Effect of ethylene-vinyl acetate concentration on ethylcellulose-walled microcapsules: preparation and release kinetics of theophylline microcapsules

The effect of concentration of ethylene-vinyl acetate (EVA) copolymer, used as a coacervation-inducing agent, on the preparation of ethylcellulose microcapsules was studied with theophylline as the core material. The influence of EVA concentration on the micromeritic properties of the microcapsules and their drug release behaviour were investigated. Particle size distribution of the microcapsules obtained was dependent on the amount of EVA copolymer. As the EVA concentration increased the quantity of larger particles was reduced and that of the smaller particles was increased. Thus EVA might be used as a protective colloid to prevent aggregation of the microcapsules. The porosity of the microcapsules decreased with respect to EVA concentration, but the wall thickness of the microcapsules showed a corresponding increase. Zero-order release kinetics, from the resulting microcapsules in the initial dissolution phase was obtained. The apparent zero-order release rate in the initial steady-state decreased with the increase of EVA concentration, but T50 increased. The higher concentration of EVA causing a thick, compact wall lead to an effective prolongation of drug release.     

A study on bioavailability of theophylline in rabbits as influenced by fatty diet.

The influence of fatty diet and standard diet on the bioavailability and plasma half life of conventional theophylline was studied in the rabbit. It was found that standard diet had significantly reduced the extent of oral bioavailability (AUC0-alpha) of theophylline compared to the fasting state. The fatty diet resulted in a significantly increased extent of oral bioavailability (AUC0-alpha and Cmax) and significantly decreased rate of bioavailability (tmax and t1/2a) of theophylline compared to the standard diet group. The plasma half life was unaffected by either standard diet or the fatty diet. Therefore, dietary composition should be actively considered while titrating the dose of theophylline since theophylline is a drug of narrow therapeutic range and requires close monitoring of therapeutic plasma level.     

In vitro dissolution and in vivo bioavailability of commercial levothyroxine sodium tablets in the hypothyroid dog model

The objective of this study was to determine whether a correlation exists between the rate of in vitro dissolution and bioavailability of levothyroxine sodium (T4) tablets. Dissolution versus time profiles for Synthroid, the Flint brand of levothyroxine sodium, and two competitors' tablets (brands A and B) were generated using an official dissolution apparatus (USP), and 0.05 M phosphate buffer (pH 7.4) as the medium. These tablets were also utilized in single-dose crossover bioavailability studies in the hypothyroid dog model (n = 6). The average areas under the serum T4 concentration versus time curve from 0 to 8 h (AUC) for Synthroid, brand A, and brand B were 8.22, 6.32, and 8.70 ng-h/mL per dose (micrograms per kg body weight), respectively. Respective peak serum concentrations (Cmax) for each tablet formulation were 1.26, 1.07, and 1.36 ng/mL per dose. The corresponding dissolution rates, expressed as t50%, were 20.5, 3.06, and 14.1 min, respectively. Data analysis indicated no correlation between dissolution kinetic parameters and the bioavailability parameters AUC and Cmax. However, a linear relationship was observed between dissolution kinetics and both the time to reach maximal serum concentration (tmax) and the observed absorption rate constant (ka).     

Influence of coacervation-inducing agents and cooling rates on the preparation and in vitro release of bleomycin hydrochloride microcapsules

Abstract

Two types of coacervation-inducing agents (EVA, PIB) and three cooling rates (0.01998, 0.03482 and 0.06725d`C/min) affecting the preparation, micromeritic and drug release properties of bleomycin hydrochloride microcapsules were investigated. Particle size distribution of microcapsules induced by EVA significantly depended on the cooling rate, but that induced by PIB was independent of the cooling rate. Higher viscosity of PIB led to a smaller particle size of microcapsules than when EVA was used. The surface topography of the microcapsules for both types of coacervation-inducing agents was obviously different. We found that the release behaviour of bleomycin hydrochloride from the microcapsules also depended on the type of coacervation-inducing agent and the cooling rate. In general, the slower the cooling rate the more prolonged the release of the drug. Higuchi matrix model was followed for bleomycin hydro chloride released from the microcapsules. T₅₀ of both types of microcapsules decreased with the increase of the cooling rate. To simulate the absorption behaviour of the GI tract, the continuous flow dialysis method was modified for drug release from the microcapsules. The data indicate that the diffusion of the dissolution medium and dissolved drug through the ethylcellulose wall of the microcapsules is the rate-limiting step before dialysis. This also implies that the release rate of the drug from dosage form significantly determined the absorption in the GI tract.     

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.     

Oral bioavailability of griseofulvin from aged griseofulvin:lipid coprecipitates: in vivo studies in rats.

The bioavailabilities of aged coprecipitates of griseofulvin (Gris), dimyristoylphosphatidylcholine (DMPC), or egg phosphatidylcholine (EPC) and cholesterol (CHOL) in rats and correlations with their in vitro dissolution behaviors were determined. In vivo absorption studies of Gris:DMPC (4:1, w/w) or Gris:DMPC:CHOL [4:1(1:0.33 mole ratio)] coprecipitates yielded evidence of a 40% increase in the peak concentration in plasma (Cmax) and a 2.5- to 3-fold decrease in the time to reach Cmax (tmax), compared with those obtained with micronized Gris but a statistically unchanged area under the concentration in plasma--time curve (AUC) when 1-day-aged samples at equivalent doses were used. On the other hand, a 10% decrease in the AUC, a 20% increase in the Cmax, and a three- to fourfold decrease in the tmax were observed for the same formulations aged for 90 days. In comparison, the Cmax produced by the 1-day-aged Gris:EPC:CHOL [4:1(1:0.33 mole ratio)] coprecipitate was the same as that produced by micronized Gris, but the tmax and the AUC were significantly lower; the Cmax produced by the 90-day-aged coprecipitate was 30% higher than that produced by micronized Gris, but the tmax and the AUC remained unchanged. The Gris concentrations after 5 and 30 min (dissolution parameters) and the percent dissolution efficiency also showed excellent correlations with the concentration in plasma after 1 h, the Cmax, and the AUC (in vivo parameters) for all formulations, but the individual in vitro parameters showed poor correlations with the AUC results.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of food on the bioavailability of theophylline from a sustained-released theophylline preparation.

In a single-dose cross-over study with 12 healthy male volunteers the relative bioavailability of theophylline (CAS 58-55-9) in a dosage of 700 mg (sustained-release preparation) under fasting- and non-fasting conditions was investigated. The areas under the plasma concentration-time curves AUC amounted to 184.2 +/- 42.7 micrograms.h/ml (fasting) and 157.9 +/- 32.9 micrograms.h/ml (non-fasting, p = 0.031). The bioavailability was reduced by approx. 15% by concomitant food intake. The 95% confidence intervals for AUC and Cmax were 76-99% and 78-105%, respectively, and therefore narrowly outside the usual 80-120% limits. There were no therapeutically relevant changes with regard to the parameters Cmax, tmax and MRT. The MRT values of 13.4 and 13.9 h respectively showed furthermore that theophylline represents a twice-daily formulation. No "dose-dumping effect" was observed.     

Nimodipine semi-solid capsules containing solid dispersion for improving dissolution

The aim of this study was to improve the dissolution and, therefore, bioavailability of the poorly water-soluble and highly permeable drug nimodipine (NMD). Present research involved the preparation of a solid dispersion (SD) consisting of NMD, Eudragit-E100 and Plasdone-S630 by hot-melt extrusion (HME). Compared with pure drug and physical mixture, the dissolution of NMD was enhanced dramatically (about 80% within 30min). Adding the nimodipine solid dispersion (NMD-SD) powder to a mixture of Plasdone-S630 and PEG400, and then transferring it to hard HPMC capsules, resulted in nimodipine semi-solid capsules (NMD-SSC). The dissolution from NMD-SSC was increased further (about 95% in 20min). In addition, the relative bioavailability of the NMD-SSC (test) and Nimotop (reference) was determined in beagle dogs after a single dose (120mg NMD) in a randomized crossover, own-control study. The results suggested that there was no significant difference in the areas under the plasma concentration-time curve and the mean peak concentration between NMD-SSC (AUC(0-infinity)=2488+/-433nghmL(-1), Cmax=321+/-78ngml(-1)) and Nimotop (AUC0-infinity=2272+/-398nghmL(-1), Cmax=293+/-73ngmL(-1)) (P>0.05). However, the apparent rate of absorption of NMD from NMD-SSC (tmax=1.3h) was markedly faster than that from Nimotop (tmax=3.1h) (P<0.05), which indicates that as a fast release preparation, NMD-SSC is well absorbed.     

那格列奈分散片的人体生物等效性研究

目的 研究两种那格列奈片剂的人体相对生物利用度,评价其生物等效性.方法 选择20名健康男性志愿者,按照两制剂两周期的随机交叉试验设计,分别单剂量口服参比制剂(普通片)和受试制剂(分散片),剂量均为120mg,采用液相色谱-串联质谱(LC-MS/MS)法测定其血浆中那格列奈的质量浓度,用DAS1.0软件计算各药物代谢动力学参数并进行生物等效性统计分析.结果 受试制剂和参比制剂的主要药物代谢动力学参数,峰浓度(Cmax)分别为(9.1±1.7)μg/mL和(7.7±2.1)mg/L,达峰时间(tmax)分剐为(0.7±0.3)h和(1.9±1.1)h,0～10 h药时曲线下面积(AUC0-10)分别为(19.7±4.0)mg/(L·h)和(20.8±3.0)mg/(L·h),0～∞药时曲线下面积(AUC0-∞)分别为(20.0±4.1)μg/(mL·h)和(21.3±3.3)mg/(L·h),半衰期(t1/2)分别为(1.7±0.2)h和(1.6±0.2)h.两制剂的Cmaxtmax,AUC0-10均存在显著性差异.双单侧t检验结果表明,受试制剂Cmax的90%置信区间落在参比制剂的75%～133%范围内,AUC的90%置信区间均落在参比制剂的80%～125%范围内,相对生物利用度为(94.9±14.4)%.结论 两制剂具有生物等效性.     

Bioequivalence of different prednisolone tablet formulations

The relative bioavailability of different prednisolone (CAS 50-24-8) tablet formulations (Prednisolon Ferring 2, 5, and 20 mg) was investigated in comparison to a reference formulation. The study was performed in a GCP/ICH-conform manner using a randomized cross-over design in 13 healthy volunteers. With respect to the pharmacokinetic parameters Cmax (maximal prednisolone concentration), AUC0-12 h (area under the concentration-time curve until 12 h after drug intake), AUC0-infinity (area under the concentration-time curve until infinity), and t1/2 (elimination half-life time), 10 x 2 mg prednisolone tablets did not show any relevant differences as compared to the reference (1 x 20 mg) meaning that the 90% confidence intervals were within the given 0.80-1.25 limits for the decision of bioequivalence. Although not statistically significant, tmax (time to reach the maximal prednisolone plasma concentration) was 11 min shorter regarding the test preparation as compared to the reference. The pharmacokinetic parameters of 4 x 5 prednisolone tablets were also well in accordance with the reference. The most important parameters Cmax, AUC and t1/2 were within the defined limits for the acceptance of bioequivalence and, in addition, tmax did not show any significant differences. The 20 mg prednisolone tablet formulation showed almost identical parameters of Cmax, AUC, t1/2 und tmax in comparison to the reference substance. Taken together, the results of the bioavailability parameters indicate the bioequivalence of the three prednisolone test preparations as compared to the reference.     

Pharmacokinetics and relative bioavailability of oral theophylline capsules

The oral bioavailability of liquid-filled theophylline capsules relative to a nonalcoholic aminophylline solution was determined in normal volunteers. In addition, theophylline absorption and elimination kinetics were reexamined. There were no statistically significant differences between the bioavailability of capsules and liquid as measured by the area under the curve (AUC) from time 0 leads to infinity (p greater than 0.05). The bioavailability parameters of Cmax, tmax, and AUC were determined from actual serum theophylline concentration-time data and from a nonlinear least-squares fit of the serum concentration-time data. Theophylline absorption from the capsules was noticeably faster than from the liquid in most subjects, although the differences in absorption rates were not significantly different (p greater than 0.05). The determined apparent volume of distribution, elimination half-life, and plasma clearance of theophylline were similar to values reported by other investigators. Marked inter- and intraindividual variations in the elimination half-life were noted.     

Influence of food on the absorption of theophylline administered in the form of sustained release tablet and microgranules

Two sustained-release formulations of theophylline, tablets (T) and microgranules (MG) forms, were administered in a randomized order to 8 healthy subjects in fasting or with a high-protein test meal (50 per cent). Blood was collected for 32h post-dose. In fasting subjects, absorption of theophylline was significantly faster for T (tmax 5 h) as compared with MG (tmax 8 h, p less than 0.05), but Cmax and AUC were comparable; intersubject variability was higher with T. Administration of a high-protein test meal with T produced a significant decrease of the zero-order absorption rate constant of theophylline (K omicron 37.8 +/- 9.1 mgh-1 after meal versus 58.8 +/- 13 mgh-1 in fasting, p = 0.01), tmax was doubled to 10 h, and Cmax increased by 25 per cent (6.33 +/- 2.16 mgl-1 versus 5.04 +/- 1.28 mgl-1, p less than 0.02); with MG, tmax were the same (8 h), Cmax were not significantly increased (4.79 +/- 0.84 mgl-1 versus 4.55 +/- 0.67 mgl-1), absorption was delayed (lag-time 1.28 +/- 0.58 h) and the absorption was slightly accelerated (K omicron 50.4 +/- 10.4 mgh-1 versus 42.3 +/- 11.9 mgh-1, NS). For each form bioavailability was not significantly modified by food. This study demonstrated that food rich in protein modifies the absorption rate of theophylline in a sustained-release tablet formulation but is without influence in a pH-independent, sustained-release microgranule formulation.     

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.     

Clinical pharmacokinetics of mizolastine

Mizolastine is a new histamine H1 receptor antagonist. Mizolastine 10 mg/day is effective in allergic rhinitis and chronic idiopathic urticaria. In young healthy volunteers, absorption of mizolastine is rapid with time (tmax) to peak concentration (Cmax) of about 1 hour. The absolute bioavailability of mizolastine 10mg tablets is about 65%. Distribution is rapid with a mean distribution half-life of 1.5 to 1.9 hours. Mizolastine is >98% bound to serum albumin and the apparent volume of distribution is between I and 1.4 L/kg. Mizolastine is extensively metabolised by hepatic glucuronidation and sulphation, with no major active metabolite, and excreted in faeces. The terminal elimination half-life (t1/2beta) is 7.3 to 17.1 hours. The apparent oral clearance after a repeated oral dose of 10mg is 6.02 L/h, with steady state reached from day 3 and no accumulation between days 1 and 7. Cmax and area under the concentration-time curve (AUC) are linearly related to dose. Mizolastine appears in vivo to be a relatively weak inhibitor of cytochrome P450 2E1, 2C9, 2D6 and 3A4. In vivo, no interactions were observed between mizolastine and lorazepam or ethanol. A significant increase in Cmax and trough plasma concentration (Cmin) of digoxin occurred after coadministration with mizolastine, without change in AUC, tmax or clinical parameters. Significant increases in theophylline Cmin and AUC were observed after coadministration with mizolastine. Mizolastine Cmax and AUC were increased when coadministered with erythromycin, with no change in t1/2beta. Concomitant administration of mizolastine and ketoconazole increased mizolastine AUC values with no change in t1/2beta. In a population analysis of the pharmacokinetics of mizolastine in patients with allergies, parameter values were close to those in healthy volunteers, except for duration of absorption, which was almost doubled in the patients. Bodyweight and creatinine clearance were found to have little influence on oral clearance, and no influence of liver transaminases was found on clearance and distribution. Pharmacokinetic parameters of mizolastine in elderly individuals were similar to those observed in healthy young volunteers. In patients with chronic renal insufficiency, t1/2beta was prolonged by 47% compared with young healthy volunteers. In patients with cirrhosis, tmax was longer, Cmax was lower, distribution half-life was prolonged and AUC was 50% higher than in healthy volunteers. In pharmacodynamic-pharmacokinetic trials, the percentage of wheal and flare inhibition was found to correlate with mizolastine Cmin values. No direct relationship was found between drug concentrations in skin blister fluid and antihistamine activity.     

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。     

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.     

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.     

Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation.

Piroxicam is a non-steroidal anti-inflammatory drug that is characterized by low solubility and high permeability. The purpose of the study was to investigate the in vitro and in vivo performance of the semi-solid dispersion prepared with Gelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing the dissolution rate of the drug. The results were evaluated by comparing with pure piroxicam filled into hard gelatin capsules (PP) and a commercially available tablet dosage form containing a piroxicam:beta-cyclodextrin complex (CD). The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). Amongst the dosage forms, GL provided at least 85% piroxicam dissolution within 30 min in each of the media, behaving like a fast-dissolving immediate release drug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP was compared after administration of a single dose to eight healthy volunteers. Three treatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64 micrograms/ml, tmax=82.5 min) was significantly higher than that of the PP (Cmax=0.999 micrograms/ml, tmax=144 min) (P<0.05) and similar to that of CD (Cmax=2.44 micrograms/ml, tmax=120 min) (P>0.05). The relative bioavailability values as the ratios of mean total AUC for GL relative to PP and CD, were 221 and 98.6%. Piroxicam is characterized by a slow and gradual absorption via the oral route and this causes a delayed onset of therapeutic effect. Thus, plain piroxicam preparations are not indicated for analgesia. The results of the in vivo study revealed that the GL dosage form would be advantageous with regards to rapid onset of action, especially in various painful conditions where an acute analgesic effect is desired.     

Enhancement of the oral bioavailability of cinnarizine in oleic acid in beagle dogs

The present study was an attempt to develop a new dosage form of cinnarizine, which is slightly soluble in water, using lipid as a vehicle. The solubility of cinnarizine in several organic solvents was determined. It was found that cinnarizine dissolved well in oleic and linoleic acids. The bioavailability of cinnarizine from the oral administration of an oleic acid solution in a hard capsule was investigated and compared with that of a cinnarizine tablet, using beagle dogs. When cinnarizine was administered in a capsule, the bioavailability was greatly enhanced [i.e., the maximum concentration (Cmax) and AUC values were 2.9 and 4.0 times larger than those of a cinnarizine tablet, respectively]. Meanwhile, the tmax value (the time to reach Cmax) was unchanged. The absorption of cinnarizine from an oleic acid solution was considered to depend on the action of bile salts. This was supported by the results of a dissolution test using a bile salts solution as the dissolution test medium.     

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.