Preparation and dissolution characteristics of controlled release diltiazem pellets

Abstract

Different series of Diltiazem pellets with slow release of the active substance were prepared, by pan coating technique, using different mixtures of acrylic polymers (Eudragit E, Eudragit L, Eudragit RL and Eudragit RS) as film coating agents. The thickness of the coatings were varied by different amounts of Eudragit. Release profiles of Diltiazem hydrochloride were investigated using USP XX rotating basket method (Erweka DT-D6) with 1000 ml buffer solution (pH values 1.5; 2.2; 5.5; 6.8; 7.0) at 37°C as solvent. In vitro dissolution findings showed that Eudragit coatings gave prolonged release of Diltiazem hydrochloride. The permeability of coatings in gastric and intenstinal juices was found to be influenced by the amount of Eudragit L in the formulation. Also, the drug release rate was found to be dependent on the amount of coating applied. In order to understand the drug release mechanism better, the release data were tested assuming common kinetic models. In the present study square - root of the time plots and Weibull plots were not sufficiently linear, although several correlation coefficients were high. When the goodness of fit of release data to first - order kinetics and Hixson - Crowell ‘s equation was evaluated, the difference between these two models was often noted to be minimal.     

Comparative Study of Aqueous and Organic Enteric Coatings of Chlorpheniramine Maleate Tablets

Two acrylic polymers (Eudragit® L 12.5 P and L 30 D) and a cellulosic polymer (cellulose acetate trimellitate, CAT) in organic and aqueous formulations were used in order to obtain an enteric coating on tablets containing clorpheniramine maleate as a water-soluble model drug. The coating of tablets was executed in a coating pan in similar conditions for each kind of solvent. The coated tablets were tested according to the delayed-release test of USP 23 (Method A). In our experimental conditions different amounts of polymers were needed to obtain an enteric coating. The lowest amount was in the case of Eudragit L 30 D (aqueous), after which appeared Eudragit L 12.5 P (organic), CAT (organic), and finally, CAT (aqueous) as the polymer that needed to be of the highest amount. During the dissolution test differences in the size and aspect of the tablets were observed according to the polymers. Acrylic polymers did not show changes in size and aspect, but CAT polymers showed a notable increase in size. me different behavior of the tablets during the dissolution test can explain the differences observed in the adjustment of the release data. The release data were tested assuming common kinetic models. In the present study it was observed that Eudragit L polymers release the drug in a first-order kinetic and that CAT releases it according to a zero-order kinetic.     

Comparative Study of Aqueous and Organic Enteric Coatings of Chlorpheniramine Maleate Tablets

Abstract

Two acrylic polymers (Eudragit® L 12.5 P and L 30 D) and a cellulosic polymer (cellulose acetate trimellitate, CAT) in organic and aqueous formulations were used in order to obtain an enteric coating on tablets containing clorpheniramine maleate as a water-soluble model drug. The coating of tablets was executed in a coating pan in similar conditions for each kind of solvent. The coated tablets were tested according to the delayed-release test of USP 23 (Method A). In our experimental conditions different amounts of polymers were needed to obtain an enteric coating. The lowest amount was in the case of Eudragit L 30 D (aqueous), after which appeared Eudragit L 12.5 P (organic), CAT (organic), and finally, CAT (aqueous) as the polymer that needed to be of the highest amount. During the dissolution test differences in the size and aspect of the tablets were observed according to the polymers. Acrylic polymers did not show changes in size and aspect, but CAT polymers showed a notable increase in size. me different behavior of the tablets during the dissolution test can explain the differences observed in the adjustment of the release data. The release data were tested assuming common kinetic models. In the present study it was observed that Eudragit L polymers release the drug in a first-order kinetic and that CAT releases it according to a zero-order kinetic.     

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.     

Formulation and Release Kinetics of Sustained Release Phenylpropanolamine Hydrochloride Granules and Tablets

Abstract

Sustained release phenylpropanolamine hydrochloride (PPH) granules and tablets were prepared using HPMC, HPMC and SCMC, Eudragit RS, Eudragit RS+L or HPMC + Eudragit RS matrices. The release pattern of PPH from the prepared granules and tablets was found to be in the following order HPMC > HPMC + SCMC > RS > RS + 1> HPMC + RS. The results revealed that, although the drug concentration was kept constant in all the prepared granules and tablets, the drug release from these formulations was clearly different and depends mainly on the type of matrix used. The presence of Eudragit L with Eudragit RS and Eudragit RS with HPMC resulted in a marked decrease in the drug release compared with that obtained from the matrix containing HPMC or Eudragit RS alone. The release data of PPH from the prepared granules and tablets were treated mathematically according to zero order, first order, Langenbuchar, modified Langenbucher and Higuchi models. The results revealed that no one model was able adequately to describe the drug release profiles from these formulations. In-vivo studies in human volunteers showed that, the peak urinary excretion of PPH occurred over a sustained period from 2 to 6.5 hr in case of HPMC + SCMC tablets and from 2 to 10 hr in case of either RS+L or HPMC + RS tablets.     

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.     

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.     

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 MiniWiD-COATER: II. Comparison of acid resistance of enteric-coated bisacodyl pellets coated with different polymers

Neutral pellets were loaded with bisacodyl and enteric-coated with hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl ethylcellulose (CMEC), cellulose acetate trimellitate (CAT), and poly(ethylacrylate, methacrylic acid) (Eudragit L 30 D) in a miniature fluid-bed pan coater called MiniWiD. Gastric juice resistance was tested by dissolution using USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours. As a measure of enteric coating quality the USP specifications were used meaning that no more than 10 % of the drug should be released within 2 hours.

Organic-solvent based films of HPMCAS, CMEC and CAT at a coating level of 18 to 25 % provided gastroresistance for more than 6 hours. Aqueous suspensions of HPMCAS and CMEC as well as the ammonium salt aqueous solutions of CAT produced films with a short gastroresistance of below 0.6 hours. By doubling the coating level of water-based HPMCSD films the protection was prolonged to 3.4 h.

Enteric coatings were obtained from all aqueous latex dispersions of Eudragit L 30 D at a coating level of 24 %. The alteration of coating temperature between 25 and 45 °C had no significant effect on the release rates, whereas the variation of type and amount of plasticizer led to a different release rate after 2 hours. Best protection was obtained using films plasticized with 20 % of dibutyl phthalate (DBP) allowing a release of only 4 % of the drug in 6 hours although the application temperature was 15 °C below the minimum film-forming temperature (MFT). All coatings dissolved in artificial intestinal fluid within 15 minutes.     

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.     

The MiniWiD-COATER: II. Comparison of acid resistance of enteric-coated bisacodyl pellets coated with different polymers

Abstract

Neutral pellets were loaded with bisacodyl and enteric-coated with hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl ethylcellulose (CMEC), cellulose acetate trimellitate (CAT), and poly(ethylacrylate, methacrylic acid) (Eudragit L 30 D) in a miniature fluid-bed pan coater called MiniWiD. Gastric juice resistance was tested by dissolution using USP Apparatus 2 (paddle) in 0.1 N hydrochloric acid under sink conditions over 6 hours. As a measure of enteric coating quality the USP specifications were used meaning that no more than 10 % of the drug should be released within 2 hours.

Organic-solvent based films of HPMCAS, CMEC and CAT at a coating level of 18 to 25 % provided gastroresistance for more than 6 hours. Aqueous suspensions of HPMCAS and CMEC as well as the ammonium salt aqueous solutions of CAT produced films with a short gastroresistance of below 0.6 hours. By doubling the coating level of water-based HPMCSD films the protection was prolonged to 3.4 h.

Enteric coatings were obtained from all aqueous latex dispersions of Eudragit L 30 D at a coating level of 24 %. The alteration of coating temperature between 25 and 45 °C had no significant effect on the release rates, whereas the variation of type and amount of plasticizer led to a different release rate after 2 hours. Best protection was obtained using films plasticized with 20 % of dibutyl phthalate (DBP) allowing a release of only 4 % of the drug in 6 hours although the application temperature was 15 °C below the minimum film-forming temperature (MFT). All coatings dissolved in artificial intestinal fluid within 15 minutes.     

Eudragit Coating of Chitosan-Prednisolone Conjugate Microspheres and In Vitro Evaluation of Coated Microspheres

Chitosan-prednisolone conjugate microspheres (Ch-SP-MS) were prepared, and Eudragit coating was applied in order to efficiently deliver the microspheres and drug to the intestinal disease sites. The Eudragit L100-coated microspheres (Ch-SP-MS/EuL100) were examined for particle characteristics and the release of drug and Ch-SP-MS in different pH media at 37°C. Ch‐SP-MS were spherical, with a mean size of 4.5 μm and prednisolone content of 3.3% (w/w). Ch-SP-MS/EuL100 were fairly spherical, with a mean size of 22. 5 μm and drug content of 0.32% (w/w). At pH 1.2, the release extent was less than 5% even at 48 h, and Eudragit coating tended to suppress the release. In contrast, at pH 6.8 and 7.4, Ch-SP-MS/EuL100 tended to show somewhat faster drug release than Ch-SP-MS. Ch-SP-MS/EuL100 displayed a release extent of 23 and 27% at pH 6.8 and 7.4, respectively. Ch-SP-MS aggregated at pH 1.2, but almost kept their initial size and shape at pH 6.8 and 7.4. Ch-SP-MS/EuL100 almost maintained their original shape and size at pH 1.2, and gradually released Ch-SP-MS at pH 6.8 and 7.4 due to dissolution of the Eudragit layer. Eudragit coating is suggested to be useful to efficiently deliver Ch-SP-MS to the intestinal disease sites.     

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.     

Eudragit coating of chitosan-prednisolone conjugate microspheres and in vitro evaluation of coated microspheres

Chitosan-prednisolone conjugate microspheres (Ch-SP-MS) were prepared, and Eudragit coating was applied in order to efficiently deliver the microspheres and drug to the intestinal disease sites. The Eudragit L100-coated microspheres (Ch-SP-MS/EuL100) were examined for particle characteristics and the release of drug and Ch-SP-MS in different pH media at 37°C. Ch-SP-MS were spherical, with a mean size of 4.5 μm and prednisolone content of 3.3% (w/w). Ch-SP-MS/EuL100 were fairly spherical, with a mean size of 22. 5 μm and drug content of 0.32% (w/w). At pH 1.2, the release extent was less than 5% even at 48 h, and Eudragit coating tended to suppress the release. In contrast, at pH 6.8 and 7.4, Ch-SP-MS/EuL100 tended to show somewhat faster drug release than Ch-SP-MS. Ch-SP-MS/EuL100 displayed a release extent of 23 and 27% at pH 6.8 and 7.4, respectively. Ch-SP-MS aggregated at pH 1.2, but almost kept their initial size and shape at pH 6.8 and 7.4. Ch-SP-MS/EuL100 almost maintained their original shape and size at pH 1.2, and gradually released Ch-SP-MS at pH 6.8 and 7.4 due to dissolution of the Eudragit layer. Eudragit coating is suggested to be useful to efficiently deliver Ch-SP-MS to the intestinal disease sites.     

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.     

Degradation kinetics of thiamine hydrochloride in directly compressed tablets iii water vapour transmission through free and applied eudragit films

Water vapour transmission through free and applied film of four Eudragit resins namely, E₁₀₀, L₁₀₀ and RS₁₀₀ to directly compressed thiamine hydrochloride tablets was investigated. The type of Eudragit film influenced both water vapour transmission and moisture absorption characteristics of the tablets compressed with either single or binary blend of vehicles. The moisture absorption rate constant K_a, for a given batch was found to be a function of vapour pressure, P, and film thickness, L. The relationship between K_a and either of these parameters is exponental and may be expressed as K_a = A exp (x/P) and K_a = K*_a exp (-x*L). In general, film coating with Eudragit resins affected the physical characteristics of the tablets. The rate of drug release, K has an exponentially relationship as K_e K_o exp (-c/L).     

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.     

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.     

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.     

Preparation and Evaluation of Sustained-Release Solid Dispersions of Drugs with Eudragit Polymers

Abstract

Coevaporates of paracetamol and rifampicin with Eudragit polymers of different natures (anionic, cationic, and zwitterionic) were prepared. Determination of dissolution rate of these coevaporates in dissolution media simulating those of the gastrointestinal tract (GIT) revealed that the release rate of paracetamol is retarded from all the coevaporates studied. In this respect, Eudragit L100-SS shows the highest sustainment of drug release, while Eudragit E100 shows the lowest. Conversely, the release of rifampicin from its coevaporates with the anionic Eudragit S100 polymer is more retarded than the corresponding coevaporate with the zwitterionic Eudragit RL100 or from coevaporates with equal mixtures of the two polymers.

Increasing the polymer weight fraction in rifampicin coevaporates with Eudragit S100 up to 0.5 resulted in a corresponding decrease in the dissolution rate. However, beyond this weight fraction, the polymer effect on the dissolution rate of the drug becomes minimized. The results confirmed that the process of dissolution of the two drugs from their coevaporates is a diffusion-controlled release process.

The biological performance of paracetamol coevaporates was monitored in rabbits; paracetamol level in plasma was found to follow first-order kinetics. for all the investigated paracetamol coevaporates, the peak plasma level was less than 50 μg/ml compared to a value of 60, μg/ml for the drug per se. The coevaporates of the drug with Eudragit L100-55 showed slowest rates of absorption and elimination as well as greatest half-peak and half-life times. Biological peformance of rifampicin coevaporates was assessed in human subjects receiving a single oral dose equivalent to 300 mg of the drug. The results depicted sustainment of drug release as a function of polymer weight fraction. A strict correlation was shown to exist between the total amount of drug excreted during 24 hr post dosing of the coevaporates and its in vitro dissolution rate.

The results depicted that paracetamol can be formulated in the form of a coevaporate with Eudragit L100-55 to prepare a more safe sustained-release formulation with minimal side effects, and also revealed the advantages of administration of rifampicin in the form of a coevaporate with Eudragit S100 (4:1) at a single oral dose equivalent to 600 mg of drug.