Controlled-release cellulose esters matrices for water-soluble diclofenac sodium: compression and dissolution studies.

Matrix tablets comprising of a blend of cellulose acetate butyrate (CAB) or cellulose acetate propionate (CAP) and alpha-lactose monohydrate were prepared by direct compression to control the release of diclofenac sodium. Tablet formulations containing CAP75000 or CAB50-54 exhibited highest extents, but lowest onsets of plastic deformation and lowest release rates in buffer medium, while tablets containing CAP15000 or CAB35-39 exhibited lowest extents, but highest rates of plastic deformation and highest release rates in buffer medium. The DA values obtained from Heckel plots and the DI values obtained from Kawakita plots showed similar trends. A plot of compression pressure or crushing strengths against T50% showed curvilinear relationship for all tablets. Tablets containing 40 % CAB35-39 (formulation F7D) was considered the best formulation in terms of T50%, compressibility and compactability.

Preparation and in vitro evaluation of propylthiouracil microspheres made of Eudragit RL 100 and cellulose acetate butyrate polymers using the emulsion-solvent evaporation method.

The objectives of this investigation are to evaluate the encapsulation efficiency of the anti-thyroid agent 6-n-propyl-2-thiouracil using two polymers of different characteristics (cellulose acetate butyrate polymer, (CAB-551-0.01) and ammonio methacrylate copolymer (Eudragit RL 100) and to study the effect of this encapsulation on the drug release properties. Polymers were used separately and in combination to prepare different microspheres. Also, the effect of polymer solution phase viscosity was studied for each of the polymers and for their combinations. An Ostwald viscometer was used to evaluate the relative viscosities of polymer solution phases and their combinations. Microspheres with 25% theoretical drug loading of 6-n-propyl-2-thiouracil core material were prepared by the emulsion solvent evaporation method. Microspheres prepared from CAB-551-0.01, which has higher relative polymer phase viscosity than Eudragit RL 100, showed significantly lower drug release rates and a noticeable lag time. Polymer combinations of CAB-551-0.01 and Eudragit RL 100 (1:1) showed an interesting synergistic increase in relative polymer solution viscosities at all concentrations. Unlike microspheres prepared from the two polymers separately which follow Higuchi spherical matrix release kinetics, microspheres prepared using a combination (1:1) of the two polymers showed near zero order with faster rates compared to those prepared using CAB-551-0.01 equivalent polymer concentrations. The results of this study suggest that 6-n-propyl-2-thiouracil was successfully and efficiently encapsulated and release rates of matrix microspheres are related to polymer solution phase viscosity, but when polymer combinations were used other factors such as structural effects must be considered.

Evaluation of enteric matrix microspheres prepared by emulsion-solvent evaporation using scanning electron microscopy.

Theophylline microspheres were prepared by the emulsion-solvent evaporation method using cellulose acetate butyrate (CAB381-20) and mixtures of CAB381-20(R) and cellulose acetate phthalate. The physical state of the drug, polymers and microspheres surfaces were determined using scanning electron microscopy. For those microspheres prepared using mixtures of CAB381-20 and cellulose acetate phthalate, scanning electron micrographs were taken before dissolution and also at different stages of dissolution (in SGF, pH 1.2 and in simulated intestinal fluid, pH 7.5). Micrographs were taken of the outside surfaces of the microspheres and of the cleaved microspheres showing their interiors (core). Drug crystals were observed on or near the surface of microspheres prepared from the polymer mixtures, while no drug particles or crystals were seen on the surfaces of microspheres prepared solely from CAB381-20. An acid wash for less than 2 min was capable of extracting all drug on the surface of the microspheres prepared from a mixture of CAB381-20 and cellulose acetate phthalate. The absence of drug crystals on the surface of CAB381-20 microspheres is believed to prevent initial drug release and create a lag time in release profiles. Results suggest that in both microsphere formulations, a layer of drug-free polymer is formed outside the core matrix and is believed to be responsible for the near zero-order release profiles.

Viscosity of polymer solution phase and other factors controlling the dissolution of theophylline microspheres prepared by the emulsion solvent evaporation method.

The objectives of this investigation are to evaluate the effect of the viscosity of polymer solution phase on microsphere properties, especially the drug release characteristics since no studies on this formulation variable have been reported. Also, since it is known that polymer molecular weight affects both the viscosity of the polymer solution and the release properties of microspheres, the interaction of these factors was studied. Microspheres with 33% theoretical drug loading of anhydrous theophylline core material were prepared by the emulsion solvent evaporation method. Two cellulose acetate butyrate polymers, (CAB381-2, CAB381-20), chemically similar but having different molecular weights, were used to prepare different polymer solutions having different apparent viscosities in acetone. A Brookfield viscometer was used to evaluate the viscosities of polymer solutions. Dissolution rates of microspheres prepared from the polymer solutions were inversely related to the initial polymer solution viscosities for both CAB381-2 and CAB381-20. The times for the release of 30 and 50% of the drug from the microspheres have a linear relationship with initial polymer solution viscosity. Initial release was significantly decreased with increasing polymer solution viscosity. Unlike CAB381-2 microspheres which follow Higuchi spherical matrix release kinetics, microspheres prepared from the higher molecular weight polymer (CAB381-20) showed extended release dissolution profiles with near zero order kinetics. It is evident that both the polymer solution viscosity and the molecular weight have an effect on the drug release from microspheres. These results suggest that release rates of matrix microspheres could be predictably optimized by adjusting the viscosity of polymer solutions.

Adsorption of allopurinol and ketotifen by chitosan.

The experimental work of studying the adsorption of ketotifen and allopurinol by chitosan focused on determining the solubilities and the adsorption isotherms of the adsorbates employed in this study. The adsorption of the aforementioned compounds by chitosan was studied using the rotating bottle method. The concentrations, both before and after the attainment of equilibrium, were determined with the aid of a reversed-phase high-performance liquid chromatography column. The results of these studies demonstrated that ketotifen and allopurinol are both adsorbed by chitosan. The nonlinear Langmuir-like and the Freundlich models both were applied to the experimental data. The correlation coefficients obtained from the nonlinear Langmuir-like model were better than those obtained from Freundlich model, suggesting that allopurinol and ketotifen interacted with certain specific binding sites on the chitosan surface. The allopurinol adsorption experiments indicated that the particle size of chitosan and therefore the surface area can significantly affect the Langmuir capacity constant, while the affinity constants are statistically the same. As expected from the solubility studies, the ketotifen adsorption experiments at 2 different pHs (7 and 10) showed that the adsorption affinity at pH 10 was much higher than at pH 7. What was not expected was that the capacity constants were significantly different, suggesting that further studies are needed using common ion buffers and multicomponent adsorption for the proper mechanism to be determined.

Importance of cryptolytic lesions and pericryptal granulomas in inflammatory bowel disease.

AIMS: To explore the diagnostic importance of pericryptal granulomas associated with epithelial lysis in colorectal biopsy specimens (cryptolytic colitis). METHODS: A series of patients with suspected inflammatory bowel disease and colorectal biopsy specimens showing either isolated pericryptal granulomas (14 cases) or non-granulomatous pericryptal inflammation (eight cases) were followed. A diagnosis of Crohn's disease was established if subsequent biopsy specimens or intestinal resections showed unequivocal non-crypt related granulomas, or if there was evidence of significant small bowel disease. RESULTS: Of the 14 patients with pericryptal granulomas and biopsy specimens, 10 were subsequently found to have Crohn's disease; of the eight patients with pericryptal inflammation only, one developed Crohn's disease. The former group also had a much higher instance of morbidity and required surgical intervention more often. CONCLUSIONS: The presence of cryptolytic granulomas in a colorectal biopsy specimen otherwise showing only non-specific inflammatory changes should always raise suspicion of Crohn's disease, especially if surgery or ileo-anal pouch formation is contemplated.

Gut mucosal protein synthesis measured using intravenous and intragastric delivery of stable tracer amino acids.

We measured the rates of mucosal protein synthesis during the simultaneous delivery of [1-13C]leucine and [1-13C]valine delivered either intragastrically or intravenously to investigate any influence of the route of supply of the tracers. Dependent on the route, there were marked differences in the gradient of labeling between the plasma and intramucosal leucine and valine; i.e., for intravenous tracers the ratio was 1.73 +/- 0.16, but for intragastric tracers it was 0.65 +/- 0.12 (P < 0.05). Incorporation of intravenous tracer into mucosal protein was linear with time, and irrespective of tracer route, the calculated fractional rates of protein synthesis were identical when based on the intracellular labeling of the leucine or valine tracer, i.e., with intravenous 2.58 +/- 0.32%/h and with intragastric 2.45 +/- 0.36%/h. The results demonstrate that a robust and reproducible method of measurement of gastrointestinal mucosal protein synthesis has been developed and that use of either intragastric or intravenous routes of tracer administration gives comparable results. The high rates measured suggest that the gastrointestinal mucosa contributes substantially to whole body protein synthesis in normal healthy subjects.