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

Wu et al. reported that the stability and absorption of insulin-liposomes double-coated by chitosan (CH) and chitosan-EDTA conjugates (CEC) was superior to that of the insulin-liposomes coated either by CH or by CEC (32). The protection of insulin against peptic and tryptic digestion was studied with HPLC after oral administration to rats. Liposomes protected insulin against the digestion of pepsin, trypsin, and gastrointestinal contents. In glucose tolerance test in normal rats, as compared with phosphate buffer solution control group, the insulin-liposomes coated by CH and CEC could reduce the glucose-induced peak of hyperglycemia. The reduction of the insulin-liposomes double-coated by CH and CEC was superior to that of other insulin-liposomes. When administered intragastrically to normal rats, the insulin liposomes coated by CH and CEC reduced glucose levels measured after an overnight fast. The hypoglycemic effect of the insulin liposomes double-coated by CH and CEC was superior to that of other insulin liposomes, and the dosage of 50 mU/kg decreased by 45.98% of initial blood glucose level after 1 h. As compared with s.c. injection, the relative pharmacological bioavailability was 17.02%, which was calculated by area under the curve of a glucose level versus time profile after oral administration of the insulin-liposomes double-coated by CH and CEC to rats. The serum insulin concentration-time curve best fit the one-compartment open model. As compared with s.c. injection, the relative bioavailability was 8.91% calculated by the area under the curve of serum insulin concentration versus time profile after oral administration of the insulin-liposomes double-coated by CH and CEC to rats.

Zhang et al. reported that liposomes promote the oral absorption of insulin becasuse of specific site combination on the gastrointestinal tract cell membrane (33). The authors prepared lectin-modified liposomes containing insulin and evaluated the potential of these modified colloidal carriers for oral administration. Wheat germ agglutinin (WGA), tomato lectin (TL), or Ulex europaeus agglutinin 1 (UEA1) were conjugated by coupling their amino groups to carbodiimide-activated carboxylic groups of N-glutaryl-phosphatidylethanolamine (N-glut-PE). Insulin liposomes dispersions were prepared with the reverse-phase evaporation technique and modified with the lectin-N-glut-PE conjugates. The hypoglycemic effect of these liposomes was observed in mice. The pharmacological bioavailability of insulin liposomes modified with WGA, TL, and UEA1 were 21.40, 16.71, and 8.38%, respectively, in comparison with abdominal cavity injection of insulin. After oral administration of the insulin liposomes modified with WGA, TL, and UEA1 to rats, the relative pharmacological bioavailabilities were 8.47,7.29, and 4.85%, the relative bioavailabilities were 9.12,7.89, and 5.37%, respectively, in comparison with s.c. injection of insulin. In the two cases, no remarkable hypoglycemic effects were observed with the conventional insulin liposomes.

Ramadas et al. developed an oral formulation based on liposome encapsulated alginate-chitosan gel capsules for insulin delivery (34). Liposome encapsulation helped to increase the encapsulation efficiency of insulin in alginate-chitosan capsules. This formulation bypassed the acidic medium in stomach and delivered insulin in the neutral environment of the intestine with increased drug absorption and bioavailability. The administration of this formulation was found to reduce blood glucose levels when tested in diabetic rats.

Nanoparticles

In a study conducted by Attivi et al., insulin nanoparticles were prepared by a water-in-oil-in-water emulsification and evaporation method (35). The polymers used for the encapsulation were blends of biodegradable poly-epsilon-caprolactone (PCL) and nonbiodegradable polymer (Eudragit RS). Poly(alkyl cyanoacrylate) nanocapsules also have been successfully used for oral administration of insulin in diabetic rats. The nanoparticles were characterized by measuring the amount of entrapped insulin, the particle size, the polydispersity of the obtained particles, the zeta potential, and the amount of insulin released after 7 h. The corresponding quantity of entrapped insulin was 25 IU per 100 mg of polymer, and the particle size was 350 nm with a polydispersity of 0.21. The quantity of released insulin was 4.8 IU per 100 mg of polymer after 7 h, and the zeta potential was +44 mV. Bhum-kar et al. prepared gold nanoparticles using various concentrations of chitosan (from 0.01% w/vto 1% w/v) (36). Varying concentrations of chitosan used for the synthesis of gold nanoparticles demonstrated that the nanoparticles obtained at higher chitosan concentrations (>0.1% w/v) were stable and showed no signs of aggregation. The nanoparticles also showed long-term stability in terms of aggregation for about 6 months. Insulin loading of 53% was obtained and found to be stable after loading. Blood glucose lowering at the end of 2 h following administration of insulin-loaded gold nanoparticles to diabetic rats was 30.41 and 20.27% for oral (50 IU/kg) and nasal (10 IU/kg) administration, respectively. Serum gold level studies have demonstrated significant improvement in the uptake of chitosan-reduced gold nanoparticles.


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