Date of Award

12-2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

Atul J. Shukla, Ph.D.

Committee

James R. Johnson, Ph.D. Abbas E. Kitabchi, M.D., Ph.D. Bernd Meibohm, Ph.D. Mitchell S. Steiner, M.D.

Abstract

The objective of the study was to develop a controlled release dosage form of
insulin, which can provide basal concentrations of insulin in diabetic rats for 1 to 2 weeks after a single subcutaneous injection.
A biodegradable injectable drug delivery gel was prepared by dissolving a
biodegradable polymer, polylactic-co-glycolic acid (PLGA), in biocompatible
plasticizer(s), triethyl citrate (TEC) and/or acetyl triethyl citrate (ATEC). Insulin was
then loaded into the blank gel to form an insulin suspension in the polymer solution.
After the insulin-loaded gel was injected subcutaneously, the plasticizer(s) dissolved in the aqueous media and were gradually taken away from the gel. The polymer precipitated after the plasticizer(s) were extracted by the aqueous medium and a solid depot of insulin was formed. The insulin was released slowly from the depot by a combination of drug diffusion and erosion of the polymer.

In the first part of this study, the effect of different water-soluble and water-
insoluble zinc salts on blood glucose lowering effect of insulin in type-2 diabetic ZDF rats was investigated. Insulin formulations containing varying concentrations of different water-soluble and water-insoluble zinc salts were prepared and injected subcutaneously in type-2 ZDF rats and blood glucose concentration lowering effect was studied. Insulin in presence of water-soluble salts of zinc could suppress blood glucose concentrations in ZDF rats for up to 16 hours.

Insulin was loaded into different gel formulations (5% PLGA (i.v. 0.09, acid end
group), ATEC:TEC (3:1) and 4% insulin) and tested in vivo. However, these insulin- loaded gel formulations only suppressed the blood glucose concentrations in the ZDF rats for 1 day after a single subcutaneous injection. In order to achieve longer control over the release of insulin from the gels, a water-soluble salt, zinc sulfate was incorporated in these insulin containing gels at different concentrations. A biodegradable injectable gel formulation prepared with zinc sulfate was able to maintain low blood glucose concentrations for up to 8 to 10 days following a single subcutaneous injection.

In order to achieve better glucose control after the release of insulin from the gels,
insulin glargine particles were purified from commercially available Lantus® formulation.
The freeze dried insulin glargine particles were then loaded into the blank gels and tested in vivo. The formulation prepared with 5% PLGA (i.v. 0.09, acid end group), ATEC:TEC (3:1) and 4% insulin glargine was able to suppress the blood glucose concentrations of the ZDF rats significantly for 10 days after a single subcutaneous injection. The concentration of insulin glargine was maintained between 260 ± 134.9 mIU/L and 188 ± 55.9 mIU/L until day 10 after single subcutaneous injection. The addition of zinc sulfate to the formulations prepared with purified insulin glargine particles further slowed down the drop in blood glucose concentrations.

DOI

10.21007/etd.cghs.2008.0013

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