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

Damge et al. prepared insulin-loaded nanospheres by polymerization of isobutyl cyanoacrylate (IBCA) in an acidic medium (37). These nanospheres displayed a mean size of 145 nm and an association rate of 1 U of insulin per milligram of polymer. These nanospheres were dispersed in an oily medium (Miglyol 812) containing surfactant (Polox-amer 188 and deoxycholic acid) and evaluated for in vitro and in vivo degradation. No degradation due to proteolytic enzyme was observed in vitro. When these nanospheres (100 U per kilogram of body weight) were administered perorally in streptozotocin-induced diabetic rats, a 50% decrease in fasted glucose levels from the second hour up to 10-13 days was observed. This effect was shorter (2 days) or absent when nanospheres were dispersed in water. Using 14 C-labeled nanospheres loaded with (125I) insulin, it was found that nanospheres increased the uptake of (125I) insulin or its metabolites in the gastrointestinal tract, blood, and liver while the excretion was delayed when compared to (125I) insulin nonassociated to nanospheres.

In another study, Damge et al. used nanoparticles prepared with a blend of a biodegradable polyester(poly(-epsilon-capro-lactone)) and a polycationic non-biodegradable acrylic polymer (Eudragit RS) as a drug carrier for oral administration of insulin (38). The rate of encapsulation of insulin was around 96%. The therapeutic efficiency of oral insulin nanoparticles (25, 50, and 100 IU/kg) in diabetic rats and the intestinal uptake of fluorescein isothiocyanate (FITC)-labelled insulin were studied. When administered orally by force-feeding to diabetic rats, insulin nanoparticles decreased fasted glycemia in a dose-dependant manner with a maximal effect observed with 100 IU/kg. These insulin nanoparticles also increased serum insulin levels and improved the glycemic response to an oral glucose challenge for a prolonged period of time.

Chalasani et al. developed a vitamin B12 (VB12) nanoparticles system to enhance the uptake capacity of both nanoparticles and VB12 transport to deliver orally effective insulin (39). Nanoparticles were prepared using various molecular-weight dextrans and epichlorohydrin as a cross-linker by an emulsion method. Nanoparticle surface was modified with succinic anhydride and conjugated with amino VB12 derivatives of carbamate linkage. VB12 attachment was confirmed by IR, XPS analysis, and was quantified by HPLC (4.0 to 4.4% w/w of nanoparticles). The preformed nanoparticle conjugates (Zave = 160–250 nm; polydisperse) were loaded with 2,3, and 4% w/w insulin, and the entrapment was 45–70%. Nanoparticulate conjugates protected 65–83% of entrapped insulin against in vitro gut proteases. In vitro release studies exhibited an initial burst followed by diffusion-controlled first-order kinetics with 75–95% release within 48 h. After oral administration of these carriers (20 IU/kg), 70–75% reduction in plasma glucose was found in 5 h, reached basal levels in 8-10 h, and a prolonged second phase was found until 54 h.

In a study by Lin et al., nanoparticles composed of chitosan and poly(gamma-glutamic acid) were prepared by a simple ionic-gelation method for oral insulin delivery (40). After insulin loading, the nanoparticles remained spherical and the insulin-release profiles were significantly affected by their stability in distinct pH environments. The in vivo results clearly indicated that the insulin-loaded nanoparticles could effectively reduce the blood-glucose level in a diabetic rat model.

Cui et al. investigated the preparation of PLGA nanoparticles (PNP) and PLGA-Hp55 nanoparticles (PHNP) as potential drug carriers for oral insulin delivery (41). The nanoparticles were prepared by a modified emulsion solvent diffusion method in water, and their physicochemical characteristics, drug release in vitro and hypoglycemic effects in diabetic rats were evaluated. The mean particle sizes of the PNP and PHNP were 150 and 169 nm, respectively. The drug recoveries of the nanoparticles were 50.30 3.1 and 65.41 2.3%, respectively. The initial release of insulin from the nanoparticles in simulated gastric fluid over 1 h was 50.46 6.31 and 19.77 3.15%, respectively. The relative bio availability of PNP and PHNP compared with s.c. injection (1 IU/kg) in diabetic rats was 3.68 0.29 and 6.27 0.42%, respectively. The results showed that the use of insulin-loaded PHNP was an effective method of reducing serum glucose levels.

Sarmento et al. prepared a nanoparticulate insulin delivery system by complexation of dextran sulfate (DS) and chitosan in aqueous solution (42). Parameters of the formulation such as the final mass of polysaccharides, the mass ratio of the two polysaccharides, pH of polysaccharides solution, and insulin theoretical loading were identified as the modulating factors of nanoparticle physical properties. Particles with a mean diameter of 500 nm and a zeta potential of approximately –15 mV were produced under optimal conditions of DS:chitosan mass ratio of 1.5:1 at pH 4.8. Nanoparticles showed spherical shape, uniform size, and good shelf-life stability. Polysaccharides complexation was confirmed by differential scanning calorimetry and Fourier transformed infrared spectroscopy. An association efficiency of 85% was obtained. Insulin release at pH below 5.2 was almost prevented up to 24 h and at pH 6.8, and the release was characterized by a controlled profile. This result suggested that the release of insulin was ruled by a dissociation mechanism and DS–chitosan nanoparticles acted as pH-sensitive delivery systems. Furthermore, the released insulin entirely maintained its immunogenic bioactivity evaluated by ELISA, confirming that this new formulation shows promising properties towards the development of an oral delivery system for insulin.


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