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The aim of this study was to develop pellet formulations that could be used to improve the dissolution and bioavailability of a poorly water-soluble model drug, cisapride. Six different types of pellets were prepared by coating sugar spheres in a fluidized bed coater. When the sugar spheres were single layered containing cisapride and solubilizer such as polysorbate 80, the resulting pellets provided an instant release of cisapride in the simulated gastric fluid. Dissolution tests carried out in the simulated intestinal fluid showed that there were negligible amounts of cisapride released, regardless of the pellet formulation. To succeed in attaining dissolution and the sustained release of cisapride at a neural pH, the single layered pellets were coated again with a coating suspension containing Eudragit RS 30D and L 30D. Scanning electron microscopy revealed that the dual layered pellets had a crack-free and spherical surface. Interestingly, the dual layered pellets provided the sustained release of cisapride in both the simulated gastric and intestinal fluids. The composition and components of the dual layers were found to be key parameters affecting the pattern of cisapride dissolution. Significant improvement in the bioavailability of cisapride was achieved when the dual layered pellets were administered orally to dogs. Overall, these results suggest that the dual layered pellets have potential as a sustained release dosage form for poorly water-soluble drugs.

A semisolid self-emulsifying system (SES) of itraconazole consisting of oleic acid, polysorbate 80 and coajuvant (citric acid) was prepared by a hot-melt technique and then compared with hydroxypropylmethylcellulose (HPMC) solid dispersion (SD) coated onto inert sugar spheres as a reference formulation for in vitro and in vivo disposition in rats. The optimal SES greatly increased dissolution rates in gastric (pH 1.2) and intestinal fluid (pH 6.8) by forming a microemulsion (150-250 nm), whereas that of SD was minimal. The tissue uptake of itraconazole from SES in whole intestine, liver and Peyer's patches of the rats was more favorable than that from SD and linearly increased as a function of administering dose. Interestingly, the uptake ratio of Peyer's patches relative to liver also increased linearly in the case of SES while that of SD was almost unchanged. After repeated dosing for 1 week, both SES and SD increased the areas of Peyer's patch region in intestinal tissues but no distinct histopathological damage of the intestine was observed except the hepatocytes. Due to the biopharmaceutical differences of SES in terms of efficient solubilization, easy dispersibility and higher lymphatic transport, the in vivo bioavailability of SES was about twice greater than that of SD in rats., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

The objectives of this study were to solubilize oxytetracycline hydrochloride (HCl) in reverse micelles to prepare poly-d,l-lactide-co-glycolide (PLGA) microspheres and to explore parameters affecting its encapsulation efficiency. Oxytetracycline HCl was dissolved in the reverse micelles consisting of cetyltrimethylammonium bromide, water, and ethyl formate. A PLGA polymer was then dissolved in the reverse micellar solution, and a modified solvent quenching procedure was carried out to prepare PLGA microspheres. Encapsulation efficiencies of oxytetracycline HCl ranged from 2.3 +/- 0.2 to 24.9 +/- 4.6%, depending on experimental conditions. Important parameters affecting its encapsulation efficiency included the amounts of water used to prepare the reverse micelles and PLGA polymer. With regard to microsphere morphology, the reverse micellar process produced the microspheres with smooth and pore-free surfaces. In particular, their internal matrices did not possess hollow cavities that were frequently observed when a typical double emulsion technique was used to make microspheres. In summary, it was possible to encapsulate oxytetracycline HCl into PLGA microspheres via the ethyl formate-based reverse micellar technique. We also anticipate that the use of ethyl formate could avoid environmental and human toxicity issues associated with methylene chloride.

A drug-containing polymeric dispersion was applied onto nonpareil sugar spheres (18/20 mesh) using a fluid-bed spray coater. Eudragit RS30D was selected as the polymeric coating material. Melatonin secreted by the pineal gland in a circadian rhythm was used as a model drug. The release behaviors of the coated sugar spheres were investigated in gastric fluid (pH 1.4) for 2 h, and then continuously in intestinal fluid (pH 7.4) for 14 h. The release rate of the coated sugar spheres decreased with increasing coating levels. The solvent (ethanol) in the coating dispersions significantly decreased the release of the drug due to the good dispersion of the low solubility melatonin in the polymeric films. The polymer (polyvinylpyrrolidone, PVP) and drug contents in the coating dispersions did not affect the release rate. Most of all, the release profiles were drastically changed according to the type and concentration of plasticizers used. The current coating methods that use drug-containing polymeric dispersions could be useful for simultaneous drug loadings and their modified release. The solubilization and controlled release of poorly water-soluble drugs can be achieved as both the solubilizers and drugs are present in the drug-containing polymeric dispersions.

The objective of this study was to formulate itraconazole semisolid dosage forms and characterize their physicochemical properties. Itraconazole and excipients such as polysorbate 80, fatty acids, fatty alcohols, oils and organic acids were melted at 160 degrees C. The fused solution was then cooled immediately at -10 degrees C to make wax-like semisolid preparations. Their physicochemical attributes were first characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectrometry. The solubility of itraconazole in semisolid preparations and their dispersability in the simulated gastric fluid were also determined. Our semisolid preparations did not show any distinct endothermic peak of a crystalline form of itraconazole around 160-163 degrees C. This suggested that it was changed into amorphous one, when it was formulated into semisolid preparations. In addition, the distinctive functional peaks and chemical shifts of itraconazole were well retained after processing into semisolid preparations. It could be inferred from the data that itraconazole was stable during incorporation into semisolid preparations by the hot melt technique. In particular, itraconazole semisolid preparations composed of polysorbate 80, fatty acids and organic acids showed good solubility and dissolution when dispersed in an aqueous medium. It was anticipated that the semisolid dosage forms would be industrially applicable to improving the bioavailability of poorly water-soluble drugs.

Bifidobacteria-loaded alginate poly-l-lysine microparticles (bap microparticles) were prepared using an air atomization method and then freeze-dried. The viability of the bap microparticles was investigated as a function of the amount of the bifidobacteria cultures, and the addition of a yeast extract, cryoprotectants, antioxidants and neutralizer. The size of the bap microparticles with and without the bifidobacteria was 84.8 +/- 28.5 microm (mean +/- standard deviation) and 113.1 +/- 38.5 microm, respectively. The surface morphology was slightly ellipsoid and wrinkled regardless of the incorporating bifidobacteria. The viability gradually decreased with increasing freeze-drying time. Free-flowing powdered bap microparticles were obtained at least 12 h after freeze-drying the wetted slurry of bap microparticles. However, the particles tended to aggregate when either lactose or ascorbic acid was added. The addition of a yeast extract, cryoprotectants (glycerol and lactose), antioxidants (NaHSO3 and ascorbic acid) and neutralizer (Mg3(PO4)2) resulted in a significantly higher viability of the bifidobacteria in the bap microparticles after freeze-drying (0.34-1.84 log) compared with the culture alone.

Circadian variations in the pharmacokinetics, tissue distribution and urinary excretion of nifedipine were examined in fasted rats after administering a single oral dose at three different dosing times (08:00 am, 16:00 pm, 00:00 am). The plasma concentrations, the areas under the plasma concentration-time curve from zero to 6 h (AUC(0-6 h)) and the peak plasma concentration (C(max)) were significantly higher in the rats dosed at 08:00 am (immediately inactive), and was lower at 16:00 pm (most inactive) and 00:00 am (most active). The time to reach the C(max) (T(max)) was the shortest in the rats dosed at 08:00 am. It was very interesting to observe the double peak phenomena in the plasma concentration profiles, showing a larger peak followed by a smaller peak. There was a dosing time dependency on the tissue distribution 30 min after administration, showing a similar tendency to the pharmacokinetic behavior. However, there was no distinct dosing time dependency observed at 2 h after administration due to the extensive disposition. The cumulative urine excretion of nifedipine in the rats dosed at 08:00 am was significantly higher (about two-fold) than in those dosed at 16:00 pm and 00:00 am. The pharmacokinetics of nifedipine in the rats was consistent with that observed in human subjects in terms of the day-night clock time but the biological time was the opposite, as marked by the rest-activity cycles. These results may help to explain the circadian time-dependency of nifedipine pharmacokinetics.

Effect of incorporating pharmaceutical excipients on the in vitro release profiles and the release mechanism of monolithic hydroxypropylmethylcellulose (4000 cps) matrix tablets (m-HPMC tablets) in terms of mimicking the dual drug release character of bi-layered Tylenol ER tablets was studied. We also compared the in vitro release profiles of optimized m-HPMC matrix tablet and Tylenol ER tablet in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid, and in vivo drug bioavailabilities in healthy human volunteers. Acetaminophen was used as the model drug. The m-HPMC tablets were prepared using a wet granulation method followed by direct compression. Release profiles and swelling rates of m-HPMC tablets were found to be highly influenced by the types and amounts of pharmaceutical excipients incorporated. Starch 1500 (Prejel) and sodium lauryl sulfate (SLS) played a key role in determining the dissolution rate of m-HPMC tablets. Additional excipients, i.e., microcrystalline cellulose (Avicel PH101) and NaH2PO4 were used to tune the release profiles of m-HPMC tablets. The effect of pharmaceutical excipients on drug release from HPMC-based matrix tablets was found to be mainly due to a change in hydrophilic gel expansion and on physical interactions between the drug and HPMC. The optimized m-HPMC tablet with a balanced ratio of Prejel, SLS, Avicel PH101, and NaH2PO4 in the formulation showed dual release profiles in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid in vitro. Dual release was defined as immediate drug release within few minutes followed by extended release over 8 h. The similarity factors of m-HPMC tablets and bi-layered Tylenol ER tablets were 79.8, 66.1, and 82.7 in water, gastric fluid and intestinal fluid, respectively, indicating the equivalence of the two release profiles. No significant in vivo bioavailability differences were observed in healthy human volunteers. The developed m-HPMC tablet with dual release characteristics can be easily prepared using a conventional high-speed tablet machine and could provide an alternative to commercially available bilayered Tylenol ER tablets.

Polyethylene glycol (PEG) 6000-based solid dispersions (SDs), by incorporating various pharmaceutical excipients or microemulsion systems, were prepared using a fusion method, to compare the dissolution rates and bioavailabilities in rats. The amorphous structure of the drug in SDs was also characterized by powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The ketoconazole (KT), as an antifungal agent, was selected as a model drug. The dissolution rate of KT increased when solubilizing excipients were incorporated into the PEG-based SDs. When hydrophilic and lipophilic excipients were combined and incorporated into PEG-based SDs, a remarkable enhancement of the dissolution rate was observed. The PEG-based SDs, incorporating a self microemulsifying drug delivery system (SMEDDS) or microemulsion (ME), were also useful at improving the dissolution rate by forming a microemulsion or dispersible particles within the aqueous medium. However, due to the limited solubilization capacity, these PEG-based SDs showed dissolution rates, below 50% in this study, under sink conditions. The PEG-based SD, with no pharmaceutical excipients incorporated, increased the maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC(0-6h)) two-fold compared to the drug only. The bioavailability was more pronounced in the cases of solubilizing and microemulsifying PEG-based SDs. The thermograms of the PEG-based SDs showed the characteristic peak of the carrier matrix around 60 degrees C, without a drug peak, indicating that the drug had changed into an amorphous structure. The diffraction pattern of the pure drug showed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of the numerous distinctive peaks of the drug in the PEG-based SDs demonstrated that a high concentration of the drug molecules was dissolved in the solid-state carrier matrix of the amorphous structure. The utilization of oils, fatty acid and surfactant, or their mixtures, in PEG-based SD could be a useful tool to enhance the dissolution and bioavailability of poorly water-soluble drugs by forming solubilizing and microemulsifying systems when exposed to gastrointestinal fluid.

Effect of solvents on physical characteristics and release characteristics of monolithic acetaminophen (APAP) hydroxypropylmethylcellulose (HPMC) matrix granules and tablets were examined. Various types and amounts of solvents were employed for granulation and cOAting. APAP and other excipients were mixed and were then wet-granulated in a high-speed mixer. The dried granules were then directly compressed and film-coated with low viscosity grade HPMC. As the amount of water increased, the size of granules also increased, showing more spherical and regular shape. However, manufacturing problems such as capping and lamination in tableting occurred when water was used alone as a granulating solvent. The physical properties of HPMC matrix granules were not affected by the batch size. The initial release rate as well as the amount of APAP dissolved had a tendency to decrease as the water level increased. Addition of nonaqueous solvent like ethanol to water resulted in good physical properties of granules. When compared to water/ethanol as a coating solvent, the release rate of film-coated HPMC matrix tablets was more sensitive to the conditions of coating and drying in methylene chloride/ethanol. Most of all, monolithic HPMC matrix tablet when granulated in ethanol/water showed dual release with about 50% drug release immediately within few minutes followed by extended release. It was evident that the type and amount of solvents (mainly water and ethanol) were very important for wet granulation and film-coating of monolithic HPMC matrix tablet, because the plastic deforming and fragmenting properties of material were changed by the different strengths of the different solvents.

Carvedilol is administered as a racemic mixture of the R(+)- and S(-)-enantiomers, although they exhibit different pharmacological effects. To investigate the stereoselective pharmacokinetics, the enantiomeric separation of carvedilol in human plasma was undertaken using capillary electrophoresis (CE). Resolution of the enantiomers was achieved using 2-hydoxypropyl-beta-cyclodextrin as the chiral selector. Phosphate buffer (50 mM, pH 4.0) containing 10 mM of 2-hydoxypropropyl-beta-cyclodextrin was used as electrolytic buffer. Achiral separation was carried out with the same electrolytic buffer without chiral selector. Following a single oral administration of 25-mg carvedilol to 11 healthy, male volunteers, stereoselective pharmacokinetic analysis was undertaken. The maximum plasma concentrations (Cmax) were 48.9 and 21.6 ng/mL for (R)-carvedilol and (S)-carvedilol, respectively, determined by the chiral method. The profiles of the plasma concentration of (RS)-carvedilol showed Cmax of 71.5, 72.2, and 73.5 ng/mL, as determined by the CE, HPLC/FD methods and calculations from the data of the chiral method, respectively.

An orally applicable nifedipine-loaded core tablets was coated using high viscosity grade HPMC (100,000 cps) in ethanol/water cosolvent. The release of coated tablet was evaluated using USP paddle method in 900 ml of simulated gastric fluid (pH 1.2) for 2 h followed by intestinal fluid (pH 6.8) for 10 h. The surface morphologies using scanning electron microscope and photo-images using digital camera of coated tablet during the release test were also visualized, respectively. The viscosity of hydro-alcoholic HPMC solution largely decreased as the amount of ethanol increased. There was no significant difference in viscosity among plasticizers used. The distinct and continuous coated layer was observed using scanning electron microscope. However, the surface morphologies were highly dependent on HPMC concentration and ratio of coating solvents. The higher ratio of ethanol/water gave a longer lag time prior to drug release. Lag time also increased as a function of the coating levels based on weight gains due to increased thickness of coated layer. Lag time is inversely correlated with HPMC concentration in ethanol/water (5:1) cosolvent. As the HPMC concentration slightly decreased from 3.8 to 3.2% in hydroalcoholic coating solution, a large increase of lag time was observed. As the swelling (mixing) time of high viscosity grade HPMC in ethanol/water cosolvent increased from 1 to 5 h, the release rate was decreased due to enough plasticization of polymer. Based on photo-imaging analysis, the coated tablet was initially swelled and gelled without erosion and disintegration over 5 h. The disintegration of the coated tablet was occurred approximately 7 h after dissolution, resulting in pulsed release of drug. The high viscosity grade HPMC can be applicable for polymeric coating after careful selection of solvent systems. The release behavior and lag time could be controlled by coating conditions such as HPMC concentration, ethanol/water ratio as a coating solvent, coating level and swelling (mixing) time of coating solution. The current time-controlled release tablet coated with high viscosity grade HPMC with a designated lag time followed by a rapid release may provide an alternative to site specific or colonic delivery of drugs. In addition, the release behavior can be matched with body's circadian rhythm pattern in chronotherapy.

To improve the bioavailability of poorly water-soluble ibuprofen in the rectum with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution and pharmacokinetic study of ibuprofen delivered by the poloxamer gels composed of poloxamer 188 and menthol were then performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that four parts menthol formed eutectic mixture with six parts ibuprofen. In the presence of poloxamer, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Release mechanism showed that the release rate of ibuprofen from the poloxamer gels without menthol was independent of the time but the drug might be released from the poloxamer gels with menthol by Fickian diffusion. Furthermore, the poloxamer gel with menthol (poloxamer/menthol/ibuprofen (15%/0.25%/2.5%)) gave significantly higher initial plasma concentrations, C(max) and AUC of ibuprofen than did solid suppository, indicating that the drug from poloxamer gel could be more absorbed than that from solid one in rats. Thus, the poloxamer gel with poloxamer 188 and menthol was a more effective rectal dosage form for ibuprofen.

To improve the solubility and in vitro dissolution of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution study of ibuprofen delivered by poloxamer gels composed of poloxamer 188 and menthol were performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6, followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that 4 parts of ibuprofen formed eutectic mixture with 6 parts of menthol. In the presence of poloxamer 188, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. Furthermore, the solution with ratio of 4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared with that without poloxamer and that without menthol, respectively. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Dissolution mechanism showed that the dissolution rate of ibuprofen from the poloxamer gels without menthol was independent of the time, but the drug might be dissolved from the poloxamer gels with menthol by Fickian diffusion. Thus, the poloxamer gels developed using eutectic mixture with menthol, which gave the improved solubility and dissolution of drug, are potential candidates for ibuprofen-loaded transdermal and rectal delivery system.

We asked whether Bifidobacterium bifidum regulates the synthesis of IgA by mucosal lymphoid cells. B. bifidum alone, but not Clostridium perfringens, significantly induced total IgA and IgM synthesis by both mesenteric lymph nodes (MLN) and Peyer's patch (PP) cells. We, further, investigated the mucosal antibody production following peroral administration of B. bifidum to mice. Ingested B. bifidum significantly increased the number of Ig (IgM, IgG, and IgA) secreting cells in the culture of both MLN and spleen cells. Nonetheless, B. bifidum itself does not induce the own specific antibody responses, implying that B. bifidum does not provoke unnecessary immune reaction. Subsequently, it was found that encapsulation of B. bifidum further augments the total IgA production in the culture of both MLN and spleen cells. Finally, we found that the immuno-stimulating activity of B. bifidum is due to its cellular components but not due to any actively secreting component(s) from bacteria.