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

Mucoadhesive system. A biologically adhesive delivery system offers important advantage over conventional drug delivery systems. Whitehead et al. (47) described a novel method of delivering insulin into systemic circulation by mucoadhesive intestinal patches. Intestinal patches localize insulin near the mucosa and protected it from proteolytic degradation. In vitro experiments confirmed the secure adhesion of patches to the intestine and the release of insulin from them. In vivo experiments performed via jejunal administration showed that intestinal insulin patches induced dose-dependent hypoglycemia in normal rats. These studies revealed that reduction in blood glucose levels were comparable with those induced by s.c. injections.

The engineered polymer microspheres made of erodible polymer display strong adhesive interactions with gastrointestinal mucus and cellular lining and can traverse both the mucosal epithelium and the follicle associated epithelium covering the lymphoid tissue of Peyer's patches. Alginate, a natural polymer recovered from seaweed is being developed as a nanoparticle for the delivery of insulin without being destroyed in the stomach. It has in addition, several other properties that have enabled it to be used as a matrix for entrapment and for the delivery of a variety of proteins such as insulin and cells. These properties include: a relatively inert aqueous environment within the matrix, a mild room temperature encapsulation process free of organic solvents, a high gel porosity that allows for high diffusion rates of macromolecules, the ability to control this porosity with simple coating procedures, and dissolution and biodegradation of the system under normal physiological conditions (48).


Thiolated chitosan insulin tablets. The efficacy of orally administered insulin has also been improved using thiolated chitosan. 2-Iminothiolane was covalently linked to chitosan and the resulting chitosan-TBA (chitosan-4-thiobutylamidine) conjugate exhibited 453.5 64.1 micromol thiol groups per gram polymer (49). Two enzyme inhibitors Bowman-Birk-Inhibi-tor (BBI) and elastatinal were covalently linked to chitosan. Chitosan-TBA conjugate (5 mg), insulin (2.75 mg), the permeation mediator reduced glutathione (0.75 mg), and the two inhibitor conjugates (in each case 0.75 mg) were compressed to make chitosan-TBA-insulin tablets. Control tablets were also prepared using chitosan and insulin. Chitosan-TBA-insulin tablets showed a controlled release of insulin over 8 h. In vitro mucoadhesion studies showed that the mucoadhesive/cohe-sive properties of chitosan were at least 60-fold improved by the immobilization of thiol groups on the polymer. After oral administration of chitosan-TBA-insulin tablets to non-diabetic rats, the blood glucose level decreased significantly for 24 h. In contrast, neither control tablets nor insulin given in solution showed a comparable effect. These results concluded that the combination of chitosan-TBA, chitosan-enzyme-inhibitor conjugates and reduced glutathione could constitute a promising strategy for the oral administration of insulin.


Dorkoosh et al. developed novel peroral peptide drug delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) (50). The authors studied the release of insulin from SPH and SPHC polymers. In addition, the stability of insulin during the release and the integrity of insulin in the polymeric matrix of SPHC was investigated. The release studies revealed that insulin was released almost completely from the polymers. SPH was more porous than SPHC, therefore, release of pep tides was faster from SPH. FTIR studies demonstrated that no covalent binding occurred between insulin and the polymeric SPHC matrix. The release profile of insulin was time controlled. There was an initial lag time of 10–15 min, followed by burst release during which more than 80% of insulin was released within 30–45 min.

Kavimandan et al. developed hydrogels as a delivery vehicle for insulin-transferrin conjugate (51). In this work, electrospray ionization mass spectrometry (ESI–MS) was used to study the modification of insulin during its reaction with transferrin. The stability of the conjugated insulin to enzymatic degradation was also studied. ESI-MS studies confirmed the site-specific modifications of insulin. The transferrin conjugation of insulin was also shown to increase the stability of insulin to enzymatic degradation.


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