Bioavailability and pharmacokinetic studies in the development of an oral formulation of stobadine dipalmitate.

The pyridoindole stobadine is a novel drug with antioxidant and cardioprotective properties. The objective of this study was to compare the bioavailability and the main pharmacokinetic parameters of two different stobadine dosage forms, STBtest and STBref, after single oral dosing in the form of gelatine capsules to 6 dogs. The dose ranged from 2.9 to 4.7 mg/kg and a randomized two-period crossover design was applied. To quantify the drug in plasma, a GC/MS method was developed with a quantification limit of 1 ng/ml. The time profiles of stobadine plasma concentrations were fitted by pharmacokinetic models. The extent of relative bioavailability ranged between 0.71 and 1.56. Practically no difference was found between the bioavailability rate of the two capsules, expressed as Cmax/AUC, with values ranging from 0.0022-0.0047 min-1 for STBtest and 0.0022-0.0045 min-1 for STBref. In conclusion, the technological difference of the capsules investigated did not yield deviations in either their extent or rate of absorption. Therefore the two stobadine formulations were concluded to be bioequivalent.     

Bioavailability of opipramol from a film-coated tablet,a sugar-coated tablet and an aqueous solution in healthy volunteers

Opipramol (4-[3-(5H-dibenz[b,f]-azepine-5-yl)-propyl]-1-piperazine-ethanol dihydrochloride, CAS 315-72-0) is regarded as an anxiolytic compound with antidepressant properties, and it is one of the most frequently prescribed psychotropic drugs in Germany. In two open, randomized cross-over studies in 20 (study 1) and 18 (study II) healthy volunteers, the relative bioavailability of 50 mg opipramol-2HCl from a sugar-coated tablet was compared with an aqueous solution, and of 100 mg opipramol-2HCl from a newly developed film-coated tablet was compared with the sugar-coated tablet. The concentrations of opipramol were determined in plasma by high-performance liquid chromatography (HPLC) with photometric detection. The mean dose corrected kinetic parameters of opipramol were similar after administration of all formulations. The peak concentrations of opipramol were 13-15 ng ml-1 (study I) and 28 ng ml-1 (study II). They were achieved after 3 h. The area under the plasma concentration-time curve was about 170 ng ml-1 h (study I) and about 320 ng ml-1 h (study II). The terminal plasma half-life was 11 h. Bioequivalence was proven between sugar-coated tablet and aqueous solution, and between film-coated tablet and sugar-coated tablet, respectively. In addition, in study II the plasma concentrations and pharmacokinetic parameters of the metabolites opipramol N-oxide and deshydroxyethyl opipramol were determined.     

Bioavailability of a commercial sustained-release quinidine tablet compared to oral quinidine solution

The bioavailability of quinidine sulfate after oral administration of a commercial sustained-release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrammes of each product was administered to each subject in standard cross-over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level-time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0–46h) value for the tablet, 8744.4 ng × h ml^?1, comparable to that of the solution, 9145.9 ng × h ml^?1.     

Bioavailability and selected pharmacokinetic parameters of clindamycin hydrochloride after administration of a new 600 mg tablet formulation.

The study was conducted to investigate the pharmacokinetics and relative bioavailability of clindamycin after administration of two oral clindamycin HCl formulations. A new tablet preparation containing 600 mg clindamycin (Clinda-saar 600, test) was compared to a marketed capsule containing 300 mg clindamycin (Sobelin 300, reference). Both preparations revealed comparable in vitro dissolution profiles with high batch conformity and homogeneity. Twenty healthy male volunteers received single doses of 600 mg clindamycin (test: 1 tablet, reference: 2 capsules) in an open, randomized, two-period crossover design. Blood samples were drawn up to 14 h p.a. and clindamycin plasma concentrations were measured using a sensitive and specific HPLC-UV method. Pharmacokinetic characteristics were similar for both preparations, arithmetic mean values (standard deviation) were computed as: AUC(0-infinity) 12.2 (4.2) and 13.1 (4.6) microg x h/ml, Cmax 3.1 (0.8) and 3.4 (0.8) microg/ml, t(max) 0.83 (0.24) and 0.85 (0.34) h, t(1/2) 2.3 (0.4) and 2.3 (0.6) h for test and reference, respectively. Mean relative bioavailability (point estimate) was 93% for AUC and 91% for Cmax. 90% confidence intervals for AUC and Cmax were within the predefined bioequivalence acceptance limits. Bioequivalence of test and reference preparations could be demonstrated. Single doses of 600 mg clindamycin orally were well tolerated without relevant differences between both preparations.     

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.     

Bioavailability of a new ketoprofen formulation for once-daily oral administration

A new sustained-release formulation (sustained release Ibifen) that gradually releases ketoprofen within 24 h and ensures therapeutic plasma concentration for the entire period has been developed. It consists of tableted pH-dependent barrier film-coated ketoprofen granules and was administered at a single dose of 200 mg to 12 volunteers. Ketoprofen plasma profiles were compared with: (1) administration of Orudis retard 200 capsule (200 mg); (2) two 12-h doses of prompt release Ibifen capsules (100 mg). In vitro dissolution kinetics and ketoprofen plasma levels were measured by HPLC. Sustained release Ibifen dissolution rate was constant for 10 h, whereas Orudis retard 200 dissolution profile presented one higher slope (0-6 h) and a lower one (6-12 h). Both formulations showed a delayed kinetics with respect to prompt release Ibifen. After sustained release Ibifen administration, ketoprofen plasma peak, reached within 2 h, remained practically constant for at least 12 h (average 4 microg/ml), which is higher than therapeutic levels. Differently, Orudis retard 200 produced a delayed, higher C(max) (5.91+/-0.66 vs. 4.51+/-0.65 microg/ml; P<0.01) and disappeared more quickly. In conclusion, sustained release Ibifen can ensure therapeutic ketoprofen plasma levels for the entire 24 h period, avoiding plasma concentration spikes, with bioavailability similar to other ketoprofen preparations.     

Flavor analysis in a pharmaceutical oral solution formulation using an electronic-nose

Flavors are commonly used in pharmaceutical oral solutions and oral suspensions to mask drug bitterness and to make the formulation more palatable. Flavor analysis during product development is typically performed by human organoleptic analysis, which is often expensive and less objective. A novel approach using a metal oxide sensor-based instrument (electronic-nose) for headspace analysis was explored to replace human sensory perception for consistent qualitative and quantitative analysis of flavors in a pharmaceutical formulation. The use of the electronic-nose technique to qualitatively distinguish among six common flavoring agents (raspberry, red berry, strawberry, pineapple, orange, and cherry) in placebo formulations was demonstrated. The instrument was also employed to identify unknown flavors in drug formulation placebos. Raspberry flavor samples from different lots made by the same manufacturer, as well as freshly prepared and aged samples, were also distinguished by electronic-nose. Therefore, the instrument can potentially be used for identity testing of different flavor raw materials and the flavored solution formulations. The electronic-nose was also employed successfully for quantitative analysis of flavors in an oral solution formulation. The quantitative method might be used to assay the flavor concentration during release testing of the oral solution formulation or to monitor flavor shelf-life in the marketed container. It can also be implemented for packaging selection for the formulation in order to ensure the flavor shelf-life. Chemometric methodologies including principal component analysis (PCA), discriminant factorial analysis (DFA), and partial least squares (PLS), were used for data processing and identification.     

A pharmacokinetic and endoscopic comparison of an oral and an experimental buccal piroxicam formulation.

We compared the endoscopic effects and pharmacokinetic profiles of an experimental buccal formulation of piroxicam to oral capsules in an attempt to determine whether nonsteroidal antiinflammatory drug-induced gastropathy is due to a local or systemic effect. Ten healthy subjects received 20 mg piroxicam daily in a double-blind, randomized, crossover, placebo-controlled study. Upper endoscopies were performed at the baseline and at the end of each 2-week dosing arm of the study. Pharmacokinetic data obtained included serum and gastric piroxicam concentrations and serum 5'-hydroxypiroxicam metabolite concentrations after the first dose and 2 weeks of dosing. No differences in endoscopy scores or patient symptom scores were noted between the two dosage forms after 2 weeks of dosing. Pharmacokinetic data of piroxicam and the metabolite revealed that the buccal formulation may not have been absorbed exclusively from the buccal mucosa.     

Zero-order release profile of metoclopramide hydrochloride sublingual tablet formulation

This report describes zero-order approximation for metoclopramide hydrochloride sublingual tablet formulation. Effects of type and concentration of excipients on release were investigated. Study revealed that highest rate of dissolution was attained with crosspovidone and decreased in the order crosspovidone > sodium starch glycolate > ac-di-sol. All formulations demonstrated flush release, except the one containing 10% crosspovidone where a lag time of 0.5?min. was depicted. Increasing the concentration of crosspovidone from 5 to 10% gave the same half-life, whereas kinetics of release changed to zero order. Differential scanning colorimetry and infrared spectroscopy did not reveal any sign of physical or chemical interaction between drug and crosspovidone. In order to study the alignment of polymeric network inside tablet matrix, scanning electron microscopy was performed on the tablet and its cross-section. Matrix with 10% crosspovidone showed higher density of interconnections extending to the interior of core enabling fast and constant release. Hence physicochemical characteristics of crosspovidone could be tailored by varying its concentration, in a way that provided a porous matrix with tight arrangement of polymeric chains, resembling to an assemblage of cylinders with constant apertures, from which zero-order release was approached.     

Bioavailability of bemetizide and triamterene from a combination formulation

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (P < 0.01) from that from a tablet containing 25mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3ngml^?1) was lower than that after administration of bemetizide alone (87.9 ngml^?1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml^?1) was higher than and significantly different (p< 0.001) from that after administration of triamterene alone (15.7 ng ml^?1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post-dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post-dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data. The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.     

Bioavailability of griseofulvin from a novel capsule formulation

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.     

Bioavailability of riboflavin from a gastric retention formulation

A gastric retention formulation (GRF) made of naturally occurring carbohydrate polymers and containing riboflavin was tested in vitro for swelling and dissolution characteristics as well as in fasting dogs for gastric retention. The bioavailability of riboflavin, a drug with a limited absorption site in the upper small intestine, from the GRF was studied in fasted healthy humans and compared to an immediate release formulation. It was found that when the GRF is dried and immersed in gastric juice it swells rapidly and releases its drug content in a zero-order fashion for a period of 24 h. In vivo studies in dogs showed that a rectangular shaped GRF stayed in the stomach of fasted dogs for more than 9 h, then disintegrated and reached the colon in 24 h. Endoscopic studies in dogs showed that the GRF hydrates and swells back to about 75% of its original size in 30 min. These in vivo results correlated with in vitro results. Pharmacokinetic parameters determined from urinary excretion data from six human subjects under fasting conditions showed that bioavailability depended on the size of the GRF. The biostudy indicated that bioavailability of riboflavin from a large size GRF was more than triple that measured after administration of an immediate release formulation. Deconvolved input functions from biostudy data suggest that the large size GRF stayed in the stomach for about 15 h.     

硝苯地平口服制剂药代动力学参数的荟萃分析

目的：荟萃分析硝苯地平的群体药代动力学参数特征。方法获取研究文献中的群体药代动力学参数,经归一化处理,用SAS软件进行荟萃分析与评价。结果中国汉族人群与东亚人群相近,归为一个亚类,与其他两个亚类相比,存在明显差异。该亚类的药代动力学参数AUC、tmax、Cmax、t1／2分别为（292.53±8.01）ng· mL－1· h、（0.61±0.03）h、（140.01±11.38）ng· mL－1、（3.27±0.50） h。结论本研究验证了人种因素为影响硝苯地平药代动力学参数的一个重要因素,中国汉族人群所属的亚类人群服用硝苯地平应注意减少剂量。     

Anti-inflammatory activity and pharmacokinetic profile of a new parenteral formulation of nimesulide.

Nimesulide, a selective COX-2 inhibitor, exerts potent anti-inflammatory and analgesic effects when administered orally, rectally or topically. The present study was designed to evaluate the anti-inflammatory activity of a new parenteral formulation of nimesulide and to correlate it with the pharmacokinetic profile. Nimesulide was administered intramuscularly at increasing doses of 1. 5, 3, 6, 12.5 and 25 mg kg-1 which produced dose-dependent anti-inflammatory effects in the carrageenan-induced rat paw edema. The anti-inflammatory activity of nimesulide was greater than that of diclofenac which was administered at identical doses though the difference was not statistically significant. Peak anti-inflammatory effects with nimesulide were observed between 2 and 3 h post-treatment which correlates well with the tmax of 115 min. The plasma concentration of nimesulide at different time points was assayed using HPLC after administration at a dose of 25 mg kg-1. Peak plasma concentration (Cmax) was 23 microgram ml-1 while t1/2 was derived as 4.2 h. Area Under Curve (AUC(0-6 h)) was calculated as 83. 31 microgram ml-1 h-1. No toxicity or adverse effects were noted at the doses administered. The present study demonstrates that nimesulide administered intramuscularly may be superior to other routes of administration when fast onset of action is required with high plasma concentration.     

Bioavailability of bromazepam in man after single administration of an oral solution

The relative bioavailability of a liquid oral form of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one (bromazepam, Lexotan, Lexotanil) in comparison with the conventional oral form (capsules) was investigated. The study was performed on six healthy volunteers who were administered both the drug products in a single oral dose of 3 mg of bromazepam in a randomized cross-over trial. An additional investigation was performed on the same subjects by administering the liquid oral solution at a lower dosage: 1.5 mg in order to confirm first-order kinetics at low dosage, too. The results showed the same bioavailability for the oral forms tested and confirmed first-order kinetics for the 1.5 mg dose, too.     

Bioavailability study of a new amoxicillin tablet designed for several modes of oral administration

A new tablet of amoxicillin (Flemoxin solutab) has been formulated with galenic properties which allow it to be taken as a tablet, either swallowed, chewed or sucked, or to be taken after dispersion in water. This study was undertaken to compare the bioavailability of the new tablet (swallowed as such, or after dispersion) with a commercially available amoxicillin capsule and, for purposes of internal reference, with a Flemoxin forte suspension. Each formulation was administered to 12 volunteers according to a repeated 4 X 4 latin square design. Statistical analysis revealed that the tablet and suspension formulations tested gave significantly higher maximum plasma levels, occurring significantly faster after intake, when compared to the capsule. Furthermore, the new tablet showed a statistically significantly greater area under the plasma concentration-time curve with a highly predictable absorption when compared to the capsule. The method of intake of the new tablet appeared to be of no relevance with respect to the observed bioavailability.     

Bioavailability of griseofulvin from a novel capsule formulation.

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.     

Bioavailability of a new controlled-release oral naproxen formulation given with and without food.

The influence of concomitant food intake on the plasma concentration of naproxen given as a new controlled-release (CR) formulation (750-mg tablet) was investigated in a crossover study design. Twelve healthy volunteers received a single tablet of naproxen on two occasions separated by a 3-week washout period:- after an overnight fast and immediately after a standard meal. Plasma naproxen levels were measured through HPLC at intervals suitable for obtaining concentration-time curves of both regimens in the range 1--48 hours. It was found that average plasma AUC values were 1978.7 mcg.hr/ml in fasting participants and 1778.6 mcg.hr/ml in postprandial participants. The confidence interval computed by Westlake's method indicated equivalence of values. Food decreased the peak plasma concentration of CR naproxen by about 14%, but the confidence interval (+/- 22%) barely exceeded equivalence limits. There were no significant differences between fasting versus postprandial values for the mean absorption time, or plasma absorption and disposition half-lifes. It is concluded that the bioavailability of CR naproxen is not substantially altered by the ingestion of food.     

An alternative paclitaxel microemulsion formulation: hypersensitivity evaluation and pharmacokinetic profile

Based on the clinical fact that paclitaxel injection (Taxol) frequently causes hypersensitivity reactions, we prepared an alternative paclitaxel microemulsion with small particle size (17.2 nm). The hypersensitivity evaluation and pharmacokinetic behavior in rats were conducted to assess the new microemulsion. The results showed that the new microemulsion was negative and the placebo Taxol solution was positive with regard to allergic reactions. In the pharmacokinetic study, five rats were administrated Taxol or paclitaxel microemulsion. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 14 h and paclitaxel determined by HPLC. The area under the curve (AUC) was significantly higher in the microemulsion group (34.98 microg ml(-1) h) than that in the Taxol group (21.98 microg ml(-1) h). Also, the K(10) was much smaller in the microemulsion group (0.57 h(-1)) compared with the Taxol group (1.29 h(-1)), showing the elimination rate was much slower in the former than in the latter. Compared with Taxol, the paclitaxel microemulsion caused less toxicity and had a longer circulation time in rats.