Use of spray-dried chitosan acetate and ethylcellulose as compression coats for colonic drug delivery: effect of swelling on triggering in vitro drug release.

Spray-dried chitosan acetate (CSA) and ethylcellulose (EC) were used as new compression coats for 5-aminosalicylic acid tablets. Constrained axial or radial swelling of pure CSA and EC/CSA tablets in 0.1 N HCl (stage I), Tris-HCl, pH 6.8 (stage II), and acetate buffer, pH 5.0 (stage III), was investigated. Factors affecting in vitro drug release, i.e., % weight ratios of coating polymers, dip speeds of dissolution apparatus or pH of medium or colonic enzyme (beta-glucosidase) in stage III, and use of a super disintegrant in core tablets, were evaluated. Swollen CSA gel dissolved at lower pH and became less soluble at higher pH. The mechanism of swelling was Fickian diffusion fitting well into both Higuchi's and Korsmeyer-Peppas models. EC:CSA, at 87.5:12.5% weight ratio, provided lag time rendering the tablets to reach stage III (simulated colonic fluid of patients), and the drug was released over 90% within 12 h. The system was a dual time- and pH-control due to the insolubility of EC suppressing water diffusion and the swelling of CSA in the stages I and II. The erosion of CSA gel in the stage III induced the disintegration of the coat resulting in rapid drug release. The lower dip speed and higher pH medium delayed the drug release, while a super disintegrant in the cores enhanced the drug release and no enzyme effect was observed.

Effect of chitosan salts and molecular weight on a nanoparticulate carrier for therapeutic protein.

The objective of this study was to investigate the potential of chitosan salts as a carrier in the preparation of protein-loaded nanoparticles. Glutamic and aspartic acids were used to prepare chitosan salts of 35, 100, and 800 KDa. Nanoparticles of chitosan base, chitosan glutamate, and chitosan aspartate were produced by ionotropic gelation with sodium tripolyphosphate (TPP). Bovine serum albumin (BSA) was applied as a model protein at loading concentrations ranging from 0.2 to 2 mg/mL. The size of the nanoparticles, as measured by photon correlation spectroscopy, was in the range of 195 to 3450 nm, depending on type and molecular weight of chitosan. Nanoparticles prepared with higher molecular weight chitosan showed larger sizes. The encapsulation was controlled by the competition of BSA in forming ionic cross-linking with chitosan and by the entrapment of BSA during the gelation process. Higher BSA encapsulation efficiency (EE) was obtained for nanoparticles prepared with chitosan salts compared to those prepared with the base. The higher EE was a result of a higher degree of ionization, causing more active sites to interact with BSA. In addition, a higher and faster release of BSA from the nanoparticles into pH 7.4 buffer medium was observed for nanoparticles of the chitosan salts than was observed for nanoparticles of the chitosan base. The higher and faster release was attributed to higher EE and lower entrapment of BSA within the matrix of the nanoparticle during the gelation process. The influence of molecular weight on the property of nanoparticles exhibited different effects. The difference was a result of different organic acids used to prepare nanoparticles leading to the difference in polymer conformation and viscosity of organic acid solution. Therefore, this study showed that the characteristics of chitosan nanoparticles loaded with a protein drug could be readily modulated by changing the salt form or the molecular weight of the chitosan carrier.

Characterization of chitosan acetate as a binder for sustained release tablets.

A chitosan derivative as an acetate salt was successfully prepared by using a spray drying technique. Physicochemical characteristics and micromeritic properties of spray-dried chitosan acetate (SD-CSA) were studied as well as drug-polymer and excipient-polymer interaction. SD-CSA was spherical agglomerates with rough surface and less than 75 microm in diameter. The salt was an amorphous solid with slight to moderate hygroscopicity. The results of Fourier transform infrared (FTIR) and solid-state (13)C NMR spectroscopy demonstrated the functional groups of an acetate salt in its molecular structure. DSC and TGA thermograms of SD-CSA as well as FTIR and NMR spectrum of the salt, heated at 120 degrees C for 12 h, revealed the evidence of the conversion of chitosan acetate molecular structure to N-acetylglucosamine at higher temperature. No interaction of SD-CSA with either drugs (salicylic acid and theophylline) or selected pharmaceutical excipients were observed in the study using DSC method. As a wet granulation binder, SD-CSA gave theophylline granules with good flowability (according to the value of angle of repose, Carr's index, and Hausner ratio) and an excellent compressibility profile comparable to a pharmaceutical binder, PVP K30. In vitro release study of theophylline from the tablets containing 3% w/w SD-CSA as a binder demonstrated sustained drug release in all media. Cumulative drug released in 0.1 N HCl, pH 6.8 phosphate buffer and distilled water was nearly 100% within 6, 16 and 24 h, respectively. It was suggested that the simple incorporation of spray-dried chitosan acetate as a tablet binder could give rise to controlled drug delivery systems exhibiting sustained drug release.

Composite film-coated tablets intended for colon-specific delivery of 5-aminosalicylic acid: using deesterified pectin.

Combinations of Eudragit RS and deesterified pectin, polygalacturonic acid (PGA), or its potassium and sodium salts, when applied as a film coat, has a potential value as a colon-specific delivery system. Dispersions of PGA in Eudragit RS were used as the film former for coating of 5-aminosalicylic acid (5-ASA) tablet cores. Drug release behavior was assessed, in vitro, under simulating conditions in term of pH and time to in vivo during their transit to the colon. Negligible drug release occurred during first 5 hr where the coated tablets were in the stomach and small intestine. After that, the pectinolytic enzymes were added into the pH 6.8 medium to simulate the in vivo condition where there is the digestion of bacteria in the colon. The release of 5-ASA from the coated tablets occurred linearly as a function of time. Drug release depended on the composition of the mixed film, as well as the ratio of Eudragit RS to PGA or its salts. The highest drug release from the coated tablets of about 40% was obtained when the ratio of Eudragit RS to potassium salt of PGA was 2.5 to 1. Drug release profiles seemed to conform to the mechanism involving the osmotically driven release and formation of channels in the film caused by dissolution of PGA salts. Channel formation was, in most cases, activated by the presence of pectinolytic enzymes, showing that the PGA in the mixed film was subjected to enzymic breakdown. In conclusion, PGA could be used as an additive in Eudragit RS films to control the release of colonic delivery system.

Drug physical state and drug-polymer interaction on drug release from chitosan matrix films.

Four different grades of chitosan varying in molecular weight and degree of deacetylation were used to prepare chitosan films. Salicylic acid and theophylline were incorporated into cast chitosan films as model acidic and basic drugs, respectively. Crystalline characteristics, thermal behavior, drug-polymer interaction and drug release behaviors of the films were studied. The results of Fourier transform infrared and solid-state 13C NMR spectroscopy demonstrated the drug-polymer interaction between salicylic acid and chitosan, resulting in salicylate formation, whereas no drug-polymer interaction was observed in theophylline-loaded chitosan films. Most chitosan films loaded with either salicylic acid or theophylline exhibited a fast release pattern, whereas the high viscosity chitosan films incorporated with salicylic acid showed sustained release patterns in distilled water. The sustained release action of salicylic acid from the high viscosity chitosan films was due to the drug-polymer interaction. The mechanism of release was Fickian diffusion control with subsequent zero order release. It was suggested that the swelling property, dissolution characteristics of the polymer films, pK(a) of drugs and especially drug-polymer interaction were important factors governing drug release patterns from chitosan films.

Physical properties and molecular behavior of chitosan films.

Chitosan films, varying in molecular weight and degree of deacetylation, were prepared by a casting technique using acetic acid as a dissolving vehicle. The physicochemical properties of the films were characterized. Both molecular weight and degree of deaceylation affected the film properties. Powder X-ray diffraction patterns and differential scanning calorimetry thermograms of all chitosan films indicated their amorphous state to partially crystalline state with thermal degradation temperature lower than 280-300 degrees C. The increase in molecular weight of chitosan would increase the tensile strength and elongation as well as moisture absorption of the films, whereas the increase in degree of deacetylation of chitosan would either increase or decrease the tensile strength of the films depending on its molecular weight. Moreover, the higher the degree of deacetylation of chitosan the more brittle and the less moisture absorption the films became. All chitosan films were soluble in HCl-KCl buffer (pH 1.2), normal saline, and distilled water. They swelled in phosphate buffer (pH 7.4), and cross-linking between chitosan and phosphate anions might occur Finally, transmission infrared and 13C-NMR spectra supported that chitosan films prepared by using acetic acid as a dissolving were chitosonium acetate films.

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of formulation and processing variables on drug release.

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.