Polymeric nanoparticles have been extensively studied as particulate carriers in the pharmaceutical and medical fields, because they show promise as drug delivery systems as a result of their controlled- and sustained-release properties, subcellular size, and biocompatibility with tissue and cells. Several methods to prepare nanoparticles have been developed during the last two decades, classified according to whether the particle formation involves a polymerization reaction or arises from a macromolecule or preformed polymer. In this review the most important preparation methods are described, especially those that make use of natural polymers. Advantages and disadvantages will be presented so as to facilitate selection of an appropriate nanoencapsulation method according to a particular application.

Purpose. To evaluate the pharmacological activity of insulin-loaded alginate/chitosan nanoparticles following oral dosage in diabetic rats. Methods. Nanoparticles were prepared by ionotropic pre-gelation of an alginate core followed by chitosan polyelectrolyte complexation. In vivo activity was evaluated by measuring the decrease in blood glucose concentrations in streptozotocin induced, diabetic rats after oral administration and flourescein (FITC)-labelled insulin tracked by confocal microscopy. Results. Nanoparticles were negatively charged and had a mean size of 750 nm, suitable for uptake within the gastrointestinal tract due to their nanosize range and mucoadhesive properties. The insulin association efficiency was over 70% and insulin was released in a pH-dependent manner under simulated gastrointestinal conditions. Orally delivered nanoparticles lowered basal serum glucose levels by more than 40% with 50 and 100 IU/kg doses sustaining hypoglycemia for over 18 h. Pharmacological availability was 6.8 and 3.4% for the 50 and 100 IU/kg doses respectively, a significant increase over 1.6%, determined for oral insulin alone in solution and over other related studies at the same dose levels. Confocal microscopic examinations of FITC-labelled insulin nanoparticles showed clear adhesion to rat intestinal epithelium, and internalization of insulin within the intestinal mucosa. Conclusion. The results indicate that the encapsulation of insulin into mucoadhesive nanoparticles was a key factor in the improvement of its oral absorption and oral bioactivity.

Insulin-loaded nanoparticles were prepared by ionotropic pre-gelation of alginate with calcium chloride followed by complexation between alginate and chitosan. The influence of the pH and stoichiometry relationship between polyelectrolytes providing individual particles with a nano-scale size was assessed by photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). Insulinpolyelectrolyte interactions at varying pH and polyelectrolytes stoichiometry were assessed by differential scanning calorimetry (DSC) and Fourier-transform infrared (FTIR) studies. Individual and smaller sizing nanoparticles, around 800 nm, were obtained at pH 4.7 with an alginate:chitosan mass ratio of 6:1. Thermograms of insulin-loaded nanoparticles originated shifts on same unloaded nanoparticle peaks and suggested polyelectrolytes-protein interactions at pH around 4.5-5.0. FTIR spectra of insulin-loaded nanoparticles showed amide absorption bands characteristic of protein spectra and revealed the formation of new chemical entities.

A nanoparticle insulin delivery system was prepared by complexation of dextran sulfate and chitosan in aqueous solution. Parameters of the formulation such as the final mass of polysaccharides, the mass ratio of the two polysaccharides, pH of polysaccharides solution, and insulin theorical loading were identified as the modulating factors of nanoparticle physical properties. Particles with a mean diameter of 500 nm and a zeta potential of approximately −15 mV were produced under optimal conditions of DS:chitosan mass ratio of 1.5:1 at pH 4.8. Nanoparticles showed spherical shape, uniform size and good shelf-life stability. Polysaccharides complexation was confirmed by differential scanning calorimetry and Fourier transformed infra-red spectroscopy. An association efficiency of 85% was obtained. Insulin release at pH below 5.2 was almost prevented up to 24 h and at pH 6.8 the release was characterized by a controlled profile. This suggests that release of insulin is ruled by a dissociation mechanism and DS/chitosan nanoparticles are pH-sensitive delivery systems. Furthermore, the released insulin entirely maintained its immunogenic bioactivity evaluated by ELISA, confirming that this new formulation shows promising properties towards the development of an oral delivery system for insulin.

Alginate nanoparticles were prepared from dilute alginate sol by inducing a pre-gel with calcium counter ions, followed by polyelectrolyte complex coating with chitosan. Particles in the nanometer size range were obtained with 0.05% alginate and 0.9 mM Ca2+. The mean particle size was influenced by time and stirring speed of nanoparticle preparation, by alginate guluronic acid content and chitosan molecular weight and by the initial alginate:chitosan mass ratio. The association efficiency of insulin into alginate nanoparticles, as well as loading capacity were mainly influenced by the alginate:chitosan mass ratio. Under optimized size conditions, the association efficiency and loading capacities were as high as 92% and 14.3%, respectively. Approximately 50% of the protein was partially retained by the nanoparticles in gastric pH environment up to 24 hours while a more extensive release close to 75% was observed under intestinal pH conditions. Mild formulation conditions, optimum particle size range obtained, high insulin entrapment efficiency, and resistance to gastrointestinal release seem to be synergic and promising factors toward development of an oral insulin delivery form.

No abstract

The pharmacological activity of insulin-loaded dextran sulfate/chitosan nanoparticles was evaluated following oral dosage in diabetic rats. Nanoparticles were mucoadhesive and negatively charged with a mean size of 500 nm, suitable for uptake within the gastrointestinal tract. Insulin association efficiency was over 70% and was released in a pH-dependent manner under simulated gastrointestinal conditions. Orally delivered nanoparticles lowered basal serum glucose levels in diabetic rats around 35% with 50 and 100 IU/kg doses sustaining hypoglycemia over 24 h. Pharmacological availability was 5.6 and 3.4% for the 50 and 100 IU/kg doses, respectively, a significant increase over 1.6%, determined for oral insulin alone in solution. Confocal microscopic examinations of FITC-labeled insulin nanoparticles showed adhesion to rat intestinal epithelium, and internalization of insulin within the intestinal mucosa. Encapsulation of insulin into dextran sulfate/chitosan nanoparticles was a key factor in the improvement of the bioavailability of its oral delivery over insulin solution.

The European Medicines Agency (EMA) and the Current Good Manufacturing Practices (cGMP) in the United States of America, define excipient as the constituents of the pharmaceutical form other than the active ingredient, i.e., any component that is intended to furnish pharmacological activity. Although dendrimers do not have a pharmacopoeia monograph and, therefore, cannot be recognized as a pharmaceutical excipient, these nanostructures have received enormous attention from researchers. Due to their unique properties, like the nanoscale uniform size, a high degree of branching, polyvalency, aqueous solubility, internal cavities, and biocompatibility, dendrimers are ideal as active excipients, enhancing the solubility of poorly water-soluble drugs. The fact that the dendrimer’s properties are controllable during their synthesis render them promising agents for drug-delivery applications in several pharmaceutical formulations. Additionally, dendrimers can be used for reducing the drug toxicity and for the enhancement of the drug efficacy. This review aims to discuss the properties that turn dendrimers into pharmaceutical excipients and their potential applications in the pharmaceutical and biomedical fields.