Studies on the Release of Theophylline from Polyvinylacetate Microspheres

Polyvinylacetate microspheres containing theophylline were prepared by emulsification and solvent removal method. The release pattern of theophylline from the microspheres was found to be best explained by diffusion controlled process. The rates of release were found to be influenced by drug-polymer ratios, size of microspheres, concentration of surfactant used for the preparation of microspheres, and pH of the dissolution media.     

Effect of Different Binders on Release Characteristics of Theophylline from Compressed Microspheres

Microspheres with 60% w/w drug loading were prepared by the solvent-evaporation method using cellulose acetate butyrate as the encapsulating polymer and micronized anhydrous theophylline as the core material. Four different binders - microcrystalline cellulose, glyceryl palmito-stearate, glyceryl stearate and glyceryl behenate were used to compress three different particle sizes of microspheres. Comparison of the in vitro drug dissolution profiles revealed that drug release was fastest from all the microspheres compressed with microcrystalline cellulose as the binder followed by those compressed with glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.     

Effect of Different Binders on Release Characteristics of Theophylline from Compressed Microspheres

Abstract

Microspheres with 60% w/w drug loading were prepared by the solvent-evaporation method using cellulose acetate butyrate as the encapsulating polymer and micronized anhydrous theophylline as the core material. Four different binders - microcrystalline cellulose, glyceryl palmito-stearate, glyceryl stearate and glyceryl behenate were used to compress three different particle sizes of microspheres. Comparison of the in vitro drug dissolution profiles revealed that drug release was fastest from all the microspheres compressed with microcrystalline cellulose as the binder followed by those compressed with glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.     

Studies on the Delivery Mechanisms of Theophylline from a Sustained Release Tablet

The in-vitro and in-vivo release of theophylline from an oral sustained release tablet (Theograd^R) was studied.

The in-vitro release profiles were determined by means of the rotating basket method, the paddle method and the modified disintegration method, described in the USP XX as apparatus 1, 2 and 3 respectively. Besides a stationary basket-rotating paddle method was used.

It was demonstrated that in the stationary basket-rotating paddle apparatus and in the paddle apparatus at low rotational speeds of the paddle, mild agitation conditions were created. Under these conditions the release of theophylline from the sustained release tablet appeared to be matrix controlled. The leached matrix was found to be structurally very weak. For a matrix type of sustained release tablet this is probably beneficial as it would be less likely to cause accumulation and gastro-intestinal obstruction. In contrast the conditions of agitation in the rotating basket apparatus and in the disintegration apparatus were found to be rather severe. This was partly due to mechanical abrasion of the dosage form caused by the gauze of the basket and the basket-rack respectively, and partly the result of high solvent agitation, especially in the disintegration apparatus. Under these conditions it appeared that the empty matrix of the sustained release tablet eroded during the release process. This was confirmed by the results of studies under non-dissolving circumstances of the drug which showed that in this case only the leached matrix of the sustained release dosage form eroded and not that part of the dosage form from which the drug had not yet been dissolved. The in-vivo absorption appears to relate to the in-vitro release. When the Theograd tablet was taken on an empty stomach, it appeared that the absorption rate could succesfully be simulated by means of the stationary basket-rotating paddle method and the paddle method, both at low rotational speeds of the paddle. It was very likely that in this case the in-vivo release from the sustained release tablet was matrix controlled too. Under these conditions the bioavailability was found to be 65% compared with an oral solution of the drug. In contrast, when the Theograd tablet was taken after a meal, a relative bioavailability of 90% was observed. It was made plausible, that the greatly enhanced bioavailability, observed on postprandial administration of the tablet, was due to partial erosion of the leached matrix. This erosion was caused by the food induced increased motility of the gastro-intestinal tract. Based on the results of this study it is recommended to take Theograd^R tablets after a meal.     

Prolonged Release of Theophylline from Aqueous Suspensions

The dissolution of theophylline from aqueous suspensions was measured by the U.S.P. paddle method. Theophylline release was retarded in the presence of xanthan gum, 1%, sodium alginate, 0.5%, and equi-weight mixtures of gelatin type B and iota carrageenan, 1%. These suspensions formed gels in situ in Simulated Gastric Fluid, U.S.P. Diffusion cell studies suggested that theophylline transport within the formed matrix was due to diffusion through immobilized liquid water. Evidence in support of a diffusion controlled dissolution mechanism in these systems were linearity of the initial section of plots of dissolution against the square route of time, the lack of effect of theophylline particle size on dissolution rate, and the tendency for release from a particular system to become independent of polymer concentration once a sufficiently high concentration was reached.     

Prolonged Release of Theophylline from Aqueous Suspensions

Abstract

The dissolution of theophylline from aqueous suspensions was measured by the U.S.P. paddle method. Theophylline release was retarded in the presence of xanthan gum, 1%, sodium alginate, 0.5%, and equi-weight mixtures of gelatin type B and iota carrageenan, 1%. These suspensions formed gels in situ in Simulated Gastric Fluid, U.S.P. Diffusion cell studies suggested that theophylline transport within the formed matrix was due to diffusion through immobilized liquid water. Evidence in support of a diffusion controlled dissolution mechanism in these systems were linearity of the initial section of plots of dissolution against the square route of time, the lack of effect of theophylline particle size on dissolution rate, and the tendency for release from a particular system to become independent of polymer concentration once a sufficiently high concentration was reached.     

Kinetic Release of Theophylline from Hydrophilic Swellable Matrices

The objective of this research was to evaluate the effect of hydroxypropylmethylcellulose (HPMC; Methocel K4M Premium) level and type of excipient on theophylline release and to attempt to predict the drug release from hydrophilic swellable matrices. Formulations containing theophylline anhydrous (10% w/w), Methocel K4M Premium (10%, 30%, and 40% w/w), different diluents (Lactose Fast Flo, Avicel PH-101, and Emcompress), and magnesium stearate (0.75% w/w) were prepared by direct compression at a target weight of 450 mg ± 5% and target hardness of 7 kp to 10 kp. It was found that, as the percentage of polymer in all formulations increased from 10% to 30% or 40%, the drug release decreased. However, there was no significant difference in drug release between formulations containing 30% polymer and formulations containing 40% polymer. At low levels of polymer, the drug release is controlled by the type of diluent used. Avicel PH-101 formulation gave the highest release, while its corresponding Emcompress formulation gave the lowest release. Formulations containing 30% or 40% polymer gave the same release profiles irrespective of the type of diluent used. In all cases, replacement of a portion of Methocel K4M Premium with any diluent resulted in increase of theophylline release. In addition, this investigation demonstrated that the drug release from hydrophilic swellable matrices can be predicted using only a minimum number of experiments.     

Controlled Release of Cyclosporine from Microspheres

Abstract

A controlled release microsphere formulation of cyclosporine is reported for the first time. Ethylene-vinyl acetate copolymer was utilized to prepare microspheres containing cyclosporine. The polymer was dissolved in methylene chloride (10% w/v) to which different quantities of cyclosporine was added to give drug loadings of 5, 25 and 50% in the microspheres. The polymer-drug solution was extruded into ethanol, where gelling of the polymer was achieved at ?78°C in an ethanol-liquid nitrogen bath. Microspheres containing 25% of cyclosporine retained their shape and gave optimum results. Lower drug loadings (5% cyclosporine) resulted in deformed microspheres, whereas high drug loadings (50 % cyclosporine) produced tear drop shaped microspheres. This method used to prepare microspheres is simple, quick and inexpensive and can be used for drugs that are unstable to heat. Furthermore, the polymer used is bio-compatible and can be used to design formulations such as films containing cyclosporine which can then be used as subcutaneous implants.     

Kinetic Release of Theophylline from Hydrophilic Swellable Matrices

The objective of this research was to evaluate the effect of hydroxypropylmethylcellulose (HPMC; Methocel K4M Premium) level and type of excipient on theophylline release and to attempt to predict the drug release from hydrophilic swellable matrices. Formulations containing theophylline anhydrous (10% w/w), Methocel K4M Premium (10%, 30%, and 40% w/w), different diluents (Lactose Fast Flo, Avicel PH-101, and Emcompress), and magnesium stearate (0.75% w/w) were prepared by direct compression at a target weight of 450 mg ± 5% and target hardness of 7 kp to 10 kp. It was found that, as the percentage of polymer in all formulations increased from 10% to 30% or 40%, the drug release decreased. However, there was no significant difference in drug release between formulations containing 30% polymer and formulations containing 40% polymer. At low levels of polymer, the drug release is controlled by the type of diluent used. Avicel PH-101 formulation gave the highest release, while its corresponding Emcompress formulation gave the lowest release. Formulations containing 30% or 40% polymer gave the same release profiles irrespective of the type of diluent used. In all cases, replacement of a portion of Methocel K4M Premium with any diluent resulted in increase of theophylline release. In addition, this investigation demonstrated that the drug release from hydrophilic swellable matrices can be predicted using only a minimum number of experiments.     

Studies on the In Vitro Release of Theophylline from Polyethylene Glycol-Polyvinyl Acetate Mixtures Liquid Filled into Hard Gelatin Capsules

The release of theophylline from mixtures of polythylene glycol (PEG) with polyvinyl acetate (PVAc) liquid filled into hard gelatin capsules has been studied in vitro. Results indicate that theophylline release can be controlled over a relative wide range by varying the concentration of PVAc, and that the reproducibility of the release profile is improved considerably if the PVAc concentration exceeds 2% w/w. Other results show that drug load, molecular weight of PEG, and pH of the dissolution medium also affect release profiles. In general, the experimental data are well described by a simple equation derived from Fickian diffusion kinetics, thus supporting the suggestion that drug release from this type of formulation is controlled by diffusion in solution through water-filled pores in a network of precipitated PVAc.     

Sustained Release Tablets of Theophylline

Sustained release tablets of theophylline (anhydrous) were prepared using hydrophilic polymers (Methyl Cellulose, Methocel K₄M and K₁₅M) and hydrophobic polymers (ethyl cellulose, cellulose acetate). In addition water soluble adjuvants were used to modify release rate. With methocel, rapid gelling was observed and release was near zero-order, whereas with hydrophobic polymers release followed Fickian law of diffusion.     

Effect of pH on Theophylline Release from Partially Esterifted Alginic Acid Matrices

The effect of dissolution medium pH on theophylline release from co-compressed matrices composed of a 40% benzyl ester of alginic acid was investigated using both the USP rotating paddle method and a modification of the USP rotating basket method. Release rates for each pH were compared using a measure of the time for approximately 80% release (t80%). Results show release of theophylline from these matrices to be significantly slower at pH 1 than at pH 2 and above. Beyond pH 2, drug release is relatively insensitive to dissolution medium pH but is affected by dissolution method because of the tendency of the alginate to form an adhesive, gel-like layer at pH values higher than four. The drug release characteristics of this polymer, under various pH conditions, make it potentially suitable for use in delayed/controlled release oral delivery systems containing compounds that are acid labile or irritating to the gastric mucosa.     

Effect of pH on Theophylline Release from Partially Esterifted Alginic Acid Matrices

The effect of dissolution medium pH on theophylline release from co-compressed matrices composed of a 40% benzyl ester of alginic acid was investigated using both the USP rotating paddle method and a modification of the USP rotating basket method. Release rates for each pH were compared using a measure of the time for approximately 80% release (t80%). Results show release of theophylline from these matrices to be significantly slower at pH 1 than at pH 2 and above. Beyond pH 2, drug release is relatively insensitive to dissolution medium pH but is affected by dissolution method because of the tendency of the alginate to form an adhesive, gel-like layer at pH values higher than four. The drug release characteristics of this polymer, under various pH conditions, make it potentially suitable for use in delayed/controlled release oral delivery systems containing compounds that are acid labile or irritating to the gastric mucosa.     

Sustained Release of Theophylline from Eudragit RLPO and RSPO Tablets

Abstract

Newer polymeric grades of Eudragit, RLPO and RSPO, were explored for their utilities by formulating a sustained-release tablet of theophylline as a model drug. Formulations selected on the basis of their lower polymer content and drug release content, over the period of 12 hr, were compared with the marketed formulation. These were evaluated for dissolution characteristics. In vitro release showed zero-order kinetics (r = 0.9879-0.994.5; p < 0.001). In vivo evaluations were carried out on healthy human volunteers (23 ± 2.68 years old; 48.64 ± 6.31 kg). Dissolution rate constant (k), C_max, T_max, AUC_0-12, AUC_0-24, and t_1/2 were evaluated statistically by two-way ANOVA. Upon t test, a highly significant difference between test products and the marketed product was observed. Wagner-Nelson analysis of the in vivo data revealed controlled-release absorption profiles for selected formulations. Linear regression analysis of the mean % of dose absorbed versus mean in vitro release, resulted in statistically significant correlation. Coefficient of correlation values between AUC_0-12 and k, and AUC_0-24 and k were found to be 0.991 (p < 0.01) and 0.984 (0.01 < p < 0.05), respectively. These data support a level-A correlation between in vitro release rate profiles and the in vivo absorptions for theophylline.     

Effect of Viscosity Increasing Agent and Electrolyte Concentration on the Release Rate of Theophylline from a HPMC Based Sustained Release Capsules

Sustained release (SR) granules (250-650∼) containing theophylline were prepared using hydroxypropyl methylcellulose (HPMC) as a rate retarding polymer. The effect of variable ionic strength and viscosity increasing agent on the theophylline release rate have been investigated. Irrespective of dissolution media the theophylline release kinetics was found to be dependent on square root of time. Thc Higuchian release rate (K) was found to increase exponentially with the increase in ionic strength of the dissolution fluid. An opposite effect was observed with the viscosity increasing agent sodium carboxy methyl cellulose (Na-CMC) in the dissolution fluid. The release rate dccreased linearly with the increase of Na-CMC concentration in the dissolution fluid.     

Effect of Surfactant Agents on the in Vitro Release of Insulin from DL-PLA Microspheres

This paper describes the effect of surfactants on the in vitro release profile of bovine insulin from DL-polyacetic acid (DL-PLA) microspheres prepared by the double-emulsion technique. The surfactants, Tween®-80 and Span®-60, were included in the water and oil phases, respectively, of the first emulsion. The presence of these agents affected the burst effect but not the subsequent release phase. The latter is more controllable by PLA molecular weight selection, with slower release being achieved as the molecular weight increases.     

Effect of Viscosity Increasing Agent and Electrolyte Concentration on the Release Rate of Theophylline from a HPMC Based Sustained Release Capsules

Abstract

Sustained release (SR) granules (250-650～) containing theophylline were prepared using hydroxypropyl methylcellulose (HPMC) as a rate retarding polymer. The effect of variable ionic strength and viscosity increasing agent on the theophylline release rate have been investigated. Irrespective of dissolution media the theophylline release kinetics was found to be dependent on square root of time. Thc Higuchian release rate (K) was found to increase exponentially with the increase in ionic strength of the dissolution fluid. An opposite effect was observed with the viscosity increasing agent sodium carboxy methyl cellulose (Na-CMC) in the dissolution fluid. The release rate dccreased linearly with the increase of Na-CMC concentration in the dissolution fluid.     

Effect of Surfactant Agents on the in Vitro Release of Insulin from DL-PLA Microspheres

Abstract

This paper describes the effect of surfactants on the in vitro release profile of bovine insulin from DL-polyacetic acid (DL-PLA) microspheres prepared by the double-emulsion technique. The surfactants, Tween®-80 and Span®-60, were included in the water and oil phases, respectively, of the first emulsion. The presence of these agents affected the burst effect but not the subsequent release phase. The latter is more controllable by PLA molecular weight selection, with slower release being achieved as the molecular weight increases.     

Effect of Steareth-20 on the Release of Nitrofurantoin from Propylene Glycol Monostearate Microspheres

In vitro release of nitrofurantoin (NFT) from microspheres of propylene glycol monostearate (PGM) was investigated at NFT:PGM ratios of 1:1, 1:1.5, 1:3, 1:4, 1:5, and 1:9 in distilled water at 37°C. The rate and extent of drug release declined with decreasing NFT:PGM ratio. A maximum drug release of 52.4% over 24 hr was recorded for the microspheres of formulation I (highest load). The effect of Steareth-20 (ESA) over the concentration range of 0.01% to 0.1% w/w of PGM on the size of the microspheres and on the release profile of nitrofurantoin from the microsphere formulations was examined at NFT.PGM ratios of 1:1 and 1:4. The cumulative % of NFT released over a 24-hr period was found to be maximum at ESA concentration of 0.03% and 0.05% w/w of PGM. The plots of T₅₀ versus %w/w of ESA exhibited two minima, the first at 0.03% ESA and a second, weaker than the first, at 0.05% ESA, paralleling the earlier observations. Scanning electron micrographs of the exhausted microspheres revealed a very porous matrix of PGM at the ESA concentration of 0.03%. The formulations containing 0.03% and 0.05% ESA had the smallest mean particle diameter and the minimum contact angles (water over PGM-ESA films) corresponding to the two critical micelle concentrations (CMC), at 0.025% and 0.05% w/w.     

Development of a New Controlled Release Theophylline Tablet: In Vitro and in Vivo Studies

Abstract

Five formulations of controlled release theophylline tablets, specially shaped to a multi scored approximately rectangular structure, manually dividable accurately and conveniently into bisectional or trisectional subdosage units were prepared, using ethyl cellulose/hydroxypropylcellulose and Eudragit RL. The influence of two parameters (fillers, granulation) on the dissolution rate of all tablets was studied. It was found that granulation yields greater retardation in dissolution rate, in comparison to direct compression. No significant differences were found among the fillers used, concerning the dissolution rate.