The preparation and evaluation of sustained release suppositories containing ketoprofen and Eudragit RL 100 by using factorial design.

The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 3(2) x 2(1) factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250-500, 500-710, and 710-1000 microm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t50 and t80 was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.

Sustained release bioadhesive effervescent ketoconazole microcapsules tabletted for vaginal delivery.

Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxymethylcellulose as a coating material. The microcapsules were mixed with effervescent granules and were tabletted. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out with a new basket method (horizontal rotating basket). A good sustained action was obtained with tablets. Micromeritic investigations were carried out on microcapsules in order to standardize the microcapsule product and to optimize the pilot production of the dosage forms prepared with these microcapsules. Bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, relative deviation, particle size distribution, density and porosity values of the microcapsules were determined. In addition, to evaluate whether some kind of glidant will be needed during tabletting of microcapsules, the Hausner ratio o and consolidaton index were also calculated and it may be concluded that microcapsules do not need any glidant.

A new in vitro/in vivo kinetic correlation method for nitrofurantoin matrix tablet formulations.

The kinetic distributions of in vitro percentage release and in vivo percentage urinary excretion rates of nitrofurantoin from matrix tablets were plotted using a kinetic program. In vitro release rates were determined using the USP paddle and half-change methods. Urinary excretion curves of the drug were characterized by means of the statistical moments. The individual linear correlations between each in vitro and in vivo kinetic distribution were established, and regression equations were calculated. The application results of the best correlations obtained were evaluated according to in vivo results. A reversed kinetic procedure was applied for transformation of the correlated kinetic values to the drug percentage release rates. The modified Langenbucher kinetic showed excellent linear correlation (r = .9985). The method that is proposed in this study, the kinetic correlation program, is simple, independent of time, and suggests that it is possible to use kinetic distributions in the in vitro/in vivo correlation. This study also suggests using kinetic correlation to investigate the suitability of the in vitro dissolution methods with the in vivo drug dissolution.

Release characteristics of implantable cylindrical polyethylene matrices.

The geometrical relationship between a hemisphere and a cylinder has been investigated for controlled-release systems. The relationship was tested by comparing dissolution results with results from mathematical calculation based on the principles of diffusion for matrix systems. A procedure has been developed for producing implantable, cylindrical, low-density polyethylene matrices, uncoated or coated with a thin impermeable film and a thick paraffin layer except for a hole on the flat faces of the cylinder. Drug matrices were prepared from a blend of sodium salicylate and polymer compressed in an appropriately designed stainless-steel mould at 150 degrees C. Differential scanning calorimetry revealed that no decomposition product was formed in the matrix. When the surface area and the number of holes is increased, drug release also increases. When density is increased, however, drug release decreases significantly. Zero-order drug release was obtained from high-density covered one-hole and two-hole matrices. The diffusion coefficient was calculated as 0.067 day-1. The study suggested that true zero-order drug release could be obtained by drug diffusion from a hole, rather than from geometric shapes in the matrix systems. In addition, for constant release the diffusion area has to increase by approximately 25 mm2 every day, compared to the area of the previous day, because the diffusion distance increases logarithmically.

In vivo/in vitro correlations of nitrofurantoin matrix tablet formulations.

In our recent study, a new sustained release dosage form of nitrofurantoin (nft) as matrix tablets by 2(2) factorial design has been prepared by using different drug:polymer ratios. The effect of the polyvinylpyrolidone contents of nft matrix tablets on dissolution rate and bioavailability of the drug have been evaluated. The ideal formulation which fitted at USP XXII dissolution norms was tested by in vivo experiments. The satisfactory correlation was also obtained between the in vivo and the in vitro results. This study suggested that the amounts of nft excreted in urine can be calculated by using in vitro dissolution results and sampling time.

3(3) factorial design-based optimization of the formulation of nitrofurantoin microcapsules.

A microcapsule form of nitrofurantoin was prepared by a simple coacervation method with carboxymethylcellulose and aluminium sulfate. 3(3) factorial design was performed for three independent variables, namely, the particle size of the drug, the size of the microcapsules and the pH of the dissolution medium. The dissolution tests with the formulated microcapsules were carried out according to the United States Pharmacopeia XXII rotating basket method at pH 1.2, 5, and 7.5, which represent the pH of gastrointestinal fluids. Release data were examined kinetically and the ideal kinetic models were estimated and t(63.2) values obtained from RRSBW distribution were used in the factorial design experiment. The influence of the independent variables on the dissolution of nitrofurantoin microcapsules could be expressed as the pH of the dissolution medium > particle size of the microcapsule > particle size of nitrofurantoin. The other aim of this study was to evaluate microcapsule formulation in terms of the United States Pharmacopeia criteria with a minimum of experiments. Our findings suggest that dosage forms which comply with the pharmacopoeia criteria for dissolution can be prepared and selected by factorial design.

Sustained-release dosage form of phenylpropanolamine hydrochloride (3). Application of factorial design.

In this study a 2(2) factorial design has been applied to the evaluation of dissolution characteristics of phenylpropranolamine hydrochloride (PPA.HCl) from tableted microcapsules. The kinetic model according to the Rosin-Rimmler-Sperling-Bennet-Weillbull (RRSBW) distribution was applied for the parametric representation of the dissolution curves. The effect of two factors; drug particle size and kind of disintegrating agent, on the dissolution rate of PPA.HCl were studied at two levels. The factorial design method proved to be useful for the examination of tableted microcapsules.

Sustained-release dosage form of phenylpropanolamine hydrochloride. Part I: Microencapsulation and in vitro release kinetics.

Microcapsules of phenylpropanolamine hydrochloride with core:wall ratios of 1:1, 2:1 and 1:2 were prepared by the coacervation-phase separation method, using ethylcellulose as the coating material. Two batches of PPA.HCl powder with different particle sizes (> 58 microns and < 28 microns) were used as the core material. The different sizes of microcapsules were separated using a range of standard sieves (840-247 microns). The effects of drug particle size, the media pH and the core:wall ratio on the dissolution kinetics were studied, and evaluated kinetically.

Sustained-release dosage form of phenylpropanolamine hydrochloride. Part II: Formulation and in vitro release kinetics from tableted microcapsules.

This work was planned to prepare sustained-action preparations of phenylpropanolamine hydrochloride by microencapsulation and by tableted microcapsules. Dissolution from both suspended microcapsules and the tablets was studied using the USP XXII basket method in simulated gastric and intestinal fluid without enzyme. The results were applied to zero-order, first-order, Hixson Crowell, RRSBW, Q/square root of t, (Bt)a and Higuchi kinetic models. Dissolution of PPA.HCl was found to be governed by the core:wall ratio, drug particle size, media pH and type of disintegrating agent. Dissolution kinetics were studied and evaluated.

Sustained-release dosage form of nitrofurantoin. Part 1. Preparation of microcapsules and in vitro release kinetics.

A new sustained-release dosage form of nitrofurantoin as microcapsules was prepared by carboxymethylcellulose-aluminium sulphate simple coacervation technique. In vitro release studies for microcapsules and their formulated hard gelatin capsule and tablet forms were performed. Release rates were studied as functions of core: wall ratios and the particle sizes of the microcapsules. Dissolution tests of microcapsules and their dosage forms were studied in simulated gastric and intestinal media without enzyme using the USP XXI basket method. Release data were examined kinetically and the ideal kinetic models were estimated for drug release. In addition, optical and electron scanning microscopic works were carried out on the microcapsules.

The effect of zinc chloride dentifrices on plaque growth and oral zinc levels.

The antiplaque potential of zinc salts has been previously demonstrated. The purpose of the present investigation was to establish the effect of zinc chloride dentifrices on plaque growth and on the concentration of zinc in saliva and plaque. Zinc levels in saliva and plaque were measured by atomic absorption spectrophotometry. Elevated zinc levels were observed in saliva and in plaque for 1 hour after contact with a zinc chloride dentifrice. Increased concentrations of zinc were also observed in plaque residue. Further analysis of data showed that subjects with high rates of plaque growth benefited more from the zinc dentifrices than did those with low rates of plaque growth.

Sustained-release dosage form of oxolamine citrate: preparation and release kinetics.

One of the principal uses of microencapsulation for pharmaceuticals has been the preparation of sustained-release dosage forms which have been usually presented in the form of a suspension or gel. However, a non-disintegrating tablet would be a better formulation to obtain sustained-release effect. Microencapsulation has been employed to provide protection of the core material against atmospheric effects, to cover the unpleasant taste and to enhance the stability. A number of drugs have also been encapsulated to reduce gastric and other GI tract irritations, to alter release properties and to change availability. Oxolamine citrate is one of the synthetic derivatives of 3,5-disubstituted 1,2,4-oxodiazole, used particularly for its antitussive activity. The usual dose of the drug is 200 mg given four times a day. Its use was limited by side-effects of nausea and vomiting. In order to prevent the disadvantages caused by taking the drug four times daily, and to reduce the side-effects, a sustained-release dosage form of oxolamine citrate was prepared by the microencapsulation technique and microcapsules thus formed were pressed into tablets. Dissolution tests were done with microcapsules and tablets formed by microcapsules by using the USPXXI paddle method and dissolution kinetics were studied and evaluated.