Cytosine Arabinoside Release from Polymeric Matrices

Abstract

Cytosine arabinoside (Ara-C) has been used in the treatment of acute myeloid leukemia. However, rapid deamination reduces its effectiveness. Polymeric matrices containing ara-C were prepared in polyether polyurethane copolymer to form a protective, supply of ara-C. Release studies from these devices showed linear relationships between Q, the amount release per unit area, versus the square root of time. Burst effects were predominant at higher loading doses. The diffusivity values indicated that enough drug could pass through the polymer for the combination to have potential application as implants in cancer therapy.     

Release Kinetics of Indomethacin from Polymeric Matrices

Polymeric matrices containing three different concentrations of indomethacin 1, 2 and 4% preparations were prepared. The release kinetics of indomethacin from matrices followed Higuchi equation. The effective diffusivity of indomethacin (D_m) was 1.32 × 10^-7 +7.4% cm²/sec. The amount released in 24 hours 2 from 10 cm² matrices with three different concentrations of indomethacin, were 12.0, 18.6 and 25.0 mg respectively. These matrices may potentially be developed as a transdermal therapeutic system.     

Drug Release from Polymeric,Multi-Perforated,Laminated Matrices

Abstract

The release of drug from a planar matrix through multiple holes in a superimposed impermeable laminate has been predicted by a relationship derived from first principles¹. In this work, drug release from a laminated matrix has been investigated and fitted to the model. Although zero-order release kinetics are not predicted by the model, zero-order release was observed possibly due to depletion of the drug from the matrix being compensated for by the modification of an essentially planar geometry.     

Polymeric Amines Induce Nitric Oxide Release from S-Nitrosothiols

Catalytic generation of nitric oxide (NO) from NO donors by nanomaterials has enabled prolonged NO delivery for various biomedical applications, but this approach requires laborious synthesis routes. In this study, a new class of materials, that is, polymeric amines including polyethyleneimine (PEI), poly-L-lysine, and poly(allylamine hydrochloride), is discovered to induce NO generation from S-nitrosothiols (RSNOs) at physiological conditions. Controlled NO generation can be readily achieved by tuning the concentration of the NO donors (RSNOs) and polymers, and the type and molecular weight of the polymers. Importantly, the mechanism of NO generation by these polymers is deciphered to be attributed to the nucleophilic reaction between primary amines on polymers and the SNO groups of RSNOs. The NO-releasing feature of the polymers can be integrated into a suite of materials, for example, simply by embedding PEI into poly(vinyl alcohol) (PVA) hydrogels. The functionality of the PVA/PEI hydrogels is demonstrated for Pseudomonas aeruginosa biofilm prevention with a ≈ 4 log reduction within 6 h. As NO has potential therapeutic implications in various diseases, the identification of polymeric amines to induce NO release will open new opportunities in NO-generating biomaterials for antibacterial, antiviral, anticancer, antithrombotic, and wound healing applications.     

Studies on Drug Release Kinetics from Carbomer Matrices

The objective of this study is to gain a mechanistic understanding of drug release kinetics from directly compressed tablets containing Carbopol 934P and 974P resins. Carbopol resins belong to a family of carbomers which are synthetic, high molecular weight, non-linear polymers of acrylic acid, crosslinked with polyalkenyl polyether. They are currently being used as polymeric matrices for controlling drug release in pharmaceutical tablets. This investigation focuses on the influence of the type of drug and the pH of the dissolution media, along with other factors on the drug release kinetics from carbomer matrices. Directly compressed tablets were prepared using a Stokes single station laboratory press and blends of polymers and lactose with drugs like theophylline, norephedrine HCI, and chlorpheniramine maleate. In vitro. drug release studies from the tablets were performed according to USP method II. Drug release rates were obtained by plotting the fraction released versus time and data fitted to the equation:     

Studies on Drug Release Kinetics from Carbomer Matrices

The objective of this study is to gain a mechanistic understanding of drug release kinetics from directly compressed tablets containing Carbopol 934P and 974P resins. Carbopol resins belong to a family of carbomers which are synthetic, high molecular weight, non-linear polymers of acrylic acid, crosslinked with polyalkenyl polyether. They are currently being used as polymeric matrices for controlling drug release in pharmaceutical tablets. This investigation focuses on the influence of the type of drug and the pH of the dissolution media, along with other factors on the drug release kinetics from carbomer matrices. Directly compressed tablets were prepared using a Stokes single station laboratory press and blends of polymers and lactose with drugs like theophylline, norephedrine HCI, and chlorpheniramine maleate. In vitro. drug release studies from the tablets were performed according to USP method II. Drug release rates were obtained by plotting the fraction released versus time and data fitted to the equation:     

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.     

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.     

In Vitro Release of Neomycin Sulfate from Polymeric Films

Abstract

A study was made of the release of neomycin sulfate from films containing ethyl cellulose or a polyamide. These films were plasticized using hexadecyl alcohol and/or tributyl citrate. Neomycin sulfate was incorporated into the film, and the release of neomycin in a desorbing media of distilled water was measured by periodically removing a sample of desorbing media and determining the neomycin sulfate content spectrophotometrically. The release of neomycin sulfate from these films was also determined microbiologically. This was carried out by measuring the zone of inhibition surrounding a circular disc containing neomycin sulfate which had been placed onto the surface of a Petri dish containing suitable media inoculated with Bacillus subtilis. Hexadecyl alcohol was noted to suppress or decrease the release of neomycin sulfate from ethyl cellulose and polyamide films. Release of neoraycin sulfate from films of ethyl cellulose plasticized with tributyl citrate showed an increase. The results of the microbiological determination were similar to the spectro-photometric results and indicated that the release of neomycin sulfate from ethyl cellulose/tributyl citrate systems was time dependent.     

Controlled Drug Release from a Compressed Heterogeneous Polymeric Matrix: Kinetics of Release

A physical model of a new matrix-type system is presented where constant drug release can be maintained irrespective of the extent of the tortuosity and receding drug boundary. Theophylline base was dispersed as discrete crystals and fine particles in a matrix formed by the cross-linking of polymeric mixtures consisting of PEG, acrylic resins and ethyl cellulose. DSC analysis was performed to identify any solid state inactivation of the drug. Concave tablets at specified pressures were prepared in order to achieve a wide range of release rates and patterns of release. It was found that the patterns of release could be controlled by the formulation components and the manufacturing procedures. Drug release rates were determined spectrophotometrically under sink conditions and the flux of drug release, dQ/dt, from these matrix-type delivery systems was almost constant over 15 hours, during which time about 85% of the active drug was released. The release rate was devoid of any hydrodynamic boundary effect and environmental pH. The cumulative amount of drug released was found to be in accordance with zero-order kinetics. The system can be modified within broad limits and have flexibility as well as a wide spectrum of applicability with respect to different types of drugs.     

Controlled Drug Release from a Compressed Heterogeneous Polymeric Matrix: Kinetics of Release

A physical model of a new matrix-type system is presented where constant drug release can be maintained irrespective of the extent of the tortuosity and receding drug boundary. Theophylline base was dispersed as discrete crystals and fine particles in a matrix formed by the cross-linking of polymeric mixtures consisting of PEG, acrylic resins and ethyl cellulose. DSC analysis was performed to identify any solid state inactivation of the drug. Concave tablets at specified pressures were prepared in order to achieve a wide range of release rates and patterns of release. It was found that the patterns of release could be controlled by the formulation components and the manufacturing procedures. Drug release rates were determined spectrophotometrically under sink conditions and the flux of drug release, dQ/dt, from these matrix-type delivery systems was almost constant over 15 hours, during which time about 85% of the active drug was released. The release rate was devoid of any hydrodynamic boundary effect and environmental pH. The cumulative amount of drug released was found to be in accordance with zero-order kinetics. The system can be modified within broad limits and have flexibility as well as a wide spectrum of applicability with respect to different types of drugs.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Abstract

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

Effects of Excipients on Swelling and Drug Release from Compressed Matrices

Polymers, and particularly hydrogels, are becoming very popular in formulating controlled-release tablets because they are excellent drug carriers. The effects of hydrophilic and hydrophobic polymers, incorporated in matrices containing soluble (propranolol HCl) or less soluble (flurbiprofen) drugs, on swelling and release kinetics were investigated. The results indicate that swelling and release profiles were affected by the amount of ingredients, the characteristics of the polymer, and the drug substances incorporated in the matrices. Swelling may influence the release rate of the drugs from the matrices. The data obtained from the in vitro dissolution study were evaluated on the basis of a theoretical dissolution equation, by linear transformation of the dissolution curve, and by the Peppas equation. The release mechanisms appeared complex and are affected by the composition of the matrix     

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.     

Stereoselective Release Behaviors of Imprinted Bead Matrices

ABSTRACT

In this work, the stereoselective release behaviors of “low”-swelling molecularly imprinted polymer (MIP) bead matrices in pressed-coat tablet type were studied. Either R-propranolol selective MIP or S-propranolol selective MIP was combined with excipients and racemic propranolol and fabricated into the matrix. Subsequently, the release of different propranolol enantiomers from the matrices was examined. Also, the microscopic structure of the hydrated “low”-swelling MIP matrix was determined using a cryogenic scanning electron microscope in order to compare with that of the hydrated “high”-swelling MIP matrix. In vitro release profiles of the “low”-swelling matrices showed a difference in the release of enantiomers, in that the non-template isomer was released faster than the template isomer. However, in the last phase of dissolution this difference reduced and later reversed, resulting at last in the type of specificity being similar to that obtained previously with “high”-swelling MIP matrices.

n summary, MIP beads can be fashioned into matrices and incorporated into different formulations to regulate the resultant stereoselectivity. From the behaviors of stereoselective release observed in MIP matrices, we can conclude that the enantioselective-controlled delivery mechanism of MIPs via formulations depends on the relative affinity of the enantiomer for the template sites, as well as the nature of the polymer, such as hydrophobicity and swellability.     

Mechanisms of Drug Release from Matrices Prepared with Aqueous Dispersion of Ethylcellulose

The objective of this study was to investigate the mechanism of acetaminophen (APAP) release from tablets prepared by the wet granulation method using an aqueous polymeric dispersion (Surelease) as a granulating agent. Tablets compressed from granules containing 10% w/w acetaminophen and 13.44% w/w total solids from Surelease released only 52.4% w/w drug after 120 min of dissolution testing, while controlled tablets without Surelease released 94.1% w/w drug. In order to prepare control tablets of 6.8 Kp hardness value, the upper compressional force recorded was 15.87 kN while tablets containing 13.44% w/w of total solids from Surelease had a recorded force of 6.28 kN. The drug release from tablets prepared with Surelease as a granulating liquid followed the diffusion-controlled model for an inert porous matrix     

Cellulose Matrices for Zero-Order Release of Soluble Drugs

Abstract

Release of two very soluble beta adrenergic blockers namely: metoprolol tartrate and alprenolol HCl from cellulose matrices containing hydroxypropylcellulose (HPC) or sodium carboxymethylcellulose (Na CMC) or methylcellulose (MC), or MC + Na CMC or HPC + Na CMC in different ratios was studied in distilled water using USP dissolution apparatus 2. Increase in the ratio of total polymer to drug has decreased the release rate in a nonlinear manner. When only one polymer (HPC or Na CMC) was used, the release profiles were of first-order or sigmoidal in nature respectively. MC matrices disintegrated in < 1 h. By mixing the drug with an optimum amount of the nonionic (HPC or MC) and anionic (Na CMC) polymers, zero-order release profiles with excellent reproducibility were obtained. Rate of erosion of the matrix was 2.5 times higher when drug, Na CMC and HPC were present compared to the matrix containing only drug and HPC. This indicates that the diffusional pathlength for the drug increases with time when HPC alone was present and the former might be constant when an optimum percent of nonionic (HPC or MC) and anionic (Na CMC) polymers were present in the matrix.     

Direct Compression Controlled Release Tablets Using Ethylcellulose Matrices

Controlled release erodible matrix tablets were manufactured by a simple, direct compression process using ethylcellulose alone as the matrix former. Each of four different viscosity grades of ethylcellulose (10, 20, 45 and 100 cp) was dry mixed with either indomethacin or theophylline and a small amount of lubricant, then directly compressed into tablets. In initial trials, compression force was held constant, resulting in tablets of varying hardness. In a second study, the compression force was varied to produce tablets of equal hardness. Lower viscosity grades of ethylcellulose were more compressible than higher viscosity grades, allowing production of harder tablets for a given drug. Harder tablets resulted in controlled release of the drug over a longer time period. Dissolution studies indicated that tablet hardness is more important in determining dissolution rate than is the polymer viscosity grade. A mathematical model combining diffusion and erosion mechanisms was developed to describe drug release. Improved r² values over pure diffusion, erosion and diffusion/relaxation models were obtained. Examination of residuals indicated that the derived composite model was more appropriate for the data