Effective insulin delivery using starch nanoparticles as a potential trans-nasal mucoadhesive carrier

• Published in: European journal of pharmaceutics and biopharmaceutics 2008-06, Vol.69 (2), p.426-435
• Main Authors: Jain, Akhlesh Kumar, Khar, Roop K., Ahmed, Farhan J., Diwan, Prakash V.
• Format: Article
• Language: English
• Subjects: Adhesives; Administration, Intranasal; Animals; Area Under Curve; Biological and medical sciences; Blood Glucose - metabolism; Cross-Linking Reagents; Diabetes Mellitus, Experimental - drug therapy; Epichlorohydrin; Excipients; General pharmacology; Glycocholic Acid; Hypoglycemic Agents - administration & dosage; Insulin; Insulin - administration & dosage; Insulin - blood; Insulin - therapeutic use; Lysophosphatidylcholines; Male; Medical sciences; Mucoadhesion; Nanoparticles; Nasal delivery; Particle Size; Permeation enhancers; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Wistar; Solvents; Starch
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2007.12.001

Mucoadhesive nanoparticles (NPs) could be an exciting prospect for trans-nasal insulin delivery as they have higher surface area to cover highly vascularised nasal absorptive area providing a greater concentration gradient; hence the present study makes an attempt in this regard. Starch NPs were prepared by different crosslinkers using various methodologies and were loaded with insulin. Emulsion crosslinked particles were smaller in size compared to gel method (351 vs 997 nm), and size is further reduced when epichlorohydrin is used as crosslinking agent compared to POCl 3 (194 vs 810 nm). NPs of epichlorohydrin emulsion were further optimized with variable crosslinking to evaluate the effect of degree of crosslinking on in vivo performance. In vitro, a size dependent first order diffusion controlled insulin release with an initial burst effect was found, which is higher with NPs of small size and least crosslinking. Formulation of EE–NPs with Na glycocholate showed a superior hypoglycemic action compared to other NPs formulations containing the former and lysophosphatidylcholine as permeation enhancers. The hypoglycemic effects were more pronounced with medium crosslinked NPs (EE–L2–NPs), which showed a nadir of 70% reduction of plasma glucose and significant effects untill 6 h. The peak plasma insulin level ( C max) of medium crosslinked EE–L2–NPs (258 μIU/ml at 1 h) vindicates the pharmacodynamic effect, which was found to be superior compared to all other formulations. The release rate and higher associated surface area might work in tandem, and could be greatly amplified when combined with permeation enhancers to make starch NPs an efficient trans-nasal mucoadhesive carrier of insulin.