Bioavailability of sustained release propranolol formulations

In this comparative bioavailability study two sustained release capsule formulations of propranolol, one a clinical trial formulation and the other the U.K. sales formulation (‘Inderal’ LA), were compared with a conventional ‘Inderal’ tablet. Twelve healthy adult male volunteers received, on a cross-over basis, on three separate occasions, 160 mg oral doses of three formulations of ‘Inderal’. Bioavailability was based on concentration of propranolol in whole blood. The peak blood level and area under the propranolol blood level curve fell as the dissolution time increased. The half-lives of the three formulations were inversely proportional to their dissolution rates, those of the sustained release formulations being considerably longer than that of the conventional tablet. The 160 mg ‘Inderal’ tablet produced a rapid 90-fold decline over 24 h in propranolol blood levels following a high initial peak. By comparison both sustained release formulations showed a less rapid fall in systemic levels and gave higher blood levels at the end of 24 h and plateau values between 8 and 14 ng ml ^?1. The ‘Inderal’ LA sustained release formulation gave consistently higher propranolol blood levels than the clinical trial sustained release formulation. This result is in good agreement with their dissolution profiles. The lowering of the systemic bioavailability as the dissolution time increases is thought to be due to an increased metabolism of propranolol.     

Bioavailability of propranolol and bendrofluazide formulations

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles of both propranolol and bendrofluazide were studied following the multiple oral administration of the drugs as a fixed combination (Inderetic®) and as a free combination at doses of 80 mg propranolol twice daily and 2.5 mg bendrofluazide twice daily. There were no statistically significant differences between the two regimens in terms of individual propranolol blood levels, half-lives and area under the curve. The half-lives were between 5 and 8 h. Thus the bioavailability of propranolol from the fixed combination is equivalent to that from the free combination. The mean peak bendrofluazide blood levels were slightly higher following the administration of the fixed combination. This difference was statistically significant only at 1 and 2 h after the first dose. There were no statistically significant differences between these two bendrofluazide regimens in terms of half-life and area under the curve. Thus the bioavailability of bendrofluazide from the fixed combination is equivalent to that from the free combination. It is concluded therefore that by combining bendrofluazide and propranolol in a fixed capsule formulation does not affect significantly the systemic bioavailability of either component.     

Development and evaluation of buccoadhesive propranolol hydrochloride tablet formulations: effect of fillers

The buccal mucosa has been investigated for local and systemic delivery of therapeutic peptides and other drugs that are subjected to first-pass metabolism or are unstable within the rest of the gastrointestinal tract. Propranolol hydrochloride (propranolol HCl) is subjected to first-pass effect, therefore formulation of buccal-adhesive dosage form can circumvent this effect. The effect of lactose (a soluble excipient) and dicalcium phosphate (DCP) (an insoluble excipient) on dissolution rate, kinetic of release and adhesion force of buccal-adhesive tablets of propranolol HCl were evaluated. Each tablet composed of 80 mg propranolol HCl, 80 mg hydroxypropylmethylcellulose (HPMC) K4M, polycarbophil AA1 and lactose or DCP with different ratios. The results showed that the presence of the fillers increased dissolution rate of the drug. The release data also showed that the effect of lactose on the dissolution rate was greater than the DCP. Kinetic release of propranolol HCl from buccal-adhesive matrices was affected by the different ratios of polymers and fillers. The fillers reduced the bioadhesion force and this effect was more considerable in formulation containing DCP. In order to determine the mode of release, the data were analyzed based on the equation Q =kt(n). The results showed that an increase in the concentration of HPMC K4M resulted in a reduction in the value of n. The value of n was not significantly affected by an increase in the concentration of lactose or DCP. The values of n in this study were calculated to be between 0.461 and 0.619, indicating both diffusional release and erosional mechanism.     

Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products

In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C_τ) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state.The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C_τ was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C_τ would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.     

HPLC-MS法测定人血浆中酮康唑浓度及其生物等效性研究

目的:建立人血浆中酮康唑的高效液相色谱-质谱测定方法.研究受试制剂酮康唑片在人体内的药代动力学特征,评价其相对生物利用度和生物等效性.方法:20 名男性健康受试者随机分成2组,进行双交叉试验,受试及参比制剂剂量均为200 mg.采用高效液相色谱-质谱法测定血药浓度.结果:志愿者口服受试和参比制剂后,酮康唑的药动学参数如下:峰浓度分别为(4.77±1.63)μg·mL-1和(5.09±1.64)μg·mL-1,达峰时间分别为(1.37±0.71) h和(1.19±0.61)h,消除半衰期分别为(1.89±0.80) h和(2.13±0.91)h,平均驻留时间分别为(3.02±0.81) h和(3.04±0.81)h,AUC0-24分别为(13.03±5.65)μg·h·mL-1和(13.99±6.54)μg·h·mL-1;相对生物利用度为95.6%±12.5%.结论:建立的分析方法准确、灵敏、可靠、简便,统计结果表明受试制剂和参比制剂生物等效.     

Relationship between plasma propranolol concentration and dose in young, healthy volunteers

The relationship between dose and bioavailability of propranolol was determined in 12 healthy male subjects. The doses employed were 10, 40, 80 or 160 mg of propranolol HCl given three times daily for 4 days. Daily minimum plasma levels showed that there was no accumulation of the drug. In all subjects, non-linear relationships were observed between peak plasma level, or area under the plasma concentration-time curve, and dose. The between subject variation of these parameters was not dose related.     

Biopharmaceutical characteristics of a new propranolol/ hydrochlorothiazide tablet combination

Experiments have been carried out in dogs and man to determine the effect of hydrochlorothiazide (HCT) on the pharmacokinetics of propranlol and to evaluate the bioavailability of two dosage forms containing both propranolol and HCT (40/25 and 80/25 mg, respectively). In adult male beagles, 50 mg of HCT had no apparent effect on AUC, C_max, T_max, and T_1/2 of propranolol administered concurrently. In man, INDERIDE® (40/25 mg) and INDERIDE® (80/25 mg) were shown to be similar in bioavailability to the reference formulations, i.e. the same amount of drugs administered as the separate tablets of INDERAL® plus HYDRODIURIL®.     

2种司帕沙星胶囊人体生物利用度与生物等效性研究

目的:比较2种司帕沙星胶囊的人体药动学参数、生物利用度,评价二者的生物等效性。方法:22名男性健康志愿者随机交叉单剂量口服200mg受试制剂或参比制剂后,应用高效液相色谱法测定血浆中司帕沙星浓度,并利用3p97程序计算药动学参数及评价二者生物等效性。结果:受试制剂与参比制剂体内药-时曲线符合二室模型,Cm ax分别为(0.85±0.23)、(0.90±0.27)μg.mL-1,tm ax分别为(5.59±2.28)、(4.95±1.17)h,AUC0~120分别为(27.92±6.09)、(29.65±8.49)μg.h.mL-1,AUC0~∞分别为(29.95±6.51)、(31.74±9.38)μg.h.mL-1。受试制剂相对生物利用度为(97.47±18.32)%。结论:受试制剂与参比制剂具有生物等效性。     

盐酸伊托必利漂浮片在家犬体内的药物动力学

目的 研究自制盐酸伊托必利漂浮片在犬体内的药物动力学.方法 6只犬分别单剂景服用100 mg自制盐酸伊托必利漂浮片和市售盐酸伊托必利分散片,1周后两组交叉给药;采用HPLC法测定犬给药后不同时间的血药浓度.结果 盐酸伊托必利漂浮片、分散片的Tmax分别为6.62±1.05、1.94±0.31 h;Cmax分别为0.512±0.056、0.798 ±0.079 μg·ml-1;漂浮片的相对生物利用度是分散片的91.7%.结论 盐酸伊托必利漂浮片具有明显的缓释特征.     

Comparative in vitro and in vivo bioavailability of naproxen from tablet and caplet formulations

A 500 mg dose of naproxen in a caplet formulation (product A) or a tablet (Naprosyn 500, product B) was administered to 14 fasting healthy subjects on two separate occasions, separated by a 1–2 week washout period in an open, randomized crossover. Blood samples were drawn periodically and plasma naproxen concentrations measured by HPLC. The median time T_max to reach peak concentration for product A was shorter than that for product B (1·025 h versus 1·5 h) but A and B were similar with respect to median peak plasma concentration C_max (77·9 mg 1^?1 versus 71·4 mg 1^?1), and average area AUC_0–∞ under the plasma concentration—time curve (1210·2 mg 1^?1 h versus 1211·0 mg 1^?1 h). In vitro parameters (A versus B) of mean dissolution time MDT (5·03 min versus 15·0 min), and time for 70% dissolution T₇₀ (6·67 min versus 20·2 min), differed significantly.     

Pharmacokinetics of teicoplanin upon multiple dose intravenous administration to normal healthy male volunteers.

Teicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg-1 in 10 normal, healthy, male volunteers, using a two-period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg-1 was administered every 12 h as a 30-min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg-1) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12 mg kg-1, median pharmacokinetic parameters included: steady-state volume of distribution of 1.4 and 1.2 l kg-1; total clearance of 12.2 and 14.0 ml h-1 kg-1; renal clearance of 11.1 and 10.3 ml h-1 kg-1; and terminal disposition half-life of 159 and 155 h, respectively. No statistically significant dose-related difference was observed. In addition, a cross-study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg-1.     

Plasma concentrations and bioavailability of propranolol by oral, rectal, and intravenous administration in man

Eight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2.2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration-time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two-fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.     

Study on requirements of bioequivalence for registration of pharmaceutical products in USA,Europe and Canada

The present study was aimed to study the requirements of bioequivalence for the registration of pharmaceutical products in the USA, Europe and Canada. Before going into bioequivalence studies it is essential for the pharmaceutical industry to study the guidelines of bioequivalence for the respective country where the industry wants to market its products and thus enter into generic market. This study reviews the requirements of bioequivalence with study parameters such as study design, fasting or fed state studies, volunteers recruitment, study dose, sampling points, analytical method validation parameters, moieties to be measured in plasma, pharmacokinetic parameters, criteria for bioequivalence, GCP requirements etc, which are needed for the pharmaceutical industry to carry out bioequivalence studies and to file ANDA. Test products and reference products are needed for this study. Test products are usually manufactured by a sponsor and reference products are provided by the government laboratories of the respective countries. Sampling points also vary with respect to the regulatory guidelines of these countries. All these countries follow ICH GCP guidelines. The criterion of bioequivalence for these countries is 90% CI 80–125% for C_max, AUC_t, AUC_0–∞.     

Bioavailability of nifedipine: A comparison between two preparations

In a random cross-over study, eight healthy volunteers received single 10 mg doses of either nifedipine capsule (Adalat, Bayer) or nifedipine tablets (Taro) after an overnight fast. The areas under the serum concentration time curves were not significantly different (AUC^{0→ ∞} 319·8 ± 28·0 (SEM) ng ml^?1 h^?1 for capsules, 260·8 ± 15·3 ng ml^?1 h^?1 for tablets). The peak serum levels and the time of their occurrence were 162·4 ± 23·4 ng ml^?1 at 30 min for capsules and 43·0 ± 3·0 ng ml^?1 at 1–2 h for tablets, indicating that the absorption of nifedipine from the capsule is faster than from the tablet form. Clinical symptoms of vasodilation corresponded with the nifedipine peak levels. We conclude that although the bioavailability in general of the two preparations is similar, the therapeutic equivalence may differ. Depending on the therapeutic indication each preparation may have its merits.     

氢溴酸西酞普兰咀嚼片人体生物利用度和生物等效性研究

目的比较国产氢溴酸西酞普兰咀嚼片与进口氢溴酸西酞普兰片的人体药动学参数及生物利用度,评价二者的生物等效性。方法 24名健康男性受试者随机交叉单剂量服用20 mg受试制剂和参比制剂,受试制剂空腹咀嚼30～60 s后直接吞咽,参比制剂空腹用200 mL温开水送服。血浆样品采用高效液相色谱-串联质谱法检测。结果受试制剂及参比制剂的主要药代动力学参数:Cmax分别为(16.56±4.12)、(18.30±4.72)μg/L;Tmax分别为(4.42±2.41)、(5.00±2.87)h;t1/2分别为(47.44±7.74)、(48.43±14.56)h;AUC0-tn分别为(819.74±261.18)、(885.38±216.22)μg.h/L;AUC0-∞分别为(939.00±336.16)、(1 016.04±315.32)μg.h/L;受试制剂的相对生物利用度F0-tn、F0-∞分别为91.92%±15.10%、92.09%±15.52%。结论受试制剂和参比制剂具有生物等效性。     

Single- and multiple-dose bioequivalence of two once-daily tramadol formulations using stereospecific analysis of tramadol and its demethylated (M1 and M5) metabolites

ABSTRACT

Objective: To assess bioequivalence of two once-daily formulations of tramadol (T) as well as delineate pharmacokinetics of its enantiomers and those of its main metabolites after single- and multiple-dose administration.

Methods: Single- and multiple-dose studies were conducted separately each in 48 healthy volunteers using an open-label, randomized, crossover design. Subjects received the 200?mg test (Tramadolor) and reference (Ultram ER) formulations in a randomized manner separated by a 7-day washout period once (single-dose study) or once daily for 7 days (multiple-dose study). Blood was sampled on days 1–2 (single-dose) or days 4–7 (multiple-dose), and plasma samples were analyzed using a stereospecific assay for quantitation of individual enantiomers of T and its active O-demethylated (M1) and N,O-demethylated (M5) metabolites. Bioequivalence was assessed using log-transformation and 90% confidence intervals.

Results: All analytes showed stereoselectivity after single and multiple doses of both products, with average concentrations of (+)?T, (–)?M1, and (–)?M5 exceeding those of their respective antipode. However, a decrease in steady-state oral clearance of T relative to single dose was not stereoselective. In both studies, the formulations were bioequivalent with regard to AUC and C_max for both enantiomers of all analytes. The T_max for the reference (10–12?h) was significantly (?p < 0.05) longer than that for the test (5–6?h). Degree of fluctuation of T enantiomers after the test was greater than the reference. Both formulations were tolerated relatively well.

Conclusions: Tramadolor and Ultram ER were bioequivalent for both enantiomers of T, M1 and M5. It is unlikely there would be any significant clinical differences between the two formulations.     

Comparison of pharmacokinetics between new quinolone antibiotics: the zabofloxacin hydrochloride capsule and the zabofloxacin aspartate tablet

Abstract

Objectives:

Zabofloxacin is being developed as a new fluoroquinolone antibiotic that is a potent and selective inhibitor of the essential bacterial type II topoisomerases and topoisomerase IV. Zabofloxacin is indicated for community-acquired respiratory infections due to Gram-positive bacteria. The aim of this study was to compare the pharmacokinetics (PK) of the zabofloxacin hydrochloride 400?mg capsule (DW224a, 366.7?mg as zabofloxacin) with the PK of the zabofloxacin aspartate 488?mg tablet (DW224aa, 366.5?mg as zabofloxacin) in healthy Korean male volunteers to assess the bioequivalence between the two drug formulations.     

奥美拉唑肠溶片生物利用度测定

目的 考察奥美拉唑肠溶片人体相对生物利用度及生物等效性。方法 10名健康男性志愿者,采用交叉给药方案,分别单剂量po 20mg国产奥美拉唑肠溶片和进口奥美拉唑胶囊,用高效液相色谱紫外检测法测定血浆中奥美拉唑浓度,进行人体相对生物利用度和生物等效性评价。结果 单次po 20mg国产奥美拉唑肠溶片和进口奥美拉唑胶囊后,达峰时间t_max分别为3.01±0.52h和2.62±0.76h;峰值血药浓度Cmax分别为543.5±214.9ng·ml^-1和520.9±167.8ng·ml^-1;药时曲线下面积AUC_0→∞分别为1023.0±542.5h·ng·ml^-1和1071.2±573.8h·ng·ml^-1。结论 国产奥美拉唑肠溶片的相对生物利用度为96.40%,主要参数的双单侧t检验,结果显示两种制剂为生物等效制剂。     

A bioequivalency study of two trifluoperazine tablet formulations using ria and GC–MS

Two sensitive analytical procedures, a radioimmunoassay (RIA) and a mass fragmentographic (GC–MS) method, were used to quantitate plasma trifluoperazine concentrations over 24 h in five healthy male volunteers following single 5 mg doses of two trifluoperazine tablet formulations (A and B) in a two-way cross-over design. Bioavailability in terms of area under the plasma concentration versus time curve to 24 h or extrapolated to infinity, maximum plasma concentration and time to maximum plasma concentration using either RIA or GC–MS was not statistically significantly different from one formulation to the other. Also, there were no statistically significant differences between GC–MS and RIA values for AUC₀²⁴ and C_max for each of the two formulations examined. However, the mean AUC₀²⁴ RIA/GC–MS ratios for formulations A and B were 3·1 and 3·4, respectively, while the mean C_max RIA/GC–MS ratios were 1·7 and 2·1, respectively. These differences in AUC and C_max are probably mainly due to the relative non-specificity of the RIA antiserum. Thus, where GC–MS is preferred for pharmacokinetic studies, both analytical procedures can be used for comparative single-dose bioequivalence studies of trifluoperazine. However, both the methods should be tested in patients in order to establish the suitability of one procedure over the other for the study of plasma level versus clinical response correlations.