp;The&nbsp;selected&nbsp;SNEDDS&nbsp;provided&nbsp;high&nbsp;loading&nbsp;capacity&nbsp;and&nbsp;homogeneous&nbsp;distribution&nbsp;for&nbsp;both&nbsp;active&nbsp;ingredients.</p><p>In&nbsp;the&nbsp;in&nbsp;vitro&nbsp;release&nbsp;study,&nbsp;Berberine&nbsp;reached&nbsp;approximately&nbsp;62%&nbsp;at&nbsp;120&nbsp;min&nbsp;in&nbsp;pH&nbsp;1.2&nbsp;and&nbsp;approximately&nbsp;98%&nbsp;at&nbsp;600&nbsp;min&nbsp;in&nbsp;pH&nbsp;6.8,&nbsp;whereas&nbsp;Liraglutide&nbsp;exhibited&nbsp;more&nbsp;than&nbsp;60%&nbsp;release&nbsp;at&nbsp;90&nbsp;min&nbsp;in&nbsp;pH&nbsp;1.2&nbsp;and&nbsp;approximately&nbsp;91%&nbsp;release&nbsp;at&nbsp;600&nbsp;min&nbsp;in&nbsp;pH&nbsp;6.8.&nbsp;Modeling&nbsp;based&nbsp;on&nbsp;fasted&nbsp;and&nbsp;fed&nbsp;transit&nbsp;assumptions&nbsp;indicated&nbsp;that&nbsp;cumulative&nbsp;intestinal-phase&nbsp;release&nbsp;could&nbsp;be&nbsp;2.11-fold&nbsp;higher&nbsp;for&nbsp;Berberine&nbsp;and&nbsp;2.18-fold&nbsp;higher&nbsp;for&nbsp;Liraglutide&nbsp;under&nbsp;fasted&nbsp;conditions.&nbsp;In&nbsp;the&nbsp;in&nbsp;vivo&nbsp;evaluation,&nbsp;comparison&nbsp;using&nbsp;dose-normalized&nbsp;parameters&nbsp;demonstrated&nbsp;that&nbsp;for&nbsp;Liraglutide,&nbsp;Dual-SNEDDS&nbsp;achieved&nbsp;a&nbsp;5.3-fold&nbsp;higher&nbsp;exposure&nbsp;(AUC/dose)&nbsp;than&nbsp;the&nbsp;oral&nbsp;solution&nbsp;and&nbsp;the&nbsp;relative&nbsp;bioavailability&nbsp;increased&nbsp;to&nbsp;57.87%&nbsp;compared&nbsp;with&nbsp;the&nbsp;subcutaneous&nbsp;reference.&nbsp;For&nbsp;Berberine,&nbsp;however,&nbsp;systemic&nbsp;levels&nbsp;could&nbsp;not&nbsp;be&nbsp;quantified&nbsp;at&nbsp;a&nbsp;reliable&nbsp;level&nbsp;in&nbsp;the&nbsp;Dual-SNEDDS&nbsp;group.</p><p>Overall,&nbsp;these&nbsp;findings&nbsp;suggest&nbsp;that&nbsp;the&nbsp;developed&nbsp;SNEDDS&nbsp;formulation&nbsp;may&nbsp;serve&nbsp;as&nbsp;a&nbsp;suitable&nbsp;drug&nbsp;delivery&nbsp;system&nbsp;for&nbsp;both&nbsp;Berberine&nbsp;and&nbsp;Liraglutide&nbsp;and&nbsp;may&nbsp;improve&nbsp;VI&nbsp;oral&nbsp;bioavailability.&nbsp;Future&nbsp;in&nbsp;vivo&nbsp;studies&nbsp;focusing&nbsp;on&nbsp;therapeutic&nbsp;efficacy&nbsp;are&nbsp;expected&nbsp;to&nbsp;further&nbsp;elucidate&nbsp;the&nbsp;clinical&nbsp;applicability&nbsp;of&nbsp;the&nbsp;proposed&nbsp;system.</p>

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