Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus.

This study compares the actions of oestradiol, tamoxifen, toremifene and raloxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxylase by the compounds showed a rapid biphasic response, while for creatine kinase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest induction level, followed by tamoxifen or toremifene and then raloxifene. RT-PCR demonstrated that all compounds decreased oestrogen receptor (ER) alpha, ERbeta and ERbeta2 gene expression, 8-24 h after the first dose, suggesting that down-regulation of ER is not the primary cause of the difference in efficacy between these compounds. Using cDNA arrays, expression of 512 genes was examined in the uteri of oestradiol- or tamoxifen-treated rats. Both compounds resulted in the up-regulation of heat-shock protein 27, telomerase-associated protein 1 and secretin. However, most surprising was the marked down-regulation of Wilms' tumour and retinoblastoma genes. We speculate that this may result in a loss of regulation of the transition from the G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.

Effect of surfactants on release of a highly water-soluble medicinal compound from an inert, heterogeneous matrix.

The release from a matrix compressed from a physical mixture of procaine hydrochloride, chlorinated poly(propylene), lactose, and a surfactant was investigated. With nonionic and cationic surfactants incorporated in the matrix, the release of procaine hydrochloride was linearly related to the square root of time, and as the concentration of the surfactants increased, the release was faster. When an anionic surfactant (sodium lauryl sulfate) was incorporated in the matrix, the release of procaine hydrochloride was linearly related to the square root of time; however, the release pattern depended on the concentration of the anionic surfactant. As the concentration of sodium lauryl sulfate increased to 4%, the release progressively slowed to a minimum because of the formation of a poorly soluble complex between the cationic procaine and the anionic surfactant. As the concentration of anionic surfactant increased further, the release increased as the complex was micellarly solubilized.

Solid-state reaction between sulfadiazine and acetylsalicylic acid.

Kinetic data for the solid-state reaction of sulfadiazine and acetylsalicylic acid are presented. A compaction method was used to observe the influence of applied pressure, particle size, and temperature on the reaction rate.

Release of highly water-soluble medicinal compounds from inert, heterogeneous matrixes. II: Melt.

The release from matrixes compressed from melts of hydrogenated castor oil and ephedrine hydrochloride or procaine hydrochloride has been studied and is compared with the release from matrixes prepared by compression of physical mixtures. In both, the release is dependent on the square root of time; however, the release is slower from the matrix prepared by the melt process. Parameters that affect the release are compared. The independence of release from stirring speed and the greater tortuosity of the matrix prepared by the melt process indicate that the release is by a matrix diffusion mechanism. In contrast, boundary layer diffusion is operative in the release from the matrixes prepared by compression of physical mixtures. It is demonstrated that for a given formulation, the method of processing may alter the mechanism and rate of release.

Release of highly water-soluble medicinal compounds from inert, heterogeneous matrixes. I: Physical mixture.

The release from a matrix compressed from a physical mixture of hydrogenated castor oil and ephedrine hydrochloride or procaine hydrochloride has been investigated. The effects on release of the concentration of medicinal compound, particle size of medicinal compound, agitation of dissolution medium, and porosity and tortuosity of the matrix are presented. An attempt is made to fit the experimental data to an acceptable diffusion model.

Chemical reaction, diffusion, and ionization model for dissolution of oxygen acids and carbon acids.

A chemical reaction, diffusion, and ionization model, which assumes the establishment of ionization equilibrium at an equilibrium plane located within the diffusion layer, is tested by use of experimental dissolution rates for some oxygen acids and carbon acids. For oxygen acids both two- and three-zone models predict observed dissolution rates; however, for barbituric acid dihydrate and phenylbutazone neither model successfully depicts the dissolution behavior. Although the three-zone model approximately predicts dissolution rates of oxygen acids, its complexity does not add to the accuracy of the calculated rate. The three-zone model does support the frequent assumption that ionization is instantaneous and can be ignored in modeling.

Solid-solid reaction between sulfacetamide and phthalic anhydride.

Thermal and kinetic data for the solid-state addition reaction of sulfacetamide and phthalic anhydride are presented. A compaction method was used so that the influence of some pharmaceutical parameters (compressional pressure, particle size, concentration, and temperature) on the reaction kinetics could be observed.

Dissolution kinetics of a three-component solid II: benzoic acid, salicylic acid, and salicylamide.

The dissolution rates of each component in compressed spheres consisting of three components were measured under sink conditions. The observed dissolution rates of benzoic acid, salicylic acid, and salicylamide compare favorably to the predicted dissolution rates according to a previously presented kinetic model.

Dissolution kinetics of a three-component solid I: ethylparaben, phenacetin, and salicylamide.

The dissolution rates of each component in compressed spheres consisting of three components were measured under sink conditions. A film diffusion model is discussed and presented diagrammatically to illustrate the 13 possible dissolution behaviors of a three-component solid. Experimental dissolution rates compare favorably to dissolution rates calculated according to the model at mass fractions representative of the 13 dissolution behaviors.

Comparison of granule strength and tablet tensile strength.

The granule strength (crushing load) of lactose granulated with 1-9% povidone was measured initially and at intervals during a 1-year period. The granule strengths of dibasic calcium phosphate dihydrate granulated with various concentrations of starch and povidone were measured. The axial and radial tensile strengths of tablets compressed from these granules were determined and related to concentration of binder and granule strength. The effect of compressional force on the integrity of granules in a tablet matrix is shown in scanning electron photomicrographs of the fractured tablets which had undergone a diametral compression test. It appears that the compressional force and the concentration of binder contribute more than granule strength to tablet tensile strength.

Relationship of dissolution rate to viscosity of polymeric solutions.

The influence of viscosity on the dissolution rate of benzoic acid in aqueous solutions of methylcellulose, hydroxypropyl cellulose, and guar gum was investigated. The viscosities were measured by capillary and rotational viscometers and were calculated from experimental diffusion coefficients by means of the Stokes-Einstein equation. The relationship of the dissolution rate to viscosity may be represented by a single curve. An equation is presented relating the dissolution rate of benzoic acid to solubility, diffusion coefficient, and viscosity for these nonionic viscosity-enhancing agents. To demonstrate that additional factors affect the dissolution rate, similar data were determined using solutions of xanthan gum, which is anionic. The electrical effect modified mass transport so the quantitative relationship of dissolution rate and viscosity was not the same as in the nonionic carbohydrate solution.

Tensile strengths and hardness of tablets.

The axial and radial tensile strengths were compared to the hardness of compressed tablets containing various concentrations of lubricants. Since radial tensile strength measurement considers the thickness of a tablet, and only tensile stress and axial tensile strength express the strength in the direction in which capping may occur, the tensile strengths characterize the strength of a tablet more completely than hardness.

General model for dissolution rates of n-component, nondisintegrating spheres.

The dissolution rates of compressed spheres consisting of two and three components were measured. A general model for dissolution rates of n-component, nondisintegrating spheres is discussed. Experimental cases are presented to support the model for two- and three-component spheres, two-component interacting spheres, and three-component spheres containing two components that complex.

Densification of powders by concavo-convex roller compactor.

By means of a concavo-convex roller compactor, several pharmaceutical powders were compressed into sheets or flakes, which then were reduced in size by an oscillating granulator to form compacted granules. Several properties (bulk density, drop density, repose angle, and flow rate) of the powders and compacted granules were determined and compared. The primary effect of the roller compactor was to increase the bulk density without a significant change in flowability. Two materials compacted at five pressures demonstrated that the bulk and drop density are linearly related to the logarithm of compaction pressure.

Thermal hardness coefficient of tablets.

The hardness of 10 commercial compressed tablets was measured at -25, 0, 24, and 50 degrees. The hardness is relatively insensitive to temperature change within normal storage and handling temperatures. Consequently, no temperature control is needed in measuring tablet hardness. Nonconventional (sustained-release) tablets behave differently.

Influence of viscosity on absorption from nitrofurantoin suspensions.

Nitrofurantoin, 200 mg, was administered orally to 11 subjects in an aqueous reference dispersion and in five suspensions having the same rheogram. Algin, carbomer, guar gum, methylcellulose, and colloidal magnesium aluminum silicate were the five suspending agents employed. Complexation was demonstrated by dialysis between nitrofurantoin and methylcellulose and between nitrofurantoin and carbomer; however, physiological availability was not altered by the interaction. The viscosity increase slowed absorption and urinary excretion, thus delaying the time of the maximum excretion rate without a decrease in bioavailability. A clinically acceptable urinary nitrofurantoin concentration was maintained for at least 2 hr longer by a viscosity increase.

Measurement of film-coating adhesiveness.

A modified balance was used to measure the adhesive force between the film coating and the tablet surface of 10 commercial film-coated tablets. The adhesiveness or force required to remove the film coating from a unit area of tablet surface ranged from 1.06 to 4.67 x 10(4) Nm-2. Measurement of at least eight film coatings from the sides of four tablets was calculated to be required to obtain a result with 95% confidence. The method also was useful in studying the influence of solvents and humidity on bonding of the film coating to the tablet.

Oral and rectal absorption of chloral hydrate and its betaine complex.

Chloral hydrate and its betaine complex was administered orally and rectally to nine healthy male subjects. The urinary excretion, which was a reflection of absorption, of a metabolite, trichloroacetic acid, was determined. No statistically significant difference was found between the oral absorption of chloral hydrate and its betaine complex and between the rectal absorption of chloral hydrate and its betaine complex. A statistical difference was found between the oral and rectal absorption of chloral hydrate and between the oral and rectal absorption of chloral betaine.