Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, II. Combination Resin Formulations

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

Ontrolled-Release Theophylline Tablet Formulations Containing Acrylic Resins. I. Dissolution Properties of Tablets

The dissolution properties of controlled-release theophylline tablets containing acrylic resins are presented. Four different resins (Eudragit RSPM, RLPM, Sl00 and Ll00) were incorporated into theophylline tablets by direct compression techniques and the properties of the resulting dosage form were evaluated in dilute acid, buffer media pH 4.0 and simulated intestinal media pH 7.5. Tablets (500 mg) containing 300 mg of theophylline were prepared with each of the four resins and compressed to a hardness level of 6.5 to 7.5 kg. Excellent flow properties, weight uniformity and drug content uniformity were observed with all tablet formulations. Preliminary data suggest that three of the four resins tested showed great promise as a retardant in a matrix controlled drug delivery system. The dissolution properties of three commercially available sustained-release theophylline tablets were also determined. A comparison of profiles from Theodur^R (300 mg) in acid and simulated intestinal media showed a similarity in release properties to those of theophylline in tablets containing the RLPM resin.     

Ontrolled-Release Theophylline Tablet Formulations Containing Acrylic Resins. I. Dissolution Properties of Tablets

Abstract

The dissolution properties of controlled-release theophylline tablets containing acrylic resins are presented. Four different resins (Eudragit RSPM, RLPM, Sl00 and Ll00) were incorporated into theophylline tablets by direct compression techniques and the properties of the resulting dosage form were evaluated in dilute acid, buffer media pH 4.0 and simulated intestinal media pH 7.5. Tablets (500 mg) containing 300 mg of theophylline were prepared with each of the four resins and compressed to a hardness level of 6.5 to 7.5 kg. Excellent flow properties, weight uniformity and drug content uniformity were observed with all tablet formulations. Preliminary data suggest that three of the four resins tested showed great promise as a retardant in a matrix controlled drug delivery system. The dissolution properties of three commercially available sustained-release theophylline tablets were also determined. A comparison of profiles from Theodur^R (300 mg) in acid and simulated intestinal media showed a similarity in release properties to those of theophylline in tablets containing the RLPM resin.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,III. Influence of Filler Excipient.

Abstract

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, III. Influence of Filler Excipient.

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Effect of Eudragit Resins and Dibasic Calcium Phosphate on the Compation and Dissolution Behavior of Directly Compressible Controlled-Relase Theophylline Tablet

The compaction behavior and release property of tablets made by the combined formulations of Eudragit RLPM and RSPM with or without diabasic calcium phosphate anhydrous (DCPA) using direct compaction were examined. The larger the amount of Eudragit RSPM or DCPA the higher the value of the tensile strenght. A linear realationship was found in the lorgrithm of tensile strength plotted against the porosity of the compacts. The Heckel plot was also used ot evalute the compaction behaviour of tablets. The results indicate that Eudargit RSPM and DCPA are responsible for the good compressiblity of compacts. The contact angle of tablets without DCPA became samller with an increase in the Eudragit RSPM, but exhibited a higher contact angle than tablests with DCPA. The controlled release behavior of theophylline from tablets without DCPA was found and showed a pH-independent property, whereas tablets with DCPA were pH-dependent and exhibited a faster dissolution than tablests without DCPA. The result suggests that controlled-relase and better compressible tablets can be prepared by adjusting the combinatin ratios of Eudragit RLPM and RSPM with or without DCPA by direct compression.     

Effect of Eudragit Resins and Dibasic Calcium Phosphate on the Compation and Dissolution Behavior of Directly Compressible Controlled-Relase Theophylline Tablet

Abstract

The compaction behavior and release property of tablets made by the combined formulations of Eudragit RLPM and RSPM with or without diabasic calcium phosphate anhydrous (DCPA) using direct compaction were examined. The larger the amount of Eudragit RSPM or DCPA the higher the value of the tensile strenght. A linear realationship was found in the lorgrithm of tensile strength plotted against the porosity of the compacts. The Heckel plot was also used ot evalute the compaction behaviour of tablets. The results indicate that Eudargit RSPM and DCPA are responsible for the good compressiblity of compacts. The contact angle of tablets without DCPA became samller with an increase in the Eudragit RSPM, but exhibited a higher contact angle than tablests with DCPA. The controlled release behavior of theophylline from tablets without DCPA was found and showed a pH-independent property, whereas tablets with DCPA were pH-dependent and exhibited a faster dissolution than tablests without DCPA. The result suggests that controlled-relase and better compressible tablets can be prepared by adjusting the combinatin ratios of Eudragit RLPM and RSPM with or without DCPA by direct compression.     

Sustained Release Tablet Formulation for a New Iron Chelator

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Sustained Release Tablet Formulation for a New Iron Chelator

Abstract

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Controlled Release Theophylline Tablet with Acrylic Polymers Prepared by Spray-Drying Technique in Aqueous System

Sustained release and enteric theophylline tablets were prepared by directly compressing spray-dried microsphers with Eudragits L30D, L100-55 and E30D. The spray-drying process was free from using organic solvent. Drug dissolution of the enteric tablet in an acidic solution (pH 1.2) was highly dependent on the polymer content of the microsphere. Completely enteric function was observed with drug-to-polymer ratio of 1:3 using Eudragit L30D or L100-55. Tablet with Eudragit E30D formulated at the 2-40% level showed good sustained drug release which was throughly independent of the pH of dissolution media. The dissolution pattern was similar to that of Theo-dur and gave a straight line in Higuchi plot. In each tablet, the controlled drug release was attributed to continuous and well-dispersed polymer matrix formed by spray-drying and subsequent compressing process     

Controlled Release Theophylline Tablet with Acrylic Polymers Prepared by Spray-Drying Technique in Aqueous System

Abstract

Sustained release and enteric theophylline tablets were prepared by directly compressing spray-dried microsphers with Eudragits L30D, L100-55 and E30D. The spray-drying process was free from using organic solvent. Drug dissolution of the enteric tablet in an acidic solution (pH 1.2) was highly dependent on the polymer content of the microsphere. Completely enteric function was observed with drug-to-polymer ratio of 1:3 using Eudragit L30D or L100-55. Tablet with Eudragit E30D formulated at the 2–40% level showed good sustained drug release which was throughly independent of the pH of dissolution media. The dissolution pattern was similar to that of Theo-dur and gave a straight line in Higuchi plot. In each tablet, the controlled drug release was attributed to continuous and well-dispersed polymer matrix formed by spray-drying and subsequent compressing process     

Xanthan Gum and Alginate Based Controlled Release Theophylline Formulations

Abstract

The oral absorption of theophylline from two sustained release formulations, formulated using xanthan gum or sodium alginate, has been investigated in the beagle dog. A commercial product was used for comparison. Dissolution tests and an in vivo dog study both indicated that the xanthan gum tablet released drug at a constant rate and performed as a pH independent zero-order controlled release formulation. With the alginate tablet, faster dissolution rates were observed when acid medium was present. The pH dependent release behavior of the alginate formulation is explained. Drug release mechanisms which are influenced by the gel behaviors in these two polymers are discussed. The relative oral bioavailabilities of these two formulations in dog were 74–84% compared to immediately releasing capsules, and three-fold that of the commercial product with an equivalent dose.     

Different Types of Direct Compressible Excipients Affecting the Release Behavior of Theophylline Controlled-release Tablets Containing Eudragit Resins

Abstract

Theophylline released from direct-compressed tablets containing Eudragit RSPM/RLPM and different types of direct compressible excipients was investigated. The influences of the type of dissolution medium and stirring speed on the release behavior of theophylline were also studied. The results showed that the type of direct compressible excipients, dissolution medium and stirring conditions significantly influenced the dissolution rate. The tablet made by dicalcium phosphate or microcrystalline cellulose exhibited the most controlled-release behavior. Almost all the release kinetics of tablets followed a Fickian-transport model.     

Different Types of Direct Compressible Excipients Affecting the Release Behavior of Theophylline Controlled-release Tablets Containing Eudragit Resins

Theophylline released from direct-compressed tablets containing Eudragit RSPM/RLPM and different types of direct compressible excipients was investigated. The influences of the type of dissolution medium and stirring speed on the release behavior of theophylline were also studied. The results showed that the type of direct compressible excipients, dissolution medium and stirring conditions significantly influenced the dissolution rate. The tablet made by dicalcium phosphate or microcrystalline cellulose exhibited the most controlled-release behavior. Almost all the release kinetics of tablets followed a Fickian-transport model.     

Xanthan Gum and Alginate Based Controlled Release Theophylline Formulations

The oral absorption of theophylline from two sustained release formulations, formulated using xanthan gum or sodium alginate, has been investigated in the beagle dog. A commercial product was used for comparison. Dissolution tests and an in vivo dog study both indicated that the xanthan gum tablet released drug at a constant rate and performed as a pH independent zero-order controlled release formulation. With the alginate tablet, faster dissolution rates were observed when acid medium was present. The pH dependent release behavior of the alginate formulation is explained. Drug release mechanisms which are influenced by the gel behaviors in these two polymers are discussed. The relative oral bioavailabilities of these two formulations in dog were 74-84% compared to immediately releasing capsules, and three-fold that of the commercial product with an equivalent dose.     

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

A prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.     

Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary Evaluation

Abstract

A prototype formulation of a gastric intestinal retention system was successfully developed. A matrix tablet containing sucralfate, Methocel E4M and the appropriate type of drug powder, granules or pellets was prepared using the Carver Press. Three different formulations were evaluated using three different drug entities, namely; theophylline sustained release pellets, aspirin granules and antacid powder. Tablets of these three different formulations showed remarkable adhesive characteristics onto the glass vessel in acidic medium up to at least eight hours. In addition, all three different formulations exhibited sustained release in-vitro dissolution profiles. These data imply that this gastric intestinal retention system can be used to prepare sustained release formulations.     

Compaction Properties of Acrylic Resin Polymers with Plastic and Brittle Drugs

Abstract

Tensile strengths of compacts consisting of acrylic resin polymers in combination with a plastic drug (theophylline) and a brittle drug (sodium sulfathiazole) were investigated. The polymers studied included Eudragit RS PM, RL PM, S 100, L 100, and L 100-55. All compacts were compressed to a solid fraction of 0.81. The solid fraction, rather than compression force, was kept constant in order to account for the differences in packing characteristics and elastic and plastic deformational properties of different materials (1). Tensile strength profiles for the blends of the Eudragit S 100 and RL PM polymers with sodium sulfathiazole included approximately linear relationships between pure drug and pure polymer. The Eudragit L 100-55 exhibited a large peak in the tensile strength of compacts containing 20% sodium sulfathiazole. Significant differences between the physical-mechanical properties of the methacrylate ester and methacrylic acid copolymers were observed where the latter proved to be much stronger at all concentrations. The differences between the two categories of polymers were greater in compacts containing the plastic drug, theophylline. Peaks in tensile strengths were seen for both drugs with all three of the methacrylic acid copolymers, while the methacrylate ester copolymers maintained approximately linear relationships for all ratios of drug and polymer.     

Interpolymer complexation between copovidone and carbopol and its effect on drug release from matrix tablets

The interaction between copovidone and Carbopol 907 is pH dependent. When the pH of an aqueous solution fell below pH 4.5, a water-insoluble complex began to form and precipitate. This complex resulted from a hydrogen-bond-induced interaction between the carboxylic groups in Carbopol 907 and the carbonyl groups of N-vinylpyrrolidone repeat units in copovidone. Consisting of these two polymers at an approximate 1:1 weight ratio, the complex was an amorphous material with a glass transition temperature of 157?°C. The interpolymer complexation in situ was applied to modify drug release properties of Carbopol 907-based theophylline matrix tablets. The effect of copovidone on drug release was dependent on the pH of the dissolution medium. In a 0.1 N hydrochloride acid solution at pH 1.2 and 50?mM acetate buffer at pH 4.0, an insoluble tablet matrix was formed as a result of the in situ interpolymer complexation, and theophylline was released therefore via Fickian diffusion. In a 50?mM phosphate buffer at pH 6.8, drug release from the matrix tablets was still impacted by the in situ interpolymer complexation because of the low-pH microenvironment induced by Carbopol 907. As a result, drug release rate of the matrix tablet containing both polymers at pH 6.8 was slower than that of the matrix tablets containing individual polymers. We observed similar drug release rates at both pH 1.2 and pH 6.8 between tablets containing the physical blend of these two polymers and tablets containing preformed interpolymer complexes.     

Compaction Properties of Acrylic Resin Polymers with Plastic and Brittle Drugs

Tensile strengths of compacts consisting of acrylic resin polymers in combination with a plastic drug (theophylline) and a brittle drug (sodium sulfathiazole) were investigated. The polymers studied included Eudragit RS PM, RL PM, S 100, L 100, and L 100-55. All compacts were compressed to a solid fraction of 0.81. The solid fraction, rather than compression force, was kept constant in order to account for the differences in packing characteristics and elastic and plastic deformational properties of different materials (1). Tensile strength profiles for the blends of the Eudragit S 100 and RL PM polymers with sodium sulfathiazole included approximately linear relationships between pure drug and pure polymer. The Eudragit L 100-55 exhibited a large peak in the tensile strength of compacts containing 20% sodium sulfathiazole. Significant differences between the physical-mechanical properties of the methacrylate ester and methacrylic acid copolymers were observed where the latter proved to be much stronger at all concentrations. The differences between the two categories of polymers were greater in compacts containing the plastic drug, theophylline. Peaks in tensile strengths were seen for both drugs with all three of the methacrylic acid copolymers, while the methacrylate ester copolymers maintained approximately linear relationships for all ratios of drug and polymer.