title: Design and evaluation of oral bioadhesive controlled release formulations of miglitol, intended for prolonged inhibition of intestinal alpha-glucosidases and enhancement of plasma glucagon like peptide-1 levels.
abstract: Alpha-glucosidase enzyme is present ubiquitously throughout the lumen of the small intestine. It is responsible for the breakdown of complex into simple carbohydrates. alpha-Glucosidase inhibitors such as miglitol, are drugs that have greater affinity towards this enzyme in comparison to carbohydrates. Miglitol regulates the postprandial glucose levels directly by inhibiting the enzyme reversibly and also indirectly by including the secretion of glucagon like peptide-1 (GLP-1). The aims of this study were (i) to design a controlled release (CR) mucoadhesive (in the intestine) formulation of miglitol which would inhibit the alpha-glucosidase enzyme for a longer duration of time (in comparison to the non-controlled release (IR) formulation) thus reducing the dosing frequency, and also controlling the postprandial glucose levels more effectively over a longer period of time; (ii) to assess the effect of different formulation parameters on the release of miglitol in vitro from the CR pellets; (iii) to evaluate the mucoadhesion of pellets in the intestine ex vivo; (iv) to study the effect of formulation parameters on plasma GLP-1 levels; and (v) to find out the effect of formulations on postprandial glucose levels. The data obtained was analysed to find out whether there was a correlation between these different parameters. Four controlled release formulations (CR1, CR2, CR3 and CR4) of miglitol comprising of multilayered pellets were designed successfully. The CR4 formulation containing 30% of 20 cps of ethyl cellulose (the retarding layer of the formulation) displayed slowest release of miglitol in vitro in comparison to other formulations. We designed an ex vivo experimental setup for studying the mucoadhesion of the pellets in the lumen of the intestine. Results indicated that amongst all of the adherent pellets, 5% were found to be adhering in the duodenal region, 61% in the jejunum, 32% in the ileum and 2% in the colon. Two of the controlled release formulations CR1 and CR4 were evaluated in vivo in dogs. Both the formulations displayed significantly higher and more prolonged (greater AUC) levels of GLP-1 in comparison to either the placebo or the immediate release (IR) formulations. They even displayed a significantly better control of postprandial glucose in comparison to either placebo or IR formulations. However, a comparison between the two controlled release formulations (CR1 and CR4) revealed that the plasma GLP-1 (AUC by CR1=63.1+/-1.32 and CR4=66.2+/-0.82) and postprandial glucose values due to both the formulations were rather similar despite their differences in in vitro release as well as pharmacokinetic profiles (plasma miglitol AUC of CR1=16.17+/-4.11 and CR4=27.17+/-4.33).
authors: Integrated Product Development, Dr. Reddy's Laboratories Ltd., Bachupally, Qutubullapur, Hyderabad, Andhra Pradesh, India. mangeshcd@yahoo.co.uk
authors: Mangesh C
authors: MC
authors: Deshpande
authors: Vobalaboina
authors: V
authors: Venkateswarlu
authors: Ravi K
authors: RK
authors: Babu
authors: Ravi K
authors: RK
authors: Trivedi
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000097:blood* / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; C045621:miglitol; D017485:1-Deoxynojirimycin; D052216:Glucagon-Like Peptide 1