Development of controlled-release matrix tablet of risperidone: influence of Methocel®- and Ethocel®-based novel polymeric blend on in vitro drug release and bioavailability.

Controlled-release (CR) matrix tablet of 4 mg risperidone was developed using flow bound dry granulation-slugging method to improve its safety profile and compliance. Model formulations F1, F2, and F3, consisting of distinct blends of Methocel® K100 LV-CR and Ethocel® standard 7FP premium, were slugged. Each batch of granules (250-1,000 µm), obtained by crushing the slugs, was divided into three portions after lubrication and then compressed to 9-, 12-, and 15-kg hard tablets. In vitro drug release studies were carried out in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using a paddle dissolution apparatus run at 50 rpm. The CR test tablet, containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness, exhibited pH-independent zero-order release kinetics for 24 h. The drug release rate was inversely proportional to the content of Ethocel®, while the gel layer formed of Methocel® helped in maintaining the integrity of the matrix. Changes in the hardness of tablet did not affect the release kinetics. The tablets were reproducible and stable for 6 months at 40 ± 2°C/75 ± 5% relative humidity. Risperidone and its active metabolite, 9-hydroxyrisperidone, present in the pooled rabbit's serum, were analyzed with HPLC-UV at λ(max) 280 nm. The CR test tablet exhibited bioequivalence to reference conventional tablet in addition to the significantly (p < 0.05) optimized peak concentration, C(max), and extended peak time, T (max), of the active moiety. There was a good association between drug absorption in vivo and drug release in vitro (R(2) = 0.7293). The successfully developed CR test tablet may be used for better therapeutic outcomes of risperidone.

Lyophilization of unit dose pharmaceutical dosage forms.

A lyophilization process for a pharmaceutical unit dosage form was developed which comprised a container closed with an impermeable membrane pierced with one or more holes through which the material in the container can be lyophilized. The hole or holes in the membrane have to be sufficiently large to allow water vapor to escape but small to ensure that the material is kept within the container. Lyophilization from sealed, perforated, unit-dose package has shown to be feasible. The technique offers a novel convenient means of lyophilizing nonsterile products in their primary pack and increases the potential for the development of lyophilized formulations for nonparenteral applications.

Dietary fibers differ in their effects on large bowel epithelial proliferation and fecal fermentation-dependent events in rats.

The effects of different fiber types and processing on putative protective mechanisms for colorectal cancer were evaluated. Rats were fed diets of similar nutrient balance containing either no added fiber or 10% fiber from various sources. The rate of distal colonic epithelial proliferation, measured by the metaphase arrest method, was dependent on fiber type; ranking of fibers from highest to lowest yielded the following order: methylcellulose > coarse wheat bran > fine wheat bran approximately parboiled and extruded rice brans > no fiber (P = 0.012). Effect on stool output ranked identically. Ranking of effect on fecal pH, from most to least acidic was as follows: coarse wheat bran approximately the rice brans > fine wheat bran > no fiber approximately methylcellulose (P = 0.00001). Coarse wheat bran gave significantly higher fecal butyrate concentrations than did the rice brans, which in turn gave higher levels than fine wheat bran, methylcellulose and the no-fiber diet. Proximal colon epithelial proliferation was unaffected by diet although cecal short-chain fatty acid concentrations and pH were affected. Different fibers have different effects on events in the fecal environment and distal colonic epithelium. Putative protective events (increased output, low fecal pH, high butyrate, low proliferation) are not equally affected and are unlikely in themselves to allow prediction of the protective effect of a fiber.