We have studied the pH-and salt-mediated response of matrix-type polyelectrolyte microcapsules. The capsules were prepared by layer-by-layer (LbL) adsorption on decomposable CaCO3 cores using model polyelectrolytes, namely poly-styrenesulfonic acid (PSS) and poly(allylamine hydrochloride) (PAH). Salt-mediated LbL-made microcapsule fusion has been reported recently with a different polycation (R. Zhang, O. Kreft, A. Skirtach, H. Mohwald and G. Sukhorukov, Soft Matter, 2010, 6, 4742-4747) resulting in merging of the capsule's content and formation of anisotropic "Janus-like'' capsules indicating no polymer exchange between the capsules. Here we have studied PAH/PSS capsule behavior as a function of pH and salt concentration. Salt (NaCl) does not induce any changes in the capsules up to saturation concentration (6.1 M). In contrast, several sequential processes have been identified for capsules in [HCl] > 0.1 M: (i) shrinkage due to polymer network annealing, (ii) transformation from matrix-type to shell-type capsules due to oscillating inflating-deflating cycles caused by CO2 formation, and (iii) collapse. The processes depend on acid concentration and the number of layers. If the capsules contact each other, there is an exchange of polymer molecules followed by fusion. The polymer exchange depends on the outermost layer that determines the overall capsule charge. Exchange is enhanced for capsules of the same outermost layer and can be caused by charge redistribution in the capsules at low pH (the negative charge of PSS is reduced (pK(a) 1) and the positive charge of PAH is in excess). Control over polymer exchange between the capsules is key in order to design capsules as well as to understand and to trigger fusion. We also show that the observed processes are not reversible and can be stopped at any time by replacement of acid with water. Stable gas-filled capsules can be produced by this method upon transformation from matrix to shell-type capsules

Multicomponent insulin-containing microparticles are prepared by layer-by-layer assembly of dextran sulfate and chitosan on the core of protein-polyanion complex with or without protease inhibitors. Oral bioavailability of the encapsulated insulin is improved due to the cumulative effect of each component. A physico-chemical study shows that the particle design allows adjustment of the pH-dependent profile of the insulin release, as well as mucoadhesive properties and Ca(2+) binding ability of the microparticles. Supplementing the microparticles with 2-3% protease inhibitors fully prevents proteolysis of human insulin. The pharmacological effect of microencapsulated insulin in doses 50-100 IU kg(-1) is demonstrated in chronic experiments after oral administration to diabetic rats fed ad libitum.

Microparticles containing recombinant human insulin and its analogs aspart and lispro were prepared using an alternate adsorption of chitosan and dextran sulfate from solutions onto microaggregates of protein-dextran sulfate insoluble complex. The following properties of polyelectrolyte hormone-containing microparticles were studied: pH stability, surface charge, mucoadhesive properties, Ca(2+) binding, degradation under the influence of proteases (trypsin, chymotrypsin). The influence of the self-association ability of encapsulated insulins on the form of protein releasing from microparticles was studied. Insulins aspart and lispro released from the microparticles as monomers were more liable to proteolysis than human insulin released as a hexamer. The combined effect of properties of polyelectrolyte microparticles and of encapsulated recombinant proteins on the bioavailability of insulin under peroral administration is discussed.

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Microparticles were fabricated by layer-by-layer deposition of chitosan (Ch) and dextran sulfate (DS) on microaggregates 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 encapsulated 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.