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 peroral dosage form was developed to deliver insulin to the colon (57). Microemulsions with insulin were gelled using Cab-O-Sil (Cabot Corp., Boston, MA), and filled into gelatin capsules pretreated with formaldehyde vapor. The capsules were coated with Eudragit NE 30 D, Eudragit S100, and cellulose acetate phthalate polymers. In vitro dissolution profiles of the capsule coating, using sodium salicylate as the marker, showed that dissolution of the capsule began at 4 h, at pH 5.5, and was completed at 8 h. An in vivo crossover study in beagle dogs was carried out using i.v. insulin, p.o. insulin micro-emulsion, and colonic release capsule dosage forms without insulin (CRC) were used as controls, a colonic release capsule dosage form with insulin (CRI) and additionally with sodium laurylsulfate (CRIL) or aprotinin (CRIA) as sorption promoter and enzyme inhibitor, respectively. The reduction in blood glucose concentration levels was measured and results were interpreted in terms of pharmacological availability. The pharmacological availability is the ratio of the area under the baseline curve, expressed as percent glucose reduction from baseline versus time of the peroral dosage forms to intravenous insulin administration, corrected for body weight and dose size. The PA for the peroral microemulsion, CRC, CRI, CRIL, and CRIA were 2.1,0.4, 5.0,2.7 and 6.2%, respectively. The release of Insulin occurred throughout the GI tract, with the exception of the stomach.


Human red blood cells have been developed as oral carrier systems for human insulin. In a study by Al-Achi et al., male Wistar rats were made diabetic by a single intraperitoneal injection of streptozocin (100 mg/kg) (58). Rats received orally one of the following (100 U, 2 mL): an insulin solution, a ghosts-insulin suspension, a vesicles-insulin suspension, a liposomes-ghosts-insulin suspension, or a liposomes-vesicles-insulin suspension. Free-carrier suspensions or sodium chloride solution (0.9%) were given orally as controls. Blood glucose concentration was determined just before administration and at 1,2,3,4, 5,6, and 7 h postadministration. Results showed that all treatment groups, except liposomes-ghosts-insulin, were significantly different statistically from their respective controls (i.e., the free carriers).

Niosomes (non-ionic surfactant vesicles)

Niosomes of sorbitan monoesters (Span 20, 40, 60, and 80) were prepared using the film-hydration method without soni-cation (59). Span 80 did not form niosomes in the absence of a sufficient amount of cholesterol. The size of vesicles depended upon the molar ratio or charge incorporation. The amount of insulin released in simulated intestinal fluid from Span 40 and 60 was lower than Span 20 and 80 vesicles. Vesicles containing Span 60 showed the highest protection of insulin against proteolytic enzymes and good stability in the presence of sodium deoxycholate and storage temperatures.

Solid lipid microparticles

Solid lipid insulin-loaded microparticles were produced by a solvent-in-water emulsion-diffusion technique, using iso-butyric acid as the solvent phase, glyceryl monostearate or cetyl palmitate as lipid, soya lecithin and taurodeoxycholate as emulsifiers (60). Isobutyric acid was used a result of its high insulin-solubilization capacity. Solid lipid microparticles of spherical shape were prepared by simple dilution of the emulsion with water. The process was conducted at 50 C using a high-shear homogenizer. Insulin encapsulation efficiency of about 80% was achieved. The in vitro release of insulin from the microparticles was very low with an initial burst effect of 20% of the dose. After treatment of the solid lipid microparticles with pepsin solution, an insulin loss of about 24% of the total insulin was observed.

Chemical modifications

Modifying the chemical structure of a peptide or protein is another approach to enhance bio availability by increasing its stability against possible enzymatic degradation or its membrane permeation. However, this approach is more applicable to peptides rather than proteins because of the structural complexity of proteins. For example, substitution of D-amino acids for L-amino acids in the primary structure can improve the enzymatic stability of peptides. A diacyl derivative of insulin maintains its biological activity and also increases absorption from the intestine (1).


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