[Pellet technology. Sustained-release pellets in hard gelatin capsules--a suitable dosage form for theophylline]. / Die Pellet-Technologie Retardpellets in Hartgelatine-Kapseln--eine geeignete Arzneiform für Theophyllin.

Reproducible gastrointestinal transit times of multiple unit dosage forms result in increasing efficacy and safety of pellets compared to single unit dosage forms. Furthermore, predictable concentration/time profiles can be achieved and local mucosa irritations can be avoided. These pharmacokinetic and clinical advantages compensate the increased investment necessary for development and production of theophylline (CAS 58-55-9) sustained release dosage forms. Several process steps are necessary to obtain the finished dosage form. After manufacturing, the pellet cores are coated and encapsulated in hard gelatine capsules. Manufacturing based on pelletization in an intensive mixer followed by drying of the pellet cores in a fluid-bed dryer and filmcoating according to the direct current principle in a Kugelcoater has become an established manufacturing technology both economically and ecologically.

[Experience in scaling up the film coating process for theophylline sustained-release pellets in mass production]. / Erfahrungen bei der Ubertragung des Filmcoating-Prozesses für Theophyllin-Retardpellets in den Produktionsmassstab.

The scale-up of the film coating process for the production of Bronchoretard pellets (theophylline, CAS 58-55-9) is an example for the successful setup of a modern production technology designed to meet the increasing GMP requirements while taking into consideration ecological and economical aspects. This technology provides a reduction in polymer losses on drying from approx. 20% to under 5% and a distinct improvement in the reproducibility of the in vitro dissolution profiles. Double batch sizes and higher spray rates allow for a substantially higher batch turnover. A production line installed exclusively for Bronchoretard pellets and specific process optimization measures resulted in considerably lower lag-times of the equipment.

[The effect of different variables on the in vitro dissolution of a theophylline sustained-release preparation]. / Einfluss verschiedener Variablen auf die In-vitro-Freisetzung eines Theophyllin-Retardpräparates.

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.

[In vivo verification of in vitro release specifications of a theophylline sustained-release preparation]. / In-vivo-Verifizierung der In-vitro-Freisetzungsspezifikation eines Theophyllin-Retardpräparates.

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.

[Pharmacokinetics of a theophylline sustained-release formulation after single and twice daily dosage]. / Pharmakokinetik einer Theophyllin-Retardformulierung nach einmal und zweimal täglicher Mehrfachdosierung.

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.

[Pharmacokinetics of theophylline in sustained-release formulation in young asthmatics]. / Pharmakokinetik von Theophyllin in einer Retardformulierung bei jugendlichen Asthmatikern.

Pharmacokinetics of two theophylline (CAS 58-55-9) sustained release preparations (T: Bronchoretard Capsules/R: Capsule formulation from the US market) were investigated in an open randomised two-way crossover design. The capsules of the test formulation were opened and administered on a tablespoonful of apple sauce. Nineteen asthmatics aged 6 to 12 years participated in this study. Following individual dosing of 100-300 mg theophylline twice a day, a pharmacokinetic profile for 24 h was derived after seven days of multiple dosing. All relevant parameters for rate (Cmax ss, Cmin ss, Cav ss, plateau time, peak-trough fluctuation, nocturnal excess, tmax ss) and extent of absorption (AUCss) were calculated for both formulations. With long plateau times (T: 17.3 h) and small peak-trough fluctuations (T: 49.0%), established quality criteria for high quality theophylline preparations were fulfilled by the test formulation. Furthermore, symmetrical peaks resulted after morning and evening administration of the test formulation. In conclusion, smooth and predictable concentration/time profiles were achieved, enabling an efficacious and safe therapy of asthma. This individual mode of administration allows not only a perfect dose titration in young asthmatics, but is also helpful to patients who have difficulty in swallowing large dosage forms.

[The effect of bile secretion on the pharmacokinetics of a theophylline sustained-release preparation]. / Einfluss einer Gallenausschüttung auf die Pharmakokinetik eines Theophyllin-Retardpräparates.

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.

[Pharmacokinetics of a new fluid theophylline sustained-release drug form. Microcapsules in a sachet]. / Pharmakokinetik einer neuen flüssigen Theophyllin-Retardarzneiform. Mikrokapseln als Sachet.

A new sustained release theophylline (CAS 58-55-9) formulation was especially designed for the elderly and children. Microcapsules of theophylline, administered as a suspension in water, proved to be a suitable dosage form for a clientele with impaired or difficult deglutition. Pharmacokinetic characteristics of 2 batches at the lower (T1) and upper (T2) in vitro dissolution specification range of this new formulation and a pellet formulation (R) as a comparator were evaluated in an open, randomised, 3-way, multiple dose, crossover study with an asymmetric dosage regimen of 400 mg and 200 mg theophylline. Smooth and safe plasma concentrations with a high and long-lasting plateau were achieved with this new formulation. Plateau times which are independent of the asymmetric dosage regimen ranged from 16.4 h (T1) to 13.8 h (T2) and could therefore cover sufficient time of the dosage interval. Maximum plasma levels of 9.6 micrograms/ml and 10.0 micrograms/ml were attained 6.6 and 6.1 h after dosing of T1 and T2, coinciding perfectly with the time of the critical morning dip at 2-6 a.m. With a nocturnal excess of 15.5% (T1) and 17.9% (T2), this circadian-tailored asymmetric dosage regimen proved to take into account the chronopathology of asthma and the chronopharmacokinetics of theophylline sustained release preparations. Bioequivalence of all 3 formulations compared with each other with regard to rate (Cmax ss) and extent (AUCss) of absorption could be established for the 2 batches at the upper and lower in vitro specification range and for both batches of the new formulation compared to the reference. All in all, the safety and efficacy of this new liquid sustained release theophylline preparation could be established. Furthermore, in vitro specifications were justified according to current EC guidelines.

Stability behaviour of molsidomine-containing pellet formulations.

Molsidomine in mixtures with different inactive ingredients has been subjected to a stability test. The fingerprint chromatogram obtained by HPLC with diode-array detection of mixtures of molsidomine with povidone 25 revealed decomposition products; the detection wavelength of 210 nm resulted in easy detection of the degradation products. Molsidomine-containing pellets were manufactured according to a compact procedure and by applying the active ingredient to placebo pellets. Compared with the nonpareil pellet formulations, compact pellets have a considerably higher water content and undergo decomposition of the active ingredient after storage for 50 months under different conditions. It is assumed that the decomposition of molsidomine is accelerated by the peroxide found in povidone.

Pharmacokinetic characteristics of a new liquid sustained-release formulation of theophylline designed for the elderly and children: microcaps as sachet.

A new sustained-release theophylline formulation was especially designed for the elderly and children. Microcapsules of theophylline, administered as a suspension in water, proved to be a suitable dosage form for a clientele with impaired or difficult deglutition. Pharmacokinetic characteristics of 2 batches at the lower (T1) and the upper (T2) in vitro dissolution specification range of this new formulation and a pellet formulation (R) as a comparator were evaluated in an open, randomized, 3-way, multiple-dose, crossover study design with an asymmetric dosage regimen of 400 mg and 200 mg theophylline. Smooth and safe plasma concentrations with a high and long-lasting plateau were achieved with this new formulation. Plateau times which are independent of the asymmetric dosage regimen ranged from 16.4 hours (T1) to 13.8 hours (T2) and could therefore span sufficient time of the dosage interval. Maximum serum levels of 9.6 micrograms/ml and 10.0 micrograms/ml were attained 6.6 and 6.1 hours after dosing of T1 and T2, coinciding perfectly with the time of the critical morning dip at 2-4 a.m. With a nocturnal excess of 15.5% (T1) and 17.9% (T2) this circadian-tailored asymmetric dosage regimen proved to take into account the chronopathology of asthma and the chronopharmacokinetics of theophylline sustained-release preparations. Bioequivalence of all 3 formulations versus each other with regard to rate (Cmaxss) and extent (AUC(tau)ss) of absorption could be established for the 2 batches at the upper and lower in vitro specification range and for both batches of the new formulation compared to the reference. All in all, safety and efficacy of this new liquid prolonged-release theophylline could be established. Furthermore, in vitro specifications could be justified according to current EU guidelines.

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.

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.