Intranasal delivery of self-assembly insulin nanocomplexes based on surface modified trimethyl chitosan / (original) (raw)
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INTRODUCTION Over the last decades, intranasal delivery has been widely investigated as an alternative route for peptide and protein drugs such as insulin. Amongst several strategies used for enhancement of the insulin absorption, the use of colloidal polymeric particulate delivery systems represents a promising concept. Due to amphoteric nature of proteins, they can interact with polyanionic and polycationic polymers below and above their isoelectric points (pI) to form protein-polyelectrolyte complexes or nanocomplexes (NC) without the use of organic solvent, heat or vigorous agitation 1 . From this concept, insulin can be formed NC with positively charged polymers, trimethyl chitosans (TMC) and PEGylated TMC copolymers at pH above its pI (apparent pI 6.4). In this study, the insulin NC based on TMC and PEGylated TMC copolymers were developed and their physicochemical properties were characterized and compared with insulin NP prepared by ionotropic gelation with tripolyphosphate (...
Langmuir, 2013
Ternary interpolyelectrolyte complexes of insulin with biodegradable synthetic cationic polymer, poly(methylaminophosphazene) hydrochloride (PMAP), and dextran sulfate (DS) were investigated by means of turbidimetry, dynamic light scattering, phase analysis, and highsensitivity differential scanning calorimetry. Formation of ternary insoluble stoichiometric Insulin-PMAP-DS complexes was detected under conditions imitating the human gastric environment (pH 2, 0.15 M NaCl). A complete immobilization of insulin in the complexes was observed in a wide range of the reaction mixture compositions. The ternary complexes were shown to dissolve and dissociate under conditions imitating the human intestinal environment (pH 8.3, 0.15 M NaCl). The products of the complex dissociation were free insulin and soluble binary Insulin-PMAP complexes. The conformational stability of insulin in the soluble complexes of various compositions was investigated by high-sensitivity differential scanning calorimetry. The dependence of the excess denaturation free energy of insulin in these complexes on the PMAP content was obtained. The binding constants of the folded and unfolded forms of insulin to the PMAP polycation were estimated. Proteolysis of insulin involved in the insoluble ternary complexes by pepsin was investigated under physiological conditions. It was found that the complexes ensure an almost 100% protection of insulin against proteolytic degradation. The obtained results provide a perspective basis for development of oral insulin preparations.
Evidence for restrictive parameters in formulation of insulin-loaded nanocapsules
European Journal of Pharmaceutics and Biopharmaceutics, 2004
Poly(isobutylcyanoacrylate) nanocapsules with an oily core were originally proposed for lipophilic drug encapsulation [Int. J. Pharm. 28 (1986) 125] but insulin, a hydrosoluble protein, has also been successfully encapsulated by Damgé et al. [Diabetes 37 (1988) 246]. The aim of this work was to understand if several parameters were restrictive for the encapsulation of insulin into the oily core of the nanocapsules prepared by interfacial polymerization. The encapsulation efficiency of insulin was not affected by the type of insulin since the peptides adopted the same association state after their addition to the organic phase. Formulation parameters mainly affected the size of the nanocapsules obtained but did not influence the insulin encapsulation efficiency. In contrast, the order of introduction of insulin and of the monomer in the organic phase was shown to control the formation and the characteristics of the nanocapsules. The key parameters, which were found to clearly influence the encapsulation efficiency of insulin, were the pH of the aqueous insulin solution and the origin of the monomer. Both of these parameters can affect the rate of the interfacial polymerization. Consequently, the ability of insulin to be entrapped into the oil containing nanocapsules appeared to be governed more by the rate of the monomer polymerization.
Probing insulin’s secondary structure after entrapment into alginate/chitosan nanoparticles
European Journal of Pharmaceutics and Biopharmaceutics, 2007
The aim of the present study was to probe the structural integrity of insulin after being entrapped into chitosan/alginate nanoparticles produced by ionotropic polyelectrolyte pre-gelation. By manipulating the alginate:chitosan mass ratio and the pH during nanoparticle production, desired nanoparticles with a mean size of 850 (±88) nm and insulin association efficiency of 81 (±2)% were obtained. Insulin secondary structure was assessed by Fourier transform infrared (FTIR) and circular dichroism (CD) after entrapment into nanoparticles and after release from the particles under gastrointestinal simulated conditions. FTIR second-derivative spectra and area-overlap compared to an insulin standard confirmed that no significant conformational changes of insulin occurred in terms of a-helix and b-sheet content. Far-UV-CD spectra corroborated the preservation of insulin structure during the nanoparticle production procedure. The presented nanoparticulate system is a promising carrier for insulin oral delivery since it preserves insulin structure and therefore also, potentially, its bioactivity.
International Journal of Peptide Research and Therapeutics, 2006
The overall objective of our research is to produce polyanion/chitosan nanoparticulate oral delivery systems for insulin. Specific objectives of the present study were to study dextran sulfate or alginate complexation with chitosan on mean particle size, insulin association efficiency, loading capacity and release profile. Nanoparticles were formed by ionotropic complexation and coacervation between polyanions (dextran sulfate and alginate) and chitosan. Diameter was evaluated with photon correlation spectroscopy, polymer interaction was confirmed by DSC and FTIR and particle morphology was assessed by SEM and TEM. Mean nanoparticle diameter ranged from 423 to 850 nm, insulin association efficiency from 63 to 94% and loading capacity from 5 to 13%. Dextran sulfate provided highest insulin association efficiency and retention of insulin in gastric simulated conditions. These nanoparticle systems show promise as insulin and potentially other therapeutic polypeptides carriers.
International Journal of Pharmaceutics, 1999
Insulin could be encapsulated very efficiently in oily containing poly(isobutylcyanoacrylate) nanocapsules obtained by interfacial polymerization. In addition, these nanocapsules showed unexpected biological activity after intragastric administration. The hypoglycemic effect was characterized by a lag time period of 2 days and a prolonged effect over a period of 20 days. To explain, the high encapsulation rate of insulin achieved in these nanocapsules and the biological effect, this work was focused on the characterization of the nanocapsules and on the study of the mechanism of nanocapsule formation. Results showed that insulin was found unmodified during the nanoencapsulation process. This was due to the large amount of ethanol used in the preparation of the nanocapsules that initiated the polymerization of isobutylcyanoacrylate preserving the peptide from a reaction with the monomer. Results also showed that insulin was located inside the core of the nanocapsules and not simply adsorbed onto their surface.
Journal of Controlled Release, 2002
The objective of this study was to investigate the insulin incorporation and release properties of poly(methacrylic acid-g-ethylene glycol) P(MAA-g-EG) microparticles as a function of copolymer composition. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral / basic environments. The microparticles containing equimolar amounts of MAA and PEG were capable of efficient insulin loading using equilibrium partitioning (>90%). Additionally, insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral / basic conditions. In contrast, as the amount of MAA of the polymer was increased, the entrapment efficiency of insulin within the gel greatly reduced and the insulin was readily released from the polymer network in the acidic and neutral / basic media. In addition, in order to evaluate the potential application of the microparticles to other drugs, theophylline, vancomycin, fluoresceinisothiocyanate-labeled dextrans (FITC-Ds) with average molecular weights of 4400 (FITC-D-4), 12,000 (FITC-D-10) and 19,500 (FITC-D-20) were utilized as model hydrophilic drugs. The incorporation profiles showed that the uptake of theophylline and vancomycin to the microparticles was lower than that of insulin. Additionally, polymer microparticles loaded with theophylline and vancomycin exhibited pH-sensitive release behavior, however, the oscillatory behavior is less pronounced than those of insulin. The values of drug incorporation ratio showed that the microparticles were capable of incorporating almost 90% of insulin and 15% of vancomycin from solution. On the other hand, the other hydrophilic drugs showed very low incorporation efficiency to the microparticles. These data suggest that gels containing equimolar amounts of MAA:EG have the potential to be used as an oral carrier of peptide drugs, especially for insulin.
Development and characterization of new insulin containing polysaccharide nanoparticles
Colloids and Surfaces B-biointerfaces, 2006
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.
Ex Vivo Evaluation of Insulin Nanoparticles Using Chitosan and Arabic Gum
2011
Polymeric delivery systems based on nanoparticles have emerged as a promising approach for peroral insulin delivery. The aim of the present study was to investigate the release of insulin nanoparticulate systems and ex vivo studies. The nanoparticles were prepared by the ion gelation method. Particle size distribution, zeta potential, and polydispersity index of the nanoparticles were determined. It was found that the nanoparticles carried positive charges and showed a size distribution in the range of 170-200 nm. The electrostatic interactions between the positively charged group of chitosan and negatively charged groups of Arabic gum play an important role in the association efficiency of insulin in nanoparticles. In vitro insulin release studies showed an initial burst followed by a slow release of insulin. The mucoadhesion of the nanosystem was evaluated using excised rat jejunum. Ex vivo studies have shown a significant increase in absorption of insulin in the presence of chitosan nanoparticles in comparison with free insulin.
The overall objective of this research is to improve the oral bioavailability of insulin through encapsulation in nanoparticles formulated by \"ionotropic pre-gelation followed by polyelectrolyte complexation technique\". The preparation variables such as initial drug concentration, polymer: polymer ratios, crosslinker concentration, stirring speed, stirring time, pH of drug / polymer mixture were investigated to study the effect of variables on nanoparticles size and drug entrapment efficiency. The optimum formula of insulin loaded nanoparticles was tested for insulin release in different pH media. The pharmacological activity of insulin loaded nanoparticles was evaluated following oral dosage in diabetic rats and then study whether insulin loaded nanoparticles would induce hypoglycemic effect after oral administration to diabetic rats. The optimum formula of nanoparticles improved insulin release characteristics. Thus, the polymer matrix provided protection for insulin in acidic gastric medium and allowed prolonged insulin release in alkaline intestinal medium. In vivo results indicated that nanoparticles kept insulin bioactivity and its hypoglycemic effect after oral administration of insulin loaded nanoparticles to diabetic rat model. It was found that natural biodegradable nanoparticles are a promising device for oral insulin delivery.