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F Stanislaus

Publications and source records attributed to F Stanislaus.

14 recordsLinked to original sources
PubMed1998

When are bioavailability studies required? A German proposal.

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their "Guidelines on interchangeability of multisource pharmaceutical products." This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.

Biological Availability↗
PubMed1998

[The effect of different variables on the in vitro dissolution of a theophylline sustained-release preparation].

In vitro dissolution studies are valuable tools to judge quality and stability of sustained release dosage forms and are often utilised to predict the in vivo performance. For this reason, in vitro dissolution experiments with varying pH, osmolarity, rotation speed, and with addition of surfactants were performed with a sustained release theophylline (CAS 58-55-9) dosage form (Bronchoretard). In order to mimic the physiological situation of the gastrointestinal tract more closely, the pH of the dissolution media was changed and human bile was added at different time points. The results obtained show that the in vitro dissolution of the dosage form differs only slightly for the parameters pH, osmolarity and stirring speed and always lies within in vivo verified dissolution limits. However, the addition of sodium dodecyl sulphate to the dissolution medium markedly altered the dissolution rate whereas addition of the physiologically surface active human bile did not change the dissolution rate. A comparison with in vivo results indicated, that only the physiologically adapted model guarantees reliable results whereas the addition of synthetic surfactants cannot allow for the prediction of bile or food effects. The meaning of in vitro dissolution tests thus is limited to development studies of dosage forms and to routine quality and stability control testing. For judging the in vivo characteristics in vitro studies have only limited value and have to be verified by pharmacokinetic studies.

Anti-Asthmatic Agents↗
PubMed1998

[In vivo verification of in vitro release specifications of a theophylline sustained-release preparation].

Especially in drugs with a narrow therapeutic range, "within product bioequivalence" i.e. "batch-to-batch bioequivalence" should be scrutinized. Therefore, pharmacokinetics and bioavailability of to batches at the upper and lower in vitro specification range as well as a batch representing the middle of the specification range was evaluated in an in vivo bioequivalence study. An open, randomized, 3-way crossover, multiple dose study in 18 healthy, male volunteers was selected for this purpose. Bioequivalence regarding rate (Cmax ss; t75%Cmax) and extent (AUCss) of absorption could be established for both extreme batches at the lower and upper in vitro specification range. Additionally both batches proved to be bioequivalent compared to the batch in the middle of the in vitro specification range. As a result, reproducible concentration-time profiles can be guaranteed for all batches of this sustained release theophylline (CAS 58-55-9) preparation. Furthermore, pharmacokinetic characteristics of all three batches meet the quality criteria defined for sustained release theophylline preparations, guaranteeing optimal concentration/time profiles for the therapy of asthma.

Adult↗
PubMed1998

[Pharmacokinetics of a theophylline sustained-release formulation after single and twice daily dosage].

Sustained release theophylline (CAS 58-55-9) preparations may be dosed once or alternatively twice-a-day, depending on the intention of a theophylline therapy. A once-a-day dosage regimen is considered appropriate in patients with nocturnal asthma attacks, whereas a twice-a-day regimen is advantageous for guaranteeing bronchodilatation and to control the underlying inflammatory disease. Therefore, pharmacokinetic characteristics of both modes of administration were evaluated in a randomised, two-way crossover study in 18 female and male elderly volunteers under multiple-dose conditions. The shape of the pharmacokinetic profiles showed the expected and pronounced differences, while the extent of absorption was bioequivalent. Twice daily administration decreased the nocturnal maximum concentration and at the same time increased the minimum concentration. At the expense of the nocturnal excess, the peak-trough fluctuations (PTF) were reduced from 92.1% to 39.5%. Plateau times of 11.4 h and 20.2 h were achieved with both modes of administration. As for theophylline with its narrow therapeutic range, high quality sustained release preparations distinguish themselves by long plateau times and small peak-trough fluctuations such as those observed with the preparation under investigation. When using this preparation, therapeutic concentrations necessary for safety and efficacy are assured under either a once- or a twice-daily dosing regimen.

Aged↗
PubMed1998

[The effect of bile secretion on the pharmacokinetics of a theophylline sustained-release preparation].

Bile excretion changes the physiological milieu of the duodenum, possibly resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying by the release of cholecystokinin on the pharmacokinetics of a sustained release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised, 3-way crossover study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained release theophylline formulation under two different cholagogia stimulating test conditions compared with a fasting reference condition. A standard breakfast and i.m. administration of cholecystokinin enabled a reproducible modulation of bile flow: a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. administration of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 microgram/kg body weight cholecystokinin resulted in fast and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained more or less constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after administration of cholecystokinin did not modify the concentration/time profile of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained release formulation for all three treatments, as not a single case of dose dumping was observed. Furthermore, in vitro dissolution investigations using synthetic surfactants can predict neither food effects nor bile influence on the in vivo absorption at least for the sustained release formulation tested.

Adult↗
PubMed1998

[Manufacture and in vitro characterization of a new fluid theophylline sustained-release form. Sachets with microcapsules for administration in a drinkable sustained-release suspension].

The administration of currently available theophylline (CAS 58-55-9) sustained release preparations with high drug doses (hard capsules, tablets) presents difficulties for certain patient groups as children and elderly, due to the large geometry of these dosage forms. Therefore, a suspension for easy administration based on the novel Liquitard technology was developed using theophylline microcapsules. This paper describes the manufacturing procedure of the new dosage form and its in vitro release characteristics as a function of various parameters. During manufacturing, the suspension-forming excipients are first granulated and then filled into sachets together with the microcapsules. The sustained release suspension is prepared by the patient himself immediately before administration. The in vitro release of theophylline from the dosage form is neither affected by the suspension-forming excipients nor by the drug amount. This allows for the manufacture of sachets with different drug strength maintaining the same qualitative composition. Furthermore, the in vitro release is independent of pH, osmolality, agitation and of the addition of surfactants and native bile to the dissolution medium. The new dosage form thus meets the current EC-guidelines for oral sustained release dosage forms. The in vitro limits of the dissolution testing were verified on the basis of the bioequivalence of the batches at the upper and lower specification limits.

Anti-Asthmatic Agents↗
PubMed1996

Effect of gallbladder contraction induced cholagogia on the pharmacokinetic profile of a sustained-release theophylline formulation.

Bile excretion might change the physiological milieu of the duodenum resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying via the release of cholecystokinin on the pharmacokinetics of a sustained-release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised 3-way cross-over study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained-release theophylline formulation under two different cholagogia stimulating test conditions and under a fasting reference condition. A standard breakfast and i.m. application of cholecystokinin enabled modulation of bile flow; a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. application of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 micrograms/kg body weight cholecystokinin resulted in quick and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained approximately constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained-release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after application of cholecystokinin did not modify concentration/time profiles of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained-release formulation for all three treatments, as not a single case of dose-dumping was observed. Furthermore, in vitro dissolution investigations using surfactants are neither predictive of food effects nor bile influence on in vivo absorption at least for the sustained-release formulation tested.

Adult↗
PubMed1995

Pharmacokinetics of physostigmine in man following a single application of a transdermal system.

1. The pharmacokinetics of physostigmine were investigated in a three-way cross-over design in six healthy, male volunteers comparing a physostigmine transdermal system (PTS), an oral solution and an i.v. infusion. 2. A single application of the patch over 24 h produced detectable plasma drug concentrations after a mean lag-time of 4 h. Thereafter, the drug was absorbed continuously from the PTS and putative therapeutic plasma concentrations were measured over approximately 18 h. 3. A mean absolute bioavailability of 36% was determined for the transdermal system and 3% for the oral solution. In comparison with the oral solution, interindividual variability of pharmacokinetics was less with the PTS. 4. The mean amount of physostigmine released from the transdermal system after 24 h was 5.7 mg. Because of extensive metabolism, only 2.2 mg of physostigmine were detected systemically. 5. After removing the PTS, the mean apparent half-life of elimination was 4.9 h, compared with 0.5 h for the i.v. infusion. This indicates continued drug absorption from a skin depot. 6. Physostigmine was well tolerated by the volunteers. With the PTS, a mild erythema was observed at the area of application, disappearing within a few hours.

Administration, Cutaneous↗
PubMed1995

Pharmacokinetics of ibuprofen following a single administration of a suspension containing enteric-coated microcapsules.

The relative bioavailability of ibuprofen (CAS 15687-27-1) was investigated following a single administration of a suspension containing enteric-coated microcapsules (A) in comparison to a rapid-release film-coated tablet (B) and a sustained-release tablet (C). The study was carried out in a three-way crossover design in 9 healthy male volunteers. Each formulation contained 800 mg ibuprofen. Plasma concentrations of ibuprofen were determined with a specific HPLC method. A mean relative bioavailability of 0.96 (B) and 1.01 (C) was determined for the test formulation. Since the corresponding 90% confidence intervals were within the recommended limits, bioequivalence for the extent of bioavailability of the test formulation can be concluded. Differences in pharmacokinetics were observed for the rate-dependent parameters. For the test formulation, the highest mean maximum plasma concentration (54.3 micrograms/ml) was measured with a corresponding tmax of 1.9 h. For the reference formulations, mean peak plasma concentrations of 45.2 micrograms/ml after 2.6 h (B) and 25.7 micrograms/ml after 5.6 h (C) were observed. Despite the enteric coating of the microcapsules, a very short lagtime of 0.03 h was determined for the suspension. For the other rapid release formulation (B), the lagtime was in a similar magnitude (0.11 h), while the absorption from the sustained-release tablet was clearly decelerated (tlag = 0.97 h). In comparison to the other rapid-release formulation (B), significant higher amounts of the drug were absorbed from the test formulation (A) within the first hour.

Adult↗
PubMed1994

[The bioavailability of enteric coated diclofenac formulations. 2. Bioavailability following single administration of a multiple-unit formulation in comparison to a single-unit formulation under fasting and non-fasting conditions].

Relative bioavailability of enteric-coated diclofenac (CAS 15307-86-5) was investigated after a single-dose administration of a multiple-unit formulation (Diclo-Puren 50, test) in comparison to a single-unit formulation (reference). The study was carried out in a four-way change-over design including a group of 12 healthy male volunteers. Each formulation was administered after 10 h of fasting or just after (5 min) finishing a meal (standard breakfast). Diclofenac plasma concentrations were measured using a selective and sensitive GLC-MS method after liquid-liquid extraction and derivatisation. Area under the curve (AUC), maximum plasma concentrations (Cmax), time of maximum plasma concentration (tmax), time of delay of first measurable concentrations (tlag) and plateau time of concentrations above minimum effective concentrations (MEC) of 50 ng/ml (tMEC(50)) and 100 ng/ml (tMEC(100)), respectively, were evaluated as pharmacokinetic characteristics. Additionally, for AUC and Cmax, 90%-confidence intervals (parametric: ANOVA, ANOVAlog, non-parametric: Mann-Whitney) were calculated to evaluate the influence of food on bioavailability of each formulation. Mean (median) relative bioavailabilities of diclofenac of the test formulation (comparison: postprandial vs. fasting conditions) were determined for the test formulation as 96% (103%) and for the reference product as 70% (83%). Mean +/- SD (median) maximum plasma concentrations of the test formulation were determined as 695 +/- 313 (677) ng/ml (fasting) and as 452 +/- 163 (456) ng/ml (postprandial). Maximum plasma concentration occurred 1.2 +/- 0.5 (1.0) h and 4.8 +/- 1.0 (5.0) h after administration, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Inhibition of cholesterol synthesis in vitro by extracts and isolated compounds prepared from garlic and wild garlic.

Using a modified liver homogenate model to assay for the inhibition of cholesterol biosynthesis, different garlic and wild garlic extracts as well as pure compounds isolated from them were investigated for their influence on cholesterol synthesis. Chloroform and acetone/chloroform extracts of garlic and wild garlic inhibited cholesterol synthesis 44-52% at a concentration of 166 micrograms/ml, while the 5 individual sulfur-containing compounds ajoene, methylajoene, allicin, 2-vinyl-4H-1,3-dithiin and diallydisulfide inhibited cholesterol synthesis by 37-72% (10(-3) M corresponding to 234, 208, 162, 144, 146 micrograms/ml, respectively). Ajoene, 2-vinyl-4H-1,3-dithiin and allicin show IC50 values of 6.4, 7.2 and 9.4 x 10(-4) M, respectively. The results demonstrate that garlic and wild garlic may reduce serum cholesterol levels primarily by inhibiting cholesterol synthesis if taken in sufficient amount and that this effect arises from a mixture of multiple compounds from the sulfur-containing class of thiosulfinates, ajoenes and dithiines. Wild garlic extracts showed nearly identical efficiency to garlic extracts.

Animals↗
PubMed1992

Pharmacokinetics of nilvadipine.

Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.

Absorption↗
PubMed1981

[Bioavailability of theophylline in a new oral sustained-release preparation (author's transl)].

On the basis of biopharmaceutic-pharmacokinetic and galenic aspects a new sustained-release preparation of theophylline according to the "divided-dose" principle was developed. The technological procedure used allows a reproducible manufacture of a stable product with narrow limits of pharmaceutical quality. The bioavailability of the sustained-release pellets in a dose corresponding to 350 mg active principle is examined in comparison to an aqueous solution or retard-tablet formulation on the marked (containing 260 mg drug/dose), respectively, after single or multiple dose administration to 7 healthy volunteers. The relative bioavailability of the new formulation is about 100%. During chronic application the controlled drug delivery from the sustained-release pellets warrants only slight fluctuations of plasma levels by avoiding peak concentrations. Formulations with a dosage of 200, 350 or 500 mg, respectively, allow adaptation of continuous plasma levels in the therapeutic range between 5--20 micrograms/ml according to the therapeutic necessities of a patient.

Adult↗