Use of Proteins to Minimize the Physical Aging of EUDRAGIT® Sustained Release Films

ABSTRACT

The objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT® RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT®/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity. The drug release rate was faster for pellets coated with acrylic dispersions containing 10% gelatin compared to the albumin–containing formulations. When sprayed films were stored at 40°C/75% RH, the water vapor permeability decreased significantly for both EUDRAGIT® films and those containing EUDRAGIT® and albumin; however, there was no significant change in this parameter when 10% gelatin was present. Albumin was released from the acrylic films when the pH of the dissolution media was below the isoelectric point of the protein while no quantitative release of gelatin was observed in pH 1.2 or 7.4 media. The effect of gelatin to prevent the decrease in drug release rate was due to stabilization in water vapor permeability of the film. Acidification of the polymeric dispersion resulted in electrostatic repulsive forces between albumin and the acrylic polymer, which stabilized the drug release rate when the dosage forms were stored in aluminum induction sealed containers at both 40°C/75% RH and 25°C/60% RH.     

Controlled release by permeability alteration of cationic ammonio methacrylate copolymers using ionic interactions

A multiparticulate drug delivery system was studied in which the drug release of a model drug theophylline could be modulated by interactions of ammonio methacrylate polymer and anions. The system consisted of a EUDRAGIT® NE coated anionic core, layered with drug and further layered with EUDRAGIT® RS. The effects of different anions like chloride, succinate, citrate, and acetate as well as the thickness of the polymer layers on the in vitro drug release were studied. It was seen that succinate and acetate anions had permeability enhancing effects and citrate and chloride anions had permeability retarding effects on the polymer. The results indicate that changing these variables would enable us to get a desired release profile and hence the proposed system could be a viable alternative to existing technologies for the development of a controlled drug delivery system.     

Influence of Eudragit NE 30 D blended with Eudragit L 30 D-55 on the release of phenylpropanolamine hydrochloride from coated pellets

The objective of this study was to investigate the influence of Eudragit® NE 30 D blended with Eudragit® L 30 D-55 on the release of phenylpropanolamine hydrochloride (PPA·HCl) from coated pellets. The miscibility of Eudragit NE 30 D/L 30 D-55 blends at different ratios was studied by using differential scanning calorimetry. The release of PPA·HCl from pellets coated with Eudragit NE 30 D alone and a Eudragit NE 30 D/L 30 D-55 blend, when stored at 40°C and 60°C, was determined by UV spectroscopy. Eudragit NE 30 D and Eudragit L 30 D-55 were miscible in ratios greater than 4:1. The curing time that was required to reach an equilibrium state decreased with the addition of Eudragit L 30 D-55. The presence of Eudragit L 30 D-55 also produced a film coating that was less tacky, and a dispersion of Eudragit NE 30 D containing Eudragit L 30 D-55 (5:1) was shown to prevent agglomeration of the pellets during coating and storage.     

The influence of polymeric subcoats and pellet formulation on the release of chlorpheniramine maleate from enteric coated pellets

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

The Influence of Polymeric Subcoats and Pellet Formulation on the Release of Chlorpheniramine Maleate from Enteric Coated Pellets

Abstract

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

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

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

Changes in Drug Release Rate: Effect of Stress Storage Conditions on Film Coated Mini-Tablets

Film coated theophylline mini-tablets were exposed to stress storage conditions to investigate the effect of changes in temperature and relative humidity (RH) on drug release and the integrity of film coatings. The mini-tablets (3mm in diameter, weighing 20±1 mg) were film coated with polymers such as ethylcellulose with PEG (2:1), ethylcellulose with Eudragit L (2:1) and Eudragit RL. Samples were exposed isothermally at 28,35 and 45°C (constant RH ranging between 55 and 60%) for 21,90 and 180 days, as well as cyclically alternating them every 24h at 45°C, 55% RH; 28°C, 20% RH; and 5°C, 10% RH for 90 days. Dissolution profiles determined after storage were compared with those 24h after initial coating. All samples showed that the coating integrity was maintained. However, dissolution was significantly impeded to a degree directly proportional to temperature, whilst the effect of RH appeared insignificant.     

Sustained-Release Pellets Prepared by Combination of Wax Matrices and Double-Layer Coatings for Extremely Water-Soluble Drugs

This study was performed in order to develop a sustained-release pellet formulation containing venlafaxine hydrochloride (VEN), an extremely water-soluble drug, prepared by combination of wax matrices and double-layer coatings. The influence of both double-layer polymeric coats and wax matrices on the release of VEN from sustained-release pellets was investigated. The pellets were prepared by wet mass extrusion spheronization methods and then coated with a fluidized bed coater. For the pellets coated with Eudragit® NE30D alone, a coating level of nearly 40% was required to pass the dissolution test compared with commercial product, and it was accompanied by an unacceptable lag time. The application of an alcohol-soluble polymeric subcoat, Opadry® I, was added before the Eudragit® NE30D coating process, which resulted in a marked delay in drug release. However, a faster release was observed for the formulation coated with a high subcoat level (10%) at the end of the dissolution test. A further delay in drug release was observed when a wax matrix, octadecanol, was added to the core pellet formulation. The kinetics of drug release changed from the Higuchi model to a zero order model and the predominant mechanism controlling drug release changed from diffusion to dissolution upon increasing the amount of octadecanol within the matrix pellets. In addition, the drug release was markedly influenced by the drug to matrix ratio. In conclusion, the 40% drug-loaded core pellets with double-layer coatings (8% Opadry® I and 12% Eudragit® NE30D) and 20% octadecanol matrix produced the desired profile for once-daily sustained release compared with the commercial product, and these pellets remained stable during storage.     

Effect of heat on characteristics of chitosan film coated on theophylline tablets

The effect of heat on the characteristics of chitosan film coated on theophylline tablets was studied. Chitosan of high viscosity grade with molecular weight in the range of 800,000-1,000,000, 80-85% degree of deacetylation was used as a film former by dissolving in 1% v/v acetic acid solution. The coated tablets had been cured at 40, 60, and 100°C for 6, 12, and 24 hr. The morphology of the film at the edge and surface of coated tablets was investigated using scanning electron microscopy. Film cracking was increased and clearly observed in the coated tablets cured at 100°C for 24 hr. As a result, more water could be absorbed into the tablets, followed by faster disintegration and faster drug release. The evidence of partial conversion of chitosonium acetate to chitin in the ¹³C nuclear magnetic resonance (NMR) spectra of chitosan films cured at 40, 60, and 100°C was observed, but it had no effect on drug release behavior. Theophylline tablets coated with chitosan films gave sustained release behavior in various media, i.e., distilled water, 0.1 N hydrochloric acid, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. In addition, the film coating temperature at 55-60°C and curing process at 40 and 60°C had no effect on the drug release from theophylline tablets coated with chitosan polymer. Finally, it might be concluded that both the physical and chemical properties of chitosan films were affected by heat.     

Eudragit RL and RS Pseudolatices: Properties and Performance in Pharmaceutical Coating as a Controlled Release Membrane for Theophylline Pellets

Theophylline Active pellets were coated with Eudragit RL and RS pseudolatices in a fluidized bed. The effects of polymer ratio, additional oven drying, addition of dispersed solids, and addition of water miscible organic solvents on sustained drug release through the lates film were determined by using a modified U.S.P. Paddle dissolution method.

The release rate of theophylline can be varied by changing the polymer ratio. permeability to the drug increases with an increase in the content of Eudragit RL. Additional oven drying at 60°C for 10 hours caused no significant change in the dissolution profiles. The addition of dispersed solids such as talcum and silica resulted in an increase in drug release rate. There is no significant change in dissolution profiles when 50% methanol or acetone was added to the Eudragit RS pseudolatex.     

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.     

Evaluation of hydroxypropyl methylcellulose phthalate 50 as film forming polymer from aqueous dispersion systems

Hydroxypropyl methylcelluose phthalate 50 (HPMCP 50) was evaluated as a film forming polymer from aqueous dispersion systems. The influence of plasticizer type and level on the elasticity of HPMCP 50 free films prepared by the casting method was studied by measuring Young's modulus using an Instron Material Testing System. The release of a water soluble drug in various dissolution media from pellets coated with HPMCP 50 with 30% plasticizer containing various levels of hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC) was also studied. The influence of coating level on drug release from pellets was also investigated. Results showed that HPMCP 50 alone without a plasticizer does not form a film. However, when a plasticizer was added HPMCP 50 did form a film. Also, as the concentration of the plasticizer triethyl citrate was increased the elasticity of HPMCP 50 films was increased. Similar results were obtained with the plasticizer diethyl phthalate. For pellets a high coating level was required to achieve adequate protection in 0.06 N HCl. Drug release from coated pellets was found to be dependent upon the type and the level of the water soluble polymer incorporated with HPMCP 50. Drug release was increased as the percentage of HPC was increased. Higher release rates were obtained with HPMC compared to HPC. Coating level significantly influenced drug release in 0.06 N HCl; however, less of an effect was observed at pH 5.5.     

Evaluation of hydroxypropyl methylcellulose phthalate 50 as film forming polymer from aqueous dispersion systems

Abstract

Hydroxypropyl methylcelluose phthalate 50 (HPMCP 50) was evaluated as a film forming polymer from aqueous dispersion systems. The influence of plasticizer type and level on the elasticity of HPMCP 50 free films prepared by the casting method was studied by measuring Young's modulus using an Instron Material Testing System. The release of a water soluble drug in various dissolution media from pellets coated with HPMCP 50 with 30% plasticizer containing various levels of hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC) was also studied. The influence of coating level on drug release from pellets was also investigated. Results showed that HPMCP 50 alone without a plasticizer does not form a film. However, when a plasticizer was added HPMCP 50 did form a film. Also, as the concentration of the plasticizer triethyl citrate was increased the elasticity of HPMCP 50 films was increased. Similar results were obtained with the plasticizer diethyl phthalate. For pellets a high coating level was required to achieve adequate protection in 0.06 N HCl. Drug release from coated pellets was found to be dependent upon the type and the level of the water soluble polymer incorporated with HPMCP 50. Drug release was increased as the percentage of HPC was increased. Higher release rates were obtained with HPMC compared to HPC. Coating level significantly influenced drug release in 0.06 N HCl; however, less of an effect was observed at pH 5.5.     

Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD

Purpose: Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. Methods: The influence of accelerated curing/storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated as a function of various formulations (sealing, plasticizer content, and pore-former type/amount) and process parameters (process humidity, thermal curing, and organic processing). Results: Conventionally cured Aquacoat/hydroxypropyl methylcellulose-coated pellets were storage stable at ambient conditions and 25°C/60% relative humidity (RH) but showed a decreasing drug release at 40°C/75% RH, which is a required test condition according to ICH guidelines. Conclusion: Only organic processing of dried Aquacoat or unconventionally harsh curing conditions (60°C/75% RH or 80°C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions.     

Effect of neutralization of poly(methacrylic acid-co-ethyl acrylate) on drug release from enteric-coated pellets upon accelerated storage

The effect of neutralization of poly(methacrylic acid-co-ethyl acrylate) or poly(MA-EA) 1:1 (Eudragit^® L 30 D-55) on drug release from enteric-coated pellets was studied upon accelerated storage. The dissolution rate of un-neutralized poly(MA-EA)-coated pellets decreased while the neutralized polymer-coated pellets maintained a constant drug release rate. Dynamic mechanical analysis showed that both un-neutralized and neutralized poly(MA-EA) films became rigid on aging. However, the un-neutralized films were affected more than those neutralized. Neutralization of poly(MA-EA) significantly changed the mechanical properties of coating films and improved the stability of poly(MA-EA) enteric-coated pellets upon accelerated storage at the studied conditions.     

The effect of storage temperatures on the in vitro properties of a polyanhydride implant containing gentamicin

Septacin® is a biodegradable sustained-release implant containing 20% (w/w) gentamicin sulfate. The matrix of the implant is a polyanhydride copolymer composed of erucic acid dimer (EAD) and sebacic acid (SA) in a one-to-one weight ratio. The effect of storage temperatures (-15°C and 25°C) on the stability of Septacin® was evaluated with respect to gentamicin potency, copolymer molecular weight, and in vitro drug release. The drug in polymer matrix was stable for at least 12 months when stored at 25°C, but the molecular weight of the copolymer declined rapidly at this temperature. At -15°C, there was no change in the molecular weight of the copolymer. However, the placebo (copolymer without gentamicin) exhibited a significant drop in copolymer molecular weight at both temperatures. The drug release profiles showed no change for samples stored at -15°C for the duration of this study, while the release of drug slowed down significantly for samples stored at 25°C for longer than one month. A pronounced difference in the morphology of the -15°C samples and the 25°C samples was observed during the in vitro dissolution test; cracking of the -15°C samples was evident, but the 25°C samples remained intact.     

Studies on modifying the tackiness and drug release of Kollicoat EMM 30 D coatings

In the search for antitack additives for Kollicoat EMM 30 D (ethyl acrylate-methyl methacrylate 30% dispersion, Ph. Eur.) film coatings, various possibilities were investigated. The best results were obtained using a combination of simethicone and talc. This mixture was tested on propranolol, theophylline, and verapamil HCl blank pellets in a previously developed Kollicoat EMM 30 D basic formulation. Almost any desired drug release rate can be obtained with all three pellet formulations by varying the two pore formers hypromellose 3mPas and microcrystalline cellulose type 105. A thin application of colloidal silica onto the coated pellets additionally prevents them from sticking together during storage.     

Eudragit NE40–Drug Mixed Coating System for Controlling Drug Release of Core Pellets

This study was aimed at developing a controlled-release coating system around core pellets with aqueous dispersion, along with some water channeling agents. Core pellets of diltiazem were prepared using the extrusion-spheronization technique and subsequently coated with aqueous dispersion of Eudragit NE40 alone, or drug–polymer mixtures using bottom-spray fluidized bed coater. The lag time in drug release profiles increased as the coating levels of Eudragit NE40 were increased, whereas no lag time was observed in core pellets coated with drug–polymer mixtures. Mixed coating at the 7% level exhibited comparatively better release profiles and provided desirable release rates during the 12-hour testing interval. Diltiazem HCl release from mixed coating was fairly independent of pH and drug loading. Curing of coated pellets was found to be an essential step for stable drug release profiles. The selection of core size range had remarkable effect on drug release rate and was considerably reduced by using greater core size.     

The Effect of Polymer Coating Systems on the Preparation, Tableting, and Dissolution Properties of Sustained-Release Drug Pellets

The preparation of sustained-release (SR) drug pellets and their tablets was evaluated. Pellets containing indomethacin, pseudoephedrine hydrochloride (P-HCl), or pseudoephedrine (P) base were prepared by spraying a mixture of drug, Eudragit S-100 resins, dibutyl sebacate, and alcohol onto nonpareil seeds via the Wurster-column process. The oven-dried drug/Eudragit S-100 (DS) pellets were coated with different levels of Eudragit RS and Eudragit S-100 acrylic resins. Tablets containing P-HCl or P-base SR pellets, microcrystalline cellulose, and Methocel K4M were compressed. The solubility of the drug entity in the polymer solution was found to be the most critical factor affecting the yield and the physical properties of the resultant DS pellets. Dissolution studies of Eudragit RS coated drug pellets demonstrated that the release profiles depended not only on the physicochemical properties of the drug, particularly aqueous solubility, but also on the coating levels. The release rate profiles of the matrix tablets can be modified by varying the types of P-HCl or P-base SR pellets in the formulation. The release of drug from the matrix tablets is primarily matrix controlled.     

Drug Release and Surface Morphology Studies on Salbutamol Controlled Release Pellets

The air suspension technique was employed to prepare controlled release pellets of Salbutamol (as the sulphate). The aim of the present study was to determine the influence of various film coating additives on the release characteristics and surface morphology features of salbutamol sulphate pellets coated with Eudragit^R RS30D which is the aqueous dispersion of a polymer synthesised from acrylic and methacrylic acid esters. Surface morphology features, which were examined using Scanning Electron Microscopy, revealed that triethyl citrate (plasticiser) was essential for the coalescence of polymeric membranes around the drug-loaded spheres. Higher concentrations (12.5%) of triethyl citrate displayed a more uniform and continuous polymer film resulting in a slower in vitro drug release. Micrographs of the cross-sections of pellets with higher concentrations of Eudragit^R RS30D indicated the formation of thicker polymer membranes which accounted for the slower drug release rates. Hydroxypropyl methylcellulose (HPMC) inclusion in the polymer film coating increased salbutamol release rates due to its hydrophilic nature which promoted the formation of pores and cracks on the polymer films. A slower in vitro release of salbutamol was observed with higher concentrations of the hydrophobic anti-tackiness agent, magnesium stearate. The addition of salbutamol sulphate powder to the polymer dispersion enhanced drug release rates due to increased film permeability. Polyethylene glycol 200 (PEG 200) resulted in an increased in vitro drug release due to both its water soluble nature as well as impairment of film formation attributed to too high a plasticiser content in the coating formulation. As compared to polyethylene glycol 300 (PEG 300) as a plasticiser, triethyl citrate retarded drug release to a greater extent and formed more homogeneous and compact polymer films. The moisture content of PEG 300 plasticised pellets showed a 0.6% increase in moisture content while triethyl citrate plasticised pellets displayed a loss of 0.01% moisture 8 weeks after storage at room temperature.