Enhanced oral bioavailability of flurbiprofen by combined use of micelle solution and inclusion compound

The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and β-cyclodextrin (β-CD) on the solubility and bioavailability of a poorly watersoluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, β-CD or mixture of surfactant and β-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of β-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to β-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and β-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM β-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 μg/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or β-CD, with surfactant alone, or with β-CD alone. Therefore, the mixed system consists of surfactant and β-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen.     

Enhanced aqueous solubility and bioavailability of capsaicin by the preparation of an inclusion complex

To increase the aqueous solubility and poor bioavailability of capsaicin (CAS 404-86-4), in this paper, the effects of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the aqueous solubility and the pharmacokinetic characteristics of capsaicin were investigated. The corresponding inclusion complex of capsaicin/HP-beta-CD at the molar ratio of 1:1 was obtained by the method of saturated aqueous solution and characterized by differential scanning calorimetry and X-ray diffractometry. The dissolution rate of capsaicin was significantly increased by the complexation with HP-beta-CD, due to its solubilizing activity. The absorption behavior and bioavailability of capsaicin and its complexation were evaluated after their subcutaneous (s.c.) injection in rats. The absorption rates of capsaicin across subcutaneous tissues and its bioavailability were significantly enhanced by the formation of an inclusion complex with HP-beta-CD. The present results indicate the potential of utilizing HP-beta-CD to improve the subcutaneous absorption and bioavailability of capsaicin.     

Enhanced solubility and oral bioavailability of itraconazole by combining membrane emulsification and spray drying technique

The objective of the present study was to enhance solubility and bioavailability of itraconazole by a combined use of membrane emulsification and spray drying solidification technique. A shirasu-porous-glass (SPG) membrane with a mean pore size of 2.5 μm was used to produce monodispersed microemulsions of itraconazole consisting of methylene chloride as the dispersed phase, a mixture of Transcutol HP and Span 20 as a stabilizer, and dextran as solid carrier dissolved in water as the continuous phase. The dispersed phase permeated through the SPG membrane into the continuous phase at an agitator speed of 150 rpm, a feed pressure of 15 kPa and a continuous phase temperature of 25°C and the resultant emulsion was solidified using spray-drying technique. Solid state characterizations of the solid emulsion showed that the crystal state of itraconazole in solid emulsion was converted from crystalline to amorphous form. The solid emulsion of itraconazole displayed a significant increase in the dissolution rate than that of pure itraconazole. Furthermore, the solid emulsion after oral administration gave about eight-fold higher AUC and about ten-fold higher C(max) in rats than pure itraconazole powder (p<0.05), indicating this formulation greatly improved the oral bioavailability of drug in rats. Thus, these results demonstrated that the SPG membrane emulsification system combined with spray-drying technique could be used as a promising technique to develop solid formulation of itraconazole with enhanced solubility and bioavailability.     

Ocular and systemic bioavailability of ophthalmic flurbiprofen

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-g intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of fluobiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 l of 0.3% flurbiprofen in saline (dose = 150 g), and left eyes were instilled with 50 l of 0.15% flurbiprofen in saline (dose=75 g). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administered dose, the 75-g dose was 30% more available to ocular tissues than was the 150-g dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-g and 150-g topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 g of flurbiprofen was 74%.     

Ocular and systemic bioavailability of ophthalmic flurbiprofen

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-micrograms intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of flurbiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 microliters of 0.3% flurbiprofen in saline (dose = 150 micrograms), and left eyes were instilled with 50 microliters of 0.15% flurbiprofen in saline (dose = 75 micrograms). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administration dose, the 75-micrograms dose was 30% more available to ocular tissues than was the 150-micrograms dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-micrograms and 150-micrograms topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 micrograms of flurbiprofen was 74%.     

Development of novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose, it was prepared using spray-drying techniques with cycloamylose at a weight ratio of 1:1. The effect of cycloamylose on aqueous solubility of ibuprofen was investigated. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with ibuprofen powder. This ibuprofen-loaded solid dispersion improved about 14-fold drug solubility. Ibuprofen was present in an unchanged crystalline state, and cycloamylose played the simple role of a solubilizing agent in this solid dispersion. Moreover, the dispersion gave 2-fold higher AUC (area under the drug concentration-time curve) value compared with a ibuprofen powder, indicating that it improved the oral bioavailability of ibuprofen in rats. Thus, the solid dispersion may be useful to deliver ibuprofen with enhanced bioavailability without crystalline change.     

Enhanced solubility,oral bioavailability and anti-osteoporotic effects of raloxifene HCl in ovariectomized rats by Igepal CO-890 nanomicelles

The purpose of the present study was to enhance the bioavailability and anti-osteoporotic effects of raloxifene HCl (RH) by increasing its solubility and inhibition of the p-glycoprotein pump using surfactant micelles of Igepal CO-890. The micelles were prepared by the direct method and their critical micellar concentration, drug dissolution rate, saturated solubility, drug loading and surface morphology were defined. The cytotoxicity of Igepal CO-890 and its ability to inhibit the p-glycoprotein pump were studied on Caco-2 cells. The pharmacokinetic parameters were analyzed by oral administration of a single dose of 15?mg/kg in Wistar rats. Anti-osteoporotic effects were studied by measuring the calcium, phosphorous, and uterus weight of rats after one month of oral administration of 6?mg/kg/day of RH in ovariectomized rats. Igepal CO-890 micelles enhanced the RH solubility by about two-fold. The FT-IR and DSC studies indicated no interaction between the drug and the surfactant. XRD spectrum showed an amorphous state of RH in the micelles. The p-glycoprotein pump was inhibited by Igepal CO-890 in Caco-2 cells comparable to verapamil. Micelles increased the uterine weight and decreased the serum calcium and phosphorus significantly compared to the untreated drug. Oral bioavailability of RH increased about four-fold by nanomicelles.     

氟比洛芬口服混悬剂的兔药物动力学及其生物利用度

目的:研究氟比洛芬口服给药的药物动力学及生物利用度。方法:利用HPLC法测定氟比洛芬的血药浓度,以交叉给药方式分别给予家兔注射剂和口服混悬剂并且对其药物动力学和生物利用度进行研究。结果:氟比洛芬在家兔体内药动学静脉注射符合二室开放模型,口服符合一室开放模型,氟比洛芬口服混悬剂的绝对生物利用度为61.9%。结论:在进行氟比洛芬剂型研究时应注重提高其口服制剂的生物利用度。     

Enhanced chartreusin solubility by hydroxybenzoate hydrotropy.

The apparent aqueous solubility of the water-insoluble cytotoxic agent, chartreusin, was increased at neutral pH in the presence of hydroxybenzoates. Water molecules play an important role in the chartreusin conformation. Studies included solubility and spectral examinations. The weakest and strongest interactants with chartreusin were sodium benzoate and sodium trihydroxybenzoate, respectively, while the effect of mono- and dihydroxybenzoates was intermediate. A plane-to-plane orientation of chartreusin and the ligand molecules brought together by electrostatic and hydrophobic interactions is postulated. The dramatic chartreusin aqueous solubility increase relative to its aglycone, chartarin, under similar conditions was best rationalized by micellization.     

Enhanced bioavailability of paclitaxel by bamboo concentrate administration

The purpose of this study was to investigate the effect of a cotreatment of bamboo concentrates (Jukcho solution; 0.75, 1.5, and 3.0 mL/kg) with the chemotherapeutic agent paclitaxel on the bioavailability of orally administered paclitaxel (50 mg/kg) in rats. The effect of a pretreatment of bamboo concentrates (1.5 and 3.0 mL/kg for 1.0 h or a consecutive 3 day) was also examined. The paclitaxel plasma concentrations of rats orally administered paclitaxel plus bamboo concentrates (coadministration, 3.0 mL/kg and pretreatment, 1.5 and 3.0 mL/kg) were significantly higher than those of rats treated with paclitaxel alone. Plasma concentrations of paclitaxel in groups pretreated with bamboo concentrates for 3 day were markedly higher than those of a paclitaxel control group at the measured time points. The areas under plasma concentration-time curves (AUCs) of paclitaxel in groups pretreated with bamboo concentrates were elevated and the absolute bioavailability (AB%) and relative bioavailability (RB%) of paclitaxel were also significantly higher than those in the control group. The peak concentration (Cmax), half-life (t1/2), and the elimination rate constant (Kel) of paclitaxel after 3 day of pretreatment with bamboo concentrates were also significantly higher than those in the control, but the time required to reach the maximum plasma concentration (Tmax) of paclitaxel was unaffected by the bamboo concentrates. Western blot analyses demonstrated that the level of CYP3A4 was increased in the livers of rats treated orally with paclitaxel, but this was reversed by pretreating with bamboo concentrates. These results show that bamboo concentrates enhance the bioavailability of orally administered paclitaxel and this effect may be associated with a diminished expression of CYP3A4 in the liver.     

Improvement of oral bioavailability of flurbiprofen from flurbiprofen/β-cyclodextrin inclusion complex by action of cinnarizine

Improvement of the oral bioavailability of flurbiprofen (Flu) after oral administration of flurbiprofen/β-cyclodextrin inclusion complex (Flu/β-CD) by the action of cinnarizine (CN) was investigated. Flu and Flu/β-CD were administered orally to fasted rats at a dose of 20 mg/kg as Flu. Thirty minutes after drug administration, CN dissolved in pH 4.0 buffer solution or pH 4.0 buffer solution alone was administered to the rats. The dose of CN was 0.17 mg/kg. Blood samples were taken from rats and Flu concentrations in plasma samples were determined by HPLC. It was found from the comparison of Flu and Flu with CN (Flu + CN) that CN had no effect on plasma concentrations of Flu after oral administration of Flu. The mean plasma levels after oral administration of Flu/β-CD with CN (Flu/β-CD + CN) were larger not only than those of Flu and Flu + CN but also than those of Flu/β-CD. The value of C_max in Flu/β-CD + CN was significantly larger than that of Flu/β-CD. This is considered to be caused by the action of CN as a competing agent. This mechanism was supported by the result of solubility study in which Flu solubility in β-CD solution decreased with the addition of CN. It was found from these results that CN had strong ability as a competing agent in vivo.     

Improving the solubility and bioavailability of dihydroartemisinin by solid dispersions and inclusion complexes

Dihydroartemisinin (DHA) is a poorly water-soluble drug that displays low bioavailability after oral administration. Attempts have been made to improve the solubility of DHA. Yet, no information is available concerning improved bioavailability. This study aimed to improve the water solubility of DHA by two systems: solid dispersions with polyvinylpyrrolidone (PVPK30, PVPK25, PVPK15) and inclusion complexes with hydroxypropyl-β-cyclodextrin (HPβCD), as well as improving the bioavailability of both systems. The phase transition of DHA with hydrophilic polymers was evaluated by X-ray diffraction (XRD) and differential scanning calorimetery (DSC). DHA became amorphous in DHA-HPβCD complexes and showed more amorphous behavior in XRD analyses with rise in molecular weight of PVP. Melting onset temperature of DHA decreased, while DSC thermograms revealed the peak area and enhanced enthalpy change (DH) in solid dispersions as well as inclusion complexes. DHA solubility was enhanced 84-fold in DHA-HPβCD complexes and 50-times in DHA-PVPK30. The improved solubility using the four polymers was in the following order: HPβCD > PVPK30 > PVPK25 > PVPK15. Values of area under curve (AUC) and half life (t_1/2) of DHA-PVPK30 were highest followed by DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25. V_d/f of DHA-PVPK30 was 7-fold. DHA-HPβCD, DHA-PVPK15 and DHA-PVPK25 showed significantly different pharmacokinetic parameters compared with DHA solutions. The 95% confidence interval was meaningful in AUC and t_1/2. Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone.     

Enhancement of dehydroepiandrosterone solubility and bioavailability by ternary complexation with alpha-cyclodextrin and glycine

In the present work we investigated the possibility of improving dehydroepiandrosterone (DHEA) solubility and bioavailability by high-energy cogrinding with alpha-cyclodextrin (alpha-Cd) in the presence or absence of different auxiliary substances (glycine, biomaltodextrin, poly(vinyl pyrrolidone), poly(ethylene glycol) 400). In all cases, ternary products exhibited higher drug solubilizing properties than the binary DHEA-alpha-Cd coground system. Glycine was the most effective component. The best combinations, corresponding to 1:1:2 and 1:2:3 drug-alpha-Cd-glycine molar ratios, were characterized by differential scanning calorimetry and X-ray powder diffractometry and evaluated for dissolution rate. The presence of glycine favored destruction of DHEA crystalline structure during cogrinding, as evidenced by the strong reduction in both time and vibration frequency of milling necessary to obtain total drug amorphization. Both ternary products showed better dissolution properties than the drug alone, affording, respectively, a 40 and 60% increase of dissolution efficiency. The 1:2:3 coground product was then selected for in vivo bioavailability studies in women suffering from adrenocortical insufficiency. DHEA and DHEA sulfate blood levels were significantly higher (p < 0.001) after oral administration of the coground product than after oral administration of untreated drug, with a 100% increase in the area under the curve (AUC) of concentration versus time. Moreover, the time to reach maximum concentration (t(max)) decreased from 2.2 with the untreated drug to 0.5 h with the coground product, and the mean permanence time of DHEA within physiological levels was four times longer for the coground product compared with the untreated drug. These results indicate that the developed product is particularly suitable for oral DHEA formulations in hormone replacement therapies.     

Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its beta-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-gamma-CyD < G2-beta-CyD < beta-CyD < HP-beta-CyD. Spectroscopic studies also revealed that HP-beta-CyD and beta-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-beta-CyD < or = beta-CyD. HP-beta-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-beta-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its beta-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-beta-CyD complex were much higher than in either that of rutin alone or in its beta-CyD complex. The in vivo absorption study suggests that HP-beta-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-beta-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.     

Cocrystals of quercetin with improved solubility and oral bioavailability

Flavonoids have been studied extensively due to the observation that diets rich in these compounds are associated with lower incidences of many diseases. One of the most studied flavonoids, quercetin, is also the most abundant of these compounds in the plant kingdom. Numerous therapeutic bioactivities have been identified in vitro. However, its in vivo efficacy in pure form is limited by poor bioavailability, primarily due to its low solubility and consequent low absorption in the gut. Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. Here, we synthesized and evaluated four new cocrystals of quercetin (QUE): quercetin:caffeine (QUECAF), quercetin:caffeine:methanol (QUECAF·MeOH), quercetin:isonicotinamide (QUEINM), and quercetin:theobromine dihydrate (QUETBR · 2H(2)O). Each of these cocrystals exhibited pharmacokinetic properties that are vastly superior to those of quercetin alone. Cocrystallization was able to overcome the water insolubility of quercetin, with all four cocrystals exhibiting some degree of solubility. The QUECAF and QUECAF·MeOH cocrystals increased the solubility of QUE by 14- and 8-fold when compared to QUE dihydrate. We hypothesized that this improved solubility would translate into enhanced systemic absorption of QUE. This hypothesis was supported in our pharmacokinetic study. The cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold.     

Comparative bioavailability of two flurbiprofen products: stereospecific versus conventional approach

In this randomized, crossover study comparing the bioavailability of a film-coated (Ansaid) with a sugar-coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 healthy young men, no significant differences were found for Cmax, tmax or AUC, using a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30-min post-dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7.8 per cent) but significant difference in AUC of the active S-configuration (Froben greater than Ansaid). No significant differences between Ansaid and Froben were found for tmax or Cmax for the S-flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products.     

Carcinogenicity of azo colorants: influence of solubility and bioavailability

In the past, azo colorants based on benzidine, 3,3'-dichlorobenzidine, 3,3'-dimethylbenzidine (o-tolidine), and 3,3'-dimethoxybenzidine (o-dianisidine) have been synthesized in large amounts and numbers. Studies in exposed workers have demonstrated that the azoreduction of benzidine-based dyes occurs in man. The metabolic conversion of benzidine-, 3,3'-dimethylbenzidine- and 3,3'-dimethoxybenzidine-based dyes to their (carcinogenic) amine precursors in vivo is a general phenomenon that must be considered for each member of this class of chemicals. Several epidemiological studies have demonstrated that the use of the benzidine-based dyes has caused bladder cancer in humans. However, in contrast to water-soluble dyes, the question of biological azoreduction of (practically insoluble) pigments has been a matter of discussion. As a majority of azo pigments are based on 3,3'-dichlorobenzidine, much of the available experimental data are focused on this group. Long-term animal carcinogenicity studies performed with pigments based on 3,3'-dichlorobenzidine did not show a carcinogenic effect. The absence of a genotoxic effect has been supported by mutagenicity studies with the 3,3'-dichlorobenzidine-based Pigment Yellow 12. Studies in which azo pigments based on 3,3'-dichlorobenzidine had been orally administered to rats, hamsters, rabbits and monkeys could generally not detect significant amounts of 3,3'-dichlorobenzidine in the urine. It, therefore, appears well established that the aromatic amine components from azo pigments based on 3,3'-dichlorobenzidine are practically not bioavailable. Hence, it is very unlikely that occupational exposure to insoluble azo pigments would be associated with a substantial risk of (bladder) cancer in man. According to current EU regulations, azo dyes based on benzidine, 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine have been classified as carcinogens of category 2 as "substances which should be regarded as if they are carcinogenic to man". This is not the case for 3,3'-dichlorobenzidine-based azo pigments.     

Enhanced bioavailability of poorly water-soluble clotrimazole by inclusion with beta-cyclodextrin

Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with beta-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of beta-cyclodextrin concentration, resulting in A(L) type phase solubility diagram which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M(-1). The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.     

Enhanced rectal bioavailability of ibuprofen in rats by poloxamer 188 and menthol

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.     

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.