Evaluation of Ethylcellulose as a Matrix for Prolonged Release Formulations. II. Sparingly Water-Soluble Drugs: Ibuprofen and Indomethacin

Abstract

The main purpose of this investigation was to evaluate ethylcellulose as a carrier for the preparation of prolonged release solid dispersions of sparingly water-soluble drugs, ibuprofen and indomethacin. Solid dispersions containing various concentrations of ethylcellulose of different viscosity grades were prepared by the solvent method. Tablets were directly compressed from solid dispersions (40/100 mesh) with 0.5% Primojel as a disintegrant and 0.5% magnesium stearate as a lubricant. In vitro release studies employed a rotating bottle system with Sorenson's buffer solution (pH 7.4). It was found that prolongation of drug release was primarily associated with an increase in amount of ethylcellulose rather than the viscosity grade. Nonetheless, the higher the viscosity grade of ethylcellulose, the slower the release of drug from granular and compressed solid dispersions. The release rate of ibuprofen was faster than that of indomethacin from different solid dispersion formulations.     

Evaluation of Ethylcellulose as A Matrix for Prolonged Release Formulations. I. Water Soluble Drugs: Acetaminophen and Theophylline

In this study ethylcellulose was evaluated as a carrier for the preparation of prolonged release solid dispersions of relatively water soluble drugs, acetaminophen and theophylline. The solid dispersions containing various concentrations (7.5, 15.0 and 30.0 % by weight of drug) of ethylcellulose of different viscosity grades (21, 95, 209 and 350 cps) were prepared by the solvent method. The concentration of polymer in the formulation was the determining factor in controlling release rate of the drug, as the results indicate prolongation in release of the drug with increase in amount of ethylcellulose. The higher the viscosity grade of ethylcellulose, slower the release of drug from the solid dispersions. The release of drug from the tablets was more prolonged compared to the granular solid dispersions. In vitro release of acetaminophen and theophylline was more or less similar in both dissolution media. The viscosity grade of ethylcellulose showed slight influence on the release rate of drug from the tablet formulations, while it was quite noticeable in granular solid dispersions.     

Evaluation of Ethylcellulose as A Matrix for Prolonged Release Formulations. I. Water Soluble Drugs: Acetaminophen and Theophylline

Abstract

In this study ethylcellulose was evaluated as a carrier for the preparation of prolonged release solid dispersions of relatively water soluble drugs, acetaminophen and theophylline. The solid dispersions containing various concentrations (7.5, 15.0 and 30.0 % by weight of drug) of ethylcellulose of different viscosity grades (21, 95, 209 and 350 cps) were prepared by the solvent method. The concentration of polymer in the formulation was the determining factor in controlling release rate of the drug, as the results indicate prolongation in release of the drug with increase in amount of ethylcellulose. The higher the viscosity grade of ethylcellulose, slower the release of drug from the solid dispersions. The release of drug from the tablets was more prolonged compared to the granular solid dispersions. In vitro release of acetaminophen and theophylline was more or less similar in both dissolution media. The viscosity grade of ethylcellulose showed slight influence on the release rate of drug from the tablet formulations, while it was quite noticeable in granular solid dispersions.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

Spray-Drying as a Method for Microparticulate Controlled Release Systems Preparation: Advantages and Limits. I. Water-Soluble Drugs

Spray-drying was used for the preparation of paracetamol/eudragit RS or RL or ethylcellulose microspheres to verify the possibility of their use in controlled-release solid-dosage forms formulation and try to determine advantages and limits of the technique of such use. Microspheres were first characterized by scanning electron microscopy, differential scanning calorimetry, x-ray diffractometry, and in vitro dissolution studies and then used for the preparation of tablets. During this step, the compressibility of the spray-dried powders was also evaluated. In vitro dissolution studies were performed also on the tablets and their release control was accessed. Although powders were unable to slow down drug release, tablets obtained from microsphere compression showed a good capability of controlling paracetamol release when eudragit RS or ethylcellulose was used, even at low polymer amounts.     

Prolonged Release Matrix Pellets Prepared by Melt Pelletization II. Hydrophobic Substances as Meltable Binders

Abstract

12 meltable substances were studied with respect to their ability to form prolonged release pellets in a melt pelletization process using a laboratory scale high shear mixer. It was found that few substances were able to pelletize a formulation with 12.5% m/m paracetamol and 87.5% m/m calcium hydrogen phosphate. Favourable technical features of glyceryl monostearate were combined with release prolonging features of more hydrophobic substances. Pellets prepared with combinations of glyceryl monostearate and microcrystalline wax demonstrated the slowest release. The release of drug could be varied within wide limits by varying the composition of the binder phase.     

Prolonged Release Matrix Pellets Prepared by Melt Pelletization II. Hydrophobic Substances as Meltable Binders

12 meltable substances were studied with respect to their ability to form prolonged release pellets in a melt pelletization process using a laboratory scale high shear mixer. It was found that few substances were able to pelletize a formulation with 12.5% m/m paracetamol and 87.5% m/m calcium hydrogen phosphate. Favourable technical features of glyceryl monostearate were combined with release prolonging features of more hydrophobic substances. Pellets prepared with combinations of glyceryl monostearate and microcrystalline wax demonstrated the slowest release. The release of drug could be varied within wide limits by varying the composition of the binder phase.     

Directly Compressed Mini Matrix Tablets Containing Ibuprofen: Preparation and Evaluation of Sustained Release

ABSTRACT

Directly compressed mini tablets were produced containing either hydroxypropylmethylcellulose (HPMC) or ethylcellulose (EC) as release controlling agent. The dynamics of water uptake and erosion degree of polymer were investigated. By changing the polymer concentration, the ibuprofen release was modified. In identical quantities, EC produced a greater sustaining release effect than HPMC. Different grades of viscosity of HPMC did not modify ibuprofen release. For EC formulations, the contribution of diffusion was predominant in the ibuprofen release process. For HPMC preparations, the drug release approached zero-order during a period of 8 h. For comparative purposes, tablets with 10 mm diameter were produced.     

Dried Molasses as a Direct Compression Matrix for Oral Controlled Release Drug Delivery II: Release Mechanism and Characteristics of Theophylline from a Molasses-Hpmc Matrix

Abstract

Investigation was conducted to evaluate dried molasses as a direct compression matrix for oral controlled release drug delivery system based on its tendency to form a gel-like layer around an inner dry core tablet when it comes in contact with fluid. Dried molasses matrix was modified by incorporation of hydroxypropylmethylcellulose (HPMC) at four concentration levels (12.5, 15.0, 20.0 and 28.57%) to obtain a gel layer of suitable characteristics, and compressed directly on an instrumented rotary tablet press. Theophylline was used as a model drug. Drug release study was performed using USP dissolution apparatus 2, rotated at 20 rpm, in distilled water, simulated gastric fluid pH 1.2, and simulated intestinal fluid pH 7.5. Theopylline was determined by a High Pressure Liquid Chromatographic method, utilizing beta-hydroxyethyl theophylline (BHET) as an internal standard. Results showed an inverse relationship between the rate of release and the level of HPMC, with release period ranging from 3 to 36 hours. Releases rate was greatest in intestinal fluid, least in distilled water, and intermediate in gastric fluid.     

Dried Molasses as a Direct Compression Matrix for Oral Controlled Release Drug Delivery II: Release Mechanism and Characteristics of Theophylline from a Molasses-Hpmc Matrix

Investigation was conducted to evaluate dried molasses as a direct compression matrix for oral controlled release drug delivery system based on its tendency to form a gel-like layer around an inner dry core tablet when it comes in contact with fluid. Dried molasses matrix was modified by incorporation of hydroxypropylmethylcellulose (HPMC) at four concentration levels (12.5, 15.0, 20.0 and 28.57%) to obtain a gel layer of suitable characteristics, and compressed directly on an instrumented rotary tablet press. Theophylline was used as a model drug. Drug release study was performed using USP dissolution apparatus 2, rotated at 20 rpm, in distilled water, simulated gastric fluid pH 1.2, and simulated intestinal fluid pH 7.5. Theopylline was determined by a High Pressure Liquid Chromatographic method, utilizing beta-hydroxyethyl theophylline (BHET) as an internal standard. Results showed an inverse relationship between the rate of release and the level of HPMC, with release period ranging from 3 to 36 hours. Releases rate was greatest in intestinal fluid, least in distilled water, and intermediate in gastric fluid.     

Communications Evaluation of Egg Albumin as a Filler for Prolonged Release Direct Compressed Tablets

Direct compressed tablets for drugs of different physico-chemical properties were prepared using egg albumin as tablet filler. The prepared tablets at different drug:egg albumin ratios as well as the powder blends used for the preparation of the tablets were evaluated. The drug dissolutions from the egg albumin tablets were slow and different release profiles were obtained depending on the type of the drug. The release kinetics from the albumin matrix were tested for different models and were found to be anomalous resembling release of drugs from swellable type of matrices. In order to elucidate the release mechanism, the interaction of drugs with egg albumin was examined by thermal analysis. In most cases release retardation was increased with the increase of egg albumin matrix density. In case of meclizine-HCl the release was not depending on the egg albumin matrix density and it was believed that the rate determining step for its release is drug solubility and/or dissociation of the drug-egg albumin complex.     

Preparation and Evaluation of Sustained Release Ibuprofen Beads

Sustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.     

Preparation and Evaluation of Controlled Release Indomethacin Microspheres

Microspheres containing indomethacin were prepared with various combinations of polymers Eudragit RS and Eudragit L. The effects of different ratios of polymers, solvent-polymer ratio, polymer-drug ratio and evaporation temperature on the physical characteristics of the microspheres as well as the in vitro release rate of the drug were investigated. All the factors studied had an influence on the physical characteristics of the microspheres. In vitro dissolution results showed that all formulations gave prolonged release of indomethacin and the release followed apparent zero order kinetics until 80% of drug had been released.     

Preparation and Evaluation of Controlled Release Indomethacin Microspheres

Abstract

Microspheres containing indomethacin were prepared with various combinations of polymers Eudragit RS and Eudragit L. The effects of different ratios of polymers, solvent-polymer ratio, polymer-drug ratio and evaporation temperature on the physical characteristics of the microspheres as well as the in vitro release rate of the drug were investigated. All the factors studied had an influence on the physical characteristics of the microspheres. In vitro dissolution results showed that all formulations gave prolonged release of indomethacin and the release followed apparent zero order kinetics until 80% of drug had been released.     

Preparation and Evaluation of Sustained Release Ibuprofen Beads

Sustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Abstract

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

Investigation of Ethylcellulose as a Matrix Former and a New Method to Regard and Evaluate the Compaction Data

Three types of ethylcellulose—having different molecular weights, i.e., different viscosity grades (7, 22, 50 cP)-were used for our polymer compression tests for the production of matrix tablets. The production methods used were direct compression and wet granulation. We tested the compactability, the compressibility, and the energy involved in compaction by the use of F-D curves and the controlled drug release from the ethylcellulose matrix tablets using the above-mentioned methods. A lower viscosity grade in ethylcellulose is more compressible than the higher grade. Wet-granulated ethylcellulose also shows a better compactibility than directly compressed ethylcellulose. Our investigation indicates also that the dissolution rates are indirectly proportional to the hardness of the tablets. Furthermore, wet-granulated tablets produce a more rapid drug release than those which are directly compressed.     

Investigation of Ethylcellulose as a Matrix Former and a New Method to Regard and Evaluate the Compaction Data

Abstract

Three types of ethylcellulose—having different molecular weights, i.e., different viscosity grades (7, 22, 50 cP)-were used for our polymer compression tests for the production of matrix tablets. The production methods used were direct compression and wet granulation. We tested the compactability, the compressibility, and the energy involved in compaction by the use of F-D curves and the controlled drug release from the ethylcellulose matrix tablets using the above-mentioned methods. A lower viscosity grade in ethylcellulose is more compressible than the higher grade. Wet-granulated ethylcellulose also shows a better compactibility than directly compressed ethylcellulose. Our investigation indicates also that the dissolution rates are indirectly proportional to the hardness of the tablets. Furthermore, wet-granulated tablets produce a more rapid drug release than those which are directly compressed.     

Matrix Type Tablet Formulation for Controlled Release of Highly Water Soluble Drugs

Matrix type formulations with dicalcium phosphate dihydrate (DCPD) using a polymeric binder (Eudragit RSPM®) to obtain controlled release of highly water soluble drugs has been investigated.

The drug, DCPD and Eudragit RSPM® were granulated using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP). Addition of Eudragit did not appear to affect the release profile. However, addition of a plasticizer had a significant effect on the rate of release. The release appears to follow first order kinetics and the rate constant decreased linearly with increasing DEP concentration.

A directly compressible mixture was also formulated by coating DCPD particles with DEP with and without Eudragit RSPM®.