The influence of tablet density on the human oral absorption of sustained release acetaminophen matrix tablets

Abstract

Low density bilayer compressed matrix tablets of acetaminophen were tested for in vitro dissolution and in vivo oral absorption. The upper layer contained a carbon dioxide-generating blend and the lower layer contained hydroxypropyl methylcellulose (HPMC) and acetaminophen. Carbon dioxide liberated by the action of the acidic dissolution medium on the upper layer is entrapped in the gelled hydrocolloid, providing buoyancy of the tablet and sustained release of the drug. For comparative purposes, similar but non-gas generating bilayer compressed matrix tablets were formulated and tested in vitro under the same conditions. These high density tablets were found to yield similar dissolution profiles as the low density tablets. The absorption characteristics of the bilayer compressed matrix tablets were compared with those of rapidly disintegrating acetaminophen tablets (TYLENOL® tablets, 500 mg) under fasted and fed conditions in six healthy subjects. Under fasted conditions, saliva profiles showed a rapid absorption for TYLENOL tablets but slower absorption for both compressed matrix tablets. Saliva profiles of TYLENOL® tablets under fed conditions were similar to those for the fasted case. In contrast, the peak saliva levels of acetaminophen for both compressed matrix tablets were significantly increased under fed conditions. The time to maximum saliva concentrations (Tmax) of all three dosage forms was not significantly affected by food intake. The relative bioavailability of the low density tablets under fasted and fed conditions was not significantly different from those of TYLENOL tablets, but vas significantly greater than that of high density tablets under fasted and fed conditions. A possibility exists that the buoyancy mechanism enabled the tablet to maintain more prolonged residence time in the gastrointestinal tract.     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.     

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.     

Spray-dried O-carboxymethyl chitosan as potential hydrophilic matrix tablet for sustained release of drug

Objective: The aim of the present investigation was to evaluate the use of spray-dried O-carboxymethyl chitosan (OCMCS) as potential hydrophilic matrix excipient for sustained release of drug.

Methods: The polymer was synthesized from chitosan, then spray-dried and characterized. Tablets with different OCMCS concentrations (80, 50, 30, 5 and 2% w/w), containing diltiazem (DTZ) as model drug, were prepared for direct compression (DC) and after the wet granulation method (WG).

Results: The spray-dried OCMCS powder was spherical, with a smooth surface and an average size of 2.2?µm. The tablets prepared for WG disintegrated in time less than 30?min. The tablets obtained for DC presented high retention of the drug, with zero order or Higuchi release kinetic. There was a direct relationship between the OCMCS concentration and the release ratio, swelling degree and water uptake behavior. DC tablets containing 80% OCMCS presented behavior as an effective swelling-control system. The DC tablets with 5% OCMCS showed a similar release profile at formulations with 30% HPMC.

Conclusion: Spray-dried OCMCS showed great potential as hydrophilic matrices for drug-sustained release.     

The effect of carboxymethyl chitin on sustained drug release of aspirin tablet

Carboxymethyl chitin (CM-chitin) was prepared at room temperature and characterized using ¹H NMR, FTIR and elemental analysis methods. The prepared CM-chitin was then used as a hydrophilic matrix for the preparation of the aspirin sustained release tablets via the wet granulation technique. The aspirin release profiles of the prepared tablets in a simulated gastric fluid and simulated intestinal fluid, respectively, were studied with the rotating-basket dissolution method. The results showed that the aspirin release rate in simulated gastric fluid was lower than that in simulated intestinal fluid. Thus, CM-chitin proved to be a pH-sensitive hydrophilic matrix.     

Investigation of the effect of tablet surface area/volume on drug release from hydroxypropylmethylcellulose controlled-release matrix tablets

The purpose of this study was to investigate the influence of tablet surface area/volume (SA/Vol) on drug release from controlled-release matrix tablets containing hydroxypropylmethylcellulose (HPMC). Soluble drugs (promethazine HCl, diphenhydramine HCl, and propranolol HCl) were utilized in this study to give predominantly diffusion-controlled release. Drug release from HPMC matrix tablets with similar values of SA/Vol was comparable within the same tablet shape (i.e., flat-faced round tablets) and among different shapes (i.e., oval, round concave, flat-faced beveled-edge, and flat-faced round tablets). Tablets having the same surface area but different SA/Vol values did not result in similar drug release; tablets with larger SA/Vol values hadfaster release profiles. Utility of SA/Vol to affect drug release was demonstrated by changing drug doses, and altering tablet shape to adjust SA/Vol. When SA/Vol was held constant, similar release profiles were obtained with f2 metric values greater than 70. Thus, surface area/volume is one of the key variables in controlling drug release from HPMC matrix tablets. Proper use of this variable has practical application by formulators who may need to duplicate drug release profiles from tablets of different sizes and different shapes.     

Directly compressed mini matrix tablets containing ibuprofen: preparation and evaluation of sustained release

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.     

Influence of technological factors on formulation of sustained release tablets

Abstract

Theoretically expected rates of release of solid drugs incorporated into solid matrices have been derived for several model systems. Mathematical relations have been obtained for cases (a) where the drug particles are dispersed in a homogeneous, uniform matrix which acts as the diffusional medium and (b) where the particles are incorporated in an essentially granular matrix and released by the leaching action of the penetrating solvent. A number of technological factors are influencing the formulation of sustained release tablets. It was found that the choice of matrix material, amount of drug incorporated in matrix, matrix additives, the hardness of the tablet, density variation, and tablet shape could markedly affect the release rate and also the formulation.     

Influence of technological factors on formulation of sustained release tablets

Theoretically expected rates of release of solid drugs incorporated into solid matrices have been derived for several model systems. Mathematical relations have been obtained for cases (a) where the drug particles are dispersed in a homogeneous, uniform matrix which acts as the diffusional medium and (b) where the particles are incorporated in an essentially granular matrix and released by the leaching action of the penetrating solvent. A number of technological factors are influencing the formulation of sustained release tablets. It was found that the choice of matrix material, amount of drug incorporated in matrix, matrix additives, the hardness of the tablet, density variation, and tablet shape could markedly affect the release rate and also the formulation.     

Formulation and evaluation of natural gum-based sustained release matrix tablets of flurbiprofen using response surface methodology

Background: This research work was done to design oral sustained release matrix tablets of water-insoluble drug, flurbiprofen, using natural gums as the matrix polymers and to evaluate the drug release characteristics using response surface methodology. The central composite design for two factors at five levels each was employed to systematically optimize drug release profile. Method: Matrix tablets were prepared by direct compression technique. Xanthan and acacia gums were taken as the independent variables. Fourier transform infrared spectroscopy studies were also performed to find out the stability of drug during the direct compression and to check the interactions between polymers and drug. Percent drug release in 2 hours and percent drug release in 8 hours were taken as response variables (Y1 and Y2, respectively). Results: Both the polymers were found to have significant effect on the drug release. Polynomial mathematical models, generated for the response variables using multiple linear regression analysis, were found to be statistically significant (P < 0.05). Contour plots were drawn to depict the relationship between response variables and independent variables. Conclusion: The formulated matrix tablets followed zero-order kinetics with negligible drug release in 0.1 N HCl at pH 1.2, which was the objective of this study to produce a formulation avoiding the gastric effects of flurbiprofen.     

Evaluation of hydrophilic,hydrophobic and waxy matrix excipients for sustained release tablets of Venlafaxine hydrochloride

Objective: Venlafaxine is freely soluble In water and administered orally as hydrochloride salt In two to three divided doses. In the present investigation different release retarding matrices have been evaluated for sustained release of venlafaxine hydrochloride (VH) from the formulated tablets.

Materials and methods: Sustained release matrix tablets were formulated using different hydrophilic, hydrophobic and waxy materials as matrix formers. Tableting was done by pre-compression, direct compression and hot melt granulation depending on the type of matrix material used and evaluated for different tests. The formulated tablets were compared with commercial venlafaxine products. In vitro drug dissolution profiles were fitted In different mathematical models to elucidate the release mechanism.

Results: Dissolution data showed that commercial formulations Venlor XR^® and Venfax PR^® released the entire drug withIn 8?h where as the formulated tablets with hydroxypropylmethylcellulose (HPMC) and cetyl alcohol as matrix formers provided sustained release of drug for 14–15?h. The release was found to follow Hixson Crowel and Higuchi kinetics for HPMC and cetyl alcohol tablets, respectively.

Conclusion: The developed matrix tablet formulations with HPMC and cetyl alcohol provided sustained release profiles for prolonged periods than commercial formulations.     

Formulation and development of orodispersible sustained release tablet of domperidone

Abstract

Commercially available domperidone orodispersible tablets (ODT) are intended for immediate release of the drug, but none of them have been formulated for sustained action. The aim of the present research work was to develop and evaluate orodispersible sustained release tablet (ODT-SR) of domperidone, which has the convenience of ODT and benefits of controlled release product combined in one. The technology comprised of developing sustained release microspheres (MS) of domperidone, followed by direct compression of MS along with suitable excipients to yield ODT-SR which rapidly disperses within 30?seconds and yet the dispersed MS maintain their integrity to have a sustained drug release. The particle size of the MS was optimized to be less than 200?μm to avoid the grittiness in the mouth. The DSC thermograms of MS showed the absence of drug-polymer interaction within the microparticles, while SEM confirmed their spherical shape and porous nature. Angle of repose, compressibility and Hausner’s ratio of the blend for compression showed good flowability and high percent compressibility. The optimized ODT-SR showed disintegration time of 21?seconds and matrix controlled drug release for 9?h. In-vivo pharmacokinetic studies in Wistar rats showed that the ODT-SR had a prolonged MRT of 11.16?h as compared 3.86?h of conventional tablet. The developed technology is easily scalable and holds potential for commercial exploitation.     

High-throughput evaluation of non-swellable controlled release matrix tablets

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as “high-throughput” in terms of amount of labor and resources required in comparison to that of dissolution.     

Designing of the fixed-dose gastroretentive bilayer tablet for sustained release of metformin and immediate release of atorvastatin

Patients with type 2 diabetes mellitus have a high risk of cardiovascular disease mainly caused by dyslipidemia. Metformin and atorvastatin are preferentially used to treat type 2 diabetes mellitus and dyslipidemia, respectively. The aim of this study was to develop a once-a-day fixed-dose combination tablet containing metformin and atorvastatin. For this purpose, we designed gastroretentive bilayer tablets consisting of 500?mg metformin in a sustained release layer and 10?mg atorvastatin in an immediate release layer. In addition, we modified the formulation to maintain a dual release pattern for the kinetically different layers for once-daily dosing. The gastroretentive bilayer tablet was developed using polyethylene oxide as a swellable polymer and ammonium methacrylate copolymer as a granule-coating polymer with minimal use of excipients. In vitro release patterns of metformin and atorvastatin from the developed formulation were similar to those of the reference drugs, Glucophage XR for metformin and Lipitor for atorvastatin, with satisfactory dissolution similarity factor (f₂) values. The pharmacokinetic study showed the sustained and immediate absorptions of metformin and atorvastatin, respectively, in beagle dogs. The 90% confidence intervals of the ratios of ln values of AUCs of test formulation F3 and respective reference formulations of metformin and atorvastatin were 0.93–1.12 and 0.89–1.17, respectively, compared with their respective reference drugs. This formulation could contribute to improving the compliance and therapeutic outcome of patients with metabolic diseases.     

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.     

Statistical evaluation of influence of xanthan gum and guar gum blends on dipyridamole release from floating matrix tablets

The present investigation explored the use of xanthan gum and guar gum for development of floating drug delivery system of dipyridamole using factorial design approach. The content of polymer blends (X(1)) and ratio of xanthan gum to guar gum (X(2)) were selected as independent variables. The diffusion exponent (n), release rate constant (k), percentage drug release at 1 hr (Q(1)) and 6 hr (Q(6)) were selected as dependent variables. Tablets of all batches had desired buoyancy characteristics. Multiple regression analysis with two way ANOVA revealed that both the factors had statistically significant influence on the response studied (p<0.05). Results of Tukey test showed the relative contribution of each level of different factors for the response studied. It was concluded that the ratio of xanthan to gaur gum had equal or dominant role as controlling factor on kinetics of drug release compared to content of polymer blends.     

Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Role of cellulose ether polymers on ibuprofen release from matrix tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Novel combination of anionic and cationic polymethacrylate polymers for sustained release tablet preparation

The objectives of this study were to prepare and evaluate a novel sustained release tablet formulation using a binary mixture of polymethacrylate polymers: Eudragit E-100 (EE) and Eudragit L-100 (EL) in their salt forms. Tablets prepared using EE-citrate and EL-Na showed the highest degree of swelling among other combinations of EE and EL. The drug release rates were independent of the pH of the dissolution medium as the release profiles exhibited a continuous release pattern with no burst effect when changing the pH of the medium. These results, along with other test results, indicated the presence of an ionic interaction between both polymers when combined in the salt forms.