The biological effects of the hypolipidaemic drug probucol microcapsules fed daily for 4 weeks, to an insulin-resistant mouse model: potential hypoglycaemic and anti-inflammatory effects.

Probucol (PB) is an hypolipidaemic drug with potential antidiabetic effects. We showed recently using in vitro studies that when PB was incorporated with stabilising lipophilic bile acids and microencapsulated using the polymer sodium alginate, the microcapsules showed good stability but poor and irregular PB release. This suggests that PB microcapsules may exhibit better release profile and hence better absorption, if more hydrophilic bile acids were used, such as ursodeoxycholic acid (UDCA). Accordingly, this study aimed to produce PB-UDCA microcapsules and examine PB absorption and antidiabetic effects in our mouse-model of insulin-resistance and diabetes (fed high-fat diet; HFD). The study also aimed to examine the effects of the microcapsules on the bile acid profile. Healthy mice (fed low-fat diet; LFD) were used as control. Seventy mice were randomly allocated into seven equal groups: LFD, HFD given empty microcapsules, HFD given metformin (M), HFD given standard-dose probucol (PB-SD), HFD given high-dose probucol (PB-H), HFD given UDCA microcapsules and HFD given PB-UDCA microcapsules. Blood glucose (BG), inflammatory biomarkers (TNF-α, IFN-γ, IL-1ß, IL-6, IL-10, IL-12 and IL-17), plasma cholesterol, non-esterified fatty acids and triglycerides were analysed together with plasma bile acid and probucol concentrations. PB-UDCA microcapsules reduced BG in HFD mice, but did not reduce inflammation or improve lipid profile, compared with positive control (HFD) group. Although PB-UDCA microcapsules did not exert hypolipidaemic or antiinflammatory effects, they resulted in significant hypoglycaemic effects in a mouse model of insulin resistance, which suggests potential applications in insulin-resistance and glucose haemostasis.

Influence of Biotechnological Processes, Speed of Formulation Flow and Cellular Concurrent Stream-Integration on Insulin Production from ß-cells as a Result of Co-Encapsulation with a Highly Lipophilic Bile Acid.

INTRODUCTION: We have shown that incorporation of the hydrophilic bile acid, ursodeoxycholic acid, into ß-cell microcapsules exerted positive effects on microcapsules' morphology and size, but these effects were excipient and method dependent. Cell viability remained low which suggests low octane-water solubility and formation of highly hydrophilic dispersion, which resulted in low lipophilicity dispersion and compromised cellular permeation of the incorporated bile acid. Thus, this study aimed at investigating various microencapsulating methodologies using highly lipophilic bile acid (LPBA), in order to optimise viability and functions of microencapsulated ß-cells. METHODS: Four different types of microcapsules were produced with (test) and without (control) LPBA, totalling eight different microcapsules. Microencapsulating methodologies were screened for best microcapsule-cell functions and microencapsulating processes were examined in terms of frequency, formulation flow, total bath-gelation time and cellular concurrent stream-integration rate, cell-viability, insulin production and inflammatory profile. RESULTS: Optimum biotechnological processes include formation frequency (Hz) of 2350, formulation flow (ml/min) of 1.2, total gelation time (min) of 18 and cellular concurrent stream-integration rate (ml/min) of 0.7. In all formulations, LPBA consistently improved cell viability, insulin production, mitochondrial activities and ameliorated inflammation. CONCLUSION: The deployed biotechnological processes and LPBA optimised formation and functions of ß-cell microcapsules, which suggests potential applications in diabetes mellitus via the creation of more stable ß-cell microcapsules capable of delivering adequate levels of insulin to control glycaemia and potentially curing diabetes.

Electrokinetic potential-stabilization by bile acid-microencapsulating formulation of pancreatic ß-cells cultured in high ratio poly-L-ornithine-gel hydrogel colloidal dispersion: applications in cell-biomaterials, tissue engineering and biotechnological applications.

INTRODUCTION: Current trials for ß-cell transplantation have been hindered by poor cell viability and function post-transplantation. Recently, electric charges of the microencapsulating formulation carrying ß-cells have shown significant effects on cell survival and function. Thus, this study aimed at investigating the effects of electric charge, of novel colloidal formulation containing ß-cells, on cell viability, biological activity and insulin release. METHODS: A new formulation, containing high ratios of poly-L-ornithine, suspending electrical-stimulation hydrogel and polystyrene sulphone (1:1:0.1 ratio), was used to form microcapsules utilizing 800 V and 2000 Hz encapsulating conditions. The bile acid, ursodeoxycholic acid, was added into the microcapsules to measure its effects on electric charges. RESULTS: The electric charge of the microencapsulating formulation was enhanced by bile acid addition, and resulted in better cell viability and function. CONCLUSION: Ursodeoxycholic acid microencapsulated with poly-L-ornithine, suspending electrical-stimulation hydrogel and polystyrene sulphone at 1:1:0.1 ratio, using 800 V and 2000 Hz microencapsulating conditions, produced enhanced electrokinetic parameters of microcapsules with optimized cell functions. This suggests that electric charge of formulations containing pancreatic ß-cell may have significant effects on cell mass and functions, post-transplantation.

Alginate-combined cholic acid increased insulin secretion of microencapsulated mouse cloned pancreatic ß cells.

AIM: A semisynthetic primary bile acid (PBA) has exerted hypoglycemic effects in Type 1 diabetic animals, which were hypothesized to be due to its anti-inflammatory and cellular glucose-regulatory effects. Thus, the research purpose aimed to examine antidiabetic effects of a PBA, in terms of cellular inflammation and survival and insulin release, in the context of supporting ß-cell delivery and Type 1 diabetic treatment. MATERIALS & METHODS: 10 formulations were prepared, five without PBA (control) and five with PBA (test). Formulations were used to microencapsulate pancreatic ß cells and the microcapsules were examined for morphology, cell viability, insulin release and inflammation. RESULTS & CONCLUSION: PBA improved cell viability, insulin release and reduced inflammation in a formulation-dependent manner, which suggests potential use in cell delivery and diabetes treatment. [Formula: see text].

New Biotechnological Microencapsulating Methodology Utilizing Individualized Gradient-Screened Jet Laminar Flow Techniques for Pancreatic ß-Cell Delivery: Bile Acids Support Cell Energy-Generating Mechanisms.

In previous studies, we developed a new technique (ionic gelation vibrational jet flow; IGVJF) in order to encapsulate pancreatic ß-cells, for insulin in vivo delivery, and diabetes treatment. The fabricated microcapsules showed good morphology but limited cell functions. Thus, this study aimed to optimize the IGVJF technique, by utilizing integrated electrode tension, coupled with high internal vibration, jet-flow polymer stream rate, ionic bath-gelation concentrations, and gelation time stay. The study also utilized double inner/outer nozzle segmented-ingredient flow of microencapsulating dispersion, in order to form ß-cell microcapsules. Furthermore, a microcapsule-stabilizing bile acid was added, and microcapsule's stability and cell functions measured. Buchi-based built-in system utilizing IGVJF technology was screened to produce best microcapsule-containing ß-cells with or without a stabilizing-enhancing bile acid. Formed microcapsules were examined, for physical characteristics, and encapsulated cells were examined for survival, insulin release, and inflammatory profiles. Optimized microencapsulating parameters, using IGJVF, were: 1000 V voltage, 2500 Hz frequency, 1 mL/min flow rate, 3% w/v ionic-bath gelation concentration, and 20 min gelation time. Microcapsules showed good morphology and stability, and the encapsulated cells showed good survival, and insulin secretion, which was optimized by the bile acid. Deployed IGVJF-based microencapsulating parameters utilizing stability-enhancing bile acid produced best microcapsules with best pancreatic ß-cells functions and survival rate, which, suggests potential application in cell transplantation.

The Effects of Ionic Gelation- Vibrational Jet Flow Technique in Fabrication of Microcapsules Incorporating β-cell: Applications in Diabetes.

BACKGROUND: In recent studies, we have incorporated bile acid and polyelectrolytes into pancreatic ß-cell microcapsules and examined their cell viability and microcapsule morphology using various encapsulating methods. OBJECTIVE: This study aimed to incorporate 3 colloids; ultrasonic gel (USG; 1%), polystyrenic sulphate (PSS; 0.1%) and polyallylamine (PAA; 3%) and ursodeoxycholic acid (UDCA; 4%) with the polymer sodium alginate (SA; 1.2%) and the copolymer poly-L-ornithine (PLO; 1%), and using a refined vibrational jet-flow microencapsulating method, test the microcapsule properties, and cell viability without or with UDCA. METHOD: The pancreatic ß-cells NIT-1 were encapsulated using concentric nozzles and a refined method using voltage > 600 mv and frequency of 1750 Hz with syringe flow of 1.5 ml/min (core) and formulation solution of 2.1 ml/min, with a mixture of SA, PLO, USG, PSS and PAA without UDCA (control) or with UDCA (test). Both formulations and microcapsules were examined for surface composition and thermal and chemical biocompatibilities. The microencapsulated cells were examined for bioenergetics and production of inflammatory biomarkers. UDCA distribution within the microcapsules was also examined. RESULTS: Using our method, viability remained low after the addition of PSS, PAA and USG, while the incorporation of UDCA enhanced cell viability, and thermal stability was maintained. CONCLUSION: Our refined microencapsulating method, when incorporating polystyrenic sulphate, polyallylamine, the gel and UDCA at 0.1:3:1:4 ratio respectively, produced stable microcapsules suggesting potential applications in cell microencapsulation and diabetes treatment.

The impact of allylamine-bile acid combinations on cell delivery microcapsules in diabetes.

OBJECTIVE: In a recent study, we developed a new microencapsulating method for ß-cell microencapsulation, but cell viability declined rapidly, post microencapsulation, due to potential polymer-polyelectrolyte chelation and non-porous microcapsules' membranes resulting in cell apoptosis. Thus, this study tested the effects of incorporating cationic polyamine at 1% w/v, on microcapsule strength and cell viability, in the absence or presence of an anionic tertiary bile acid (ATBA) with potential cell-protective effects. METHODS: 1% w/v polyamine was used without or with ATBA, to form ß-cell microcapsules and physical and biological analyses was carried out 50 h post microencapsulation. RESULTS: Microcapsules containing 1% w/v polyamine showed weak physical properties and low cell viability and ATBA incorporation resulted in >30% reduction in cell viability and increased levels of pro-inflammatory cytokines. CONCLUSION: Neither 1% w/v polyamine nor the presence of ATBA resulted in optimised cell viability, but rather reduced cell viability, enhanced inflammation and lowered insulin secretion.

Flow vibration-doubled concentric system coupled with low ratio amine to produce bile acid-macrocapsules of ß-cells.

BACKGROUND: Pancreatic ß-cell microencapsulation using sodium alginate (SA), polylornithine (PLO) copolymers, and ultrasoluble hydrogels, polystyrenes and polyallamines (PAA), has been heavily studied. However, long-term success remains limited due to poor macrocapsules' physical properties and cell functions. Our study aimed to incorporate percentages of PAA and ursodeoxycholic acid, into SA and PLO dispersion mixture and examine best microencapsulating methods and best macrocapsules containing ß-cells. METHODS/RESULTS: Microencapsulating parameters were examined and the Flow-Vibrational Nozzle built-in system was screened and found to be most efficient at high frequency (1900 Hz). Macrocapsules were produced with or without ursodeoxycholic acid in percentages: 0.018SA:0.01PLO:0.005PAA:0.04ursodeoxycholic acid (up to 100% H2O). Using the refined microencapsulation method with vibrational frequency of 1900 Hz, macrocapsules with ursodeoxycholic acid had optimized cell viability and biological functions and ameliorated inflammatory biomarkers. CONCLUSION: High frequency and air-pressure with Flow-Vibrational encapsulation using the mixture: 0.018SA:0.01PLO:0.005PAA:0.04ursodeoxycholic acid resulted in better cell biology suggesting potentials in ß-cell transplantation.

The Influence of Stabilized Deconjugated Ursodeoxycholic Acid on Polymer-Hydrogel System of Transplantable NIT-1 Cells.

PURPOSE: The encapsulation of pancreatic ß-cells in biocompatible matrix has generated great interest in diabetes treatment. Our work has shown improved microcapsules when incorporating the bile acid ursodeoxycholic acid (UDCA), in terms of morphology and cell viability although cell survival remained low. Thus, the study aimed at incorporating the polyelectrolytes polyallylamine (PAA) and poly-l-ornithine (PLO), with the polymer sodium alginate (SA) and the hydrogel ultrasonic gel (USG) with UDCA and examined cell viability and functionality post microencapsulation. METHODS: Microcapsules without (control) and with UDCA (test) were produced using 1% PLO, 2.5% PAA, 1.8% SA and 4.5% USG. Pancreatic ß-cells were microencapsulated and the microcapsules' morphology, surface components, cellular and bile acid distribution, osmotic and mechanical stability as well as biocompatibilities, insulin production, bioenergetics and the inflammatory response were tested. RESULTS: Incorporation of UDCA at 4% into a PLO-PAA-SA formulation system increased cell survival (p < 0.01), insulin production (p < 0.01), reduced the inflammatory profile (TNF-α, IFN-ϒ, IL-6 and IL-1ß; p < 0.01) and improved the microcapsule physical and mechanical strength (p < 0.01). CONCLUSIONS: ß-cell microencapsulation using 1% PLO, 2.5% PAA, 1.8% SA, 4.5% USG and the bile acid UDCA (4%) has good potential in cell transplantation and diabetes treatment.

Designing anti-diabetic ß-cells microcapsules using polystyrenic sulfonate, polyallylamine, and a tertiary bile acid: Morphology, bioenergetics, and cytokine analysis.

PURPOSE: Recently sodium alginate (SA)-poly-l-ornithine (PLO) microcapsules containing pancreatic ß-cells that showed good morphology but low cell viability (<27%) was designed. In this study, two new polyelectrolytes, polystyrenic sulfonate (PSS; at 1%) and polyallylamine (PAA; at 2%) were incorporated into a microencapsulated-formulation, with the aim of enhancing the physical properties of the microcapsules. Following incorporation, the structural characteristics and cell viability were investigated. The effects of the anti-inflammatory bile acid, ursodeoxycholic acid (UDCA), on microcapsule morphology, size, and stability as well as ß-cell biological functionality was also examined. METHODS: Microcapsules were prepared using PLO-PSS-PAA-SA mixture and two types of microcapsules were produced: without UDCA (control) and with UDCA (test). Microcapsule morphology, stability, and size were examined. Cell count, microencapsulation efficiency, cell bioenergetics, and activity were also examined. RESULTS: The new microcapsules showed good morphology but cell viability remained low (29% ± 3%). UDCA addition improved cell viability post-microencapsulation (42 ± 5, P < 0.01), reduced swelling (P < 0.01), improved mechanical strength (P < 0.01), increased Zeta-potential (P < 0.01), and improved stability. UDCA addition also increased insulin production (P < 0.01), bioenergetics (P < 0.01), and decreased ß-cell TNF-α (P < 0.01), IFN-gamma (P < 0.01), and IL-6 (P < 0.01) secretions. CONCLUSIONS: Addition of 4% UDCA to a formulation system consisting of 1.8% SA, 1% PLO, 1% PSS, and 2% PAA enhanced cell viability post-microencapsulation and resulted in a more stable formulation with enhanced encapsulated ß-cell metabolism, bioenergetics, and biological activity with reduced inflammation. This suggests potential application of UDCA, when combined with SA, PLO, PSS, and PAA, in ß-cell microencapsulation and diabetes treatment. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:501-509, 2016.

The incorporation of water-soluble gel matrix into bile acid-based microcapsules for the delivery of viable ß-cells of the pancreas, in diabetes treatment: biocompatibility and functionality studies.

In recent studies, we microencapsulated pancreatic ß-cells using sodium alginate (SA) and poly-L-ornithine (PLO) and the bile acid, ursodeoxycholic acid (UDCA), and tested the morphology and cell viability post-microencapsulation. Cell viability was low probably due to limited strength of the microcapsules. This study aimed to assess a ß-cell delivery system which consists of UDCA-based microcapsules incorporated with water-soluble gel matrix. The polyelectrolytes, water-soluble gel (WSG), polystyrenic sulphate (PSS), PLO and polyallylamine (PAA) at ratios 4:1:1:2.5 with or without 4% UDCA, were incorporated into our microcapsules, and cell viability, metabolic profile, cell functionality, insulin production, levels of inflammation, microcapsule morphology, cellular distribution, UDCA partitioning, biocompatibility, thermal and chemical stabilities and the microencapsulation efficiency were examined. The incorporation of UDCA with PSS, PAA and WSG enhanced cell viability per microcapsule (p < 0.05), cellular metabolic profile (p < 0.01) and insulin production (p < 0.01); reduced the inflammatory release TNF-α (p < 0.01), INF-gamma (p < 0.01) and interleukin-6 (IL-6) (p < 0.01); and ceased the production of IL-1ß. UDCA, PSS, PAA and WSG addition did not change the microencapsulation efficiency and resulted in biocompatible microcapsules. Our designed microcapsules showed good morphology and desirable insulin production, cell functionality and reduced inflammatory profile suggesting potential applications in diabetes.

Advanced bile acid-based multi-compartmental microencapsulated pancreatic ß-cells integrating a polyelectrolyte-bile acid formulation, for diabetes treatment.

This study utilized the Seahorse Analyzer to examine the effect of the bile acid ursodeoxycholic acid (UDCA), on the morphology, swelling, stability, and size of novel microencapsulated ß-cells, in real-time. UDCA was conjugated with fluorescent compounds, and its partitioning within the microcapsules was examined using confocal microscopy. UDCA produced microcapsules with good morphology, better mechanical strength (p < 0.01), and reduced swelling properties (p < 0.01), but lower cell viability (p < 0.05) and cell count per microcapsule (p < 0.01). UDCA reduced the cells' biochemical activities, mitochondrial respiration, and energy production, post-microencapsulation. This is the first time biological functions of microencapsulated ß-cells have been analyzed in real-time.

Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic ß-cells.

INTRODUCTION: In a recent study, we confirmed good chemical and physical compatibility of microencapsulated pancreatic ß-cells using a novel formulation of low viscosity sodium alginate (LVSA), Poly-L-Ornithine (PLO), and the tertiary bile acid, ursodeoxycholic acid (UDCA). This study aimed to investigate the effect of UDCA on the morphology, swelling, stability, and size of these new microcapsules. It also aimed to evaluate cell viability in the microcapsules following UDCA addition. MATERIALS AND METHODS: Microencapsulation was carried out using a Büchi-based system. Two (LVSA-PLO, control and LVSA-PLO-UDCA, test) pancreatic ß-cells microcapsules were prepared at a constant ratio of 10:1:3, respectively. The microcapsules' morphology, cell viability, swelling characteristics, stability, mechanical strength, Zeta potential, and size analysis were examined. The cell contents in each microcapsule and the microencapsulation efficiency were also examined. RESULTS: The addition of UDCA did not affect the microcapsules' morphology, stability, size, or the microencapsulation efficiency. However, UDCA enhanced cell viability in the microcapsules 24 h after microencapsulation (p < 0.01), reduced swelling (p < 0.05), reduced Zeta potential (- 73 ± 2 to - 54 ± 2 mV, p < 0.01), and increased mechanical strength of the microcapsules (p < 0.05) at the end of the 24-h experimental period. DISCUSSION AND CONCLUSION: UDCA increased ß-cell viability in the microcapsules without affecting the microcapsules' size, morphology, or stability. It also increased the microcapsules' resistance to swelling and optimized their mechanical strength. Our findings suggest potential benefits of the bile acid UDCA in ß-cell microencapsulation.

Swelling, mechanical strength, and release properties of probucol microcapsules with and without a bile acid, and their potential oral delivery in diabetes.

We have demonstrated a permeation-enhancing effect of deoxycholic acid (DCA), the bile acid, in diabetic rats. In this study, we designed DCA-based microcapsules for the oral delivery of the antilipidemic drug probucol (PB), which has potential antidiabetic effects. We aimed to further characterize these microcapsules and examine their pH-dependent release properties, as well as the effects of DCA on their stability and mechanical strength at various pH and temperature values. Using the polymer sodium alginate (SA), we prepared PB-SA (control) and PB-DCA-SA (test) microcapsules. The microcapsules were examined for drug content, size, surface composition, release, Micro-CT cross-sectional imaging, stability, Zeta potential, mechanical strength, and swelling characteristics at different pH and temperature values. The microencapsulation efficiency and production yield were also examined. The addition of DCA resulted in microcapsules with a greater density and with reduced swelling at a pH of 7.8 and at temperatures of 25°C and 37°C (p < 0.01). The size, surface composition, production yield, and microencapsulation efficiency of the microcapsules remained similar after DCA addition. PB-SA microcapsules produced multiphasic PB release, while PB-DCA-SA microcapsules produced monophasic PB release, suggesting more controlled PB release in the presence of DCA. The PB-DCA-SA microcapsules showed good stability and a pH-sensitive uniphasic release pattern, which may suggest potential applications in the oral delivery of PB in diabetes.

Multicompartmental, multilayered probucol microcapsules for diabetes mellitus: Formulation characterization and effects on production of insulin and inflammation in a pancreatic ß-cell line.

CONTEXT: We have shown that the primary bile acid, cholic acid (CA), has anti-diabetic effects in vivo. Probucol (PB) is a lipophilic drug with potential applications in type 2 diabetes (T2D). OBJECTIVE: This study aimed to encapsulate CA with PB and examine the formulation and surface characteristics of the microcapsules. We also tested the microcapsules' biological effects on pancreatic ß-cells. METHODS: Using the polymer, sodium alginate (SA), two formulations were prepared: PB-SA (control), and PB-CA-SA (test). Complete characterizations of the morphology, shape, size, chemical, thermal, and rheological properties, swelling and mechanical strength, cross-sectional imaging (Micro CT), stability, Zeta-potential, drug contents, and PB release profile were carried out, at different temperature and pH values. The microcapsules were applied to a NIT-1 cell culture and the supernatant was analyzed for insulin and TNF-α concentrations. RESULTS: CA incorporation optimized the PB microcapsules, which exhibited pseudoplastic-thixotropic rheological characteristics. The size of the microcapsules remained similar after CA addition, and the microcapsules showed even drug distribution and no chemical alterations of the excipients. Micro-CT imaging, differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy showed consistent microcapsules with uniform shape and morphology. PB-CA-SA microcapsules enhanced NIT-1 cell viability under hyperglycemic states and resulted in improved insulin release as well as reduced cytokine production at the physiological glucose levels. CONCLUSIONS: The addition of the primary bile acid, CA, improved the physical properties of the microcapsules and enhanced their pharmacological activity in vitro, suggesting potential applications in diabetes treatment.

The effect of a tertiary bile acid, taurocholic acid, on the morphology and physical characteristics of microencapsulated probucol: potential applications in diabetes: a characterization study.

In recent studies, we designed multi-compartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in an animal model of type 2 diabetes (T2D). Probucol (PB) is a highly lipophilic, antihyperlipidemic drug with potential antidiabetic effects. PB has low bioavailability and high inter-individual variations in absorption, which limits its clinical applications. In a new study, the bile acid, taurocholic acid (TCA), exerted permeation enhancing effects in vivo. Accordingly, this study aimed to design and characterize TCA-based PB microcapsules and examine the effects of TCA on the microcapsules' morphology, stability, and release profiles. Microcapsules were prepared using the polymer sodium alginate (SA). Two types of microcapsules were produced, one without TCA (PB-SA, control) and one with TCA (PB-TCA-SA, test). Microcapsules were studied in terms of morphology, surface structure and composition, size, drug contents, cross-sectional imaging (using microtomography (Micro-CT) analysis), Zeta potential, thermal and chemical profiles, rheological parameters, swelling, mechanical strength, and release studies at various temperature and pH values. The production yield and the encapsulation efficiency were also studied together with in vitro efficacy testing of cell viability at various glucose concentrations and insulin and TNF-α production using clonal-mouse pancreatic ß-cells. PB-TCA-SA microcapsules showed uniform structure and even distribution of TCA within the microcapsules. Drug contents, Zeta potential, size, rheological parameters, production yield, and the microencapsulation efficiency remained similar after TCA addition. In vitro testing showed PB-TCA-SA microcapsules improved ß-cell survival under hyperglycemic states and reduced the pro-inflammatory cytokine TNF-α while increasing insulin secretions compared with PB-SA microcapsules. PB-TCA-SA microcapsules also showed good stability, better mechanical (p < 0.01) and swelling (p < 0.01) characteristics, and optimized controlled release at pH 7.8 (p < 0.01) compared with control, suggesting desirable targeted release properties and potential applications in the oral delivery of PB in T2D.

Novel chenodeoxycholic acid-sodium alginate matrix in the microencapsulation of the potential antidiabetic drug, probucol. An in vitro study.

CONTEXT: We previously designed, developed and characterized a novel microencapsulated formulation as a platform for the targeted delivery of Probucol (PB) in an animal model of Type 2 Diabetes. OBJECTIVE: The objective of this study is to optimize this platform by incorporating Chenodeoxycholic acid (CDCA), a bile acid with good permeation-enhancing properties, and examine its effect in vitro. Using sodium alginate (SA), we prepared PB-SA (control) and PB-CDCA-SA (test) microcapsules. RESULTS AND DISCUSSION: CDCA resulted in better structural and surface characteristics, uniform morphology, and stable chemical and thermal profiles, while size and rheological parameters remained unchanged. PB-CDCA-SA microcapsules showed good excipients' compatibilities, as evidenced by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy studies. CDCA reduced microcapsule swelling at pH 7.8 at both 37 °C and 25 °C and improved PB-release. CONCLUSION: CDCA improved the characteristics and release properties of PB-microcapsules and may have potential in the targeted oral delivery of PB.

Probucol release from novel multicompartmental microcapsules for the oral targeted delivery in type 2 diabetes.

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6 ± 0.25% PB content, and zeta potential of -66 ± 1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p < 0.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85 ± 5 and 92 ± 2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules.