Evaluation of Thermal and Film Forming Properties of Acrylic Aqueous Polymer Dispersion Blends: Application to the Formulation of Sustained-Release Film Coated Theophylline Pellets

Abstract

Aqueous acrylic polymer dispersions were blended in order to improve processing and film formation from acrylic polymers with poor film forming properties and/or to obtain sustained-release film coated pellets with optimal barrier properties according to the physicochemical and pharmacokinetic requirements of the active substance.

Heterogeneous film structures are generally obtained from blends containing an association of hard acrylic polymers (Eudragit* RS30D, S100) with the soft Eudragit* NE30D when the drying temperature is lower than the minimum film forming temperature (MFT) of the hard acrylic polymers. The Tg and MFT values of the hard acrylic polymers are not modified in the presence of the soft polymer as shown by the thermograms of these blends which are generally characterized by two individual glassy transitions.

On the other hand, a wide range of drug dissolution profiles can be obtained from film coated pellets either by using, in different proportions, the insoluble but readily permeable Eudragit* RL30D in association with the less permeable Eudragit* RS30D in order to obtain pH-independent permeability membrane, or by mixing the anionic methacrylic acid copolymers (L30D, S100) with the neutral NE30D in order to obtain pH-dependent permeability film coated pellets showing higher dissolution release rates at intestinal pH values.     

The MiniWiD-Coater. III. Effect of Application Temperature on the Dissolution Profile of Sustained-Release Theophylline Pellets Coated with Eudragit Rs 30 D

Theophylline pellets were coated with Eudragit RS 30 D in a miniature fluid-bed pan coater called MiniWiD developed recently. The dispersions were plasticized with varying amounts of triethyl citrate (TEC), dibutyl phthalate (DBP), and polyethylene glycol 6000 (PEG) and applied at different temperatures ranging from 25 to 45 °C. Theophylline release was tested by dissolution using the USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours.

At a coating level of 4 % (0.7 mg/cm²) sustained-release profiles were obtained from dispersions plasticized with TEC or DBP. By reducing the amount of plasticizer from 20 to 10%, films with higher permeabilities were obtained. This effect was compensated by tempering the pellets at 50 deg;C for 24 hours. The coating temperature had little effect on the dissolution profiles of TEC-plasticized films and no effect on films with DBP.

Coatings plasticized with 20% PEG were applied at temperatures ranging from 25 to 45 °C. These films required a coating level of about 18 % (3.3 mg/cm²) to provide comparable sustained-release properties. In contrast to DBP and TEC, a strong influence of the coating temperature on the release rates was observed in which higher temperatures led to slower release rates. This behavior can be explained by the minimum film-forming temperature (MFT). Since PEG does not lower the MFT of Eudragit RS 30 D, the application of these films below the MFT of 45 °C is associated with a lower degree of film formation.     

Acrylic Latices from Redispersable Powders for Peroral and Transdermal Drug Formulations

Aqueous dispersions of acrylic resins may be converted to pow ders by spray or freeze drying. Such solids contain loose ag glomerates of discrete latex particles, that disintegrate easily into the original latex particles of less than 2 µ;m in diameter. No film formation occurs, provided that the minimum film forming temperature of the latex is not exceeded during drying.

Such powders can be redispersed in water in the presence of 3-6 mol% of alkali or organic bases to obtain a stable latex system. This can be used for enteric film coating in the same way as the original latex dispersions.

Redispersed methacrylic acid copolymers can be mixed with neu tral, permeable emulsion polymers to adapt the release profile of drugs more specifically to match their pharmacokinetic prop erties. In this way the pH-dependent solubility of methacryic acid copolymers, which controls the release in the gut by dissolution or increasing permeability can be combined with the pH-independent permeability of neutral acrylic ester polymers, to give time controlled retardation. Similar formulations of acrylic resins can also be used to solve several problems of transdermal delivery systems.

The described redispersable polymer powders are stable under normal storage conditions, so their handling and use as redispersed aqueous coating formulations is much more easier and will open an extended field of application.     

Peroral Sustained-Release Film-Coated Pellets as a Means to Overcome Physicochemical and Biological Drug-Related Problems. I. In Vitro Development and Evaluation

Abstract

In vitro preformulation testing has shown that the solubility and dissolution rate of the model drug compound ucb 11056 are highly pH dependent. Considering this, different sustained-release (SR) oral dosage forms of ucb 11056 were developed aiming to obtain the most constant and complete release of the drug during transit in the gastrointestinal (GI) tract. Classical approaches based on the use of SR formulations such as hydrophilic matrix tablets or pellets coated with one film-forming polymer (Eudragit NE30D or L30D-55) did not fulfill all expectations on the basis of their in vitro evaluation, i.e., the drug release and pattern remained highly dependent on the pH of the dissolution medium. Therefore, taking advantage of the flexibility of release adjustment obtainable from coating of pellets with different kinds of pH-sensitive film layers, a quite satisfactory pH independence of the release characteristics was obtained using formulation blends of neutral and anionic acrylic polymers. For the selected SR pellets batch 15 coated with NE30D/L30D-55 (7:3), the tridimensional topographic representation of the drug release versus time and pH showed that, notwithstanding the pH-dependent aqueous solubility of the drug, the release profiles were relatively homogeneous for any pH value ranging between 1 and 7.     

Compression Behavior of Acetylsalicylic Acid Pellets

An instrumented tablet press was used to study the compression behavior of different acetylsalicylic acid (AAS) formulations. Formulations of AAS crystals and uncoated AAS pellets have compression behavior similar to formulations of AAS pellets coated with acrylic resins (Eudragit RS) and mixed with a 20% of microcrystalline cellulose. Formulations of AAS coated pellets without any excipient exhibited a more plastic compression behavior then the other formulations. Matrix tablets of AAS were produced by compression of formulations of AAS coated pellets without any excipients.

The drug release profile of the pellets before and after compression was also studied. Microcrystalline cellulose concentrations higher than 15% w/w were required to obtain tablets of coated pellets with drug release profiles similar to the coated pellets before compression. It can be concluded from the present work that compression data of coated particles can be useful to study the possible damage of the film coat of the particles during tableting. Futhermore, instrumented tablet press data can be a good complement of in vitro drug release studies.     

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.     

Use of proteins to minimize the physical aging of EUDRAGIT sustained release films

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.     

Use of Colloidal Silica as a Separating Agent in Film Forming Processes Performed with Aqueous Dispersion of Acrylic Resins

Aqueous dispersion of polymers are going to take the place of the corresponding organic solution in the film forming process of tablets, pellets and granules, because of some definite advantages.

Among the additives used in formulation techniques, talc, that is normally utilized as an antiadherent and polishing agent, presents some problems connected with its tendency to form sedimentation. For this reason, during the film coating operation, the dispersion must be always kept under constant and proper agitation, however, the danger of blocking the piping and the spraying system of the equipment employed cannot be completely avoided.

On the bases of these observations, the aim of this research work is to evaluate the possibility of substituting talc with colloidal silica as separating agent in aqueous dispersion of film acrylic resins, normally used in the preparation of prolonged release systems.

Results concerning fluid bed coating processes of pellets prepared by extrusion-spheronization technique have been reported, with particular attention to usable concentration of colloidal silica and to possible influence of these on the drug release characteristics of the systems obtained.     

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.     

Preparation and bioavailability of sustained-release doxofylline pellets in beagle dogs

The objective of this study was to develop doxofylline-loaded sustained-release pellets coated with Eudragit NE30D alone (F1) or blend of Eudragit RL30D/RS30D (F2) and further evaluate their in vitro release and in vivo absorption in beagle dogs. Doxofylline-loaded cores with a drug loading of 70% (w/w) were prepared by layering drug-MCC powder onto seed cores in a centrifugal granulator and then coating them with different kinds of polymethacrylates in a bottom-spray fluidized bed coater. Dissolution behaviour of these formulations was studied in vitro under various pH conditions (from pH 1.2 to pH 7.4) to evaluate the effect of pH on drug release profiles. It was found that F2 produced a better release profile than F1 did and two different release mechanisms were assumed for F1 and F2, respectively. The relative bioavailability of the sustained-release pellets was studied in six beagle dogs after oral administration in a fast state using a commercially available immediate release tablet as a reference. Coated with Eudragit NE30D and a blend of Eudragit RL30D/RS30D (1:12), at 5% and 8% coating level, respectively, the pellets acquired perfect sustained-release properties and good relative bioavailability, with small fluctuation of drug concentration in plasma. But combined use of mixed Eudragit RL30D/RS30D polymers with proper features as coating materials produced a longer T(max), a lower C(max) and a little higher bioavailability compared to F1 (coated with Eudragit NE30D alone). The C(max), T(max) and relative bioavailability of F1 and F2 coated pellets were 15.16 microg/ml, 4.17 h, 97.69% and 11.41 microg/ml, 5 h, 101.59%, respectively. Also a good linear correlation between in vivo absorption and in vitro release was established for F1 and F2, so from the dissolution test, formulations in vivo absorption can be properly predicted.     

Preparation and Bioavailability of Sustained-Release Doxofylline Pellets in Beagle Dogs

The objective of this study was to develop doxofylline-loaded sustained-release pellets coated with Eudragit® NE30D alone (F1) or blend of Eudragit® RL30D/RS30D (F2) and further evaluate their in vitro release and in vivo absorption in beagle dogs. Doxofylline-loaded cores with a drug loading of 70% (w/w) were prepared by layering drug-MCC powder onto seed cores in a centrifugal granulator and then coating them with different kinds of polymethacrylates in a bottom-spray fluidized bed coater. Dissolution behaviour of these formulations was studied in vitro under various pH conditions (from pH 1.2 to pH 7.4) to evaluate the effect of pH on drug release profiles. It was found that F2 produced a better release profile than F1 did and two different release mechanisms were assumed for F1 and F2, respectively. The relative bioavailability of the sustained-release pellets was studied in six beagle dogs after oral administration in a fast state using a commercially available immediate release tablet as a reference. Coated with Eudragit® NE30D and a blend of Eudragit® RL30D/RS30D (1:12), at 5% and 8% coating level, respectively, the pellets acquired perfect sustained-release properties and good relative bioavailability, with small fluctuation of drug concentration in plasma. But combined use of mixed Eudragit® RL30D/RS30D polymers with proper features as coating materials produced a longer T_max, a lower C_max and a little higher bioavailability compared to F1 (coated with Eudragit® NE30D alone). The C_max, T_max and relative bioavailability of F1 and F2 coated pellets were 15.16 μg/ml, 4.17 h, 97.69% and 11.41 μg/ml, 5 h, 101.59%, respectively. Also a good linear correlation between in vivo absorption and in vitro release was established for F1 and F2, so from the dissolution test, formulations in vivo absorption can be properly predicted.     

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.     

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.     

The MiniWiD-Coater. III. Effect of Application Temperature on the Dissolution Profile of Sustained-Release Theophylline Pellets Coated with Eudragit Rs 30 D

Abstract

Theophylline pellets were coated with Eudragit RS 30 D in a miniature fluid-bed pan coater called MiniWiD developed recently. The dispersions were plasticized with varying amounts of triethyl citrate (TEC), dibutyl phthalate (DBP), and polyethylene glycol 6000 (PEG) and applied at different temperatures ranging from 25 to 45 °C. Theophylline release was tested by dissolution using the USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours.

At a coating level of 4 % (0.7 mg/cm²) sustained-release profiles were obtained from dispersions plasticized with TEC or DBP. By reducing the amount of plasticizer from 20 to 10%, films with higher permeabilities were obtained. This effect was compensated by tempering the pellets at 50 deg;C for 24 hours. The coating temperature had little effect on the dissolution profiles of TEC-plasticized films and no effect on films with DBP.

Coatings plasticized with 20% PEG were applied at temperatures ranging from 25 to 45 °C. These films required a coating level of about 18 % (3.3 mg/cm²) to provide comparable sustained-release properties. In contrast to DBP and TEC, a strong influence of the coating temperature on the release rates was observed in which higher temperatures led to slower release rates. This behavior can be explained by the minimum film-forming temperature (MFT). Since PEG does not lower the MFT of Eudragit RS 30 D, the application of these films below the MFT of 45 °C is associated with a lower degree of film formation.     

Studies of Hie Effect of Powder Moisture Content on Drug Release from Hard Gelatin Capsules

The in vitro dissolution of model formulations from hard gelatin capsules containing drug: diluent powder mixtures at different moisture levels has been studied. The capsules were filled to a constant porosity of 50%. to contain either sodium barbitone or barbitone in 50:50 mixture with lactose or maize starch, the latter at one of three moisture levels. In addition, capsules containing drug alone were examined. The wettability and polarity indeces of the individual powders and binary mixtures, as well as the permeability and liquid penetration rates of powder beds were also determined.

The presence of either excipient was found to modify the time for 50% drug dissolution (t₅₀) compared with drug alone for all formulations examined, apart from the sodium barbitone: lactose capsules. The rate of drug dissolution was also dependent on the initial powder moisture content for the drug:starch formulations. Open storage of capsules at 20^%/75%. R.lt. generally increased t₅₀figures.

The findings are discussed in terms of the nature of the surfaces of the powder particles, moisture sorption phenomena and factors such as powder bed permeability and water penetitration lates.     

Technological Evaluation of three Enteric Coating Polymers I. With an Insoluble Drug

The enteric properties of a recent cellulose polymer, cellulose acetate trimellitate (CAT, EASTMAN KODAK) were evaluated on an insoluble substract for comparison, included in this paper are the properties of two other cellulose esters: cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HP55).

The physical properties and disintegration time at pH 1.2 and 6.5 were influenced by the level of coating solution. The gastroresistance was obtained more fastly with CAT and CAP than for HP55.

The influence of coating solution on drug release from tablet was investigated. The dissolution studies were made allowing the variation of pH in the dissolution medium during the kinetics.

Drug release from coated tablets was found to be dependent upon the type of polymers used to form film: higher release rates were obtained with CAT compared to CAP and HP55.     

Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters

d-Indobufen pellets containing pH adjusters (acids, buffer, salt) were prepared by extrusion-spheronization technology.

The interaction effect between some processing variables (feeding/agitator speeds of extruder, plate speed and residence time of spheronizer) was evaluated by comparing the basic formulation pellets with the pellets in which the soluble filler (lactose) was substituted by fumaric, tartaric and citric acids and also sodium citrate.

The criteria of formulation and process evaluation were the reproducibility of the particle size distribution, the density, the hardness and morphological properties, in addition to the reproducibility of the drug dissolution rates.

In all cases, the physical/technological characteristics were not influenced very much by pH adjuster incorporation, but the drug dissolution profiles showed some significant variations in the first hour. As a logical extension of this work, wet granulations with aqueous ethylcellulose and acrylic resin dispersions instead of only water were tested to evaluate the wetting effect of the release modifier inclusion. The results confirmed the validity of polymeric systems in the preparation of pellets and their ability to produce a further delay of d-Indobufen release.     

Preparation and Dissolution Characteristics of Prolonged Release Mebeverine-HCL Beads

Different batches of slow release mebeverine-HCl beads were prepared by pan coating technique using different release retarding polymers viz Eudragit RL₁₀₀, Eudragit RS₁₀₀ and Ethyl cellulose. The thickness of the coats was controlled by changing the amounts of the added polymers. Pre- and overcoating of the beads with bees wax was also carried out. Mixtures of pre-waxed Eudragit RS₁₀₀ coated and uncoated beads in different ratios were prepared to control both drug content and release.

Dissolution profiles of mebeverine HCl from the prepared beads were investigated using USP XX rotating basket method. Prolonged release of mebeverine-HCl was obtained from different batches of the coated beads with the advantage of no initial dumping of the water soluble drug. The release of mebeverine-HCl from the beads coated with acrylic resins and ethyl cellulose as well as waxed acrylic resins coated beads was diffusion controlled according to Higuchi model. Beads coated with ethyl cellulose showed a different release pattern when pre-or overcoated with wax. By altering the ratios of prewaxed Eudragit Rs₁₀₀ coated and uncoated beads in formulated mixtures, it was possible to control both mebeverine-HCl content and release rate.     

Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

Aqueous Acrylic Resin for Coating an Original Theophylline Granulate

Spherical granules of theophylline, microcrystalline cellulose and lactose are prepared in a high speed granulator using an original method. Successively, the fraction of granules selected is coated with Eudragit RS 30D in a fluid bed coating machine using the bottom spray system and the wurster column. Finally, these granules are compressed into tablets of different hardnesses.

Dissolution studies reveal a zero order release of theophylline from the coated granules. After compression, the kinetics is modified but the tablets remain efficient to control the theophylline release during 8 hours.