Stability and Release Kinetics of an Advanced Gliclazide-Cholic Acid Formulation: The Use of Artificial-Cell Microencapsulation in Slow Release Targeted Oral Delivery of Antidiabetics

Introduction: In previous studies carried out in our laboratory, a bile acid (BA) formulation exerted a hypoglycaemic effect in a rat model of type-1 diabetes (T1D). When the antidiabetic drug gliclazide (G) was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-cholic acid (G-CA), with good structural properties, excipient compatibility and exhibits pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH-controlled properties of this new formulation. The aim is also to examine the effect of CA on G release kinetics at various pH values and different temperatures. 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. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, pH 3, pH 7.4 and pH 7.8 and temperatures of 20 and 30 °C. Results: The new formulation is further optimised by the addition of CA. CA reduced microcapsule swelling of the microcapsules at pH 7.8 and pH 3 at 30 °C and pH 3 at 20 °C, and, even though microcapsule size remains similar after CA addition, percent G release was enhanced at high pH values (pH 7.4 and pH 7.8, p < 0.01). Conclusion: The new formulation exhibits colon-targeted delivery and the addition of CA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and CA to the lower intestine

The applications of microencapsulated formulation of gliclazide and bile acids in Type-1 diabetes mellitus

Gliclazide is used in Type 2 diabetes (T2D) to stimulate insulin production but it also has beneficial extra-pancreatic effects which make it potentially useful in T1D. In this thesis, gliclazide was formulated with different bile acids, to enhance its effects, and formed microcapsules were examined in-vitro and in-vivo. In-vitro examinations of the microcapsules included complete characterization of the microcapsules in terms of interactions between gliclazide and a primary bile acid (chenodeoxycholic acid), a secondary bile acid (taurocholic acid) and a tertiary bile acid (ursodeoxycholic acid), and in-vitro release of gliclazide from microcapsules, while in-vivo examination of the microcapsules included gliclazide absorption and hypoglycemic and antiinflammatory effects in a rat model of T1D

Histological effects of pharmacologically active human bile acid nano/micro-particles in Type-1 diabetes

Aim: Gliclazide (G) is a drug prescribed for Type 2 diabetics, although recent studies suggest it has desirable effects in both types of diabetes, Type 1 diabetes and Type 2 diabetes. G has an inconsistent absorption due to poor formulation and bile acids (BAs) have shown significant promise in drug formulation optimization. Hence, the study aimed to examine G effects on histopathological, anti-inflammatory and antidiabetic effects when encapsulated with BAs. Materials &amp; methods: Rats were randomized into eight groups, of which seven were made Type 1 diabetes and treated with various BA-based treatments. Tissue histopathology, inflammation and the bile acid profile were analyzed. Results &amp; conclusion: G capsules showed no histological but the most anti-inflammatory effects, which suggest significant beneficial effects in diabetes treatment. </jats:p

Formulation buoyancy of nanoencapsulated gliclazide using primary, conjugated and deconjugated bile acids

Aim: Recent studies suggest potential applications of endogenously produced human bile acids as formulation-excipient and drug tissue permeation enhancers in Type 1 diabetes. We aimed to examine the stability, tissue permeation and ex vivo muscle-cell effects of microencapsulated gliclazide (G) incorporated with a primary (chenodeoxycholic acid [CDCA]), a secondary (ursodeoxycholic acid [UDCA]) or a tertiary (taurocholic acid [TCA]) bile acid. Materials &amp; methods: Four formulations made of sodium alginate, CDCA, UDCA and TCA were examined for buoyancy, tissue-enhancing effects ( in vivo) and local ( ex vivo) viability effects. Results &amp; conclusion: CDCA, UDCA and TCA improved buoyancy and cell viability but not tissue-specific uptake. G-TCA-sodium alginate microcapsules exerted hypoglycemic effects, suggesting significant improvement of G gut-uptake by TCA, possibly via improving buoyancy. </jats:p

Intramammary Immunization of Pregnant Mice with Staphylococcal Protein A Reduces the Post-Challenge Mammary Gland Bacterial Load but Not Pathology - Fig 3

<p>Fig 3A; Mammary tissue specimen from lactating mouse immunized with Protein A vaccine (s/c route) and challenged using strong biofilm forming <i>S</i>. <i>aureus</i> 51. Marked inflammatory cell infiltration within intralobular (A) and perilobular tissue (B). Level 3 category inflammation. H&E x 100, bar, 200 μm; Fig 3B; Mammary tissue specimen from lactating mouse immunized by Protein A vaccine (i/mam route) and challenged using strong biofilm forming <i>S</i>. <i>aureus</i> 51. Abscess in mammary tissue (A). Level 3 category inflammation. H&E x 100, bar, 200 μm; Fig 3C; Mammary tissue specimen from lactating mouse immunized by Protein A vaccine (i/mam route) and challenged using strong biofilm forming <i>S</i>. <i>aureus</i> 51. Gram positive bacteria and associated inflammatory cell infiltrate (Arrow). Gram Twort x 400, bar, 100 μm; Fig 3D; Mammary tissue specimen from lactating mouse injected with PBS and challenged using strong biofilm forming <i>S</i>. <i>aureus</i> 51. Abscess in mammary tissue with tissue necrosis (A). Level 3 category inflammation. H&E x 40, bar, 500 μm; Fig 3E; Mammary tissue specimen from lactating mouse infected with PBS and challenged using strong biofilm forming <i>S</i>. <i>aureus</i> 51(from Fig 3D); Fig 3E(i) Inflammatory abscess shows inflammatory exudate in fibrinous capsule (A). Level 3 category inflammation. H&E x 100, bar, 200 μm; Fig 3E(ii) Gram positive bacteria (Arrow) in inflammatory material Gram Twort x1000, bar, 500 μm.</p

IFN-γ production by splenocytes of mice immunised with Protein A and PBS by s/c and i/mam routes following stimulation with Protein A.

<p>IFN-γ production by splenocytes of mice immunised with Protein A and PBS by s/c and i/mam routes following stimulation with Protein A.</p

Experimental groups of mice used in the immunogenicity and protective potential trials of Protein A vaccines (n = 48).

<p>Experimental groups of mice used in the immunogenicity and protective potential trials of Protein A vaccines (n = 48).</p

Clinical signs observed in different groups of mice immunized with Protein A (Observations up to 5 days post challenge).

<p>Clinical signs observed in different groups of mice immunized with Protein A (Observations up to 5 days post challenge).</p

Detection of bacterial load and histopathological changes in the mammary glands of mice immunized with Protein A.

<p>Detection of bacterial load and histopathological changes in the mammary glands of mice immunized with Protein A.</p

Antigen-specific antibody isotypes of mice vaccinated with Protein A by s/c or i/mam routes.

<p>Antigen-specific antibody isotypes of mice vaccinated with Protein A by s/c or i/mam routes.</p