A novel three-layered tablet for extended release with various layer formulations and in vitro release profiles

A novel three-layered tablet consisting of a water-soluble mid-layer and two barrier layers with swellable polymers was investigated to develop a preferable once-a-day formulation containing terazosin HCl as a hydrophilic model drug. When the tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. It facilitated the tablet to absorb a lot of water compared with monolithic matrix. Moreover, formation of a lot of pores in the tablet during dissolution could be observed, suggesting significant water absorption in the inner matrix and swollen polymers of the tablet. Barrier layers influenced drug release profiles significantly, potentially due to differences in viscosity after swelling that produce different diffusion coefficients and mechanical strength. The drug in the mid-layer showed the sigmoid type of release pattern because a period of time might be needed to release the drug from the mid-layer through the barrier layers, but the drug in barrier layers showed the typical release pattern of monolithic matrix. As the amount of water-soluble excipient in the mid-layer increased, the degree of swelling also increased, suggesting that its amount in the layer may affect the overall swelling properties of the tablet. It was also shown that more hydrophilic mid-layer caused faster erosion rate, which was related to the results of swelling property. The three-layered tablets showed more consistent release kinetics than the matrix tablets. These results can give good information for the development of sustained drug delivery systems, especially once-a-day administration.     

A novel three-layered tablet for extended release with various layer formulations and in vitro release profiles

A novel three-layered tablet consisting of a water-soluble mid-layer and two barrier layers with swellable polymers was investigated to develop a preferable once-a-day formulation containing terazosin HCl as a hydrophilic model drug. When the tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. It facilitated the tablet to absorb a lot of water compared with monolithic matrix. Moreover, formation of a lot of pores in the tablet during dissolution could be observed, suggesting significant water absorption in the inner matrix and swollen polymers of the tablet. Barrier layers influenced drug release profiles significantly, potentially due to differences in viscosity after swelling that produce different diffusion coefficients and mechanical strength. The drug in the mid-layer showed the sigmoid type of release pattern because a period of time might be needed to release the drug from the mid-layer through the barrier layers, but the drug in barrier layers showed the typical release pattern of monolithic matrix. As the amount of water-soluble excipient in the mid-layer increased, the degree of swelling also increased, suggesting that its amount in the layer may affect the overall swelling properties of the tablet. It was also shown that more hydrophilic mid-layer caused faster erosion rate, which was related to the results of swelling property. The three-layered tablets showed more consistent release kinetics than the matrix tablets. These results can give good information for the development of sustained drug delivery systems, especially once-a-day administration.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

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

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

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

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

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

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

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.     

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.     

In vitro and in vivo evaluation of controlled-release matrix tablets of highly water-soluble drug applying different mw polyethylene oxides (PEO) as retardants

The aim of the work presented is to prepare a controlled-release hydrophilic matrix tablet (CMT) controlling release of highly water-soluble drug applying pure combination of high- and low-Mw PEO as matrix materials, to avoid the lag time of drug release, and to overcome incomplete release in later stages. The influences of types and amounts of different Mw PEOs used, drug loading, pH of release medium and agitation rate on drug release were evaluated. The study of uptake and erosion of matrix was conducted and mechanism of improving drug release was discussed. In vivo pharmacokinetics of the CMT and reference preparation self-made controlled-release osmotic pump tablets (COPT) were performed in beagle dogs. The optimized formulation containing 43% PEO WSR 303 and 32% PEO N750 showed a zero order release from 1?h to 12?h. In vivo results demonstrated that the CMT had similar AUC_0-48?h and C_max with the COPT but smaller T_max than the COPT and provided a more stable therapeutic concentration compared to the COPT. In conclusion, hydrophilic matrix tablet combining only different Mw PEOs as matrix materials had very good potential to be developed into a controlled-release drug delivery system for highly water-soluble drug. Besides, its manufacturing processes were succinct which would be preferable for modern medicine industry.     

Polysaccharide matrices for microbially triggered drug delivery to the colon

Matrix tablets were prepared using xanthan gum (XG) and guar gum (GG) in varying proportions, and the suitability of the prepared tablets was evaluated for colon specific drug delivery. Indomethacin was used as a model drug. The ability of the prepared matrices to retard drug release in the upper gastrointestinal tract (GIT) and to undergo enzymatic hydrolysis by the colonic bacteria was evaluated. For this, drug release studies were carried out in the presence of rat cecal content. Further cecal content of rats with induced enzymatic activity were used. To ascertain the role of bacterial flora in carrying out the hydrolysis of the tablet, cecal content of rats treated with antibiotics were used in the dissolution media. Presence of XG in combination with GG in the tablets could retard drug release in the conditions of the upper GIT. However, the presence of GG and starch made these matrices microbially degradable. Guar gum alone as a drug release-retarding excipient in the matrices does not achieve the desired retardation. Presence of XG in the tablets not only retards the initial drug release from the tablets, but due to high swelling, makes them more vulnerable to digestion by the microbial enzymes in the colon.     

Mechanistic Study on Hydration and Drug Release Behavior of Sodium Alginate Compacts

ABSTRACT

The influence of sodium alginate viscosity on the dynamics of matrix hydration, solvent front movement, swelling, erosion, and drug release from alginate matrix tablets were examined. The solvent front showed preferential penetration from the radial direction even though matrix swelling showed axial predominance. This study proposed alternative views for the anisotropic behavior of hydrating alginate compacts, namely, formation of gel barrier with different permeability characteristics, tension at the gel-core interface and preferential radial erosion, in addition to an in-depth examination on the contribution of stress relaxation of hydrated polymer as well as core expansion. Alginate matrices demonstrated pH-dependent hydration, swelling and erosion behavior, resulting in pH-dependent drug release mechanisms. Dissolution profiles for alginate matrices of different viscosities were similar in acid but differed upon increase of pH. This was due to the influence of alginate viscosity grade on liquid uptake, erosion and pronounced swelling at near neutral pH.     

Resistant starch as a carrier for oral colon-targeting drug matrix system

In this study, a novel tablet of protein drug matrix for colon targeting was developed using resistant starch as a carrier prepared by pre-gelatinization and cross-linking of starch. The effects of pre-gelatinization and cross-linking on the swelling and enzymatic degradation of maize starch as well as the release rate of drug from the matrix tablets were examined. Cross-linked pre-gelatinized maize starches were prepared by double modification of pre-gelatinization and cross-linked with POCl₃, and bovine serum albumin was used as a model drug. For in vitro drug release assays, the resistant starch matrix tablets were incubated in simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid, respectively. The content of resistant starch and swelling property of maize starch were increased by pre-gelatinization and cross-linking, which retarded its enzymatic degradation. Drug release studies have shown that the matrix tablets of cross-linked pre-gelatinized maize starch could delivery the drug to the colon. These results indicate that the resistant starch carrier prepared by pre-gelatinization and cross-linking can be used for a potential drug delivery carrier for colon-targeting drug matrix delivery system.     

Investigation of prandial effects on hydrophilic matrix tablets.

The prolonged release of drug from hydrophilic matrix tablets can be greatly affected by administration in connection with the intake of food. Changes of the tablet erosion are one of the main components of this effect. The aim of the present study was to identify the postprandial factors responsible for changes in tablet erosion and to develop predictive in vitro tests. Two formulations, one sensitive and the other robust to prandial effects in vivo, were investigated in vitro (a) in a complex physiological media simulating fasting and fed conditions; (b) according to a factorial experimental design that included agitation and pH concentrations of salt, surface-active agent, and nonionic solute as factors; and (c) at varying agitation intensities in three different sets of dissolution apparatus. Of the studied factors, only increased agitation enhanced the erosion of tablets in accordance with the in vivo effects of a meal. The other factors retarded erosion or had only minor effects. The hydrodynamic mechanical stress was thus considered to be the main factor responsible for postprandial effects on tablet erosion. The influence of changes in agitation and the opportunity to discriminate between sensitive and robust formulations differed among the three sets of dissolution apparatus. The modified USP II apparatus, operated at speeds of 50 and 100 rpm, is proposed as a discriminatory test.     

Mechanistic study on hydration and drug release behavior of sodium alginate compacts

The influence of sodium alginate viscosity on the dynamics of matrix hydration, solvent front movement, swelling, erosion, and drug release from alginate matrix tablets were examined. The solvent front showed preferential penetration from the radial direction even though matrix swelling showed axial predominance. This study proposed alternative views for the anisotropic behavior of hydrating alginate compacts, namely, formation of gel barrier with different permeability characteristics, tension at the gel-core interface and preferential radial erosion, in addition to an in-depth examination on the contribution of stress relaxation of hydrated polymer as well as core expansion. Alginate matrices demonstrated pH-dependent hydration, swelling and erosion behavior, resulting in pH-dependent drug release mechanisms. Dissolution profiles for alginate matrices of different viscosities were similar in acid but differed upon increase of pH. This was due to the influence of alginate viscosity grade on liquid uptake, erosion and pronounced swelling at near neutral pH.     

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.     

In vitro and in vivo evaluation of two extended release preparations of combination metformin and glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.     

Transformation of essential minerals into tablet formulation with enhanced stability

Essential minerals play a very important role in maintaining our physical well-being. In this work, essential minerals; copper sulphate, zinc sulphate, selenium dioxide, chromium picolinate, sodium molybdate and potassium iodide were prepared into tablet formulation with enhanced stability. These minerals are prepared in a coated or as an adsorbate form so as to increase the stability of the minerals. The coated/adsorbate form was formulated into matrix tablets using hydroxypropyl methyl cellulose (HPMC) by the direct compression technique. The distinctively formed tablet was assessed for its physicochemical properties, in-vitro release, microbiological and stability studies. SEM analysis showed that the surface topography of the tablet displayed mechanical interlocking between the trace elements and polymer. During dissolution, the hydrated tablet shows highly porous network of the polymer matrix. Afterwards, they undergo surface erosion from the porous network and the trace minerals gets released. The in-vitro release of zinc sulphate with polymer HPMC K4M showed a sustained release behaviour and fits into the first order and Korsemeyer-Peppas model. The formulation of the trace mineral tablet shows a sustained release profile with increased stability. This trace element matrix tablet supplements is expected to gain acceptance than the marketed products owing to its sustained release behaviour.     

In Vitro and In Vivo Evaluation of Two Extended Release Preparations of Combination Metformin and Glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.     

The Stability of Theophylline Tablets with a Hydroxypropylcellulose Matrix

The behavior of 40:60 anhydrous theophylline/hydroxypropylcellulose (HPC) direct compression tablets obtained using a variety of hydroxypropylcelluloses with low or medium-high degrees of substitution (L-HPCs and HPCs, respectively) was determined immediately following their preparation and after storage for 6 months at 20°C and a relative humidity (RH) of either 70.4% or 93.9%. The lower relative humidity did not bring about hydration of the active principle in any formulation, but the higher relative humidity totally hydrated the drug in all except one L-HPC formulation, in which hydration remained incomplete. Both relative humidities caused significant tablet swelling, with L-HPC formulations being more affected than HPC formulations. Drug release was slowed by hydration of the active principle, but accelerated with tablet swelling. The lower relative humidity caused significant alteration of drug release characteristics in only two L-HPC formulations, release from which was accelerated, while the higher relative humidities only failed to cause such alterations in two HPC formulations, with release from all except one of the others slowed (in the exceptional formulation, which exhibited incompletely hydrated theophylline and the greatest swelling of all, release was accelerated).     

The stability of theophylline tablets with a hydroxypropylcellulose matrix

The behavior of 40:60 anhydrous theophylline/hydroxypropylcellulose (HPC) direct compression tablets obtained using a variety of hydroxypropylcelluloses with low or medium-high degrees of substitution (L-HPCs and HPCs, respectively) was determined immediately following their preparation and after storage for 6 months at 20°C and a relative humidity (RH) of either 70.4% or 93.9%. The lower relative humidity did not bring about hydration of the active principle in any formulation, but the higher relative humidity totally hydrated the drug in all except one L-HPC formulation, in which hydration remained incomplete. Both relative humidities caused significant tablet swelling, with L-HPC formulations being more affected than HPC formulations. Drug release was slowed by hydration of the active principle, but accelerated with tablet swelling. The lower relative humidity caused significant alteration of drug release characteristics in only two L-HPC formulations, release from which was accelerated, while the higher relative humidities only failed to cause such alterations in two HPC formulations, with release from all except one of the others slowed (in the exceptional formulation, which exhibited incompletely hydrated theophylline and the greatest swelling of all, release was accelerated).     

Optimization of Slow-Release Tablet Formulations: Containing Montmorillonite I. Properties of Tablets

Slow-release tablets containing 20%. sodium sul fathiazole and 30%. magnesium aluminum silicate were prepared by direct compression techniques. Dissolution studies indicated that tablet hardness exerted a negligible influence on drug release from the tablets. During the dissolution process the clay slowly swelled to form a gelatinous hydrated layer around the tablet matrix. At faster stirring speeds, friction between the dissolution basket and the tablet rapidly removed the hydrated boundary region and resulted in a more rapid dissolution rate of the sulfonamide. Faster rates of dissolution were seen in deionized water than in dilute acid since the clay hydrated more readily at the higher pit.     

Influence of hydroxypropyl methylcellulose mixture,apparent viscosity,and tablet hardness on drug release using a 2(3) full factorial design

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3-6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000-19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

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

Abstract

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.