Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique.

The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, itraconazole, by a solid dispersion technique. Solid dispersion particles of itraconazole were prepared with various pH-independent and -dependent hydrophilic polymers and were characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. Of the polymers tested, pH-dependent hydrophilic polymers, AEA and Eudragit E 100, resulted in highest increases in drug solubility (range, 141.4-146.9-fold increases). The shape of the solid dispersion particles was spherical, with their internal diameter ranging from 1-10 microm. The dissolution rate of itraconazole from the tablets prepared by spray drying (SD-T) was fast, with > 90% released within 5 min.SD-T prepared with AEA or Eudragit E 100 at a 1:1 drug hydrophilic polymer ratio (w/w) showed approximately 70-fold increases in the dissolution rate over a marketed product.     

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets.

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.     

Microenvironmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices

For weakly basic drugs, pH-dependent solubility characteristics can translate into low and incomplete release of these drugs from sustained release formulations. The objective of this study was to quantitatively analyze the relationship between microenvironmental pH modulation and release enhancement of a weakly basic drug in the free base form. A prototype matrix system primarily consisting of trimethoprim (pK(a) 6.6), hydroxypropyl methylcellulose (HPMC), and a polymeric or nonpolymeric pH modulator was used. Incorporation of the methacrylic acid polymer, Eudragit L100-55 resulted in marginal release enhancement as the pH modulation effected by this polymer was attenuated by the basicity of the drug. Water uptake and scanning electron microscopy (SEM) studies suggested that Eudragit L100-55 incorporation also resulted in reduced water uptake and matrix permeability. The effect of nonpolymeric pH modulators on release enhancement was also studied. The lowering in microenvironmental pH by malic acid was sufficiently high and persistent to result in pH-independent release. A correlation plot between the experimentally determined microenvironmental pH, effected by the polymeric and nonpolymeric pH modulators, and percent drug release, exhibited good linearity with a correlation coefficient of 0.83; thereby, indicating that drug diffusion across the gel barrier is the predominating mechanism of release.     

Design of pH-independent extended release matrix tablets of minocycline hydrochloride for the treatment of dementia

The aim of this study was to develop a pH-independent extended release matrix tablet of minocycline HCl for the treatment of dementia. The matrix tablets were prepared by wet granulation technique using Eudragit L and S as release modifiers at different w/w ratios (1:0, 1:1 and 0:1) and PEO as a matrix former. In the case of the matrix tablet without any release modifiers, the drug release rate at pH 1.2 was much higher than that of pH 7.4. By adding the release modifier, the drug release rate at pH 7.4 increased close to that of pH 1.2 and the pH-independent release was obtained. In addition, it was shown that lubricants containing a divalent cation such as Mg stearate inhibited minocycline release in basic medium. Therefore, the incorporation of Eudragit L and S (1:1 ratio) as release modifiers and Na stearyl fumarate as a lubricant into PEO-based matrix tablets effectively produced pH-independent minocycline release profiles.     

Formulation optimization of solid dispersion of mosapride hydrochloride

Mosapride citrate (MSP) is a gastroprokinetic agent that acts as a selective 5-HT₄ agonist and accelerates the gastric emptying, and is used for the treatment of acid reflux, irritable bowel syndrome, and functional dyspepsia. The purpose of this study is to investigate the solid dispersion formulations of MSP with controlled release characteristic using various polymers, elucidate the release mechanism, and characterize the interaction patterns between MSP and polymers. Solid dispersions of MSP with different drug-to-polymer ratios were prepared by a solvent evaporation method and characterized in comparison with the simple physical mixtures. Eudragit RSPO, Eudragit RLPO, hydroxypropylmethylcellulose (HPMC) or Kollidon SR® was used as a controlled-release polymer along with polyvinylpyrrolidone (PVP) as a carrier. Characterization of MSP solid dispersion was performed using thermal analysis (DSC), powder X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, where the drug was converted from the crystalline state to amorphous state in all polymeric carriers used. In vitro dissolution studies showed that the drug release has been extended up to 24 h by using Eudragit RSPO or HPMC. Moreover, the formulations containing higher polymer content ratio showed better slow-release profile. These results indicate that the solid dispersion formulation containing PVP/Eudragit RSPO or HPMC mixture could serve as a good controlled-release system for MSP.     

Combination of time-dependent and pH-dependent polymethacrylates as a single coating formulation for colonic delivery of indomethacin pellets

The objective of this study was to evaluate the combination of pH-dependent and time-dependent polymers as a single coating for design of colon delivery system of indomethacin pellets. Eudragit S100 and Eudragit L100 were used as pH-dependent polymers and Eudragit RS was used as a time-dependent polymer. A statistical full factorial design was used in order to optimize formulations. Factors studied in design were percent of Eudragit RS in combination with Eudragit S and L and coating level. Dissolution studies of pellets in the media with different pH (1.2, 6.5, 6.8 and 7.2) showed that drug release in colon could be controlled by addition of Eudragit RS to the pH-dependent polymers. The lag time prior to drug release was highly affected by coating level. With combination of two factors, i.e. the percent of Eudragit RS and coating level, the optimum formulation was found to be the one containing 20% Eudragit RS, 64% Eudragit S and 16% Eudragit L, and a coating level of 10%. This formulation was reproduced and tested in continuous condition of dissolution, and also separately at pH 7.5. The results of in vitro experiments indicate that the proposed combined time-dependent and pH-dependent polymethacrylate polymer coating may provide a colonic delivery system for indomethacin.     

Enteric polymers as acidifiers for the pH-independent sustained delivery of a weakly basic drug salt from coated pellets

Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK_a 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.     

Design,optimization and evaluation of mesalamine matrix tablet for colon drug delivery system

The aim of the present investigation was to develop and evaluate matrix tablet of mesalamine for colonic delivery by using Eudragit RSPO, RLPO and combination of both. The tablets were further coated with different concentration of pH-dependent methacrylic acid copolymers (Eudragit S100), by dip immerse method. The physicochemical parameters of all the formulations were found to be in compliance with the pharmacopoeial standards. The in vitro drug release study was conducted using sequential dissolution technique at pH 1.2 (0.1N) HCl, phosphate buffers pH 6.8 and 7.4, with or without rat cecal content mimicking different regions of gastro intestinal tract. The result demonstrated that the tablet containing Eudragit RLPO coated with Eudragit S100 (1 %) showed a release of 94.91 % for 24 h whereas in the presence of rat cecal content the drug release increases to about 98.55 % for 24 h. The uncoated tablets released the drug within 6 h. The in vitro release of selected formulation was compared with marketed formulation (Octasa MR). In vitro dissolution kinetics followed the Higuchi model via non-Fickian diffusion controlled release mechanism. The stability studies of tablets showed less degradation during accelerated and room temperature storage conditions. The enteric coated Eudragit S100 coated matrix of mesalamine showing promising site specific drug delivery in the colon region.     

Design of pH-independent controlled release matrix tablets for acidic drugs

The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility. This dependency of drug release on pH may lead to additional inter- and intra-subject variability in drug absorption. In the present study, a pH-independent controlled release matrix system for acidic drugs was designed by incorporating release-modifiers in the formulation. Controlled release matrix tablets were prepared by compression of divalproex sodium, Methocel K4M and Eudragit E 100 or Fujicalin as the release-modifier. For formulations without any release-modifier, the extent and rate of drug release at pH 6.8 was much higher than that at pH 1.0. Formulations containing Eudragit E 100 provided drug release that was essentially independent of pH. This was achieved because Eudragit E 100 significantly increased the drug release in acidic medium and slightly decreased the release rate at higher pH. The increased release in the acidic medium can be attributed to the elevation of the micro-environmental pH in the swollen polymer gel layer. Formulations containing Fujicalin were less effective than those containing Eudragit E 100. This was attributed to the relative inability to elevate the pH and shorter residence time of Fujicalin in the matrix relative to Eudragit E 100.     

pH-independent release of a basic drug from pellets coated with the extended release polymer dispersion Kollicoat SR 30 D and the enteric polymer dispersion Kollicoat MAE 30 DP.

The objective of this study was to obtain pH-independent release profiles from coated pellets containing drugs with pH-dependent solubility. pH-independent release of the basic model drug verapamil HCl was achieved by coating with a combination of the neutral polymer dispersions Kollicoat SR 30 D (aqueous dispersion of polyvinyl acetate) and the enteric polymer dispersion Kollicoat MAE 30 DP (aqueous dispersion of methacrylic acid and ethyl acrylate copolymer; methacrylic acid copolymer type C). The two polymers where applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers allowed the achievement of a pH-independent release. Higher amounts of the enteric polymer in the polymer blend resulted in a reversal of the pH-dependency, e.g. a faster release at pH 6.8 than in 0.1 N HCl.     

Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-beta-cyclodextrin.

The low bioavailability and short half-life of metformin hydrochloride (MH) make the development of sustained-release forms desirable. However, drug absorption is limited to the upper gastrointestinal (GI) tract, thus requiring suitable delivery systems providing complete release during stomach-to-jejunum transit. This study was undertaken to develop a MH sustained-release formulation in compliance with these requirements. The strategy proposed is based on direct-compressed matrix tablets consisting of a combination of MH with the hydrophobic triacetyl-beta-cyclodextrin (TAbetaCD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. hydroxypropylmethylcellulose, xanthan gum, chitosan, ethylcellulose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer (hydroxypropylmethylcellulose or chitosan) with a pH-dependent one (Eudragit L100-55) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TAbetaCD system preparation method (i.e. grinding or spray-drying) in determining the behaviour of the final formulation was evidenced. In fact, for a given matrix-tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH-TAbetaCD as ground or spray-dried product. In particular, the 1:1 (w/w) blend of such systems, dispersed in a Eudragit-chitosan polymeric matrix, fully achieved the prefixed goal, giving about 30% released drug after 2h at gastric pH, and overcoming 90% released drug within the subsequent 3h in jejunal fluid.     

Design and evaluation of pH modulated controlled release matrix systems for colon specific delivery of indomethacin

Indomethacin, a potent non steroidal anti-inflammatory drug (NSAID), is indicated for the local treatment of colorectal carcinoma. The aim of the present study was to design and investigate various matrix systems for controlled and site specific delivery of indomethacin to the colon. Various pH sensitive and hydrophobic polymers were investigated for their effect on drug release and site specificity. Effect of proportion of Eudragit L100 and Eudragit S100 in matrix either alone or in combination was evaluated. Effect of hydrophobic non-swellable polymer ethyl cellulose on the release pattern of drug from the Eudragit bases was also investigated. Matrix tablets prepared with Eudragit showed pH dependent release profile with the formulations of Eudragit L100 showing faster rate of drug release than Eudragit S100 in alkaline pH. The release profile from matrix tablets containing Eudragit L100 and Eudragit S100 in combination or with ethyl cellulose correlated well with the relative proportion of the two polymer types in the matrix base. Selected formulations when evaluated in simulated gastric fluid pH without enzymes showed negligible to low drug release (less than 10%) in the first 4-6 h followed with controlled release for 14-16 h. It was concluded that pH sensitive matrix bases in combination with a hydrophobic polymer like ethyl cellulose canbe ideal for site specific delivery of drugs to colon with controlled release profile.     

Use of enteric polymers for production of microspheres by extrusion-spheronization

To simplify the manufacture of enteric dosage forms, incorporation of enteric polymers into the matrix of phenylbutazone microspheres produced by extrusion-spheronization was compared to the coating of cores. The effect of different polymers, cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate (HPMCP) and Eudragit L100-55 and the amount of granulating liquid were evaluated for the effect of selected physical properties and drug release behavior. Using the enteric polymers in the microsphere cores showed a similar pattern of release to the coated spheres with no notable difference in drug release behavior being observed between the dosage forms. The microspheres with Eudragit L100-55 in the matrix were less friable and disintegration times were much closer to the coated microspheres than formulations including the other polymers. Variation of the amount of Eudragit L100-55 in the cores allowed optimization of disintegration and drug release profiles.     

Preparation and in vitro evaluation of propylthiouracil microspheres made of Eudragit RL 100 and cellulose acetate butyrate polymers using the emulsion-solvent evaporation method

The objectives of this investigation are to evaluate the encapsulation efficiency of the anti-thyroid agent 6-n-propyl-2-thiouracil using two polymers of different characteristics (cellulose acetate butyrate polymer, (CAB-551-0.01) and ammonio methacrylate copolymer (Eudragit RL 100) and to study the effect of this encapsulation on the drug release properties. Polymers were used separately and in combination to prepare different microspheres. Also, the effect of polymer solution phase viscosity was studied for each of the polymers and for their combinations. An Ostwald viscometer was used to evaluate the relative viscosities of polymer solution phases and their combinations. Microspheres with 25% theoretical drug loading of 6-n-propyl-2-thiouracil core material were prepared by the emulsion solvent evaporation method. Microspheres prepared from CAB-551-0.01, which has higher relative polymer phase viscosity than Eudragit RL 100, showed significantly lower drug release rates and a noticeable lag time. Polymer combinations of CAB-551-0.01 and Eudragit RL 100 (1:1) showed an interesting synergistic increase in relative polymer solution viscosities at all concentrations. Unlike microspheres prepared from the two polymers separately which follow Higuchi spherical matrix release kinetics, microspheres prepared using a combination (1:1) of the two polymers showed near zero order with faster rates compared to those prepared using CAB-551-0.01 equivalent polymer concentrations. The results of this study suggest that 6-n-propyl-2-thiouracil was successfully and efficiently encapsulated and release rates of matrix microspheres are related to polymer solution phase viscosity, but when polymer combinations were used other factors such as structural effects must be considered.     

Development of enteric-coated timed-release matrix tablets for colon targeting

A new oral drug delivery system for colon targeting has been developed based on enteric-coated matrix tablets which suitably exploits both pH-sensitive and time-dependent functions. Matrix-tablets were prepared by direct compression of mixtures of hydroxyethylcellulose (HEC), a hydrophilic swellable polymer, with the inert insoluble ethylcellulose (EC) or micro-crystalline cellulose (MCC) polymers, in which theophylline, selected as model drug, was dispersed. Eudragit S100, a methacrylic acid copolymer soluble at pH 7, was used as pH-sensitive coating polymer. The influence of varying the cellulose-derivative combinations and their relative ratios as well as the level of the coating polymer was investigated. Surface morphology of the tablets was monitored by SEM analysis before and after the release test. The results of release studies, performed according to the USP basket method using a sequence of dissolution media simulating the gastrointestinal physiological pH variation, indicated that the Eudragit S100 enteric-coated matrix tablets were successful in achieving gastric resistance and timed-release of the drug, assuring an adequate lag time for the intended colonic targeting, followed by a controlled-release phase. The enteric-coating level emerged as the critical factor in determining the duration of the lag-phase, whereas the release rate mainly depended on the matrix composition. Formulations with higher HEC content showed a faster drug release rate than those with greater content in inert polymer and the MCC-HEC combinations were more effective than the corresponding EC-HEC ones. The best results were given by the 27% coated 1:0.3:0.7 (w/w) drug/MCC/HEC tablets, which, after a 260 min lag time, regularly released the drug, achieving about 90% of release after 10 h.     

Development and release mechanism of diltiazem HCl prolonged release matrix tablets

A coated matrix tablet formulation has been used to develop controlled release diltiazem HCl (DIL) tablets. The developed drug delivery system provided prolonged drug release rates over a defined period of time. DIL tablets prepared using dry mixing and direct compression and the core consisted of hydrophilic and hydrophobic polymers such as hydroxypropylmethylcellulose (HPMC), Eudragits RLPO/RSPO, microcrystalline cellulose, and lactose. Tablets were coated with Eudragit NE 30D, and the influence of varying the inert hydrophobic polymers and the amount of the coating polymer were investigated. The release profile of the developed formulation was described by the Higuchi model. Stability trials up to 6 months displayed excellent reproducibility.     

Preparation and characterization of metoprolol controlled-release solid dispersions

In recent years, great attention has been paid to using solid dispersions to make sustained-release drugs. The objective of this study is to produce sustained-release systems of metoprolol tartrate using solid dispersion techniques and to evaluate their physicochemical characteristics. The solid dispersions were produced by melting and solvent methods, containing 7%, 15%, or 25% of the drug and different ratios of Eudragit RLPO and RSPO in ratios of 0:10, 3:7, 5:5, 7:3, and 10:0. Drug release profiles were determined by USP XXIII rotating paddle method in phosphate buffer solution (pH 6.8). XRD, DSC, IR, and microscopic observations were performed to evaluate the physical characteristics of solid dispersions. Results showed that the drug release from dispersions was at a slower rate than pure drug and physical mixtures. Moreover, the formulations containing greater ratios of Eudragit RSPO showed slower release rates and smaller DE_8% but larger mean dissolution time than those containing greater ratios of Eudragit RLPO. Dispersions with particle size of less than 100 μm containing 7% of metoprolol and Eudragit RL:RS 5:5 (solvent method) and those with the ratio of 3:7 (melting method) had similar release pattern to Lopressor® sustained-release tablets by zero-order and Higuchi kinetics, respectively.     

Physico-chemical analysis of metronidazole encapsulation processes in Eudragit copolymers and their blending with amphiphilic block copolymers

A physico-chemical analysis of metronidazole–Eudragit copolymers L100 and RLPO (a cationic polymeric matrix with an electrophilic character) was carried out in order to explore the drug–polymer interaction and its possible effects on the encapsulation and release profiles. An oil-in-oil encapsulation procedure was designed to obtain more intimate drug–matrix mixtures and to obtain a better insight into the details of the interaction. The encapsulation efficiency obtained in these cases was high (in the range of 85–95%), but the release rates were quite rapid. Solubility and interaction between metronidazole and copolymers are discussed in detail with a view to explaining the results. Amphiphilic block copolymers of poly(ethylene)-b-(polyethylene oxide) (20, 50 and 80% PEO) were tested as a matrix for metronidazole release in order to improve drug profiles. The performance of RLPO as the matrix for drug release was improved by blending it with amphiphilic block copolymer poly(ethylene)-b-(polyethylene oxide) (20% PEO). The release mechanism of metronidazole is governed mainly by the swelling of RLPO, yielding a better fit with the second-order Schott equation.     

Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers

Solid dispersions were prepared of itraconazole-Eudragit E100, itraconazole-PVPVA64, and itraconazole-Eudragit E100/PVPVA64 using a corotating twin-screw hot-stage extruder. Modulated temperature differential scanning calorimetry (MTDSC) was used to evaluate the miscibility of the extrudates, and dissolution experiments were performed in simulated gastric fluid without pepsin (SGF(sp)). Itraconazole and Eudragit E100 are miscible up to 13% w/w drug loading. From that concentration on, phase separation is observed. Pharmaceutical performance of this dispersion was satisfactory because 80% of the drug dissolved after 30 min. Extrudates of itraconazole and PVPVA64 were completely miscible but the pharmaceutical performance was low, with 45% of drug dissolved after 3 h. Combination of both polymers in different ratios, with a fixed drug loading of 40% w/w, was evaluated. MTDSC results clearly indicated a two-phase system consisting of itraconazole-Eudragit E100 and itraconazole-PVPVA64 phases. In these extrudates, no free crystalline or glassy clusters of itraconazole were observed; all itraconazole was mixed with one of both polymers. The pharmaceutical performance was tested in SGF(sp) for different polymer ratios, and Eudragit E100/PVPVA64 ratios of 50/50 and 60/40 showed significant increases in dissolution rate and level. Polymer ratios of 70/30 and 80/20, on the other hand, had a release of 85% after 30 min. Precipitation of the drug was never observed. The combination of the two polymers provides a solid dispersion with good dissolution properties and improved physical stability compared with the binary solid dispersions of itraconazole.     

Effects of the permeability characteristics of different polymethacrylates on the pharmaceutical characteristics of verapamil hyhdrochloride-loaded microspheres

Microspheres containing verapamil hydrochloride (VRP) were prepared with various polymethacrylates, with different permeability characteristics (Eudragit RS 100, Eudragit RL 100, Eudragit L 100 and Eudragit L 100-55) and also with mixtures of these polymers in a 1:1 ratio using the solvent evaporation method. The aim was to investigate the effects of the permeability of the polymers on drug release rates and the characteristics of the microspheres. To achieve these aims, yield, incorporation efficiency, particle size and the distribution of microspheres were determined, and the influence of the inner phase viscosities prepared with different polymer and polymer mixtures on particle size and the distribution of microspheres were evaluated. Surface morphologies of microspheres were observed by scanning electron microscope. Drug release rates from microspheres were determined by the half-change method using a flow-through cell. The results indicate that microspheres with different surface morphologies and statistically different yields and incorporation efficiencies could be prepared and their particle size and distribution xariances resulted from the viscosity of the inner phase. Dissolution profiles showed that the drug release rate could be modified depending on the permeability characteristics of polymethacrylates.