deoxycholic-acid and Diabetes-Mellitus--Type-1

Proteins and peptides are poorly absorbed via oral administration because of the gastrointestinal tract environment and lysosomal digestion after apical endocytosis. A delivery system, consisting of a deoxycholic acid-conjugated nanometer-sized carrier, may enhance the absorption of proteins in the intestine via the bile acid pathway. Deoxycholic acid is first conjugated to chitosan. Liposomes are then prepared and loaded with the model drug insulin. Finally, the conjugates are bound to the liposome surface to form deoxycholic acid and chitosan conjugate-modified liposomes (DC-LIPs). This study demonstrates that DC-LIPs can promote the intestinal absorption of insulin via the apical sodium-dependent bile acid transporter, based on observing fluorescently stained tissue slices of the rat small intestine and a Caco-2 cell uptake experiment. Images of intestinal slices revealed that excellent absorption of DC-LIPs is achieved via apical sodium-dependent bile acid transporter, and a flow cytometry experiment proved that DC-LIPs are a highly efficient delivery carrier. Caco-2 cells were also used to study the lysosome escape ability of DC-LIPs. We learned from confocal microscopy photographs that DC-LIPs can protect their contents from being destroyed by the lysosome. Finally, according to pharmacokinetic analyses, insulin-loaded DC-LIPs show a significant hypoglycemic effect with an oral bioavailability of 16.1% in rats with type I diabetes.

Topics: Administration, Oral; Animals; Biological Availability; Caco-2 Cells; Chitosan; Deoxycholic Acid; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Liberation; Humans; Hypoglycemic Agents; Insulin; Intestinal Absorption; Intestinal Mucosa; Liposomes; Male; Nanoconjugates; Nanoparticles; Organic Anion Transporters, Sodium-Dependent; Particle Size; Rats; Streptozocin; Symporters

In previous studies carried out in our laboratory, a bile acid formulation exerted a hypoglycaemic effect in a rat model of type 1 diabetes (T1D). When the antidiabetic drug gliclazide was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-deoxycholic acid (G-DCA), with good structural properties, excipient compatibility and which exhibited 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 DCA on G release kinetics at various pH values and different temperatures. Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared including: G-SA (control) and G-DCA-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, 3, 7.4 and 7.8 and temperatures of 25 °C and 37 °C. The new formulation is further optimised by the addition of DCA. DCA reduced bead-swelling of the microcapsules at pH 7.8 and 3 at 25 °C and 37 °C, and even though bead size remains similar after DCA addition, the percentage of G release was enhanced at high pH values (pH 7.4 and 7.8, p < 0.01). The new formulation exhibits colon-targeted delivery and the addition of DCA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and DCA to the lower intestine.

Topics: Alginates; Animals; Capsules; Deoxycholic Acid; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Delivery Systems; Gliclazide; Glucuronic Acid; Hexuronic Acids; Hypoglycemic Agents; Rats

Topics: Amphotericin B; Antifungal Agents; Child; Child, Preschool; Debridement; Deoxycholic Acid; Diabetes Mellitus, Type 1; Drug Combinations; Humans; Mucormycosis; Rhinitis; Sinusitis

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.

Topics: Alginates; Animals; Artificial Cells; Capsules; Chemistry, Pharmaceutical; Deoxycholic Acid; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Excipients; Gliclazide; Glucuronic Acid; Hexuronic Acids; Hypoglycemic Agents; Particle Size; Rats; Rheology

Efficacy and reproducibility of insulin administered intranasally as an insulin-deoxycholate 1% (w/v) aerosol to normal and diabetic subjects were assessed by measurements of blood glucose and serum insulin levels. Following administration of 0.5 U insulin/kg with the unconjugated bile salt to fasting volunteers (N = 29), peak serum insulin levels of 103 +/- 49 microU/ml above baseline were observed at 10 min. Blood glucose concentration began to fall by 10 min, reaching 54 +/- 14% of control levels by 30 min, and returning to baseline by 60-80 min. Blood glucose response and peak serum insulin levels were reproducible when the same aerosol dose was repeatedly administered to the same subjects; however, intersubject variations were noted. By comparing serum insulin levels after i.v. and nasal routes of administration, nasal insulin absorption was approximately 10% as efficient as intravenous insulin. Dose response studies revealed that peak serum insulin concentrations were a linear function of the administered dose. In subjects with type I and type II diabetes mellitus, serum insulin levels increased in a manner similar to controls, and resulted in a prompt reduction of blood glucose concentration. However, in contrast to normal subjects, the duration of the glucose response was more prolonged, lasting as long as 5 h. Nasal administration of insulin as an aerosol with bile salts or bile salt analogs should be further evaluated as a possible nonparenteral approach to insulin therapy.

Topics: Absorption; Administration, Intranasal; Adult; Aerosols; Blood Glucose; Deoxycholic Acid; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Middle Aged; Nasal Mucosa