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.     

The Use of Precirol® to Prepare Sustained Release Tablets of Theophylline and Quinidine Gluconate

Tablets were made using theophylline, lactose and Precirol by a granulation technique, resulting in more than 12 hours release. Granulation and hot fusion methods were used to prepare admixtures of quinidine gluconate and Precirol at different ratios of Precirol: drug, 1:9, 3:7 and 1:1. Dissolution studies in 0.1N HCl showed drastic differences in the release of quinidine gluconate from tablets made by the two different methods; granulation method gave a faster release while the hot fusion method gave slower and incomplete release at higher Precirol content. The release rate decreases with higher Precirol content.     

Development and Mathematical Simulation of Theophylline Pulsatile Release Tablets

ABSTRACT

Theophylline pulsatile release tablets consisting of a fast-swelling core with a water-insoluble ethylcellulose were developed. Effects of coating material, the amount of the plasticizer, subcoating, the type of the disintegrant, and coating level on the release profiles were investigated. Results showed that ethylcellulose was the best candidate polymer for pulsatile release tablets. Rupture time increased with increasing the amount of the plasticizer, but 15% plasticizer provided the best release profiles. Tablets with Methocel® E50 as subcoating was most optimal in order to achieve a long lag time and followed by a rapid release. The lag time of tablets containing different disintegrants increased in the following order: croscarmellose (Ac-Di-Sol®) < sodium starch glycolate (Explotab®) < low-substituted hydroxypropyl cellulose (L-HPC) < crospovidone (Kollidon® CL). And the rupture time increased with higher coating level. A mathematical model was presented to predict the lag time prior to rupture. Results of the water uptake experiment were used to estimate the apparent diffusion coefficient of the coating tablets. The prediction of the lag time based on the presented model is in good agreement with the experimental results.     

Development and In-Vitro Evaluation of a Multiparticulate Sustained Release Theophylline Formulation

A multiparticulate sustained release formulation of theophylline was developed and evaluated in-vitro. The formulation comprised spherical pellets of high drug loading, coated with a rate controlling membrane. The pellets were prepared using an extrusion spheronisation method, whilst coating was performed with an aqueous dispersion of ethylcellulose using a fluidized bed coating technique. When ethylcellulose was used alone as the coating polymer, the drug release profile was unsatisfactory, but could be improved by incorporating a coating additive. Several additives were evaluated and methylcellulose of high Viscosity grade was found most satisfactory. The in-vitro theophylline release was relatively linear and pH independent, and could be varied in a predictable manner by manipulating the coat thickness. In addition, when the coated pellets were subjected to additional thermal treatment, the drug release was stable after storage for one year.     

Formulation and Release Kinetics of Sustained Release Phenylpropanolamine Hydrochloride Granules and Tablets

Abstract

Sustained release phenylpropanolamine hydrochloride (PPH) granules and tablets were prepared using HPMC, HPMC and SCMC, Eudragit RS, Eudragit RS+L or HPMC + Eudragit RS matrices. The release pattern of PPH from the prepared granules and tablets was found to be in the following order HPMC > HPMC + SCMC > RS > RS + 1> HPMC + RS. The results revealed that, although the drug concentration was kept constant in all the prepared granules and tablets, the drug release from these formulations was clearly different and depends mainly on the type of matrix used. The presence of Eudragit L with Eudragit RS and Eudragit RS with HPMC resulted in a marked decrease in the drug release compared with that obtained from the matrix containing HPMC or Eudragit RS alone. The release data of PPH from the prepared granules and tablets were treated mathematically according to zero order, first order, Langenbuchar, modified Langenbucher and Higuchi models. The results revealed that no one model was able adequately to describe the drug release profiles from these formulations. In-vivo studies in human volunteers showed that, the peak urinary excretion of PPH occurred over a sustained period from 2 to 6.5 hr in case of HPMC + SCMC tablets and from 2 to 10 hr in case of either RS+L or HPMC + RS tablets.     

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.     

Characterization of the In Vitro Dissolution of Some Commercial Sustained Release Theophylline Dosage Forms

A dissolution study of five commercial sustained release theophylline dosage forms, concerning their pH dependency, is described. The experiment was carried out in a flow through dissolution apparatus, at constant pH and at pH gradient, being the pH values of 1, 2, 6, 5 and 7, 5. In both cases, they were treated in terms of the dissolution profile and the dissolution rate, complemented with the dissolution efficiency at pH gradient in order to make a correlation with the in vivo experiments that will be done in the future. The absorbance was measured at a wavelength of 264 nm. According to the results obtained, was selected the best pharmaceutical form, concerning the pH dependency and taking as a basis, just, the in vitro experiments.     

Pharmacokinetic Evaluation of a Sustained Release Preparation of Theophylline In Asthmatic Children and Adults

Abstract

A sustained release preparation of theophylline (SRP of Th) was evaluated pharmacokinetically in asthmatic children and adults and it was found to have good SR properties. Different dosage requirements for equal pharmacokinetic behaviour in these two groups have been explained by the influence of the factors which can be responsible, such as bioavailability, liver mass and free drug concentration.     

Development of Novel Sustained Release Bioadhesive Vaginal Tablets of Povidone Iodine

Iodine has long been used as an antiseptic for the prevention and treatment of vaginal infections. The present study was aimed at the development of rapidly disintegrating, bioadhesive and sustained release vaginal tablets of an iodophore, polyvinylpyrrolidone (povidone iodine), their evaluation and comparison with the marketed formulations. The formulation development included drug-excipient compatibility studies, optimization of performance parameters like disintegration time, bioadhesion and drug release profile and comparison of physical properties and performance parameters with the marketed formulation. The developed formulation provided a sustained release of polymer complexed iodine (up to 8 hrs), rapid disintegration (< 1 min.), desired bioadhesive properties and retention for a prolonged time.     

Investigation of Hypromellose Particle Size Effects on Drug Release from Sustained Release Hydrophilic Matrix Tablets

Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 μm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.     

Evaluation of Xanthan Gum in the Preparation of Sustained Release Matrix Tablets

The objective of this study was to evaluate xanthan gum as a matrix former for the preparation of sustained release tablets. Preliminary experiments indicated that a fine particle sue of xanthan gum produced the slowest and most reproducible release profiles. Based on single surface experiments and tablet erosion studies, it was concluded that release of a soluble drug (chlorpheniramine maleate) and an insoluble drug (theophylline) from tablets containing low concentraions of xanthan gum was mainly via diffusion and erosion, respectively. Drug release from tablets containing xanthan gum was slightly faster in acidic media due to more rapid initial surface erosion than at higher pH. After hydration of the gum, drug release was essentially pH-independent. The amount released was directly proportional to the loading dose of drug and inversely proportional to gum concentration in tablets. Release profiles of chlorpheniramine maleate and theophylline remained unchanged after three months storage of the tablets at 40°C/80% RH and 40°C. Model tablets containing 5% xanthan gum exhibited release profiles similar to tablets containing 15% hydroxypropyl methylcellulose.     

Chitosan and Sodium Sulfate as Excipients in the Preparation of Prolonged Release Theophylline Tablets

The major objectives of this study were to monitor the effect of cross-linking of cationic chitosan in acidic media with sulfate anion during granules preparation by wet granulation method prior to tableting using theophylline (TPH) as a model drug. The prepared granules and the compressed tablets were subjected to in vitro evaluation. The properties of the prepared matrix granules and the compressed tablets were dependent on chitosan:sodium sulfate weight ratios, chitosan content, and molecular weight of chitosan. The prepared granules of all batches showed excellent to passable flowability and were suitable for compression into tablets. Most of the granules were hard and expected to withstand handling during the subsequent compression into tablets. Granules with high friabilities were only those prepared with a high amount of sodium sulfate or low amount of chitosan. Compression of granule batches yield nondisintegrating tablets that showed a decrease in tensile strength with the increase of sodium sulfate content at high chitosan:sodium sulfate weight ratio or with decrease of chitosan content. On the other hand, friability of tablets was increased in the presence of an excessive amount of sodium sulfate and low chitosan content as observed with granules. Slow TPH release from the formulated tablets was achieved at 1:0.5 and 1:1 chitosan:sodium sulfate weight ratios where all or most of the cationic chitosan and sulfate anions were used in a cross-linking reaction during wet granulation. Ratios of 1:2 and 1:3 showed fast drug release, which support the hypothesis that excessive unreacted water-soluble sodium sulfate might increase the porosity of the nondesintegrating tablets during dissolution. Slow drug release was also obtained with high molecular weight chitosan, whereas changing the hardness of the tablets did not significantly change the release profile of the drug as long as the tablets are intact during dissolution. Furthermore, slow drug release was observed as the total amount of chitosan was increased in the formulated tablets. A comparative in vivo study between the chosen formulated tablets (1:1 chitosan:sodium sulfate ratio that contains 10% high molecular weight chitosan) and the commercial Quibron® tablets indicated prolonged appearance of the drug in dogs' plasma for both formulations with no significant differences (p > 0.05) in rate and extent of drug absorption. The formulated tablets showed 103.16% bioavailability relative to that of the commercial tablets.     

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 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.     

Sustained Release from Precirol® (Glycerol Palmito-Stearate) Matrix. Effect of Mannitol and Hydroxypropyl Methylcellulose on the Release of Theophylline

The release of theophylline embedded in a Precirol® (glycerol palmitostearate) matrix containing varying amounts of mannitol and/or hydroxypropyl methyl cellulose 4000 (HPMC) was studied. The results indicated that HPMC or mannitol when incorporated alone, the drug release followed the diffusion-controlled matrix model where the quantity of drug released was proportional to the square root of time. The release rate was found to increase with increase in the amount of HPMC or mannitol in the matrix. When both mannitol and HPMC were incorporated in the matrix, the mechanism of release changed from the Higuchi model to a first-order release. A linear relationship was found between the fraction of HPMC or mannitol in the matrix and the rate constant. An optimum combination of Precirol®, mannitol and HPMC was found for a 12 hour theophyll ine sustained release preparation     

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.     

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.     

Controlled-Release Hydrophilic Tablets for Individualized Theophylline Therapy

Directly compressible controlled-release (CR) theophylline tablet formulations with a non-zero-order drug release were prepared using various grades of Methocels®. These tablet formulations were employed in the individualization of therapy with the aid of a pharmacokinetic simulation model developed with STELLA®II computer software. In vitro drug release data were used to simulate plasma concentration-time (C,t) profiles based on a wide range of previously reported patient pharmacokinetic parameters (clearances of 2–5 L/hr and apparent volumes of distribution of 20–50 L). The simulations indicated that formulations containing low-viscosity Methocels (E4, K4, and K4CR) were suitable for individualizing theophylline therapy. Average steady-state concentrations were well within the therapeutic range of 10–20 μg/ml. High-viscosity polymers such as E10CR, K15, and K15CR yielded subtherapeutic concentrations and were deemed unsuitable. Thus, a pharmacokinetic simulation program capable of predicting in vivo C,t profiles (even though theophylline release occurred by a non-zero order) may be useful for individualizing theophylline therapy that involves CR formulations.