Characteristics of drug-phospholipid coprecipitates. II: Bioavailability studies of griseofulvin in rats

The bioavailabilities of griseofulvin and dimyristoylphosphatidylcholine (DMPC) coprecipitates prepared from chloroform have been determined in rats. The dissolution rate of griseofulvin in pH 2.0 HCl:KCl buffer under sink conditions increased nonlinearly with an increase in DMPC in the coprecipitates. The initial dissolution rate, the amount dissolved after 60 min, Cmax, and AUC were all approximately twofold greater for coprecipitates than for griseofulvin over the range of 19:1 to 1.5:1 griseofulvin:DMPC weight ratio. In contrast, physical mixtures of griseofulvin:DMPC yielded results which were not significantly different from those of griseofulvin alone. The correlation between in vitro and in vivo parameters was at least 0.95. Thus, the reduction in particle size and solubilization of griseofulvin which is observed in vitro are believed to also occur in vivo and provide improved bioavailabilities.     

Microencapsulation of Solid Dispersions: Release of Griseofulvin from Griseofulvin:Phospholipid Coprecipitates in Microspheres

The preparation, characteristics, and behavior of microspheres of poly(L-lactic acid) (PLA) containing griseofulvin (Gris) or Gris:phospholipid coprecipitates are described. Microspheres were spherical and increased in size from 17 µm (empty) to 30 µm, containing 22% Gris. The release of coprecipitated Gris after 60 min from 146,000 MW PLA microspheres in pH 2.0 buffer at 37°C was twofold greater than that from microspheres containing pure Gris. Also, the release profile from pure Gris microspheres was 25% lower than its dissolution profile, whereas the dissolution and mi-crosphere release profiles of Gris coprecipitate were the same. Microspheres of Gris coprecipitate suspended in PEG 600 in hard gelatin capsules for 1 week released Gris at levels comparable to the dissolution of coprecipitate. Decreasing the MW of PLA substantially increased the release of Gris from microspheres of coprecipitate after 20 min but insignificantly from microspheres of pure Gris. These findings suggest that microsphere formulation offers some new opportunities in the development of solid dispersions which normally encounter processing difficulties.     

不同厂家卡马西平片质量对比考察

考察不同厂家卡马西平片体外溶出度与崩解时限及生物利用度的相关性。方法：按中国药典１９９５年版要求测定其含量、崩解时限、溶出度。紫外分光义法测定免的血药浓度计算其动力学参数Ｔｍａｘ、Ｃｍａｘ和ＡＵＣ。结论不同玫家的卡马西平片的体外溶出度与崩解时限有相关性,与Ｔｍａｘ、ＣｍａｘＡＵＣ无相关性。     

Use of rabbits for GI drug absorption studies: relationship between dissolution rate and bioavailability of griseofulvin tablets

The correlation between the dissolution rate and bioavailability of griseofulvin tablets was studied in stomach-emptying-controlled rabbits and in humans. Three different test tablets, each consisting of two dose levels (62.5 or 125 mg) of griseofulvin, were used. The dissolution rates in 0.5 hr were approximately 75, 40, and 12%. With oral administration at 62.5 mg/rabbit, the ratio of peak plasma level, Cmax, was 1.00:0.66:0.40 and that of the area under the curve (AUC) was 1.00:0.73:0.46 for the three tablets. The corresponding C'max ratio was 1.00:0.74:0.34 and the AUC ratio was 1.00:0.72:0.33 in humans at the dose level of 500 mg. A good correlation was observed for the rank order of Cmax and AUC between rabbits and humans, but such a correlation was not seen between in vivo data and in vitro data at a larger dose of 125 mg/rabbit. This finding was attributable to the dose, which exceeded the GI drug dissolution or absorption capacities. These results suggest that the stomach-emptying-controlled rabbit is useful for evaluating oral dosage forms for human use and that dose level selection is important in the bioavailability study of a barely water-soluble drug.     

Pharmacokinetics and bioequivalence evaluation of 2 levosulpiride preparations after a single oral dose in healthy male Korean volunteers

OBJECTIVE: To evaluate the bioequivalence of a single oral 25 mg dose of 2 levosulpiride preparations in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as a randomized, 2-period crossover design in 28 healthy male Korean volunteers who received a single oral dose of 25 mg levosulpiride tablet in each study period. There was a 6-day washout period between the doses. Serum concentrations of levosulpiride up to 36 hours after the administration were determined using a validated HPLC method with fluorescence detection. In addition, in vitro dissolution profiles of both preparations were examined. The pharmacokinetic parameters such as AUC(0-t) (the area under the curve from zero to the time), AUC(0-infinity) (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life) were analyzed by non-compartmental analysis, and the analysis of variance (ANOVA) was carried out using logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax, and untransformed Tmax. RESULTS: In vitro dissolution profiles were similar by calculating similarity factor (f2 = 67.73). There were no significant differences between the 2 preparations in AUC(0-t), AUC(0-infinity) and Cmax. The point estimates (90% confidence intervals) for AUC(0-t), AUC(0-infinity) and Cmax were 1.085 (1.003-1.173), 1.069 (0.991-1.153) and 1.075 (0.954 to 1.210), respectively, satisfying the bioequivalence criteria of 0.80-1.25 as proposed by the US FDA and the Korean legislation. No statistically significant difference was found for tmax and t1/2 values. CONCLUSION: From the results of the present study, it is indicated that the 2 preparations of levosulpiride are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.     

Bioavailability studies with etodolac in dogs and man

The effects of formulation, particle size, coadministration of food, antacids, or antiulcer agents on the bioavailability of etodolac (ULTRADOL, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid), a novel non-steroidal anti-inflammatory agent, have been evaluated in dogs and man. The effects of dosage regimen and/or repetitive dosing on bioavailability were also determined. In man, capsule and tablet dosage forms containing micronized etodolac were shown to have a bioavailability (AUC) equal to that of the reference etodolac solution. Etodolac from tablets and capsules was rapidly absorbed since only minor decreases in Cmax and increases in tmax were observed compared to the etodolac solution. In a comparison of regular and micronized etodolac dosage forms, both in dogs and man, similar findings, i.e. no change in AUC but small parallel changes in Cmax and tmax, were noted. Administration of etodolac with food had no effect on etodolac bioavailability in dogs but tended to cause a delay in its absorption. Coadministration of an antacid, magaldrate, or the antiulcer agent, sucralfate, had no effect on the bioavailability of etodolac in dogs, although with the latter, a significant reduction in Cmax was noted. In man, etodolac may be administered as a single bolus dose or in divided (b.i.d.) doses without any loss in bioavailability. With either regimen, on repeat administration for 7 days, no etodolac accumulation was noted.     

Studies on hydrophobic drug-soluble carrier coprecipitates(I)

In order to increase the dissolution rate of furosemide(4-chloro-N-furfuryl-5-sulfamoyl anthranilic acid), various ratio coprecipitates with water-soluble polymers, such as polyvinylpyrrolidone and polyethylene glycol, of different molecular weight, were prepared and quantitatively studied by comparing their dissolution characteristics of furosemide at powder state and at nondisintegrating disk state containing constant surface area at various temperatures and rotating velocities. The dissolution characteristics of furosemide from pure furosemide disks and 1∶2(w/w) furosemide-PVP coprecipitate disks were in accordance with Noyes-Nernst equation and the rate constant of dissolution was proportional to the square root of rotating velocity of the disks. The intrinsic rate of dissolution at 150 rpm, 37°C was 2.21×10^?7 for the PVP 10,000 coprecipitate, 1.64×10^?7 for the PVP 40,000 coprecipitate, and 1.44×10^?7 for the PVP 360,000 coprecipitate, while the rate was 1.27×10^?8M/cm² min for pure furosemide, respectively. The activation energy of dissolution was about 17,000 for furosemide and about 7,300 cal/mole for the 1∶2 furosemide-PVP 40,000 coprecipitate, respectively.     

Comparative bioavailability of clarithromycin formulations in healthy brazilian volunteers

OBJECTIVE: To compare the bioavailability of clarithromycin 500 mg tablets (Merck S.A Industrias Quimicas, Sao Paulo, SP, Brazil, used as test formulation) and Klaricid (Abbott Laboratórios do Brasil Ltda, Sao Paulo, SP, Brazil, used as reference formulation) in 24 healthy volunteers. MATERIAL AND METHODS: The study was conducted using an open, randomized, two-period crossover design with one-week interval between doses. Blood samples were collected at pre-dose, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours after the administration. AUC was calculated by the trapezoidal rule extrapolation method. Cmax and tmax were compiled from the plasmatic concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(0-inf), AUC(0-24 h), Cmax and untransformed tmax. RESULTS: Intraindividual coefficient of variation (CV%) values were 14.25% and 12.62%, respectively for Cmax and AUC(0-24 h). The geometric mean values (+/- SD) for AUC(0-24 h) (microg x h/ml), AUC(0-inf) (microg x h/ml), and Cmax (microg/ml) for test medication were 18.56 (+/- 6.87), 18.8 (+/- 5.70) and 2.45 (+/- 0.88); the obtained values for reference medication were 18.29 (+/- 5.39), 19.10 (+/- 7.21) and 2.5 (+/- 0.69). 90% Cl for clarithromycin geometric mean of AUC(0-24 h), AUC(0-inf) and Cmax ratios (test/reference) were: 93.6-105.9%, 93.8-106.2% and 89- 103.2%. CCONCLUSION The test medication was considered bioequivalent to the reference medication based on the rate and extent of absorption.     

Lack of interaction between levofloxacin and oxycodone: pharmacokinetics and drug disposition

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and levofloxacin. Eight healthy volunteers were randomized in an open-label, two-way crossover study to receive oxycodone, 5 mg p.o. Q4H, and levofloxacin, 500 mg p.o. 1 hour after starting the oxycodone or levofloxacin 500 mg p.o. alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours for Cmax, tmax, and AUC determinations. There was not a significant difference (p > 0.05) in AUC (48.59 +/- 8.52 vs. 49.9 +/- 9.93), Cmax (7.73 +/- 2.6 vs. 6.6 +/- 2.0), and tmax (1.1 +/- 0.6 vs. 1.6 +/- 1.1) for levofloxacin versus levofloxacin/oxycodone regimens. It was concluded that oral oxycodone and levofloxacin can be administered concomitantly without a significant decrease in AUC, Cmax, or tmax.     

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.     

Bioavailability studies of theophylline ethylcellulose microcapsules prepared by using ethylene-vinyl acetate copolymer as a coacervation-inducing agent

The bioavailability of theophylline microcapsules prepared by using ethylene-vinyl acetate (EVA) copolymer as a coacervation-inducing agent was studied in rats. The dissolution rate of the microcapsules was determined by the rotating-basket and rotating-bottle methods. The higher the concentration of EVA copolymer used, the more sustained was the release of theophylline from the microcapsules. The mean maximum serum levels (Cmax) and time to maximum serum levels (tmax) were not significantly different for theophylline microcapsules prepared by a lower concentration of EVA copolymer (0 and 0.83%, respectively), compared with those for theophylline powder; whereas a significant difference was found when the higher concentration of EVA copolymer was used (greater than 1.7%). With regards to the area-under-the-curve (AUC) value, there was no significant difference between the theophylline powder and theophylline microcapsules. The elimination kinetics and the corresponding half-life (t1/2) were significantly different when the concentration of EVA copolymer was greater than 3.3%. From the above results, it is evident that theophylline microcapsules prepared by using 3.3 and 5.0% EVA copolymer as the coacervation-inducing agent may act as sustained-release dosage forms. The correlation between the dissolution rate in vitro and the bioavailability in rats for theophylline microcapsules was investigated. The mean Cmax and tmax correlated well with the time taken to release 75% of the drug in vitro (t 75%); however, the mean AUC showed no valid correlation with t 75%. This implies that the dissolution rate correlated better with the rate of absorption (Cmax, tmax) than with the extent of absorption (AUC).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioequivalence of two oral ciprofloxacin tablets formulations

The relative bioavailability of a new 750 mg tablet formulation of ciprofloxacin (test formulation supplied by Dr. August Wolff GmbH and Co., Germany) was compared with that of Ciprobay tablets 750 mg (reference formulation from Bayer Vital GmbH and Co., Germany). Twenty-four healthy volunteers (12 male and 12 female) were included in this single-dose, 2-sequence, crossover randomized study. Blood samples were obtained prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 30 hours after drug administration. Plasma concentrations of ciprofloxacin were determined by HPLC. No differences were found when the in vitro dissolution profiles of both formulations were compared. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were tested for bioequivalence after log-transformation of data, and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following mean values for the test/reference ratios (90% standard confidence intervals in parenthesis (ln-transformed data): 1.01 (0.95-1.07) for AUC(0-t), 0.99 (0.93-1.05) for AUC(0-infinity), 1.05 (0.97-1.14) for Cmax and 1.06 (0.97-1.15) for Cmax/AUC(0-infinity). The nonparametric confidence interval for tmax was 0.77-1.15. All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80-1.25 limits; the 90% confidence interval for tmax slightly exceeded limits of bioequivalence. We conclude that both formulations show bioequivalence for both the rate and the extent of absorption.     

In vitro and in vivo characteristics of some commercial phenobarbital tablets

Using an incompletely randomized crossover study design, the oral bioavailability characteristics of 7 different brands of phenobarbital tablets, USP, 100 mg was investigated in 5 adult, male volunteers. From plasma drug concentration-time data, best estimates for the bioavailability parameters of peak plasma phenobarbital concentration (Cmax) and time to peak concentration (tmax) were obtained by curve fitting and area under the plasma drug concentration-time curve (AUC) computed with the trapezoid rule. No significant difference in Cmax or normalized AUC was seen for the 7 products investigated. Additionally, a difference in tmax was observed between 2 preparations (A and E) only (p less than or equal to 0.05). All drug products met USP requirements for weight variation and tablet disintegration and all but one product (D) exhibited reasonably good and similar dissolution characteristics in simulated gastric fluid. No correlation between various in vitro dissolution parameters and in vivo bioavailability of phenobarbital could be found for the 7 phenobarbital products studied.     

In vivo pharmacokinetic-pharmacodynamic relationship and in vitro equivalence of two oral furosemide tablet formulations

A randomized, cross-over, open study of bioequivalence between two different furosemide (CAS 54-31-9) formulations was performed; simultaneously, diuretic effects (urine output, sodium, potassium and chloride excretion) were also compared. Both products meet the British Pharmacopoeia specification and the results of a previous in vitro comparative study ensure equivalence of the two dissolution curves. Twenty-four healthy volunteers (male/female) participated in the bioequivalence study. Each treatment was given as a single 40-mg tablet following an overnight fast. Furosemide concentrations in plasma (measured by HPLC) and electrolyte amounts in urine were determined up to 12 h after treatment. The pharmacokinetic parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity were tested for bioequivalence after ln-transformation of data and ratios of tmax were evaluated nonparametrically. The parametric analysis revealed the following test/reference ratios and their 90% confidence intervals (90% CI): 1.06 (0.94-1.19) for AUC0-infinity, 1.12 (0.96-1.31) for Cmax, and 1.06 (0.97-1.16) for Cmax/AUC0-infinity. The 90% CI for tmax was 0.55-1.00. Bioequivalence between both formulations was concluded for all parameters except for tmax. No significant diuretic differences between both formulations (test and reference) were observed after drug administration in relation to the baseline period. Systolic and diastolic blood pressure and heart rate showed a similar time-course after the drug administration and there were no differences between both formulations. Both products were well tolerated. It can be concluded that both formulations are equivalent in vitro and in vivo.     

Comparative bioavailability of two immediate-release tablets of lisinopril/hydrochlorothiazide in healthy volunteers

AIM: Two formulations of lisinopril/hydrochlorothiazide (20 mg/12.5 mg) were evaluated for bioequivalence after single dosing in healthy volunteers. METHODS: The study was conducted according to an open, randomized, 2-period crossover design with a 2-week washout interval between doses. Twenty-four volunteers participated and all completed the study successfully. Lisinopril and hydrochlorothiazide were determined in plasma by HPLC. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated non-parametrically. RESULTS: For lisinopril, the parametric analysis revealed the following test/reference ratios and their confidence intervals (90% CI): 1.01 (0.84-1.22) for AUC(0-t), 0.98 (0.81-1.19) for AUC(0-infinity), 1.02 (0.83-1.25) for Cmax and 1.03 (0.99-1.08) for Cmax/AUC(0-infinity). The 90% CI for tmax was 0.94-1.07. All parameters showed bioequivalence between both formulations. As for hydrochlorothiazide, test/reference ratios and their confidence intervals (90% CI) were: 1.05 (0.95-1.17), 1.02 (0.93-1.12) for AUC(0-infinity), 0.99 (0.89-1.07) for Cmax and 0.97 (0.90-1.04) for Cmax/AUC(0-infinity). The 90% CI for tmax was 1.00-1.41. All parameters showed bioequivalence between both formulations except for tmax. A discrete fall in both systolic (SBP) and diastolic (DBP) blood pressure was observed after drug administration. The time course of both parameters was similar for the 2 formulations. Heart rates also followed a similar time profile. CONCLUSIONS: The bioequivalence of the 2 formulations of lisinopril/hydrochlorothiazide was demonstrated.     

Bioequivalence between omeprazole MUPS 20 mg as tablet and omeprazole MUPS 20 mg as tablet encapsulated in a hard gelatine capsule

AIMS: To investigate pharmacokinetic characteristics of omeprazole MUPS 20 mg tablets and its encapsulated form. MATERIAL AND METHODS: Bioequivalence of omeprazole MUPS 20 mg tablet (Reference) and omeprazole MUPS 20 mg tablet in a hard gelatine capsule (Test) was evaluated in a randomized, 2-period crossover study in 38 healthy male Caucasian subjects who received a single oral dose of 20 mg omeprazole in each study period. Serum concentrations of omeprazole MUPS 20 mg were measured using an HPLC assay. In addition, in vitro dissolution profiles were studied. RESULTS: Both formulations were bioequivalent as assessed by the primary pharmacokinetic characteristics AUC(0-infinity) and Cmax, the corresponding ratios (Test/Reference) being 0.97 and 0.98, respectively. Thus, the 90% CI of these ratios were within the equivalence range of 0.8 to 1.25 for AUC(0-infinity) (CI 0.90-1.04) and 0.67 to 1.50 for Cmax (Cl 0.86-1.10). The ratios of the secondary criteria, Cmax/AUC(0-infinity) and t 1/2, were also within the equivalence range. Median tmax of Reference and Test was identical. Both formulations revealed comparable dissolution profiles with high batch conformity and homogeneity releasing > 80% omeprazole within 1 hour. Both study formulations were well tolerated without relevant differences. CONCLUSION: The encapsulation of omeprazole MUPS 20 mg tablets does not influence the extent and rate of absorption as indicated by the AUC and Cmax ratios. Thus, bioequivalence could be demonstrated.     

The use of microdialysis for the study of drug kinetics: some methodological considerations illustrated with antipyrine in rat frontal cortex.

1. The neuropharmacokinetics of antipyrine, a readily dialysable drug, in rat frontal cortex were studied and the effect of sampling time and contribution of period sampling and dialysate dead volume investigated in relation to tmax, Cmax, AUC and t1/2 values. 2. After i.p. administration, antipyrine (35 mg kg-1, n = 5) concentrations rose rapidly in rat frontal cortex (tmax, 12 min) and then declined exponentially tmax, Cmax, AUC and t1/2 values were determined after 2 min dialysate sampling and compared to values obtained from simulated sampling times of 4, 6, 8, 10 and 20 min. 3. Antipyrine tmax and Cmax values were directly dependent on sampling frequency. Thus, mean 2 min sampling tmax and Cmax values were 63% lower and 27% higher, respectively, compared to 20 min sampling values. AUC and t1/2 values were unaffected. 4. Adjustment for dialysate dead volume (the volume of dialysate within the dialysis probe and sampling tube) reduced tmax values significantly but did not affect the other neuropharmacokinetic parameters. 5. Contribution of period sampling on neuropharmacokinetic parameters were investigated by comparing plots of antipyrine concentration data at midpoint and at endpoint of sampling time interval. Only tmax values were affected with values decreasing with increasing sampling time interval. 6. In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinetic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, particularly during monitoring of periods of rapid change, is very important since Cmax and tmax values will be significantly underestimated and overestimated respectively, if sampling time is longer rather than shorter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers

Hypericins, hyperforin and flavonoids are discussed as the main components contributing to the antidepressant action of St. John's wort (Hypericum perforatum). Therefore, the objective of the two open phase I clinical trials was to obtain pharmacokinetic data of these constituents from a hypericum extract containing tablet: hypericin, pseudohypericin, hyperforin, the flavonoid aglycone quercetin, and its methylated form isorhamnetin. Each trial included 18 healthy male volunteers who received the test preparation, containing 900 mg dry extract of St John's wort (STW 3-VI, Laif 900), either as a single oral dose or as a multiple once daily dose over a period of 14 days. Concentration/time curves were determined for the five constituents, for 48 h after single dosing and for 24 h on day 14 at the end of 2 weeks of continuous daily dosing. After single dose intake, the key pharmacokinetic parameters were determined as follows: Hypericin: Area under the curve (AUC(0-infinity)) = 78.33 h x ng/ml, maximum plasma concentration (Cmax) = 3.8 ng/ml, time to reach Cmax (tmax) = 7.9 h, and elimination half-life (t1/2) = 18.71 h; pseudohypericin: AUC(0-infinity) = 97.28 h x ng/ml, Cmax = 10.2 ng/ml, tmax = 2.7 h, t1/2 = 17.19 h; hyperforin: AUC(0-infinity) = 1550.4 h x ng/ml, Cmax = 122.0 ng/ml, tmax = 4.5 h, t1/2 = 17.47 h. Quercetin and isorhamnetin showed two peaks of maximum plasma concentration separated by about 3-3.5 h. Quercetin: AUC(0-infinity) = 417.38 h x ng/ml, Cmax (1) = 89.5 ng/ml, tmax (1) = 1.0 h, Cma (2) = 79.1 ng/ml, tmax (2) = 4.4 h, t1/2 = 2.6 h; isorhamnetin: AUC(0-infinity) = 155.72 h x ng/ml, Cmax (1) = 12.5 ng/ml, tmax (1) = 1.4 h, Cmax (2) = 14.6 ng/ml, tmax (2) = 4.5 h, t1/2 = 5.61 h. Under steady state conditions reached during multiple dose administration similar results were obtained. Further pharmacokinetic characteristics calculated from the obtained data were the mean residence time (MRT), the lag-time, the peak-trough fluctuation (PTF), the lowest observed plasma concentration (Cmin), and the average plasma concentration (Cav). The data obtained for the five consitituents generally corresponded well with values previously published. The trial preparation was well tolerated.     

Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate

OBJECTIVE: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. SUBIECTS AND METHODS: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. RESULTS: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 microg/ml, 6.8 microg/ml and 12.8 microg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-infinity as well as Cmax related to each other approximately according to the expected ratios of 0.33:0.5:1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-infinity, Cmax) were included by the acceptance range of 80-125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. CONCLUSION: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.     

In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers

PURPOSE: The objective of this study was to evaluate the in vitro dissolution and in vivo absorption of D,L-threo-methylphenidate (MPH) from a novel bimodal release formulation (Ritalin LA capsule) compared with an immediate-release formulation (Ritalin IR tablet) in healthy volunteers. METHODS: The bimodal release formulation contains 50% of the dose in the immediate-release (IR) beads and 50% in polymethacrylate-coated, delayed-release (DR) beads. To better understand the impact of dissolution from the DR beads on oral absorption of MPH, three Ritalin LA formulations with different dissolution profiles for the DR beads (referred to as slow-, medium and fast-release formulations) were prepared, and tested together with the immediate-release formulation in 18 healthy male and female volunteers after a single oral dose under fasted conditions. The rate and extent of oral absorption of MPH were evaluated based on the overall Cmax, tmax and AUC values, as well as the Cmax, tmax and AUC values for each individual peak of the bimodal plasma concentration-time profile. The in vivo absorption-time profile was also examined by deconvolution. RESULTS: All three Ritalin LA formulations demonstrated similar bimodal plasma concentration-time profiles with two peak concentrations observed at approximately 2 and approximately 6 h post dose, mimicking that of Ritalin IR tablets given 4 h apart. Deconvolution results showed that the absorption of MPH was biphasic, with a rapid absorption phase between 0 to approximately 2 h, and a somewhat slower second absorption between approximately 3-6 h, consistent with the in vitro bimodal release characteristics of Ritalin LA formulation. The three Ritalin LA formulations were bioequivalent to one another based on the overall Cmax and AUC values and the corresponding values describing the first and second peaks, although their in vitro dissolution profiles for the DR beads were different. Compared with Ritalin IR, the Ritalin LA formulation demonstrated a similar rate of absorption for the first peak, a lower second Cmax and a higher trough concentration between peaks, as well as similar overall plasma AUC. CONCLUSIONS: Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The in vivo biphasic absorption of MPH appeared to be well correlated with the bimodal dissolution characteristics of this new Ritalin LA formulation, and some changes in the dissolution profiles for the DR beads appeared not to affect the overall bioavailability of MPH in humans.