Abstract
Microparticles were fabricated by layer-by-layer deposition of chitosan (Ch) and dextran sulfate (DS) on microag - gregates formed by human insulin and DS. Consecutive treatment of the negatively charged microaggregates with Ch, DS, and Ch yielded small (ca. 10 μm) positively charged microparticles with high insulin encapsulation efficiency (65% of initial amount of insulin) and loading (50% w/w). Virtually all immobilized protein remained insoluble in the pH range 1.0–6.0 corresponding to the aggressive media of stomach and upper small intestine, while at pH 7.4, about 90% of the insulin was released during one-hour incubation. Encapsulated insulin was more resistant to the protease action than native insulin in solution: after 1-h incubation in simulated pancreatic juice only 60% of encap - sulated insulin degraded, while insulin in solution degraded almost completely. Experiments in vivo demonstrated that insulin encapsulated in microparticles preserved biological activity and exerted a prolonged hypoglycemic effect after peroral administration in rabbits and diabetic rats. Bioavailability of the encapsulated insulin administered per os was 11%. The produced microparticles are biocompatible, biodegradable, and mucoadhesive and may be used for the development of oral insulin delivery systems in humans.
Highlights
Insulin is used for treatment of type 1 diabetes mellitus, which is characterized by lack of the internally produced hormone
We studied a hypoglycemic activity of insulin zinc salt (Ins)-containing microparticles after peroral administration of a low Ins dose of 4 IU/kg, similar to subcutaneous injections
Microparticles containing human recombinant insulin were prepared by layer-by-layer adsorption of oppositely charged biocompatible polysaccharides dextran sulfate (DS) and Ch onto Ins–DS microaggregates
Summary
Insulin is used for treatment of type 1 diabetes mellitus, which is characterized by lack of the internally produced hormone. Traditional injection dosage forms of insulin have a number of serious shortcomings, e.g., permanent violation of skin, variable absorption, and significant intra- and interindividual differences of the pharmacological effect. The main problem is the pharmacological profile of traditional insulin preparations that are not able to maintain the plasma concentration of insulin at the physiological level. Various alternative ways of insulin delivery are intensively developed [1]. There is only one noninvasive form of insulin (transbuccal Oral-LynTM, Generex, USA), which is available in Ecuador and India [2]. Peroral formulation is still considered as the most safe, consistent with natural way of insulin delivery, and of high patient compliance. In turn, controls the peripheral insulin concentration [3]
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