Rebecca Negrulj

Inflammatory bowel disease: clinical aspects and treatments

Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results from host-microbial interactions in a genetically susceptible individual. IBDs are a group of autoimmune diseases that are characterized by inflammation of both the small and large intestine, in which elements of the digestive system are attacked by the body’s own immune system. This inflammatory condition encompasses two major forms, known as Crohn’s disease and ulcerative colitis. Patients affected by these diseases experience abdominal symptoms, including diarrhea, abdominal pain, bloody stools, and vomiting. Moreover, defects in intestinal epithelial barrier function have been observed in a number of patients affected by IBD. In this review, we first describe the types and symptoms of IBD and investigate the role that the epithelial barrier plays in the pathophysiology of IBD as well as the major cytokines involved. We then discuss steps used to diagnose this disease and the treatment options available, and finally provide an overview of the recent research that aims to develop new therapies for such chronic disorders.

Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study.

Gliclazide (G) is an antidiabetic drug commonly used in type 2 diabetes. It has extrapancreatic hypoglycemic effects, which makes it a good candidate in type 1 diabetes (T1D). In previous studies, we have shown that a gliclazide-bile acid mixture exerted a hypoglycemic effect in a rat model of T1D. We have also shown that a gliclazide-deoxycholic acid (G-DCA) mixture resulted in better G permeation in vivo, but did not produce a hypoglycemic effect. In this study, we aimed to develop a novel microencapsulated formulation of G-DCA with uniform structure, which has the potential to enhance G pharmacokinetic and pharmacodynamic effects in our rat model of T1D. We also aimed to examine the effect that DCA will have when formulated with our new G microcapsules, in terms of morphology, structure, and excipients’ compatibility. Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) at a ratio of 1:30, and G-DCA-SA (test) at a ratio of 1:3:30. Complete characterization of microcapsules was carried out. The new G-DCA-SA formulation was further optimized by the addition of DCA, exhibiting pseudoplastic-thixotropic rheological characteristics. The size of microcapsules remained similar after DCA addition, and these microcapsules showed no chemical interactions between the excipients. This was supported further by the spectral and microscopy studies, suggesting microcapsule stability. The new microencapsulated formulation has good structural properties and may be useful for the oral delivery of G in T1D.

An advanced microencapsulated system: a platform for optimized oral delivery of antidiabetic drug-bile acid formulations

Abstract Introduction: In previous studies, we have shown that a gliclazide–cholic acid derivative (G–CA) mixture resulted in an enhanced ileal permeation of G (ex vivo). When administered orally to diabetic rats, it brought about a significant hypoglycaemic effect. In this study, we aim to create a novel microencapsulated-formulation of G–CA with uniform and coherent structure that can be further tested in our rat model of type 1 diabetes (T1D). We also aim to examine the effect of CA addition to G microcapsules in the morphology, structure and excipients’ compatibility of the newly designed microcapsules. Method: Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G–SA (control) and G–CA–SA (test) at a constant ratio (1:3:30), respectively. Complete characterizations of microcapsules were carried out. Results: The new G–CA–SA formulation is further optimized by the addition of CA exhibiting pseudoplastic-thixotropic rheological characteristics. Bead size remains similar after CA addition, the new microcapsules show no chemical interactions between the excipients and this was supported further by the spectral studies suggesting bead stability. Conclusion: The new microencapsulated-formulation has good and uniform structural properties and may be suitable for oral delivery of antidiabetic-bile acid formulations.

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.

Microencapsulation as a novel delivery method for the potential antidiabetic drug, Probucol

Introduction In previous studies, we successfully designed complex multicompartmental microcapsules as a platform for the oral targeted delivery of lipophilic drugs in type 2 diabetes (T2D). Probucol (PB) is an antihyperlipidemic and antioxidant drug with the potential to show benefits in T2D. We aimed to create a novel microencapsulated formulation of PB and to examine the shape, size, and chemical, thermal, and rheological properties of these microcapsules in vitro. Method Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using the polymer, sodium alginate (SA), empty (control, SA) and loaded (test, PB-SA) microcapsules were prepared at a constant ratio (1:30). Complete characterizations of microcapsules, in terms of morphology, thermal profiles, dispersity, and spectral studies, were carried out in triplicate. Results PB-SA microcapsules displayed uniform and homogeneous characteristics with an average diameter of 1 mm. The microcapsules exhibited pseudoplastic-thixotropic characteristics and showed no chemical interactions between the ingredients. These data were further supported by differential scanning calorimetric analysis and Fourier transform infrared spectral studies, suggesting microcapsule stability. Conclusion The new PB-SA microcapsules have good structural properties and may be suitable for the oral delivery of PB in T2D. Further studies are required to examine the clinical efficacy and safety of PB in T2D.

An optimized probucol microencapsulated formulation integrating a secondary bile acid (deoxycholic acid) as a permeation enhancer

The authors have previously designed, developed, and characterized a novel microencapsulated formulation as a platform for the targeted delivery of therapeutics in an animal model of type 2 diabetes, using the drug probucol (PB). The aim of this study was to optimize PB microcapsules by incorporating the bile acid deoxycholic acid (DCA), which has good permeation-enhancing properties, and to examine its effect on microcapsules’ morphology, rheology, structural and surface characteristics, and excipients’ chemical and thermal compatibilities. Microencapsulation was carried out using a BÜCHI-based microencapsulating system established in the authors’ laboratory. Using the polymer sodium alginate (SA), two microencapsulated formulations were prepared: PB-SA (control) and PB-DCA-SA (test) at a constant ratio (1:30 and 1:3:30, respectively). Complete characterization of the microcapsules was carried out. The incorporation of DCA resulted in better structural and surface characteristics, uniform morphology, and stable chemical and thermal profiles, while size and rheological parameters remained similar to control. In addition, PB-DCA-SA microcapsules showed good excipients’ compatibilities, which were supported by data from differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray studies, suggesting microcapsule stability. Hence, PB-DCA-SA microcapsules have good rheological and compatibility characteristics and may be suitable for the oral delivery of PB in type 2 diabetes.

Potentials and Limitations of Bile Acids in Type 2 Diabetes Mellitus: Applications of Microencapsulation as a Novel Oral Delivery System

Type 2 diabetes (T2D) is a chronic metabolic disorder resulting from genetic and environmental factors that bring about tissue desensitization to insulin and consequent hyperglycemia. Despite strict glycemic control and the fact that new and more effective antidiabetic drugs are continuously appearing on the market, diabetic patients still suffer from the disease and its complications. Recent findings present a strong link between diabetes, inflammation, altered gut microbiota and bile acid (BA) disturbances. BAs are naturally produced in humans and are gaining an appreciable interest as an adjunct treatment for T2D due to their endocrine signalling and anti-inflammatory properties. However a significant limitation to their efficacy is their low oral absorption, poor targeted delivery, gut metabolism and inter- and intra-individual dose variations. Thus there is a need for a novel and robust formulation that will encapsulate the BAs and protect them until they reach the lower intestine allowing them to be clinically beneficial. Artificial Cell Microencapsulation (ACM) is a novel oral delivery system for biologically active molecules and has been used significantly in the delivery of various cells and therapeutics. ACM-BA formulation has the potential to optimise BA efficacy and safety profiles and may have a place in the treatment of diabetes. This review aims to investigate the applications of BAs in T2D and the use of ACM as a novel delivery system for their optimum delivery.

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

Introduction: In a recent study, we confirmed good chemical and physical compatibility of microencapsulated pancreatic β-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 β-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 β-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 β-cell microencapsulation.

Designing anti-diabetic β-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 β‐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 β‐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 β‐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 β‐cell metabolism, bioenergetics, and biological activity with reduced inflammation. This suggests potential application of UDCA, when combined with SA, PLO, PSS, and PAA, in β‐cell microencapsulation and diabetes treatment.

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