Abstract
We developed a dual microencapsulation platform for the type 2 diabetes drug metformin (MTF), which is aimed to increase its bioavailability. We report the use of Lycopodium clavatum sporopollenin (LCS), derived from their natural spores, and raw Phoenix dactylifera L. (date palm) pollens (DPP) for MTF microencapsulation. MTF was loaded into LCS and DPP via a vacuum and a novel method of hydration-induced swelling. The loading capacity (LC) and encapsulation efficiency (EE) percentages for MTF-loaded LCS and MTF-loaded DPP microcapsules were 14.9% ± 0.7, 29.8 ± 0.8, and 15.2% ± 0.7, 30.3 ± 1.0, respectively. The release of MTF from MTF-loaded LCS microcapsules was additionally controlled by re-encapsulating the loaded microcapsules into calcium alginate (ALG) microbeads via ionotropic gelation, where the release of MTF was found to be significantly slower and pH-dependent. The pharmacokinetic parameters, obtained from the in vivo study, revealed that the relative bioavailability of the MTF-loaded LCS-ALG beads was 1.215 times higher compared to pure MTF, following oral administration of a single dose equivalent to 25 mg/kg body weight MTF to streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats. Significant hypoglycemic effect was obtained for STZ-induced diabetic rats orally treated with MTF-loaded LCS-ALG beads compared to control diabetic rats. Over a period of 29 days, the STZ-induced diabetic rats treated with MTF-loaded LCS-ALG beads showed a decrease in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides, cholesterol, and low-density lipoprotein-cholesterol (LDL-C) levels, as well as an increase in glutathione peroxidase (GPx) and a recovery in the oxidative stress biomarker, lipid peroxidation (LPx). In addition, histopathological studies of liver, pancreas, kidney, and testes suggested that MTF-loaded LCS-ALG beads improved the degenerative changes in organs of diabetic rats. The LCS-ALG platform for dual encapsulation of MTF achieved sustained MTF delivery and enhancement of bioavailability, as well as the improved biochemical and histopathological characteristics in in vivo studies, opening many other intriguing applications in sustained drug delivery.
Highlights
IntroductionTo reach MTF therapeutic efficacy, repeated high doses (2.5 g/day dosage) are frequently required, resulting in poor patient compliance, the occurrence of GI tract adverse effects, and the uncommon lactic acidosis incidences [30,31]
MTF was encapsulated into the Lycopodium clavatum sporopollenin (LCS) sporopollenin and raw DPP pollens using vacuum and natural hydration-induced swelling techniques, respectively
The optimized MTF-loaded LCS-ALG beads exhibited the slowest and most sustained in vitro MTF release profile, where 14% of MTF was slowly released in SGF within
Summary
To reach MTF therapeutic efficacy, repeated high doses (2.5 g/day dosage) are frequently required, resulting in poor patient compliance, the occurrence of GI tract adverse effects, and the uncommon lactic acidosis incidences [30,31] These concerns have stimulated researchers to explore novel formulation approaches in efforts to decrease MTF adverse effects and repeated dosing as well as to enhance its bioavailability and the patient compliance [11,13,32,33]. Unlike the above-mentioned studies, we propose a different strategy for microencapsulation of MTF into plant-based pollen microcapsules and their secondary encapsulation into composite ALG beads We explore their feasibility in improving MTF sustainable and targeted in vitro and in vivo delivery, enhancing its pharmacokinetic properties and bioavailability.
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