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

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

Effect of Various Polymers on Formulation of Controlled Release (CR) Ibuprofen Tablets by Fluid Bed Technique

Abstract

The need for controlled release (CR) formulations of ibuprofen tablet, is well recognized. Some such formulations have been marketed but in general only patented.

The purpose of this study was to develop an air suspension method, using a laboratory scale fluidized bed drier to coat the ibuprofen granules. Different polymers including, Eudragits L100, S100, RL100, RS100, L100+S100 (1:1), RL100+RS100 (1:1), ethyl cellulose (EC) and Eudragit RS100+EC (1:1) were utilized. The drug release medium consisted of buffer pH 1.2 for 1st 2h, buffer pH 4.5 for 2nd 2h and buffer pH 7.5 for remaining period of time in all experiments, but the release behaviour of the drug from some formulations was also studied using distilled water. Of the polymers investigated, Eudragit RS100, EC, Eudragit S100 and Eudragit RS100+EC (1:1) exhibited proper release characteristics when used as coating materials. The release patterns were analyzed from the standpoint of diffusion-controlled processes and as first-order kinetics.     

Effect of Various Polymers on Formulation of Controlled Release (CR) Ibuprofen Tablets by Fluid Bed Technique

The need for controlled release (CR) formulations of ibuprofen tablet, is well recognized. Some such formulations have been marketed but in general only patented.

The purpose of this study was to develop an air suspension method, using a laboratory scale fluidized bed drier to coat the ibuprofen granules. Different polymers including, Eudragits L100, S100, RL100, RS100, L100+S100 (1:1), RL100+RS100 (1:1), ethyl cellulose (EC) and Eudragit RS100+EC (1:1) were utilized. The drug release medium consisted of buffer pH 1.2 for 1st 2h, buffer pH 4.5 for 2nd 2h and buffer pH 7.5 for remaining period of time in all experiments, but the release behaviour of the drug from some formulations was also studied using distilled water. Of the polymers investigated, Eudragit RS100, EC, Eudragit S100 and Eudragit RS100+EC (1:1) exhibited proper release characteristics when used as coating materials. The release patterns were analyzed from the standpoint of diffusion-controlled processes and as first-order kinetics.     

Controlled Drug Delivery of Ph Dependent Soluble Drug-Pindolol

Pindolol, a pH dependent soluble beta adrenoceptor blocker has been formulated into a controlled drug delivery system. Drug pellets were prepared by extrusion spheronization technique. These were coated with different retardant polymers, namely ethylcellulose and Eudragit RS 100. The effect of different variables such as coating level and pH of dissolution medium have been studied. Drug release from pellets were found to be influenced by the pH of the dissolution medium. A flux release of the drug in the acidic buffer was observed from pellets coated with these polymers. To avoid this flux, a top coat using different pH sensitive polymers, namely Hydroxypropylmethyl cellulose phthalate (HPMCP 55) and Eudragit S 100 was successfully attempted and the drug release from the pellets was modified.     

A pH-dependent colon-targeted oral drug delivery system using methacrylic acid copolymers. II. Manipulation of drug release using Eudragit L100 and Eudragit S100 combinations

Tablets containing mesalazine as a model drug were coated using various combinations of two methacrylic acid copolymers, (Eudragit® L100 and Eudragit S100) by spraying from aqueous systems. The Eudragit L100-Eudragit S100 (w/w) combinations studied were 1:0, 4:1, 3:2, 1:1, 2:3, 1:4, 1:5, and 0:1. The coated tablets were tested in vitro for their suitability for pH-dependent colon-targeted oral drug delivery. The dissolution profiles of the drug obtained from the studied tablets demonstrate that the release of the drug could be manipulated by changing the Eudragit L100-Eudragit S100 ratios in the combinations within the pH range between 6.0 and 7.0 in which the individual polymers are soluble, and a coating formulation consisting of a combination of the two polymers can overcome the issue of high gastrointestinal (GI) pH variability among individuals. The results also demonstrate the feasibility of using aqueous dispersions of Eudragit L100-Eudragit S100 combinations for coating tablets for colon-targeted delivery of drugs, and that the formulation can be adjusted to deliver drug(s) at any other desirable site of the intestinal region of the GI tract in which pH of the fluid is within the range 6.0 to 7.0. For colon-targeted delivery of drugs, the proposed combination system is superior to tablets coated with either Eudragit L100 or Eudragit S100 alone.     

Optimization studies on floating multiparticulate gastroretentive drug delivery system of famotidine

The objective of this study was to optimize floating microballoons of famotidine by the emulsion solvent diffusion technique using central composite design. Formulations F1-F15 were prepared using three independent variables (pH of medium, drug: Eudragit S100 ratio and ethanol : dichloromethane ratio) and evaluated for dependent variables (shape, percentage buoyancy, and encapsulation). The optimized formulation F9 was fractionated and a polymer combination of (Eudragit S100 : Eudragit L100-55, 9.5:0.5) resulted in microballoons that exhibited zero order release (94.73%) with 84.20% buoyancy at the end of the eighth hour when studied in the mesh-designed modified USP type II apparatus.     

Preparation of the Traditional Chinese Medicine Compound Recipe Heart-Protecting Musk pH-Dependent Gradient-Release Pellets

ABSTRACT

In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100–Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100–Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.     

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.     

Elaboration and "in vitro" characterization of 5-ASA beads

The purpose of this research was to perform the design and in vitro evaluation of alginate beads containing 5-ASA in order to achieve an oral system that protects the drug until it reaches the colon. Alginate beads were prepared by the well-known ionic gelation reaction (Ca2+). The influence of the incorporation of several polymers (Eudragit FS 30D, Eudragit S100, and chitosan) in the initial formulation was studied. In all formulations, entrapment efficiencies of the drug higher than 70% were obtained. The scanning electron microscopy (SEM) study of beads showed homogeneous sizes and shapes in all cases. Finally, the release behavior of these polymeric beads were also studied and compared. The results indicated that Eudragit FS 30D (26%) showed the most favorable dissolution behavior in terms of achieving a controlled release of 5-ASA. To determine the mechanism of drug release from these beads, the Korsmeyer equation was applied. Qt/Qinfinity <0.9 can be described using a Higuchi model and Qt/Qinfinity=0.7 showed a zero-order release period. This formulation was assayed at other different pH values (pH=6; 6.8; 7.2) to assure that there is no release of 5-ASA until the system reaches the colon. No release was observed at pH 6.0. Release was very slow at pH 6.8; averages about 20% an hour at pH 7.2 and was complete within 4 hour at pH 7.4. So, these Eudragit FS beads exhibited interesting dissolution profiles for the therapy of colon pathologies.     

Preparation of the traditional Chinese medicine compound recipe heart-protecting musk pH-dependent gradient-release pellets

In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100-Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100-Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, II. Combination Resin Formulations

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

Preparation, Physical Characterization, Mechanisms of Drug/Polymer Interactions, and Stability Studies of Controlled-Release Solid Dispersion Granules Containing Weak Base as Active Substance

Verapamil hydrochloride solid dispersion granules were prepared using solvent evaporation technique. Ethyl cellulose, hydroxypropyl cellulose, Eudragit L or Eudragit S were used as polymers for controlling the dissolution rate of the drug substance, and to avoid the continuous decrease of drug dissolution rate at higher pH values. By incorporating Eudragit L in ethyl cellulose network it is possible to prepare controlled-release formulation with increased release rate of active substance (weak base) at higher pH values without causing abrupt drug release at lower pH values. The release rate at low pH values was not highly influenced by Eudragit L content. The behavior of Eudragit L and Eudragit S in coprecipitates was different relating to the solubilization effect and the release of active substance. In order to understand the drug release mechanism better, the release data were tested assuming Higuchi model and first-order kinetic model. Since the calculated correlation coeflcients were very close for both kinetics, to distinguish between the mechanisms the differential forms of first-order and square root of time equation were used. The differential test showed that diffusion-controlled release was operative in solid dispersions, except for series with higher content of Eudragit S. X-ray powder difSraction method, IR spectroscopy studies, and differential thermal analysis were used for physical characterization of coprecipitates and drugpolymer interaction evaluation. After 24 months of real time stability studies, the prepared coprecipitates were still x-ray amorphous, with no changes in their IR spectra and DTA studies. Ehe dissolution rates of the tested formulations showed no significant changes during the stability studies, reflecting the stability of x-ray amorphous drug phase.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,II. Combination Resin Formulations

Abstract

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

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.     

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.     

Formulation development and in-vitro/in-vivo correlation for a novel sterculia gum-based oral colon-targeted drug delivery system of azathioprine

The present study was aimed at designing a microflora triggered colon-targeted drug delivery system (MCDDS) based on swellable polysaccharide, sterculia gum in combination with biodegradable polymers with a view to target azathioprine (AZA) in the colon for the treatment of IBD with reduced systemic toxicity. The microflora degradation study of gum was investigated in rat cecal medium. The polysaccharide tablet was coated to different film thicknesses with blends of chitosan/Eudragit RLPO and over coated with Eudragit L00 to provide acid and intestinal resistance. Swelling and drug release studies were carried out in simulated gastric fluid (SGF) (pH 1.2), simulated intestinal fluid (SIF) (pH 6.8) and simulated colonic fluid (SCF) (pH 7.4 under anaerobic environment), respectively. Drug release study in SCF revealed that swelling force of the gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the chitosan/Eudragit coating in microflora-activated environment. Chitosan in the mixed film coat was found to be degraded by enzymatic action of the microflora in the colon. Release kinetic data revealed that, the optimized MCDDS was fitted well into first order model and apparent lag time was found to be 6?h, followed by Higuchi spherical matrix release. The degradation of chitosan was the rate-limiting factor for drug release in the colon. In-vivo study in rabbit shows delayed T_max, prolonged absorption time, decreased C_max and absorption rate constant (K_a) indicating reduced systemic toxicity of the drug as compared to other dosage forms.     

Studies on Controlled Release Formulations of Pentazocine Hydrochloride

This work embodies studies, performed with micropellet type dosage forms of Pentazocine Hydrochloride (Pz-HCl), using single and composite matrices of Eudragit RS100 (RS) and RL100 (RL). The effects of formulation parameters on various dosage form criteria - namely drug loading, particle size distribution, release profiles etc. have been investigated. Results indicate, that the two polymers can be successfully combined to produce different changes in release kinetics, with simple modifications of coating composition and initial drug loads.     

Preparation and Preliminary Evaluation of Eudragit RL and RS Pseudolatices for Controlled Drug Release

Eudragit RL and RS pseudolatices were prepared by the solvent change technique, which consisted of dissolving the polymer in a water miscible organic solvent or in a mixed water miscible organic solvent system, followed by dispersian in deionized water under mild agitation. The organic solvent (s) was removed from the aqueous organic solution to leave a stable Eudragit latex.

Eudragit pseudolatex coated theophylline pellets were prepared in a fluidized-bed coating machine. The effects of polymer type and coating level, plasticizer concentration, and PH of the dissolution medium on drug release were investigated. The higher content of quaternary ammonium groups attached to the polymer backbone make the coatings produced from Eudragit RL too water sensitive; and hence unsuitable for controlling theophylline release. On the other hand, Eudragit RS films retarded theophylline release. On the other hand, Eudragit RS films retarded theophylline release over a wide pH range. Release of the drug was found to be a function of the polymer coating level, plasticizer concentration and dependent on pH of the dissolution medium.     

Influence of Formulation and Other Factors on the Release of Chlorpheniramine Mateate from Polymer Coated Beads

Controlled release beads containing chlorpheniramine maleate, coated with Eudragit RL and RS, were prepared using the Wurster process. The effect of membrane thickness, polymer ratio of the coating material, agitation speed and pH of the dissolution medium on drug release were investigated using the USP dissolution basket method. The in vitro release of drug was described adequately by a previously published equation. The release rate constant (K) was dependent on the membrane thickness, the polymer ratio and pH of the dissolution medium. On the other hand, agitation speed used in this study did not have any influence on the release of the drug.     

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.