Design of pH-sensitive microspheres for the colonic delivery of the immunosuppressive drug tacrolimus.

Recently, tacrolimus was shown to be effective in mitigating inflammatory bowel disease (IBD). In the treatment of IBD, oral drug delivery using pH-dependent polymers is one of the most successful therapeutic strategies. Eudragit P-4135F, a pH-sensitive polymer for colonic delivery was used to prepare tacrolimus microparticles using an oil/oil emulsification or an oil/water emulsification technique combined with a solvent extraction or evaporation step. Although the pH-dependent drug release was similar for all types of microspheres, it was generally found that encapsulation rates of oil/water systems (extraction 38.8 +/- 9.4%; evaporation 56.3 +/- 1.9%) were superior to the oil/oil emulsification (4.8 +/- 0.4%). Eudragit P-4135F was found to limit drug leakage at pH 6.8 to levels lower than 10% within 6 h. At pH 7.4, almost immediate release (within 30 min) was observed. From differential scanning calorimetry and X-ray analyses, the drug inside the polymeric microsphere matrix was concluded to be present in a molecular dispersion. Generally, all formulations proved their applicability in vitro as a promising device for pH-dependent colonic delivery of tacrolimus, however, the oil/water technique was found to be superior to the oil/oil approach and among them solvent evaporation seemed to be more advisable, due to the higher encapsulation rate.     

Application of Eudragit P-4135F for the delivery of ellagic acid to the rat lower small intestine

Based on the assumption that the delivery of ellagic acid to its site of action would show an antiinflammatory activity in inflammatory bowel disease (IBD), we have prepared microspheres using a new pH-sensitive polymer, Eudragit P-4135F (P-4135F), to deliver ellagic acid to the lower small intestine in rats. The microspheres were spherical in shape and the mean diameters were approximately 100-150 microm. The amount of ellagic acid released from the microspheres decreased by increasing the formulated amount of P-4135F. The release characteristics of ellagic acid were pH-dependent. By considering the factors loading efficiency and microsphere particle size distribution, ellagic acid-2 microspheres (P-4135F/ellagic acid = 1.65) were selected for further investigation. In a dissolution study, more than 95% ellagic acid was released within 0.5 h in pH 7.4 and 8.0 buffers. The release percent of ellagic acid was less than 40% in pH 6.8 and 7.0 and was less than 10% in pH 5.6 and 5.9. To observe the dissolution sites of the microspheres in the rat small intestine fluorescein was formulated in the microspheres as a tracer drug along with ellagic acid (50 mg kg(-1)). After intraduodenal administration of fluorescein-labelled microspheres to rats, the plasma fluorescein level started to increase at 0.5 h, by which time the microspheres had reached the middle part of the ileum. Microspheres started to dissolve within 1.0 h and the peak plasma fluorescein concentration was observed at 3.0 h, when the majority of the administered microspheres were dissolved in the terminal ileum. These results suggested that P-4135F microspheres could deliver ellagic acid to the lower part of the small intestine, and that the released ellagic acid would be distributed into the caecum and the ascending colon.     

Characterization of norfloxacine release from tablet coated with a new pH-sensitive polymer, P-4135F

A new pH-sensitive polymer, P-4135F, was evaluated as a colon delivery device for norfloxacine (NFLX) which is used for the therapy of patients with Vero toxin-producing Escherichia coli gastroenteritis. P-4135F has a dissolution threshold pH of 7.2 which is higher than the conventional pH-sensitive polymers, Eudragit S100 and L100. To compare the dissolution site of P-4135F coated tablets with other enteric polymer coatings, mini-tablets containing sodium fluorescein (FL) as a model drug were prepared by coating them with the three polymers. After oral administration of FL mini-tablets to rats, the first-appearance time, Ti, of FL into the systemic circulation was measured. The Tis were 0.7+/-0.2 h for Eudragit L100, 1.8+/-0.4 h for S100 and 2.0+/-0.3 h for P-4135F. Direct inspection of the dissolution process of the FL mini-tablets after oral administration to rats was performed by abdominal incision studies. All of the coated FL mini-tablets started to dissolve in the rat ileum. The dissolution sites were identified to be proximal to the ileocecal junction for P-4135F, at the middle part of the ileum for Eudragit S100 and at the proximal part of the ileum for Eudragit L100. NFLX tablets with different membrane thicknesses of P-4135F were prepared and were orally administered to beagle dogs. The colon delivery efficiency was evaluated by measuring the Ti of NFLX into the systemic circulation. The mean Tis were 1.33+/-0.33 h for 56.8+/-0.5 microm membranes, 3.75+/-0.25 h for 64.6+/-0.7 microm membranes, 4.00+/-1.00 h for 70.5+/-0.5 microm membranes and 3.00+/-1.00 h for 74.9+/-0.4 microm membranes. By comparing the Ti, 4.33+/-0.33 h, obtained after oral administration of NFLX in a pressure-controlled colon delivery capsule, and the colon arrival time, 3.5+/-0.3 h, determined by a sulfasalazine test in beagle dogs. P-4135F coated NFLX tablets appeared to dissolve and disintegrate before reaching the colon. Studies using rats and beagle dogs have suggested that P-4135F dissolves in the lower part of the small intestine, i.e., the ileum. These studies also suggest that this new polymer will be useful for the delivery of NFLX to the lower part of the small intestine.     

A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery

The aim of this study was to investigate the in vitro dissolution characteristics of pH-responsive polymers in a variety of simulated fluids. Prednisolone tablets were fabricated and coated with the following polymer systems: Eudragit S (organic solution), Eudragit S (aqueous dispersion), Eudragit FS (aqueous dispersion) and Eudragit P4135 (organic solution). Dissolution tests were conducted using a pH change method whereby tablets were transferred from acid to buffer. Three different buffer media were investigated: two compendial phosphate buffers (pH range 6.8-7.4) and a physiological buffer solution (Hanks buffer) with very similar ionic composition to intestinal fluid (pH 7.4). There was considerable drug release from tablets coated with Eudragit P4135 in acid, prompting discontinuation of further investigations of this polymer. Eudragit S (organic solution), Eudragit S (aqueous dispersion) and Eudragit FS on the other hand prevented drug release in acid, though subsequent drug release in the buffer media was found to be influenced by the duration of tablet exposure to acid. At pH 7.4 drug release rate from the polymer coated tablets was similar in the two compendial media, however in the physiological buffer, they were found to differ in the following order: Eudragit S (aqueous dispersion)>Eudragit FS>Eudragit S (organic solution). The results indicate that the tablets coated with the newer Eudragit FS polymer would be more appropriate for drug delivery to the ileo-colonic region in comparison to the more established Eudragit S. More importantly, however, dissolution in the physiological buffer was found to be markedly slower for all the coated tablets than in the two compendial buffers, a result akin to reported slower dissolution of enteric coated tablets in vivo. There is therefore the need to adequately simulate the ionic composition of the intestinal fluid in the dissolution media.     

Potential of calcium pectinate beads for target specific drug release to colon

A pectin-based colon specific delivery system bearing 5-fluorouracil (5-FU) was developed for effective delivery of drug to the colon. Calcium pectinate gel (CPG) beads were prepared by ionotropic gelation method followed by enteric coating with Eudragit S-100. The CPG beads formed were spherical with smooth surfaces. CPG beads size was found to be in the range of 1.32+/-0 . 12-1.88+/-0.08 mm. The in vitro drug release was investigated using USP dissolution rate test paddle type apparatus in different simulated mediums. Release in PBS (pH 7.4) and simulated gastric fluid showed almost similar pattern and rate, whereas a significant increase in percent cumulative drug release (58.3+/-1.36%) was observed in medium containing rat caecal content, i.e. the amount of the drug released from the formulation was found to be 49.2+/-2.29 and 58.3+/-1.36% of drug with 2 and 4% w/v caecal matter after 24 h whereas in control study 33.2+/-1.19% of drug was released. Moreover, to induce the enzymes that specifically act on pectin, the rats were treated with 1 ml of 1% w/v dispersion of pectin for 2 and 4 days and release rate studies were repeated in SCF in the presence of 2 and 4% w/v of caecal matter. A marked improvement in the drug release was observed in presence of caecal matter obtained after induction when compared to those without induction. The percentage of drug released after 24 h release was observed to be 69.3+/-2.81 and 86.7+/-3.15%, respectively, with 2 and 4% w/v rat caecal matter obtained after 2 days of enzyme induction, and 82.4+/-3.15 and 98.7+/-4.26%, respectively, after 4 days of enzyme induction. In vivo data showed that Eudragit S-100 coated calcium pectinate beads delivered most of its drug load (93.2+/-3.67%) to the colon after 9 h, which reflects its targeting potential to the colon. It is concluded that orally-administered 5-FU loaded Eudragit S-100 coated calcium pectinate beads can be used effectively for the specific delivery of drug to the colon.     

Engineering polymer blend microparticles: An investigation into the influence of polymer blend distribution and interaction

The aim of this work was to understand the influence of polymer interaction and distribution on drug release from microparticles fabricated from blends of polymers. Blends of pH dependent polymer (Eudragit S, soluble above pH 7) and pH independent polymer (Eudragit RL, Eudragit RS or ethylcellulose) were incorporated into prednisolone loaded microparticles using a novel emulsion solvent evaporation method. Microparticles fabricated from blends of Eudragit S and Eudragit RL or RS did not modify drug release compared to microparticles fabricated from Eudragit S alone. This can be attributed to the high degree of miscibility of Eudragit S with Eudragit RS or Eudragit RL within the microparticles as confirmed by glass transition temperature measurements and confocal laser scanning microscopy. In contrast, microparticles prepared from blends of Eudragit S (75%) and ethylcellulose (25%) extended the release of prednisolone at pH 7.4 (compared to Eudragit S microparticles). This change in release profile was related to the immiscibility of Eudragit S and ethylcellulose as assessed by thermal analysis, and confirmed by microscopy which showed pores within the microparticle structures following dissolution of the Eudragit S domains. The ability of water insoluble polymers to extend drug release from enteric polymer microparticles is dependent on the miscibility and interaction of the polymers. This knowledge is important in the design of pH responsive microparticles capable of extending drug release in the gastrointestinal tract.     

Eudragit RS 100 microparticles containing 2-hydroxypropyl-beta-cyclodextrin and glutathione: physicochemical characterization, drug release and transport studies.

The aim of this study was to encapsulate glutathione (GSH) alone or in combination with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in Eudragit RS 100 microparticles (MPs), and to evaluate these novel delivery systems for oral administration of the considered tripeptide. The MPs were prepared by an O/O emulsion-solvent evaporation method according to a multilevel experimental design involving the volume of liquid paraffin, the HP-beta-CD amount, and the drug/polymer ratio as independent variables. The effects of these parameters on particle size, entrapment efficiency, and drug release were investigated. Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) analysis and differential scanning calorimetry (DSC) studies were performed to evaluate possible interactions between GSH and Eudragit RS 100 polymer and to characterize the physical state of drug within the MPs. The release profiles of GSH from MPs were examined in vitro at pH 1.2, 6.8. and 7.4 using the USP III (BioDis) dissolution apparatus. In general, a slow and zero-order release of GSH from MPs at pH 1.2 occurred, while at higher pH values considerable amounts of glutathione disulfide (i.e., GSSG) were observed. The enzymatic stability and the intestinal permeability of some GSH-containing MPs were assessed by using pepsin, alpha-chymotrypsin, gamma-glutamyl-transpeptidase and everted frog intestinal sac methodology, respectively. The results suggest that GSH-loaded Eudragit RS 100 MPs containing HP-beta-CD represent a new sustained GSH delivery system useful for the oral administration of the examined tripeptide.     

Preparation and in vitro dissolution profile of zidovudine loaded microspheres made of Eudragit RS 100, RL 100 and their combinations

The objective of present investigation was to evaluate the entrapment efficiency of the anti-HIV drug, zidovudine, using two Eudragit polymers of different permeability characteristics and to study the effect of this entrapment on the drug release properties. In order to increase the entrapment efficiency optimum concentration of polymer solutions were prepared in acetone using magnesium stearate as droplet stabilizer. The morphology of the microspheres was evaluated using a scanning electron microscope, which showed a spherical shape with smooth surface. The mean sphere diameter was between 1000-3000 microm and the entrapment efficiencies ranged from 56.4-87.1%. Polymers were used separately and in combination to prepare different microspheres. The prepared microspheres were studied for drug release behavior in phosphate buffer at pH 7.4, because the Eudragit polymers are independent of the pH of the dissolution medium. The release profiles and entrapment efficiencies depended strongly on the structure of the polymers used as wall materials. The release rate of zidovudine from Eudragit RS 100 microspheres was much lower than that from Eudragit RL 100 microspheres. Evaluation of release data reveals that release of zidovudine from Eudragit RL 100 microspheres followed the Higuchi rule, whereas Eudragit RS 100 microspheres exhibited an initial burst release, a lag period for entry of surrounding dissolution medium into polymer matrix and finally, diffusion of drug through the wall material.     

Influence of an enteric polymer on drug release rates of theophylline from pellets coated with Eudragit RS 30D

The purpose of this research study was to investigate the influence of an enteric polymer on the drug release properties of theophylline pellets coated with Eudragit RS 30D. Theophylline pellets were coated with aqueous colloidal dispersions of Eudragit RS 30D containing various amounts of Eudragit L 100-55. The effect of storage conditions on the release of drug from coated pellets was determined as a function of the pH of the dissolution medium. The results from the dissolution study showed significant changes in the dissolution rate of theophylline from pellets coated with Eudragit RS 30D when cured at 40 degrees C for 4 days. No change in the drug release rate was observed when Eudragit L100-55 was present in the Eudragit RS 30D dispersion. Increasing the ratio of Eudragit L100-55 to Eudragit RS 30D resulted in faster drug release rates from the coated pellets. An increase in the pH of the dissolution medium was found to enhance drug release from the pellets coated with Eudragit RS 30D containing Eudragit L 100-55. Theophylline pellets when coated with Eudragit RS 30D containing the enteric polymer Eudragit L100-55 demonstrated no aging effects when stored at elevated temperatures. The overcoating of the pellets with Eudragit RD 100 did not affect the drug release profiles and prevented the particles from agglomerating during curing and storage.     

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.     

Con-A conjugated mucoadhesive microspheres for the colonic delivery of diloxanide furoate

The aim of the research work was to develop cyst-targeted novel concanavalin-A (Con-A) conjugated mucoadhesive microspheres of diloxanide furoate (DF) for the effective treatment of amoebiasis. Eudragit microspheres of DF were prepared using emulsification-solvent evaporation method. Formulations were characterized for particle size and size distribution, % drug entrapment, surface morphology and in vitro drug release in simulated gastrointestinal (GI) fluids. Eudragit microspheres of DF were conjugated with Con-A. IR spectroscopy and DSC were used to confirm successful conjugation of Con-A to Eudragit microspheres while Con-A conjugated microspheres were further characterized using the parameters of zeta potential, mucoadhesiveness to colonic mucosa and Con-A conjugation efficiency with microspheres. IR studies confirmed the attachment of Con-A with Eudragit microspheres. All the microsphere formulations showed good % drug entrapment (78+/-5%). Zeta potential of Eudragit microspheres and Con-A conjugated Eudragit microspheres were found to be 3.12+/-0.7mV and 16.12+/-0.5mV, respectively. Attachment of lectin to the Eudragit microspheres significantly increases the mucoadhesiveness and also controls the release of DF in simulated GI fluids. Gamma scintigraphy study suggested that Eudragit S100 coated gelatin capsule retarded the release of Con-A conjugated microspheres at low pH and released microspheres slowly at pH 7.4 in the colon.     

5-氟尿嘧啶结肠定位释药微丸的研制及释药特性

采用流化床喷雾包衣法,研制了2种5-氟尿嘧啶结肠定位释药微丸.以羟丙甲纤维素为溶胀层,乙基纤维素水分散体为控制层,制备时间依赖型包衣微丸;另以肠溶型丙烯酸树脂Eudragit S100为包衣材料,制备pH依赖型微丸.测定了2种微丸在模拟胃肠道各区段pH环境下的释放度.结果表明,时间依赖型包衣微丸体外持续、缓慢释放;pH依赖型包衣微丸在模拟胃和小肠中上部pH的介质中基本不释药,在模拟回盲部区段pH介质中脉冲释药,即后者在体外显示出较好的结肠定位释药特性.     

Low molecular weight heparin loaded pH-sensitive microparticles

Low molecular weight heparins (LMWH) have shown efficacy in the treatment of inflammatory bowel disease after parenteral administration however risking severe hemorrhagic adverse effects. Therefore, an oral colonic targeted heparin dosage form allowing the release of LMWH directly in the inflamed tissue would be of major interest. Enoxaparin was entrapped into pH-sensitive microspheres using Eudragit P4135F that dissolves at pH>7.2. Particle preparation was based on a double emulsion technique with either solvent extraction or evaporation. In order to increase the entrapment efficacy several preparation parameters were optimized, such as inner phase volume, polymer concentration, stabilization of the internal interface by surfactants. Solvent evaporation led to higher entrapment rates (evaporation: 70.1+/-9.9%; extraction: 46.5+/-6.4%). When increasing the volume of the inner aqueous heparin phase, lower encapsulation rates and larger microspheres ( approximately 100-400 microm) were obtained. Sorbitan monostearate (1.75-28% of the total particle mass) had a stabilizing effect on the primary water/oil emulsion. Indeed, higher encapsulation rates (7%: 78.2+/-3.5%; 14%: 76.4+/-10.1%) and smaller particles ( approximately 120-160 microm) were obtained whereas hexadecyltrimethylammonium bromide destabilized the primary emulsion. Interfacial tension studies at a simulated internal water/oil interface confirmed these results. As expected, in vitro drug release was found to be strongly pH-dependent; LMWH was retained in microspheres at pH<6 (<20% release within 4h) whereas a fast drug release was obtained at pH 7.4. The developed microspheres exhibited a particle size adapted to the needs of inflammatory bowel disease therapy, an efficient LMWH encapsulation, and a pH-controlled drug release. These microspheres represent a promising tool for the selective oral delivery of heparin to the colon, especially interesting in the treatment of inflammatory bowel disease.     

In vitro release and in vivo absorption in beagle dogs of meloxicam from Eudragit FS 30 D-coated pellets

The objective of this study was to develop meloxicam-loaded colon-specific pellets coated with Eudragit FS 30 D and further evaluate their in vitro release and in vivo absorption in beagle dogs. Meloxicam-loaded cores (drug loading, 4.8%, w/w) were prepared by layering drug-binder (HPMC)-solubilizer (beta-cyclodextrin) solution onto nonpareils (710-850 microm) and then coated with a copolymer of methyl acrylate, methyl methacrylate and methacrylic acid (Eudragit FS 30 D). The obtained pellets with 15% (w/w) coating level had a spherical form and a smooth surface with coating thickness approximately 28 microm. The in vitro drug release from the pellets was pH-dependent with sufficient gastric resistance (pH 1.2: no release; pH 6.8: 6%; pH 7.0: 52%; pH 7.2: 100%; pH 7.4: 100%, after 3 h incubation). In vivo study was carried out using pentagastrin-pretreated beagle dogs. The onset of meloxicam absorption from the coated pellets with 15% (w/w) Eudragit FS 30 D (3.0+/-0.8 h) was significantly delayed (p<0.05) compared to that from the uncoated drug-layered cores (0.6+/-0.3 h). The area under the meloxicam plasma concentration-time curve (AUC(0-->96)(h) was not significantly different between the two preparations (p>0.05), although AUC(0-->96)(h) obtained after oral administration of coated pellets (142.5+/-59.6 microg h/ml) was lower than that obtained after administration of uncoated drug-layered cores (180.8+/-61.9 microg h/ml). These results suggested that meloxicam could be delivered to the colon with 15% (w/w) coating level of Eudragit FS 30 D and this polymer coating had no significant influence on the relative bioavailability of meloxicam of the pellets.     

Tailoring of drug delivery of 5-fluorouracil to the colon via a mixed film coated unit system

The study was carried out to establish the effectiveness of a mixed film composed of ethylcellulose/Eudragit S100 for colonic delivery of 5-flourouracil (5-FU). Tablets cores containing 5-FU were prepared by direct compression method by coating at different levels (2-9%, m/m) with a non-aqueous solution containing ethylcellulose/Eudragit S100. Coated tablets were studied for the in vitro release of 5-FU and the samples were analyzed spectrophotometrically at 266 nm. Drug release from coated systems depended on the thickness of the mixed film and the composition of the core. Channel formation was initiated in the coat by dissolution of the Eudragit S100 fraction at higher pH in the colonic region. The release was found to be higher in tablets containing Avicel as filler owing to its wicking action compared to that from lactose containing cores. Furthermore, batches containing superdisintegrant (1%, m/m Cross-PVP) along with Avicel in the core released approximately 81.1% drug during the colonic transit time. Kinetic studies indicated that all the formulations followed first-order release kinetics. The developed delivery system will expectedly deliver the drug to the colon.     

Statistical optimization of indomethacin pellets coated with pH-dependent methacrylic polymers for possible colonic drug delivery

The objective of this study was to evaluate the effect of two factors (ratio of Eudragit S100 and Eudragit L100 and the coating level) on indomethacin release from pellets in order to optimize coating formulations for colonic delivery. Coating formulations were designed based on the full factorial design. Two independent variables were the ratio of Eudragit S100:Eudragit L100 (1:4, 1:1 and 1:0) and the level of coating (10%, 15% and 20%, w/w), respectively. The evaluated responses were lag time prior to drug release at pH 6.8 (the time required for drug release up to 2%) and percent of drug release at pH 6.8 in 5h. Polymers were coated onto the pellets containing 20% (w/w) indomethacin, using a fluidized bed coating apparatus. Dissolution test was carried out in media with different pH (1.2, 6.5, 6.8 and 7.2). The dissolution data revealed that the level of coating and the ratio of polymers are very important to achieve optimum formulation. Using responses and resulted statistical equations, optimum formulation consisted of Eudragit S100:L100 in 4:1 ratio and the level of coating (20%) was predicted. Practical results showed that the pellets prepared according to above formulation released no indomethacin at pH 1.2 (simulating stomach pH) and pH 6.5 (simulating proximal part of small intestine pH); drug release was slowly at pH 6.8 (simulating lower part of small intestine pH), but it was fast at pH 7.2 (simulating terminal ileum pH). The results of this study revealed that factorial design is a suitable tool for optimization of coating formulations to achieve colon delivery. It was shown that coating formulation consisted of Eudragit S100:Eudragit L100 in 4:1 ratio at 20% coating level has potential for colonic delivery of indomethacin loaded pellets. The optimized formulation produced dissolution profiles that were close to predicted values.     

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.     

Novel time and site specific “tablets in capsule” system for nocturnal asthma treatment

The objective of present work was to develop a “tablets in capsule” system for facilitating both immediate and pulsatile drug deliveries of theophylline to mimic the circadian rhythm of nocturnal asthma. The system comprised of capsule filled with two tablets, first pulse and second pulse tablet prepared by wet granulation method. First pulse tablet was not coated and was responsible for providing loading dose whereas; second pulse tablet was coated with Eudragit L100 and Eudragit S100 to release drug in colon after specific lag time. Two independent variables, amount of polymers and coating thickness, were optimized by 3² full factorial design. The optimum formulation consisted of Eudragit L100: Eudragit S100 in 1:1.5 ratio and coating thickness of 20 % (w/w). In vitro drug release of “tablets in capsule” system in three different media (pH 1.2, pH 6.8, and pH 7.4) revealed immediate and pulsatile release patterns.     

Composite film-coated tablets intended for colon-specific delivery of 5-aminosalicylic acid: using deesterified pectin

Combinations of Eudragit RS and deesterified pectin, polygalacturonic acid (PGA), or its potassium and sodium salts, when applied as a film coat, has a potential value as a colon-specific delivery system. Dispersions of PGA in Eudragit RS were used as the film former for coating of 5-aminosalicylic acid (5-ASA) tablet cores. Drug release behavior was assessed, in vitro, under simulating conditions in term of pH and time to in vivo during their transit to the colon. Negligible drug release occurred during first 5 hr where the coated tablets were in the stomach and small intestine. After that, the pectinolytic enzymes were added into the pH 6.8 medium to simulate the in vivo condition where there is the digestion of bacteria in the colon. The release of 5-ASA from the coated tablets occurred linearly as a function of time. Drug release depended on the composition of the mixed film, as well as the ratio of Eudragit RS to PGA or its salts. The highest drug release from the coated tablets of about 40% was obtained when the ratio of Eudragit RS to potassium salt of PGA was 2.5 to 1. Drug release profiles seemed to conform to the mechanism involving the osmotically driven release and formation of channels in the film caused by dissolution of PGA salts. Channel formation was, in most cases, activated by the presence of pectinolytic enzymes, showing that the PGA in the mixed film was subjected to enzymic breakdown. In conclusion, PGA could be used as an additive in Eudragit RS films to control the release of colonic delivery system.     

Bumadizone calcium dihydrate microspheres compressed tablets for colon targeting: formulation,optimization and in vivo evaluation in rabbits

Abstract

The objective of this study was the development of a colon-targeted microspheres which were compressed into tablets containing the non-steroidal anti-inflammatory bumadizone calcium dihydrate. A 3² full factorial design was adopted for the evaluation of the prepared microspheres. The effect of two independent variables namely polymer type (Eudragit RS100, ethyl cellulose and cellulose acetate butyrate), and drug: polymer ratio (1:1, 9:1 and 18:1) was studied on the entrapment efficiency and in vitro drug release for 12?h. Colon targeting aims to minimize the release of the drug off target area (pH 1.2 and 6.8) and to maximize the release of the drug in target area (pH 7.4). Candidate formulae were compressed into core tablets and colon targeting was achieved using the enzyme-dependent polymer (pectin) as coat in three different concentrations 50, 75 and 90%. Candidate formula F15 (microspheres prepared using BDZ:CAB in a ratio of 18:1 and compressed into tablets using 50% pectin and 50% Avicel in the coat) was able to adequately modulate drug release avoiding drug release in the gastric ambient, and reaching the colonic targeting where 99.7% release was achieved within 12?h following zero-order model. In vivo studies showed that F15 achieved significant decrease in myeloperoxidase activity and inflammation with delayed T_max (4?h) and lower C_max (2700?ng/ml) when compared to marketed product.