Evaluation of Drug-Containing Polymer Films Prepared from Aqueous Latexes

Polymeric films containing salicylic acid or propranolol HC1 were prepared by casting and drying a drug-containing, aqueous colloidal polymer dispersion (Eudragit NE 30D) as an alternative to films cast from organic polymer solutions. The drug was either dissolved (salicylic acid) or dissolved/ dispersed (propranolol HC1) in the polymeric matrix. Incompatibilities (flocculation or coagulation) between salts of basic drugs and two ethylcellulose latexes were overcome by substituting the anionic surfactants with a nonionic surfactant (Pluronic P103). The drug release was studied as a function of drug loading, film thickness, amount of hydrophilic additive (hydroxypropyl methylcellulose), and storage humidity. The release of propranolol HC1 (monolithic dispersion) was a combination of diffusion through the polymer and pores or channels; the extent of each release mechanism depended on the drug loading. On DSC thermograms, melting transitions were obtained with monolithic dispersions but not with monolithic solutions. The heat of fusion was linearly correlated to the amount of drug in the films. The amount of drug remaining in the film after the dissolution study was not detectable and corresponded to the drug dissolved in the polymer. The drug release increased with increased drug loading and increased amount of hydroxypropyl methylcellulose but was independent of film thickness and relatively insensitive to different storage humidities.     

Development and characterization of membrane for local delivery of cephalexin

Laminated films composed of drug-containing reservoir layer and drug-free membrane were prepared. Zero-order drug release with lag time was achieved by laminating drug-free film onto the reservoir layer, while burst effect was observed on cast-on film. The rate controlling membrane was either attached to or cast directly into the reservoir. The release rate was independent on the reservoir composition but dependent on the composition of rate-controlling membrane. In growth inhibitory test of cephalexin from Eudragit RS film toStreptococcus Mutans, the disk even after release test for 72 hours showed more bacterial growth inhibition than that of control. Permeation of drug through rat skin was proportional to the HPC fraction in the film. We could control the release of cephalexin from the film by changing the fraction of Eudragit RS, HPC and DEP content. Consequently, Eudragit RS/HPC film was found to be very effective system for local delivery of drugs.     

Physical and chemical factors influencing the release of drugs from acrylic resin films

An investigation was conducted to evaluate the factors influencing the release of salicylic acid and chlorpheniramine maleate from polymethacrylate amino-ester copolymer films (Eudragits RL PM and RS PM). Differential scanning calorimetry was performed on the films to study the solubility of drug in the polymer and to determine the effect of added drug on the thermal properties of the film. Incorporation of drug into the polymers decreased the glass transition temperature of the polymers. Dissolution of drug from monolithic slabs was followed as a function of temperature, drug concentration in the films, and ionic strength of the release media. In addition, adsorption studies were conducted with each drug:polymer combination to help explain release results and further characterize the drug:polymer interactions that occurred. The rate of drug release increased with increasing temperature. Adsorption of salicylic acid by the polymers was believed to influence the drug release profiles observed for different drug loadings and ionic strengths. Eudragit RL was found to adsorb salicylic acid to a greater extent than the Eudragit RS. Chlorpheniramine maleate was not found to be adsorbed by either polymer.     

Relationship of film properties to drug release from monolithic films containing adjuvants.

The rate of drug release from a polymeric matrix system was influenced by the physical and chemical properties of the monolithic films. The model drugs, salicylic acid and chlorpheniramine maleate, and two poly(methyl methacrylate) copolymers of different permeabilities (Eudragit RL and Eudragit RS), with and without additional adjuvants, were used to form monolithic matrix films for controlled drug release. Adjuvants, including polyethylene glycols (PEG 400 and PEG 8000) and poly(vinylpyrrolidones) (PVP-K15 and PVP-K90), were incorporated into films of Eudragit RL PM and Eudragit RS PM. The moisture permeation constant, glass transition temperature (Tg), tensile strength, and drug release profiles were determined for each acrylic resin slab to correlate the physicochemical and physicomechanical film properties to observed drug release. Faster rates of drug diffusion were observed with the addition of PEG 400 to the films, because of its plasticizing effect and the resultant increased moisture permeability of the matrix. An exception existed with the Eudragit RL PM film containing salicylic acid where drug-polymer interactions inhibited drug diffusion. The small changes in moisture permeability, Tg, and tensile strength observed with incorporation of the PVPs had an insignificant influence on the dissolution results for salicylic acid from Eudragit RS PM films. Increases in the tensile strength and Tg after addition of PVP to the Eudragit RS PM matrix support the observed decreased rate of diffusion for chlorpheniramine maleate. The pores formed by migration of the hydrophilic adjuvants from the films altered the diffusion kinetics of the matrix, compared with that of the nonporous polymer, when only the antihistamine was present.     

Mechanical Properties of Dry and Wet Cellulosic and Acrylic Films Prepared from Aqueous Colloidal Polymer Dispersions Used in the Coating of Solid Dosage Forms

The mechanical properties of dry and wet polymeric films prepared from various aqueous polymeric dispersions were evaluated by a puncture test. They were studied with respect to type of polymer dispersion [cellulosic: Aquacoat and Surelease; acrylic: Eudragit NE, L, RS, and RL 30 D], plasticizer type (water-soluble or water-insoluble), drying or curing conditions, method of film preparation (pseudolatex- vs solvent casting) and ratio of Eudragit RS/RL 30 D in mixed Eudragit RS/RL films. Dry and wet mechanical strengths of the polymeric films depended primarily on the types of the colloidal polymer dispersion and the plasticizer. Films prepared from ethylcellulose dispersions resulted in very weak and brittle films when compared to the acrylic films. Pseudolatex-cast ethylcellulose films showed lower puncture strength and elongation values when compared to those of the solvent-cast films. Curing of the pseudolatex-cast ethylcellulose films had minimal effects on their mechanical properties. Eudragit L 30D, an enteric polymer dispersion, resulted in brittle films in the dry state, but in very flexible films in the wet state because of the plasticization effect of water. Wet Eudragit RS 30 D polymer films plasticized with water-insoluble plasticizers were significantly more flexible than the corresponding wet films plasticized with water-soluble plasticizers. The water-soluble plasticizers leached from the films during exposure to the aqueous medium, while the water-insoluble plasticizers were almost completely retained within the wet films. The low permeability of a water-soluble drug, chlorpheniramine maleate, and the weak mechanical properties of Aquacoat films could suggest osmotic driven/rupturing effects as the release mechanisms from Aquacoat-coated dosage forms.     

Linear drug release from laminated hydroxypropyl cellulose-polyvinyl acetate films.

Release of drug from a single-layer film containing dispersed drug follows a diffusion-controlled matrix model, where the quantity released per unit area is proportional to the square root of time. The kinetics may be made linear with time (zero order) by laminating a second film without drug to the releasing side of the film with dispersed drug. In this manner, the drug layer serves as a reservoir and controls the duration of drug release, while the nondrug layer functions as a rate-controlling membrane. Zero-order drug release was demonstrated in such laminated films using 18-45 percent pentobarbital, methapyrilene, or salicylic acid contained in hydroxypropyl cellulose as the reservoir layer and mixtures of hydroxypropyl cellulose and polyvinyl acetate as the membrane layer. Inverse relationships between the release rate and membrane thickness and between the logarithm of the rate and the percentage of polyvinyl acetate in the membrane layer were observed. Of the three drugs tested, salicylic acid gave the fastest release rates while pentobarbital gave the slowest.     

Zero order drug delivery from double-layered porous films: release rate profiles from ethyl cellulose,hydroxypropyl cellulose and polyethylene glycol mixtures

Laminated double-layered films comprising a drug-containing and drug-free layer were prepared using tripelennamine, barbitone, salicylic acid and caffeine dispersed in hydroxypropylcellulose (HPC) attached to ethyl cellulose (EC) films containing various proportions of polyethylene glycol (PEG) or HPC to enhance permeability. Drug release in vitro followed zero-order kinetics, rate constants being dependent on the thickness of the drug-free membrane, which was rate-controlling. Thickness-corrected zero order constants were independent of drug-loading, which did, however, control the duration of release. Permeability coefficient measurements on the same rate-controlling films used as single barrier membranes enabled the effective drug concentration (C_o) at the interface between the laminated membranes to be estimated; C_o was independent of drug loading and was of the order expected from the aqueous solubilities of the drugs. Release rates were enhanced by addition of hydrophilic polymer to the rate-controlling membranes, either linearly with fraction of additive for PEG to 0·6 or HPC to 0·4, or logarithmically for HPC from 0·4 to 0·8. Enhancement coefficients, which were different for each system, reflected the different mechanisms of hydrophilic polymer action. PEG was leached out rapidly, pores being formed in the matrix. In contrast, HPC was largely retained, so that the enhancement was less. The logarithmic enhancement stemmed from formation of swollen hydrated channels, which, unlike the low HPC fractions or the PEG systems, allowed entry of buffer ions, so that only in these channel systems were the release rates altered by change of the external pH.     

Non-traditional plasticization of polymeric films

The objective of this study was to investigate the influence of methylparaben, ibuprofen, chlorpheniramine maleate and theophylline on the thermal and mechanical properties of polymeric films of Eudragit RS 30 D. The effects of methylparaben and ibuprofen in the film coating on the rate of drug release from Eudragit RS 30 D coated beads were also studied. The physical and mechanical properties of the cast films and coated beads were investigated using thermal analysis, tensile testing, X-ray diffraction analysis and dissolution testing. The results demonstrated that the glass transition temperature of the Eudragit RS 30 D decreased with increasing levels of methylparaben, ibuprofen and chlorpheniramine maleate in the film. Theophylline exerted no influence on the thermal properties of the polymer. The higher levels of the ibuprofen and methylparaben incorporated into the film resulted in a decrease in the tensile strength of the film. The decrease in Young's modulus of Eudragit RS 30 D coated beads was attributed to an increase in the flexibility of the polymeric films when the level of methylparaben or ibuprofen in the polymeric dispersion was increased. The dissolution data demonstrated that the rate of release of the ibuprofen from coated beads was decreased by increasing the amount of ibuprofen and methylparaben in the polymeric film coating.     

Effect of physical and chemical properties on drug release from selected thermosoftening vehicles.

The release profile of several drugs, (chlorpheniramine maleate, salicylic acid, hydrochlorothiazide, p-hydroxy benzoic acid, sulphafurazole, anhydrous theophylline) and the marker (D&C yellow No. 10) was detailed to determine the effect of physical and chemical properties on release from selected thermosoftening matrices (Gelucire 50/02 and 50/13). At a concentration of drug or marker of 2.5% w/w, hydrochlorothiazide showed the slowest release from G50/02, due to its low aqueous solubility, while theophylline showed the highest release owing to its low mol. wt and moderate aqueous solubility. Release reflected two of the selection criteria, aqueous solubility and mol. wt, set forth for the drug/markers used in the study. The hydrophobic matrix, G50/02, offered no enhancement in drug release and functioned in a manner commensurate with other hydrophobic matrices. No hydrogen bonding was noted between any of the drugs or markers and the matrix. As drug or marker concentration increased from 2.5 to 15% w/w, potential hydrogen bonding was noted between p-hydroxy benzoic acid and the matrix. Theophylline no longer had the highest release being replaced by chlorpheniramine maleate and D&C yellow No. 10. With Gelucire excipient G50/13, chlorpheniramine maleate showed the highest release; it dissolved within the matrix at experimental temperature and lowered the matrix melting point. The matrix swelled upon exposure to the dissolution medium and it was from this swollen layer that release occurred. Sulphafurazole, hydrochlorothiazide, salicylic acid and p-hydroxy benzoic acid exerted a similar effect to chlorpheniramine maleate on the matrix. No hydrogen bonding was observed between the drugs and matrix.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of films used in development of a novel controlled-release system for gastric retention

A novel gastric retention system was developed consisting of a tablet coated with a porous membrane. The membrane consisted of aqueous dispersions of methyl methacrylate copolymers, plasticizers, anti tacking and anti foaming agents. This article presents research work performed in order to characterize these membranes. The films were cast on glass plates coated with teflon. The films were dried at 30°C in a vacuum oven. The three main properties studied on these films were as follows: (1) Transport of drugs across the membrane; (2) mechanical properties; (3) thermo-mechanical properties. These properties were studied to produce a film having the desired characteristics for drug release and mechanical strength. It was observed that the permeability of the drug decreased slightly with increase in the Eudragit® NE 30D concentration. This result correlated well with dissolution rate constants of tablets at 15% coating level. The thermo-mechanical studies helped to understand the results from permeability studies. Based on mechanical properties, a 70:30 ratio of Eudragit® RL 30D and NE 30D was found to be optimum. The study has shown that the evaluation of films will be helpful in providing guidelines in selecting the membrane for the gastric retention system.     

The stability of insulin in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol

Abstract

Non-pareil cores were spray-coated with a chlorpheniramine maleate (an alkylamine antihistamine) layer and a Eudragit^R N overcoat in a Wurster air-suspension apparatus. In vitro dissolution studies demonstrated that drug release was a function of polymer membrane thickness. Polyethylene glycol 6000, as a hydrophillic additive, increased the in vitro release of chlorphenir amine maleate from the pellets. Pellets coated with 8 0% Eudragit^R N, 0 0% talc and 0% polyethylene glycol 6000 were found to display desirable controlled release characteristics for chlorpheniramine maleate over the 8-h testing period, which were also comparable with that of Dykatuss^R capsules. The controlled release pellets exhibited first-order release characteristics for chlorpheniramine maleate. Reproducibility of the manufacturing conditions employed in the study were confirmed thus ensuring reproducibility of drug release characteristics between batches of chlorpheniramine maleate pellets. Drug release from the pellets was shown to be independent of the dissolution method and medium used. Pellets displayed no significant change in drug release characteristics relative to the initial drug release data when stored for 12 weeks at room temperature (20+2) and for 8 weeks at a low temperature (5 + 1 °C). However, pellets stored at 37 °C with 80% relative humidity and at 40 + 2 showed a slower in vitro drug release after 8-week storage and therefore failed to maintain their initial drug release profile.     

Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate

Theophylline pellets were coated with cellulosic (Aquacoat ECD 30, Surelease clear) or acrylic (Eudragit NE30D, RS30D) polymer aqueous dispersions, containing 10% (related to the insoluble polymer content) of pectin HM or calcium pectinate, using a Uni-Glatt fluidized-bed coating apparatus. When commercial pectinolytic enzymes were added to the dissolution media (0.05 M acetate - phosphate buffer, pH 6.0), the release of theophylline from the coated pellets was generally slower than that observed in the media without enzymes. The enzymatic slowing down of the drug release, depending on the type of the aqueous polymer dispersion used, is more important with mixed Eudragit NE/calcium pectinate coated pellets. The results obtained have been examined with regard to the validity of the approach based on the combination of pectins and the insoluble polymer aqueous dispersions intended for specific-delivery of drugs to the colon. The mechanism of the hydrophilic drug release from pellets coated with insoluble polymer aqueous dispersions containing an aqueous gel-forming polymer has been also discussed.     

Influence of hydroxyethylcellulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D.

The objective of this study was to investigate the influence of a hydrophilic polymer, hydroxyethylcellulose (HEC), on the release properties of theophylline from pellets coated with Eudragit RS 30 D, and the physicochemical properties of Eudragit RS 30 D cast films. The release rate of theophylline from Eudragit RS 30 D coated pellets decreased during storage at 25 degrees C/60% RH due to the further coalescence of colloidal acrylic particles. In addition, water-vapor permeability and tensile strength of Eudragit RS 30 D cast film decreased after 1-month storage at 25 degrees C/60% RH. The presence of 10% hydroxyethylcellulose in the coating formulation was shown to stabilize the drug release rate from coated pellets, the water-vapor permeability and the tensile strength of free films. Atomic force microscopy and scanning electronic microscopy were used to demonstrate that the HEC was immiscible with Eudragit RS 30 D in the cast films. The stabilization effect of HEC was investigated and determined to be due to the formation of an incompatible phase between the latex particles which impaired further coalescence of the colloidal acrylic particles.     

扑尔敏缓释微丸的制备及释药动力学研究

应用沸腾包衣工艺经处方、工艺筛选、改变微丸粒径、包衣厚度、膜材料种类及配比等，得到了体外具较理想释药行为的扑尔敏控释微丸。释药动力学研究表明，其前５０％和后５０％药物的释放分别符合零级和一级动力学过程。     

Novel use of Eudragit NE 30D/Eudragit L 30D-55 blends as functional coating materials in time-delayed drug release applications

The objectives of this study were to evaluate the mechanical and thermal properties of films prepared from Eudragit^® NE 30D/Eudragit^® L 30D-55 blends and to examine the dissolution behavior of beads coated with the polymer blends up to 120% weight gain. Eudragit^® NE 30D and L 30D-55 dispersions were blended at 50:50, 67:33, 75:25, and 80:20 ratios. Cast films were evaluated by texture analysis and differential scanning calorimetry. Increasing Eudragit^® NE 30D concentration increased miscibility, softness, and decreased stiffness of the films. At 80:20 ratio, the polymer blend was completely miscible whereby Eudragit^® L 30D-55 was molecularly distributed in the mixture. This was confirmed by SEM analysis. The surface morphology of films and beads was evaluated before and after dissolution by scanning electron microscopy. SEM analysis demonstrated that the size of the pores formed after the dissolution of Eudragit^® L 30D-55 at pH 6.8 was dependent on the miscibility of the Eudragit^® blend. The implications of this effect were apparent in dissolution studies. For the 75:25 and 80:20 blends, a linear increase in lag time up to 7 h was observed with an increase in coat weight gain from 15 to 120%. At 60% weight gain, the 80:20 blend delayed drug release by approximately 7 h whereas the less miscible 75:25 blend delayed drug release by only 3.5 h. A lag time could therefore be controlled by manipulating both the theoretical weight gain of the beads and the concentration of Eudragit^® NE 30D in the blend.     

Development and Evaluation of Oral Controlled Release Chlorpheniramine-Ion Exchange Resinate Suspension

An oral controlled release suspension of chlorpheniramine maleate was prepared using ion-exchange resin technology. A strong cation exchange resin Indion 244 was utilized for the sorption of the drug and the drug resinates was evaluated for various physical and chemical parameters. The drug-resinate complex was microencapsulated with a polymer Eudragit RS 100 to further retard the release characteristics. Both the drug-resinate complex and microencapsulated drug resinate were suspended in a palatable aqueous suspension base and were evaluated for controlled release characteristic. Stability study indicated that elevated temperature did not alter the sustained release nature of the dosage form indicating that polymer membrane surrounding the core material remained intact throughout the storage period.     

Effect of plasticizer on the dynamic surface tension and the free volume of Eudragit systems

The purpose of the present study was to determine the changes of dynamic surface tension of aqueous Eudragit dispersions quantitatively and compare these data with the free volume of the free films formed from several dispersions of different dibutyl sebacate (DBS) concentrations. Eudragit L 30D and Eudragit RL 30D aqueous colloidal polymer dispersions and their cast free films were examined. The concentration of DBS varied in the dispersions from 0 to 20%. The dynamic surface tension of the dispersions were measured by the Du Nouy ring method while the free volume of cast films were determined by positron annihilation spectroscopy. The obtained results show that dynamic surface tension measurements indicate the white point (WP) of Eudragit dispersions by a significant standard deviation increase. This may suggest the applicability of dynamic surface tension measurements for the determination of the WP of polymeric dispersions. A decrease in the WP temperature of Eudragit dispersions with an increasing plasticizer concentration was observed up to the DBS concentration of 10% w/w. Above this concentration neither the WP of the polymer dispersion nor the free volume of the free films of the polymer were changed remarkably.     

Modified release from hydroxypropyl methylcellulose compression-coated tablets

The goal of this study was to obtain flexible extended drug release profiles (e.g., sigmoidal, pulsatile, increasing/decreasing release rates with time) with hydroxypropyl methylcellulose (HPMC) compression-coated tablets. Drugs of varying solubility (carbamazepine, acetaminophen, propranolol HCl and chlorpheniramine maleate) were incorporated into the tablet core in order to evaluate the flexibility/limitations of the compression-coated system. The HPMC-compression-coating resulted in release profiles with a distinct lag time followed by different release phases primarily determined by the drug solubility. Carbamazepine, a water-insoluble drug, was released in a pulsatile fashion after a lag time only after erosion of the HPMC compression-coat, while the more soluble drugs were released in a sigmoidal fashion by diffusion through the gel prior to erosion. With carbamazepine, increasing the molecular weight of HPMC significantly increased the lag time because of the erosion-based release mechanism, while, in contrast, molecular weight did not affect the release of the more soluble drugs. The lag-time and the release rate could also be well controlled by varying the HPMC amount in and the thickness of the compression-coating. A pulsatile release could also be achieved for water-soluble drugs by introducing an enteric polymer coating between the drug core and the HPMC compression-coating. This novel concept of introducing an enteric subcoating eliminated drug diffusion through the gelled HPMC layer prior to its erosion. Incorporating drug in the compression-coating in addition to the tablet core in varying ratios resulted in release profiles with increasing, decreasing or constant release rates. In conclusion, a versatile single-unit delivery system for a wide range of drugs with great flexibility in release profiles was presented.     

Modified release of coated sugar spheres using drug-containing polymeric dispersions

A drug-containing polymeric dispersion was applied onto nonpareil sugar spheres (18/20 mesh) using a fluid-bed spray coater. Eudragit RS30D was selected as the polymeric coating material. Melatonin secreted by the pineal gland in a circadian rhythm was used as a model drug. The release behaviors of the coated sugar spheres were investigated in gastric fluid (pH 1.4) for 2 h, and then continuously in intestinal fluid (pH 7.4) for 14 h. The release rate of the coated sugar spheres decreased with increasing coating levels. The solvent (ethanol) in the coating dispersions significantly decreased the release of the drug due to the good dispersion of the low solubility melatonin in the polymeric films. The polymer (polyvinylpyrrolidone, PVP) and drug contents in the coating dispersions did not affect the release rate. Most of all, the release profiles were drastically changed according to the type and concentration of plasticizers used. The current coating methods that use drug-containing polymeric dispersions could be useful for simultaneous drug loadings and their modified release. The solubilization and controlled release of poorly water-soluble drugs can be achieved as both the solubilizers and drugs are present in the drug-containing polymeric dispersions.     

Microparticles prepared by grinding of polymeric films

Microparticles were prepared by a film grinding method, whereby thin drug-containing ethylcellulose films were cryogenically ground into microparticles. The particle size and shape of the microparticles could be controlled by the thickness of the films and by the milling time. The encapsulation efficiency as well as the in vitro drug release depended on the physical state of the drug in the ethylcellulose matrix (dispersed vs dissolved). Increased drug loadings and decreased particle size and film thickness increased the drug release. Microparticles prepared from cast films were more dense and had a slower drug release compared to microparticles prepared from sprayed films or from films prepared from an aqueous colloidal ethylcellulose dispersion, Aquacoat ECD. Lamination of the drug-containing film with a drug-free polymer layer on both sides resulted in a reduced drug release. Hydrophilic plasticizers acted as pore-formers and accelerated drug release, while lipophilic plasticizers reduced the drug release. The solubility of the drug in the organic polymer solution was one of the main parameters to achieve high encapsulation efficiencies and extended drug release, while dispersed drug was released much faster. The drug release from microparticles prepared by film grinding was faster than from microparticles prepared by the solvent evaporation method. The faster release was attributed to the fractured surface of the ground particles. Grinding of microparticles, which were prepared by the solvent evaporation, also resulted in a faster release.