Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole-cyclodextrin formulations

The current research evaluated and compared the efficacy of hydroxybutenyl-beta-cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17-fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form.     

Pharmacokinetics of tamoxifen after intravenous and oral dosing of tamoxifen-hydroxybutenyl-beta-cyclodextrin formulations

Oral and intravenous administration of tamoxifen base and tamoxifen citrate formulated with hydroxybutenyl-beta-cyclodextrin (HBenBCD) to Sprague-Dawley rats significantly increased the oral bioavailability of tamoxifen relative to that of parent drug (no HBenBCD). When formulated with HBenBCD, the form of tamoxifen (base vs. salt) made no difference in the oral bioavailability of tamoxifen. Liquid formulations (PG:PEG400:H2O) provided higher oral bioavailability than solid formulations dissolved and dosed as aqueous oral solutions. The oral bioavailability of tamoxifen was significantly influenced by both dietary status and time of dosing of the animals. Tamoxifen metabolite plasma concentrations were not affected by complexation of tamoxifen with HBenBCD. Collectively, the data indicated that dosing of fasted animals in the morning with tamoxifen:HBenBCD formulations provided a very significant increase in tamoxifen oral bioavailability (up to 10- to 14-fold).     

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.     

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.     

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol-polysorbate 80 solid dispersion carrier system

Different formulation approaches were evaluated to ensure that the formulation of a poorly water soluble compound chosen during early development achieves optimum bioavailability. The insoluble compound has an aqueous solubility of 0.17 micro g/mL at 25 +/- 1 degrees C, a relatively high permeability (Caco2 P(app) = 6.1 x 10(-4) cm/min), and poor bioavailability in dogs (dry blend formulation). Based on the prediction by GastroPlus, the oral absorption of this compound is sensitive to its apparent solubility and particle size. The oral bioavailability of three different formulations was compared in a dog model: a cosolvent-surfactant solution, a solid dispersion in a mixture of polyethylene glycol 3350 and polysorbate 80, and a dry blend of micronized drug with microcrystalline cellulose. In absence of a parenteral injection, the bioavailability of the solution was considered to be 100%, and the relative oral bioavailability of the three formulations was 100, 99.1, 9.8, respectively. Comparable bioavailability was obtained with the solid dispersion and the cosolvent-surfactant solution, both of which showed a 10-fold higher bioavailability than the dry blend. Thus, a 20 mg dose strength capsule containing the solid dispersion formulation was selected for clinical development. The selected solid dispersion system was physically and chemically stable for at least 16 months at 25 degrees C/60% RH. In conclusion, the bioavailability of a poorly water soluble drug was greatly enhanced using the solid dispersion formulation containing a water soluble polymer with a surface active agent.     

Pharmacokinetics and absolute bioavailability of sitafloxacin,a new fluoroquinolone antibiotic,in healthy male and female Caucasian subjects

1. The aim was to compare the pharmacokinetics of sitafloxacin from a capsule formulation (dose of 500mg sitafloxacin) and an intravenous (i.v.) formulation infused over 1?h (dose of 400?mg sitafloxacin) in healthy male and female subjects and to estimate the absolute bioavailability of sitafloxacin from the capsule formulation. 2. Following oral administration, sitafloxacin was rapidly absorbed, with a mean maximum concentration in plasma (C max) of 4.65 μg ml -1 occurring at a median t max = 1.25?h giving a mean AUC(0- ∝) = 28.1 μg?h ml -1. For the i.v. administration, a mean C -max = 5.53 μ ml -1 occurred at the end of the 1-h infusion with a mean AUC(0- ∝) = 25.4μg?h ml -1. The mean terminal elimination half-life was 7.0?h (oral) and 6.6?h (i.v.). For the oral and i.v. formulations, the mean total plasma clearance was 296 and 263 ml?min -1, respectively and the mean volume of distribution was 180 and 150 litres, respectively. 3. Within 48h post-dose, 61% (range 26-86%) of the administered dose was excreted unchanged in urine following capsule administration, compared with 75% (range 42-101%) following the i.v. formulation. For both formulations, the renal clearance of sitafloxacin (means of 181 and 198 ml min-1 for the capsule and i.v. doses, respectively) implies active tubular secretion of the drug. 4. The absolute bioavailability of sitafloxacin from the capsule formulation was high at 89%, with a 95% CI of 84-94%. The intersubject variability (CV%) in the sitafloxacin AUC(0- ∝) for the capsule was low at 18.6%. 5. Gender differences in the pharmacokinetics of sitafloxacin were small and would not warrant dose adjustment. 6. The findings show that the capsule formulation offers good oral bioavailability and merits further clinical evaluation of sitafloxacin as an orally effective fluoroquinolone antibacterial.     

Lack of bioequivalence between different formulations of isosorbide dinitrate and hydralazine and the fixed-dose combination of isosorbide dinitrate/hydralazine: the V-HeFT paradox

OBJECTIVE: To investigate whether the apparent discrepancy between the efficacy of the combination of isosorbide dinitrate (ISDN) and hydralazine demonstrated in the first V-HeFT trial (V-HeFT I) and that in V-HeFT II could be explained by pharmacokinetic differences in the study drug formulations, and to compare the pharmacokinetic profile of the fixed-dose combination of ISDN/hydralazine (FDC ISDN/HYD; BiDil) formulation used in A-HeFT with that of the V-HeFT study drug formulations. STUDY PARTICIPANTS AND METHODS: A bioequivalence study was performed (n = 18-19 per group) comparing the ISDN and hydralazine formulations used in V-HeFT I, V-HeFT II and A-HeFT in healthy volunteer men and women aged 18-40 years. In phase A of the study, subjects received a reference solution of hydralazine hydrochloride/ISDN (37.5mg/10mg) orally. Slow acetylators were identified and randomised into three groups in phase B to receive a single oral dose of identical amounts of hydralazine hydrochloride/ISDN (37.5mg/10mg) from either (i) a hydralazine capsule plus an ISDN tablet (the V-HeFT I formulation); (ii) a hydralazine tablet plus an ISDN tablet (the V-HeFT II formulation); or (iii) FDC ISDN/HYD (the A-HeFT formulation). Blood/plasma concentrations of hydralazine and ISDN were determined from the blood samples taken between 0 and 36 hours. RESULTS: In phase B, the maximum observed concentrations (C(max)) were 65.9 +/- 53.9, 28.2 +/- 15.8 and 51.5 +/- 54.3 ng/mL of unchanged hydralazine, and 23.1 +/- 12.3, 21.7 +/- 13.4 and 26.7 +/- 18.7 ng/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. The area under the blood/plasma concentration-time curve (AUC) values were 32.6 +/- 13.4, 23.3 +/- 15.1 and 32.6 +/- 18.5 ng x h/mL of hydralazine, and 24.4 +/- 9.0, 24.8 +/- 8.0 and 23.5 +/- 6.3 ng x h/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. For comparison of bioequivalence, the C(max) and AUC were normalised to 65kg bodyweight, and point estimates and 90% confidence intervals of the C(max) ratios, AUC ratios and ratios of the AUC in phase B normalised for clearance by the AUC in phase A (AUCR) were calculated. The three formulations were not bioequivalent based on the C(max) and AUC comparisons. CONCLUSIONS: The blood concentrations of hydralazine obtained with the tablet formulation tested in V-HeFT II were markedly lower than those obtained with the capsule formulation tested in V-HeFT I or the FDC ISDN/HYD single tablet used in A-HeFT. The apparently modest effect on survival observed in V-HeFT II could be explained in part by the poor hydralazine bioavailability of the tablet preparation used in this trial. ISDN exposures were similar in the two trials. The ISDN-hydralazine formulation used in V-HeFT II was not bioequivalent to the formulation used in V-HeFT I or to the FDC ISDN/HYD that had demonstrated a significant survival benefit in A-HeFT.     

Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers.

Self-microemulsifying drug delivery systems (SMEDDS) represent a possible alternative to traditional oral formulations of lipophilic compounds. This study was designed to compare the oral bioavailability and food-effect of SMEDDS of itraconazole (ITRA-GSMP capsule containing 50mg itraconazole) to that of the currently marketed formulation (Sporanox capsule containing 100mg itraconazole). Eight healthy volunteers received Sporanox or ITRA-GSMP capsule in the fasted state or after a high-fat diet on four separate dosing occasions with a 2-week washout period. Blood samples were collected and analyzed. After administration of the ITRA-GSMP capsule, AUC0-24 and Cmax were 1.9- and 2.5-fold higher in the fasted state and 1.5- and 1.3-fold higher in the fed state, respectively, than those of the Sporanox capsule. Moreover, ITRA-GSMP capsules yielded more reproducible blood-time profiles than Sporanox capsules. Food had a marked effect on itraconazole absorption from the Sporanox capsule, whereas the influence was less pronounced for the ITRA-GSMP capsule. Collectively, our data suggest that a new self-microemulsifying formulation may provide an alternative oral formulation for itraconazole with improved oral bioavailability and reduced food-effect.     

Bioequivalence assessment of two formulations of spironolactone in Chinese healthy male volunteers

The bioavailability of a new spironolactone ((7alpha,17alpha)-7-(acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid gamma-lactone, CAS 52-01-7) formulation (test) was compared with a commercially available original formulation (reference) of the drug in 20 Chinese healthy male volunteers, aged between 21 and 27. The trial was designed as an open, randomized, single blind two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 100 mg spironolactone as a test or reference formulation with a 7-day washout period between the two formulations. The plasma concentrations of spironolactone and its active metabolite canrenone (CAS 976-71-6) were analyzed by a sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) method. The pharmacokinetic parameters included AUC(0.t), AUC(0-infinity), C(max), t1/2, and T(max). Values of AUC(0-t) demonstrate nearly identical bioavailability of spironolactone from the examined formulations. The AUC(0.12) of spironolactone was 148.35 +/- 39.5 and 144.39 +/- 53.02 ng x h/ml for the test and reference formulation, respectively. The AUC(0-60) of the metabolite canrenone was 1873.36 +/- 318.10 and 1911.28 +/- 355.60 ng h/ml for test and reference formulation, respectively. The maximum plasma concentration (C(max)) of spironolactone was 48.34 +/- 21.16 ng/ml for the test and 47.40 +/- 23.40 ng/ml for the reference product and the C(max) of the metabolite was 122.90 +/- 27.70 and 123.35 +/- 27.29 ng/ml for the test and reference product, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration-time curve for both spironolactone and its active metabolite canrenone. 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of spironolactone and its metabolite were included in the bioequivalence range (80%-125% for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for spironolactone and its main active metabolite canrenone.     

Pharmacokinetics and comparative bioavailability of two terbinafine hydrochloride formulations after single-dose administration in Chinese healthy subjects

The bioavailability of a new terbinafine (CAS 91161-71-6) preparation was compared with a commercially available original preparation (reference) of the drug in 19 Chinese healthy male volunteers. The study was performed in an open, randomized, single blind two-sequence, two-period crossover design. Under fasting conditions, each subject received a single oral dose of 250 mg terbinafine as a test or reference formulation with a 7-day washout period between the two preparations. The plasma concentrations of terbinafine were analyzed by a sensitive liquid chromatography-ultraviolet spectrometry method. The pharmacokinetic parameters included AUC(0-t) AUC(0-infinity), C(max), t1/2, and T(max). The values of AUC(0-t) demonstrated nearly identical bioavailability of terbinafine from the examined formulations. The AUC(0.48) of terbinafine was 5982.85 +/- 2449.17 and 6761.63 +/- 3140.33 ng x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (C(max)) of terbinafine was 1656.25 +/- 623.18 ng/ml for the test and 1552.07 +/- 660.35 ng/ml for the reference product, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration time curve for terbinafine. The 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of terbinafine were within the bioequivalence range (80%-125% for AUC). This study shows that the test formulation is bioequivalent to the reference formulation of terbinafine.     

Phase I clinical study to select a novel oral formulation for ibandronate containing the excipient sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)

The aim of this study was to select a novel oral formulation for ibandronate (IBN, CAS number: 13892619). In four cohorts of 28, 21, 19 and 29 healthy volunteers, the impact of the carrier molecule sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, CAS number: 203787-91-1) on the bioavailability of IBN was investigated. Within each cohort different oral formulations with one dose of ibandronate (30 mg) and three different ratios of IBN:SNAC (1:5, 1:10 and 1:20) were compared to the approved oral IBN tablet formulations (150 and 50 mg IBN) in a 4-way cross-over design and a one week washout between the administrations. The highest mean IBN exposure was achieved with a capsule formulation containing drug-coated beadlets and an IBN:SNAC ratio of 1:5. AUC(last) and C(max) of IBN were approximately 1.3- and 2.2-fold higher compared to the reference treatment (150 mg IBN without SNAC). Increasing the post-dose fasting duration from 15 to 30 min resulted in a more than 2-fold increase in AUC(last), while superimposable IBN serum concentration-time profiles were achieved after a 30 and 60 min fast. The tolerability of the IBN/SNAC treatments in all cohorts was similar to that in the IBN reference groups and most adverse events (AEs) were of mild to moderate intensity.     

普罗布考包合物胶囊在家犬体内的药代动力学与相对生物利用度

目的研究普罗布考包合物胶囊在家犬体内的药代动力学与相对生物利用度。方法用高效液相色谱法测定6条健康犬po 250 mg普罗布考片(制剂A)或普罗布考包合物胶囊(制剂B)后不同时间血浆中活性药物的浓度,绘制药-时曲线,计算药代动力学参数及相对生物利用度。结果制剂A和制剂B的药-时曲线符合二室模型,其T_max均为(9.3±2.1) h,C_max分别为(1.5±1.0) μg·mL^-1和(2.3±0.9) μg·mL^-1,AUC_0～240分别为(85±56) μg·h·mL^-1和(134±55) μg·h·mL^-1。以制剂A为参比,制剂B中普罗布考的相对生物利用度为(198±90)%,两种制剂的AUC_0～240有显著性差异(P<0.05)。结论初步分析认为,改善普罗布考的水溶性是提高普罗布考生物利用度的关键因素之一。     

Comparative bioavailability study of two oral omeprazole formulations after single and repeated administrations in healthy volunteers

OBJECTIVE: Two oral enteric-coated pellet formulations of omeprazole, Pepticum((R)) (test formulation) and Mopral((R)) (reference), were administered to 24 healthy volunteers for 5 days at a daily dose of 20mg omeprazole in order to investigate the comparative bioavailability of the two formulations. RESULTS: The data obtained in this study demonstrated the bioequivalence of the two formulations. No statistical differences were observed for the area under the plasma concentration-time curve (AUC(0-t)), the parameter to which the inhibition of acid secretion induced by omeprazole is directly related. Differences observed in maximum plasma drug concentration (C(max)) at day 1 for both formulations were not statistically significant. At steady-state, the differences found in C(max) were associated with a p-value <0.05 with the 90% confidence interval lying between the acceptance range (70 to 140%). Regarding time to reach C(max) (t(max)), p < 0.01 was found both after single and repeated doses. In both cases, Pepticum((R)) showed a delay in reaching C(max) compared with Mopral((R)): 2.15 +/- 1.11 vs 1.48 +/- 0.52h (day 1) and 1.94 +/- 0.66 vs 1.31 +/- 0.75h (day 5). CONCLUSION: This study confirmed the reported increases in AUC and C(max) after repeated administrations, the important intersubject variability and the excellent biological and clinical tolerability of both formulations.     

A simple high-performance liquid chromatographic method for the determination of acyclovir in human plasma and application to a pharmacokinetic study

A rapid, simple and sensitive reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the measurement of acyclovir (CAS 59277-89-3) concentrations in human plasma and its use in bioavailability studies is evaluated. The method was linear in the concentration range of 0.05-4.0 microg/ml. The lower limit of quantification (LLOQ) was 0.05 microg/ml in 0.5 ml plasma sample. The intra- and inter-day relative standard deviations across three validation runs over the entire concentration range were less than 8.2%. This method was successfully applied for the evaluation of pharmacokinetic profiles of acyclovir capsule in 19 healthy volunteers. The main pharmacokinetic parameters obtained were: AUC(o-t) 6.50 +/- 1.47 and 7.13 +/- 1.44 microg x h/ml, AUC(0-infinity) 6.77 +/- 1.48 and 7.41 +/- 1.49 microg x h/ml, C(max) 2.27 +/- 0.57 and 2.27 +/- 0.62 microg/ml, t(1/2) 2.96 +/- 0.41 and 2.88 +/- 0.33 h, t(max) 0.8 +/- 0.3 and 1.0 +/- 0.5 h for test and reference formulations, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration--time curve for acyclovir. 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of acyclovir were included in the bioequivalence range (0.8-1.25 for AUC).     

Absorption characteristics of EC-MPS--an enteric-coated formulation of mycophenolic sodium

Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine. OBJECTIVE: Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine. METHODS: Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered. RESULTS AND CONCLUSIONS: In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.     

Pharmacokinetics and absolute bioavailability of sitafloxacin, a new fluoroquinolone antibiotic, in healthy male and female Caucasian subjects.

1. The aim was to compare the pharmacokinetics of sitafloxacin from a capsule formulation (dose of 500 mg sitafloxacin) and an intravenous (i.v.) formulation infused over 1 h (dose of 400 mg sitafloxacin) in healthy male and female subjects and to estimate the absolute bioavailability of sitafloxacin from the capsule formulation. 2. Following oral administration, sitafloxacin was rapidly absorbed, with a mean maximum concentration in plasma of 4.65 microgml(-1) occuring at median tmax = 1.25 h giving a mean AUC(0-infinity) = 28.1 microg h ml(-1). For the i.v. administration, a mean Cmax = 5.53 microm(-1) occurred at the end of the 1-h infusion with a mean AUC(0-infinity) = 25.4 microg h ml(-1). The mean terminal elimination half-life was 7.0 h (oral) and 6.6 h (i.v.). For the oral and i.v. formulations, the mean total plasma clearance was 296 and 263 mlmin(-1), respectively and the mean volume of distribution was 180 and 150 litres, respectively. 3. Within 48 h post-dose, approximately 61% (range 22-86%) of the administered dose was excreted unchanged in urine following capsule administration, compared with approximately 75% (range 42-101%) following the i.v. formulation. For both formulations, the renal clearance of sitafloxacin (means of 181 and 198 ml min(-1) for the capsule and i.v. doses, respectively) implies active tubular secretion of the drug. 4. The absolute bioavailability of sitafloxacin from the capsule formulation was high at 89%, with a 95% CI of 84-94%. The intersubject variability (CV%) in the sitafloxacin AUC(0-infinity) for the capsule was low at 18.6%. 5. Gender differences in the pharmacokinetics of sitafloxacin were small and would not warrant dose adjustment. 6. The findings show that the capsule formulation offers good oral bioavailability and merits further clinical evaluation of sitafloxacin as an orally effective fluoroquinolone antibacterial.     

The bioequivalence of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin

OBJECTIVE: To compare the bioavailability and tolerability of liquid and freeze-dried formulations of recombinant human chorionic gonadotrophin (r-hCG). SUBJECTS AND METHODS: In an open-label, randomised, single-centre, Phase I study, healthy adult volunteers (18-50 years of age) received single injections of r-hCG 250 microg from reconstituted freeze-dried (1.0 mL of 250 microg/mL) and liquid (0.5 mL of 250 microg/0.5 mL) formulations in random order, separated by a 10-day wash-out period. Pharmacokinetics (C(max), AUC, AUC(last), t(max)) and local and systemic tolerability were assessed. RESULTS: Pharmacokinetic properties of the two formulations were very similar, with mean C(max) 125 mIU/mL (liquid formulation) vs 129 mIU/mL (freeze-dried formulation), mean AUC 10,350 mIU.h/mL vs 10,480 mIU(.)h/mL, mean AUC(last) 10,050 mIU.h/mL vs 10,210 mIU.h/mL, and median t(max) 20 vs 24h. The 90% confidence intervals of the ratios of the treatment means for C(max), AUC and AUC(last) all fell within the pre-defined FDA acceptance range of 0.8-1.25, demonstrating the bioequivalence of the two formulations. Both formulations were equally well tolerated; the most frequent adverse events were headache and nausea. CONCLUSION: The liquid formulation of r-hCG was shown to be bioequivalent to the freeze-dried formulation, with no clinically significant differences in tolerability.The liquid formulation of r-hCG can be expected to provide the same efficacy and tolerability as the freeze-dried formulation when used to trigger final follicular maturation in women undergoing therapies for assisted reproduction, together with a greater convenience of use.     

Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations

Ritonavir is a large, lipophilic molecule that is practically insoluble in aqueous media and exhibits an exceedingly slow intrinsic dissolution rate. Although it has favorable lipophilicity, in vitro permeability studies have shown that ritonavir is a substrate of P-glycoprotein. Thus, the oral absorption of ritonavir could be limited by both dissolution and permeability, thereby making it a Class IV compound in the Biopharmaceutics Classification System. Because formulations rarely exert direct influence on local intestinal permeability, the effect of enhanced dissolution rate on oral absorption was explored. More specifically, poly(ethylene glycol) (PEG)-amorphous ritonavir solid dispersions were prepared with different drug loadings, and the in vitro and in vivo performances of the dispersions were evaluated. In vitro dissolution was conducted in 0.1N HCl with a USP Apparatus I. A crossover design was used to evaluate the oral bioavailability of amorphous dispersions relative to crystalline drug in beagle dogs. Intrinsic dissolution measurements of the two solid phases indicated a 10-fold improvement in intrinsic dissolution rate for amorphous ritonavir compared with the crystalline counterpart. In vitro dissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivo study results indicate that amorphous solid dispersions containing 10-30% drug exhibited significant increases in area under the curve of concentration versus time (AUC) and maximum concentration (C(max)) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and C(max), respectively. However, both in vitro dissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro-in vivo relationship for this Class IV compound. The established relationship between in vitro dissolution and in vivo absorption can help guide formulation development.     

A new oral formulation of tiapride (drops): pharmacokinetic profile and therapeutic applications

Tiapride is a substituted benzamide widely used in the management of agitation and aggressiveness in the elderly. The development of an oral solution is of particular interest in geriatric medicine and in patients with difficulties swallowing solid formulations. The bioequivalence between a sweetened, flavoured oral drop and tablet forms of tiapride was investigated in a crossover design in 18 healthy male volunteers after a 100mg single-dose administration of each formulation. Plasma concentration profiles were determined. No significant differences in the extent and rate of absorption (t(max), C(max), AUC(0-t) or AUC(0-infinity), C(max )/AUC(0-infinity)) were observed, where t(max) is the time to reach the maximum plasma concentration (C(max)), AUC(0-t) is the area under the concentration-time curve from zero to the last sample at which plasma concentration could be quantified, and AUC(0-infinity) is the area under the curve extrapolated to infinity. The plasma elimination half-lives were similar (4.37 hours and 4.61 hours) and the relative bioavailability of the drop formulation was 99.7%. These results demonstrated the bioequivalence of the two formulations. The drop formulation in this bioequivalence study was the one used for clinical evaluation in the target population of elderly patients experiencing restlessness and aggressive behaviour that was assessed in a prospective double-blind, randomised, previously published trial in 176 patients. In that study, tiapride as a drop formulation compared with melperone was safe and effective with regard to restlessness and aggressive behaviour in elderly patients.     

Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension

Oral bioavailability of the highly lipophilic and poorly water-soluble immunosuppressive agent cyclosporin A (CyA) in two different formulations was investigated in male Wistar rats. An aqueous microsuspension and a self-dispersing formulation composed of the surface-active ingredients Solutol HS 15:Labrafil M2125CS:oleic acid=7:2:1 (v/v/v) were administered to the animals at a dose level of 20 mg/kg. In order to calculate the absolute oral bioavailability, CyA was additionally administered intravenously at 10 mg/kg as microsuspension. It was found that the oral bioavailability of CyA in the Solutol HS 15-based formulation was twofold higher as compared to the microsuspension (69.9+/-2.8 vs. 35.7+/-3.3%, P=0.001). By contrast, the time to reach maximum plasma concentration (t(max)) and the terminal half-life (t(1/2)) did not differ significantly with the different formulations (t(max): 7.0+/-1.0 vs. 6.3+/-1.7 h; t(1/2): 20.5+/-2.9 vs. 16.7+/-4.7 h). In vitro solubility experiments demonstrated a marked increase in the aqueous solubility of CyA in the presence of the self-dispersing formulation as compared to the micronized powder alone (solubility after 120 min at 37 degrees C: 136 vs. 23.2 microg/ml in human gastric juice; 133 vs. 10.8 microg/ml in simulated intestinal juice). Most likely, the enhanced systemic exposure of CyA in the self-dispersing formulation was caused by improved solubility of CyA in the gastrointestinal fluids in the presence of the surface-active ingredients. Additional factors that may have contributed to increased oral bioavailability are inhibition of metabolism and/or transport processes as well as permeability enhancement by the co-administered excipients.