Novel Approaches for Oral Insulin Delivery - Pharmaceutical Technology

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Novel Approaches for Oral Insulin Delivery
The authors review various oral drug delivery systems that have been explored to increase patient compliance for insulin.

Pharmaceutical Technology
Volume 33, Issue 7


A liquid formula that can be easily dispersed in water to produce particles named "Nanocubicles" was developed by Chung et al. (52). These nanocubicles containing insulin were administered to fasted streptozotocin induced diabetic rats. For comparison, an aqueous solution of insulin in water was also administered. Nanocubicles without insulin and insulin in phosphate buffer saline (PBS) were administered as controls. Blood glucose concentration and insulin concentration were measured 1, 2, 3, 4, and 6 h after the administration of the insulin formulations. In vitro experiments showed that the particles were taken up by the Caco-2 cells at a high ratio. It was observed in these studies that the serum glucose concentration was controlled for more than 6 h after oral insulin administration but returned to the basal concentration in 3 h when 1 IU/kg of insulin was injected intravenously.


Cilek et al. (53) prepared microemulsions using Labrafil M 1944 CS, Phospholipon 90 G (lecithin), absolute alcohol and bi-distilled water. Aprotinin (2500 KIU/g) was added as the enzyme inhibitor to the formulation. Upon the administration of intragastric recombinant human DNA (rDNA) insulin solution to nondiabetic rats no significant change in blood-glucose level was observed. The microemulsions of rDNA insulin and aqueous solution (200 IU/kg) were administered intragastri-cally by a canulla to diabetic and nondiabetic rats. Therefore, the hypoglycemic effect of s.c. rDNA insulin solution, micro-emulsion containing rDNA insulin (IME) and microemulsion containing insulin and aprotinin (IMEA) were analyzed in diabetic rats. The area above the plasma-glucose levels time curves (AAC), minimum glucose concentration (C min ) and time to C min (t min ) were derived from the plasma glucose profiles. IME and IMEA caused approximately 30% decrease in plasma glucose levels. The highest AAC value was obtained when IMEA was administered to rats. Thus aprotinin an enzyme inhibitor can increase the bioavailability of insulin.

Phase diagrams containing the microemulsion region were constructed for pseudo-ternary systems composed of polyglycerol fatty acid ester/cosurfactant/Captex 300/water (54). It was necessary to add ethanol, 1-propanol and 1-butanol as cosurfactant to produce microemulsions. Results demonstrated that microemulsions were formed when polyglycerol fatty acid esters with hydrophile-lipophile balances (HLBs) between 8 and 13 (e.g., MO500, MO750, SO750, and ML310) were used. Microemulsions were thermodynamically stable for long periods. Further, several microemulsion formulations had enough acid-protection efficiency.

Ma et al. developed a stable self-emulsifying formulation for the oral delivery of insulin (55). This formulation enabled changes in barrier properties of Caco-2 monolayers, as referred by transepithelial electrical resistance (TEER) and apparent permeability coefficients P(app) of the paracellu-lar marker ranitidine (20-fold greater than control) but not transcellular marker propranolol, suggesting that the opening of tight junctions was involved. In diabetic beagle dogs, the bioavailability of this formulation was as much as 15.2% at a dose of 2.5 IU/kg in comparison with the hypoglycemic effect of native insulin (0.5 IU/kg) delivered by s.c. injection.

Ritschel et al. reported the gastrointestinal absorption of insulin from microemulsions (56). The routes of administration were peroral, intralumenal, or rectal. The experiments were carried out in dogs, rabbits, and rats. An absorption model for pep tides using microemulsions as delivery systems was presented.


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