Pilot Study On A Novel Formulation For Controlled Insulin Release

Insulin is the mainstay of drug therapy for patients with insulin-dependent diabetes mellitus.However,there are several limitations to the delivery of proteins and peptides drugs including insulin,such as poor stability,a short lifetime as a result of the inactivation and digestion by various proteolytic enzymes.Thus,most patients need to administer injections of insulin per day to reach near normal glycemia control,resulting in lots of inconvenient sufferings and side effects.Therefore,the delivery of insulin by nonparenteral routes and controlled release system has been studied by more and more pharmaceutists over the world.In this study,insulin-loaded microcapsules were prepared via layer-by-layer(LbL) deposition of oppositely charged Fe³⁺and dextran sulphate(DS)onto the surface of insulin microparticles.And protamine was used as the outermost layer of the insulin-loaded microcapsules to facilitate nuclear delivery.The main results were as follows:(1)The morphology of hollow microcapsules of(Fe³⁺/DS)_n was examined by an optical microscope and a confocal laser scanning microscope.The thickness of capsule wall for(Fe³⁺/DS)_n was examined by an atomic force microscopy,and the thickness of the capsule wall for one bilayer of Fe³⁺/DS is approximately 7.7 nm.(2)The morphology of insulin-loaded microcapsules was also examined by a confocal laser scanning microscope.The layer-by-layer deposition process was easily monitored by Zeta-potential measurements of coated microaggregates alternately exposed to DS and Fe³⁺(or PRO),respectively.And the sufficient charge reversal with successive deposition cycles provided strong evidences for the growth of(Fe³⁺/DS)_n multilayer on the surface of microparticles.(3)The encapsulation efficiency and drug loading content were examined by a UV-vis spectrophotometer.The experiments showed that the microcapsules successfully entrapped insulin with encapsulation efficiency of 70.56±0.97% and drug loading content of 46.15±0.97%.(4)The centrifuge method was used in vitro release experiments.The results indicated that the insulin-loaded microcapsules showed significantly good controlled release effect compared with the release curve of free insulin.As the number of bilayers increased,the increasing significance controlled release was observed.(5)The results of in vivo hypoglycemic effect experiments indicated that,as the number of bilayers increased,the insulin-loaded microcapsules significantly improved glucose tolerance from 2 hours(insulin solution)to even 12 hours(insulin-loaded microcapsules with 10 bilayers).These findings indicate that such microcapsules can be a promising approach for the construction of an effective controlled release delivery system of insulin as well as other proteins with short half-life time.