Optimization and development of a core-in-cup tablet for modulated release of theophylline in simulated gastrointestinal fluids

A triple-layer core-in-cup tablet that can release theophylline in simulated gastrointestinal (GI) fluids at three distinct rates has been developed. The first layer is an immediate-release layer; the second layer is a sustained-release layer; and the last layer is a boost layer, which was designed to coincide with a higher nocturnal dose of theophylline. The study consisted of two stages. The first stage optimized the sustained-release layer of the tablet to release theophylline over a period of 12 hr. Results from this stage indicated that 30% w/w acacia gum was the best polymer and concentration to use when compressed to a hardness of 50 N/m². The second stage of the study involved the investigation of the final triple-layer core-in-cup tablet to release theophylline at three different rates in simulated GI fluids. The triple-layer modulated core-in-cup tablet successfully released drug in simulated fluids at an initial rate of 40 mg/min, followed by a rate of 0.4085 mg/min, in simulated gastric fluid TS, 0.1860 mg/min in simulated intestinal fluid TS, and finally by a boosted rate of 0.6952 mg/min.     

Simultaneous In Vitro Release of Levodopa and Carbidopa from Biocompatible Core-in-Cup Implants

Most implantable drug delivery systems do not release drug at a zero-order rate of release due to their geometry of a decreasing releasing surface. Microcapsules which can release drug at a zero-order rate are very difficult to produce and are prone to dose dumping. The purpose of this study was to test the in vitro release of levodopa and carbidopa from a new core-in-cup bioerodible implantable tablet. Core-in-cup implantable tablets with cups of Resomer® 207, and cores of Resomer RG 746 and Resomer RG 858 were tested. The core-in-cup implantable tablets were tested as to whether they released levodopa or carbidopa at a zeroorder rate. Their rate and extent of erosion in normal saline were also examined. The results indicate that levodopa and carbidopa were released at a zero-order rate in vitro for up to 100 days depending on the inherent viscosity of the polymer used in the core of the implant. It was also found that the rate and extent of erosion of the cup portion of the core-in-cup implantable tablet did not adversely affect the zero-order release of the drugs.     

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6000 (PEG 6000), and hydroxyethyl-cellulose (HEC) as possible alternatives to the use of HPMC to control the release of caffeine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most effective for the release of caffeine from the core-in-cup compressed tablets, and that PEG 6000 was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.     

The Effect of Processing Variables on the Release of Ibuprofen and Caffeine from Controlled-Release Nonswellable Core-in-Cup Compressed Tablets

Abstract

An aqueous soluble polymer such as hydroxypropyl methylcellulose (HPMC), which is widely used in oral sustained-release drug delivery systems, swells when it comes into contact with an aqueous environment. In core-in-cup systems the swelling of the HPMC splits open the cup portion of the tablet. This study investigated the use of acacia, tragacanth, polyethylene glycol 6000 (PEG 6000), and hydroxyethyl-cellulose (HEC) as possible alternatives to the use of HPMC to control the release of caffeine (soluble) and ibuprofen (insoluble) from core-in-cup compressed tablets. It also investigated the possibility of producing a core-in-cup system that had the ability to release caffeine and ibuprofen for a maximum time of constant release of 8-12 hr. A preliminary study revealed that acacia was most effective for the release of caffeine from the core-in-cup compressed tablets, and that PEG 6000 was most effective for the release of ibuprofen from the core-in-cup compressed tablets. On further investigation it was found that by means of adjusting the hardness of compression and the concentration of polymers used, it was possible to formulate a core-in-cup system that could release drug at a constant rate from the core-in-cup compressed tablets for 8 to 12 hr.     

In Vitro Release of Disopyramide from Cellulose Acetate Butyrate Microspheres

Disopyramide was microencapsulated with cellulose acetate butyrate (CAB) using an emulsion-solvent evaporation process. Drug dissolution from microcapsules was studied in both simulated gastric (SGF) and intestinal fluids (SIF) under sink conditions using the USP paddle method. There was no significant difference between drug release into SIF and SGF. As the CAB to drug ratio decreased from 3:1 to 2:1 at constant polymer mass, the drug release rate increased and the T50Y0 decreased from 2.3 hr to 0.3 hr for 303 pm particles. Dissolution T50% increased from 0.4 hr to 2 hr when the mean microcapsule size was increased from 153 to 428 μm (26% drug loading). The addition of acetone to the external phase during preparation shifted the size distribution toward larger particles, but resulted in a higher drug dissolution rate for a given particle size range. A shift to smaller particles was obtained upon increasing the concentration of surfactant. The dissolution profiles were described by the Higuchi and Baker-Lonsdale equations for drug release from spherical matrices up to 90% of the drug release.     

Sustained release characteristics of tablets prepared with mixed matrix of sodium carrageenan and chitosan: effect of polymer weight ratio, dissolution medium, and drug type

The interpolymeric complexation of carrageenan and chitosan was investigated for its effect on drug release from polymeric matrices in comparison to single polymers. For this purpose, matrices with carrageenan: chitosan (CG:CS) ratios of 100%, 75%, 50%, 25%, and 0% were prepared at 1:1 drug to polymer ratio. The effect of dissolution medium and drug type on drug release from the formulations was addressed. Two model drugs were utilized: diltiazem HCl (DZ) as a salt of a basic drug and diclofenac Na (DS) as a salt of an acidic drug. Three dissolution media were used: water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). Some combinations of the two polymers showed remarkable sustained release effect on DZ in comparison to the single polymers in water and SGF. However, no apparent effect for the combination on DZ release was shown in SIF. The medium effect was explained by the necessity of chitosan ionization, which could be attained by the acidic SGF or microacidic environment created by the used acidic salt of DZ in water, but not in SIF. An interaction between the medium type and CG:CS ratio was also found. With DS, the polymer combinations had similar dissolution profiles to those of the single polymers in water and SIF, which was explained by the lack of chitosan ionization by the medium or the drug basic salt. The dissolution profiles could not be obtained in SGF, which was attributed to the conversion of DS into diclofenac free acid. The importance of chitosan ionization for its interaction with CG to have an effect on the release of DS was demonstrated by performing dissolution of SGF presoaked tablets of DS in SIF, which showed an effect of combining the two polymers on sustaining the drug release.     

In Vitro Release of Disopyramide from Cellulose Acetate Butyrate Microspheres

Abstract

Disopyramide was microencapsulated with cellulose acetate butyrate (CAB) using an emulsion-solvent evaporation process. Drug dissolution from microcapsules was studied in both simulated gastric (SGF) and intestinal fluids (SIF) under sink conditions using the USP paddle method. There was no significant difference between drug release into SIF and SGF. As the CAB to drug ratio decreased from 3:1 to 2:1 at constant polymer mass, the drug release rate increased and the T50Y0 decreased from 2.3 hr to 0.3 hr for 303 pm particles. Dissolution T50% increased from 0.4 hr to 2 hr when the mean microcapsule size was increased from 153 to 428 μm (26% drug loading). The addition of acetone to the external phase during preparation shifted the size distribution toward larger particles, but resulted in a higher drug dissolution rate for a given particle size range. A shift to smaller particles was obtained upon increasing the concentration of surfactant. The dissolution profiles were described by the Higuchi and Baker-Lonsdale equations for drug release from spherical matrices up to 90% of the drug release.     

Development of polysaccharide-based colon targeted drug delivery systems for the treatment of amoebiasis

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30-40% drug release during the initial 4-5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18-24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

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.     

Design and Evaluation of a Two-Layer Floating Tablet for Gastric Retention Using Cisapride as a Model Drug

A new kind of two-layer floating tablet for gastric retention (TFTGR) with cisapride as a model drug was developed. The in vitro drug release was determined, and the resultant buoyancy and the time-buoyancy curve were plotted. Because of the sodium bicarbonate added to the floating layer, when immersed in simulated gastric fluid (SGF) the tablet expands and rises to the surface, where the drug is gradually released. The in vitro drug release of this kind of two-layer dosage was controlled by the amount of hydroxypropylmethylcellulose (HPMC) in the drug-loading layer. Generally, the more HPMC, the slower the drug releases. Because cisapride has greater solubility in SGF than simulated intestinal fluid (SIF), its in vitro drug dissolution in SGF is faster than in SIF. One of the distinguishing characteristics of this kind of tablet is the separate regulation of buoyancy and drug release. The idea developed in this experiment can be used as a general model for the design of other tablets for gastric retention.     

Design and Evaluation of a Two-Layer Floating Tablet for Gastric Retention Using Cisapride as a Model Drug

A new kind of two-layer floating tablet for gastric retention (TFTGR) with cisapride as a model drug was developed. The in vitro drug release was determined, and the resultant buoyancy and the time-buoyancy curve were plotted. Because of the sodium bicarbonate added to the floating layer, when immersed in simulated gastric fluid (SGF) the tablet expands and rises to the surface, where the drug is gradually released. The in vitro drug release of this kind of two-layer dosage was controlled by the amount of hydroxypropylmethylcellulose (HPMC) in the drug-loading layer. Generally, the more HPMC, the slower the drug releases. Because cisapride has greater solubility in SGF than simulated intestinal fluid (SIF), its in vitro drug dissolution in SGF is faster than in SIF. One of the distinguishing characteristics of this kind of tablet is the separate regulation of buoyancy and drug release. The idea developed in this experiment can be used as a general model for the design of other tablets for gastric retention.     

Development of Polysaccharide-Based Colon Targeted Drug Delivery Systems for the Treatment of Amoebiasis

ABSTRACT

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30–40% drug release during the initial 4–5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18–24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

Hydration,Erosion, and Release Behavior of Guar-Based Hydrophilic Matrix Tablets Containing Total Alkaloids of Sophora alopecuroides

It is a challenge to deliver water-soluble drug based on hydrophilic matrix to colon because of swelling and erosion of polysaccharides in contact with media. In our study, guar-based hydrophilic matrix tablets containing water-soluble total alkaloids of Sophora alopecuroides prepared by wet granulation technique were evaluated. A novel method was established to investigate the changes of swelling and volume for guar-based tablets in undynamic state, which generally showed a rapid swelling and volume change in the first 9 h, then the hydrated speed slowed down. On the other hand, the influence of different pH of the media on water uptake and erosion of various guar-based formulations in dynamic state indicated that the hydrated constants in simulated gastric fluid (SGF) was higher than that in SIF, which followed varied mechanism of water penetration by fitting Davidson and Peppas model. The extent of erosion was between 22.4 and 32.6% in SIF within 360 min. In vitro sophoridine release studies in successive different mimicking media showed that the guar matrix tablets released 13.5–25.6% of sophoridine in the first 6 h; therefore it was necessary to develop the bilayer matrix tablet by direct-compressing coating 100 mg guar granula on core tablet. The initial release of coated tablet was retarded and the bilayer matrix tablet was suitable for colon target.     

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.     

Crosslinked Starch as Sustained Release Agent

Different types of crosslinked starches and pregelatinized-crosslinked starches were evaluated for their use as hydrophilic matrices. Some fundamental properties of these chemically modified starches, e.g. granule swelling power and viscosity of the dispersion in function of pH and ionic strength, were studied. Dissolution tests and the rate and amount of water uptake were evaluated on tablets containing theophylline and modified starch (40/60 w/w), compressed on an instrumented tablet press at three different pressures (50,200 and 300 MPa.). Theophylline releasing profiles were determined using the paddle system at a rotational speed of 50 rpm Water, simulated gastric fluid, and simulated intestinal fluid were used as dissolution media. Crosslinked starches showed a poor swelling power and dispersion viscosity in comparison to pregelatinized starch and pregelatinized-crosslinked starches. The pregelatinized-crosslinked starches developed less swelling power than the pregelatinized starch, but they showed higher dispersion viscosity than the pregelatinized starch. The viscosity of all starch dispersions was not affected by ionic strength. An alkaline pH dramatically increased the dispersion viscosity of pregelatinized starch and pregelatinized-crosslinked starches. Drug dissolution rate was lower for tablets containing pregelatinized starch than for tablets containing pregelatinized-crosslinked starches. This phenomenon can be related to the rate and amount of water uptake. The dissolution rate seemed not to be influenced by the compression force nor by the composition of the dissolution media. The results indicate that crosslinked starches, either pregelatinized or not, are not suitable as sustained release agents.     

Matrix tablets of carrageenans. II. Release behavior and effect of added cations

Carrageenans are hydrocolloids in the rubbery state at standard conditions. They are useful excipients for controlled-release tablets. Three carrageenans, two κ-carrageenans (Gelcarin® GP-812 NF and GP-911 NF) and one ι-carrageenan (Gelcarin GP-379 NF), are analyzed regarding their release behavior in combination with sorption, swelling, and rheology. The l-carrageenan has a higher substitution by sulfate groups. The κ-carrageenan Gelcarin GP-812 NF contains a small amount of potassium chloride left over from processing. Water sorption of the pure materials was studied gravimetrically, and the rheology of different solutions (2% and 5% w/w) was studied by cup-cylinder rotation viscosimetry. Swelling was determined as the vertical expansion of the tablets with a specially designed swelling apparatus. Drug release from the tablets was performed by the USP paddle method for 8 hr. The data indicate that drug release increases when water sorption and swelling extent decrease and as viscosity increases. The order of release is nearly zero-order kinetics for theophylline monohydrate, a nonionic drug. Diffusion of the anionic drug diclofenac sodium is anomalous. In addition, the influence of the added salts potassium and calcium chloride on swelling and release was studied. Before tableting, physical mixtures of these salts with and without theophylline monohydrate were prepared. Swelling and release change in the same order, but this is only valid when the ionic interactions responsible for this are strong enough. Besides this, physical mixing of salts with the carrageenans can result in an increased release of drug caused by decreased cohesion of the matrix during drug release, mainly for calcium chloride.     

Matrix Tablets of Carrageenans. II. Release Behavior And Effect of Added Cations

Carrageenans are hydrocolloids in the rubbery state at standard conditions. They are useful excipients for controlled-release tablets. Three carrageenans, two κ-carrageenans (Gelcarin® GP-812 NF and GP-911 NF) and one ι-carrageenan (Gelcarin GP-379 NF), are analyzed regarding their release behavior in combination with sorption, swelling, and rheology. The l-carrageenan has a higher substitution by sulfate groups. The κ-carrageenan Gelcarin GP-812 NF contains a small amount of potassium chloride left over from processing. Water sorption of the pure materials was studied gravimetrically, and the rheology of different solutions (2% and 5% w/w) was studied by cup-cylinder rotation viscosimetry. Swelling was determined as the vertical expansion of the tablets with a specially designed swelling apparatus. Drug release from the tablets was performed by the USP paddle method for 8 hr. The data indicate that drug release increases when water sorption and swelling extent decrease and as viscosity increases. The order of release is nearly zero-order kinetics for theophylline monohydrate, a nonionic drug. Diffusion of the anionic drug diclofenac sodium is anomalous. In addition, the influence of the added salts potassium and calcium chloride on swelling and release was studied. Before tableting, physical mixtures of these salts with and without theophylline monohydrate were prepared. Swelling and release change in the same order, but this is only valid when the ionic interactions responsible for this are strong enough. Besides this, physical mixing of salts with the carrageenans can result in an increased release of drug caused by decreased cohesion of the matrix during drug release, mainly for calcium chloride.     

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0-t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Comparative Pharmacokinetics of New Theophylline Preparations as Egifilin® 200 mg and 400 mg Retard Tablets After Single Dose in Healthy Volunteers

Pharmacokinetic properties of Egifilin® retard tablets (containing 200 or 400 mg of theophylline, EGIS Pharmaceuticals Ltd., Budapest, Hungary) were investigated in 12 healthy volunteers (six women, six men). Pharmacokinetic analysis was performed according to a one-compartment open model. The retard nature of both 200 and 400 mg tablets could be demonstrated. Comparison of the pharmacokinetic curves of women and men indicated that there was no sex difference in the pharmacokinetics of two retard tablets.

Egifilin retard tablets ensured plasma levels for almost 30 hr after single drug intake with an extremely long retard plateau between 6 and 30 hr. For study purposes, an improved rapid HPLC-UV analytical method (less than 3.5 min chromatogram) has been elaborated for the determination of theophylline in human plasma. The range of the calibration is 0.6-18 μg/ml.     

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.