Sustained-release Theophylline Tablets Research Articles

Preparation and Evaluation of Theophylline Sustained-Release Tablets

Formulations were prepared containing 50% theophylline; 0%, 5%, 10%, 20%, 30%, or 49.5% of a new sustained-release agent (Carbopol® 974P); 0.5% lubricant, with the remainder of the formula consisti...

Statistical Comparison of Two Methods of Dissolution of Sustained-Release Theophylline Tablets

AbstractA comparative study of two methods of dissolution (Simoons Apparatus and USP XXII Apparatus II) has been accomplished using sustained-release 50 mg anhydrous theophylline tablets. Sovic® 374 MB, Eudragit® RL PM, Aquacoat®, Methocel® K-15M, and Cutina® HR were some of the excipients used to elaborate inert, hydrophilic, and lipidic matrices. Theophylline release was prolonged in all cases, except when Aquacoat was used as matrix constituent. Simoons device was found to be more accurate for inert matrix tablets, whereas USP apparatus was advantageous for hydrophilic and lipidic matrix. ANOVA showed significant differences among all the factors analyzed. The drug release kinetics was adjusted better to Higuchi's kinetic model than to the Noyes-whitney or Weibull models, from 10% to 70% release.

Prevention of Drug Absorption in Simulated Theophylline Overdose

To assess the effectiveness of oral activated charcoal and catharsis in preventing theophylline absorption, 12 healthy subjects, aged 20-35 years, received 3 x 200 mg sustained-release theophylline tablets and 16 radio-opaque placebo tablets on six occasions. On each occasion, they received either no treatment (control) or one of five treatments. Treatments were a) oral activated charcoal (Carbomix): 50 g at 1 h, 25 g at 5 h and 9 h; b) sorbitol 70%: 150 mL at 1 h; c) activated charcoal: 50 g at 6 h, 25 g at 10 h and 14 h; d) sorbitol 70%: 150 mL at 6 h; e) charcoal commencing at 6 h plus sorbitol at 6 h (i.e. a combination of treatments c and d). Plasma theophylline concentrations were measured and all stools collected over 36 h to assess placebo tablet recovery by radiography. Charcoal administration at 1 h was 91.2% effective in preventing theophylline absorption and at 6 h was 57.3% effective, while combined charcoal and catharsis at 6 h was 63.3% effective. Sorbitol-induced catharsis at 1 h and 6 h did not reduce theophylline absorption despite greater tablet recovery. Oral activated charcoal may be the most effective treatment for sustained-release theophylline overdose, with maximum benefit when administered soon after an overdose, though later administration might still be of value. Sorbitol catharsis is of no benefit either alone or in combination with charcoal.

Comparative Pharmacokinetics and Bioequivalence of Two Theophylline 300 MG Sustained Release Formulations at Oral Dosing Steady-State

The steady-state blood levels of a reformulated Theophylline sustained release tablet formulation (Quibron-T/SR®) were compared with Theo-dur® tablets 300mg SR. Statistical analysis was performed, using the two one-sided tests procedure, on the In-transformed values of maximum Theophylline plasma concentrations, trough plasma concentrations and Area Under the plasma concentration - time Curve. Data regarding Time to reach maximum plasma concentration were analyzed by analysis of variance on rank transformed values. In every case, the reformulated test treatment was found within the limits required to demonstrate bioequivalence.

Utility of gastrointestinal physiology regulated-dogs: bioavailability study of a commercial sustained-release dosage form of theophylline.

The utility of gastrointestinal physiology regulated-dogs (regulated-dogs) was evaluated in a bioavailability study. The gastrointestinal physiology of beagle dogs was regulated with a combined-treatment of intramuscular pentagastrin and intravenous atropine sulfate. Theophylline has been regarded as a drug that is absorbed completely in the entire gastrointestinal tract but slowly in the colon for humans. A commercial sustained-release tablet (SR tablet) of theophylline and a commercial conventional tablet of aminophylline (theophylline hemiethilenediamine salt) were chosen as model preparations in this study. In the regulated-dogs, the drug absorption was almost complete for the conventional tablet. The bioavailability of the SR tablet accounted for 76% in the regulated-dogs and 71% in intact dogs relative to that of the conventional tablet in the regulated-dogs, respectively, but no significant difference was detectable between these values. An advantage of the regulated-dogs over the intact dogs was, however, revealed in the time-profiles of the cumulative percentage of theophylline absorbed from the SR tablet, suggesting a modification of drug absorption by the prolonged arrival of the tablet to the colon.

Effect of humidity and packaging on the long-term aging of commercial sustained-release theophylline tablets

This paper discusses the influence of relative humidity and packaging on the dissolution rate of three commercial brands of theophylline Controlled-release tablets, paying particular attention to the experimental design and data treatment. The reduction in the amount of theophylline released during an 8 h period after 3 years' storage varied depending on the product and storage conditions; the greatest reduction observed amounted to 41% of the original content. To interpret the data, a statistical model was used, based on the subdivision of the sum of the squares of the term ‘treatments’ from the variance analysis by orthogonal polynomials chosen in terms of the design of the storage conditions. In all instances, the factors responsible for the reduction could be indentified.

Theophylline mitigates the bronchoconstrictor effects of sulfur dioxide in subjects with asthma

The objective of the study was to investigate the ability of a sustained-release (SR) theophylline tablet (Uniphyl; Purdue Frederick Co., Norwalk, Conn.) to block or mitigate sulfur dioxide (SO 2)—induced bronchoconstriction in adult subjects with asthma. Eight subjects participated in a double-blind, crossover study with a 400 mg theophylline tablet or placebo once a day for a week before a 10-minute SO 2 challenge. FEV 1 and total respiratory resistance (R T) were measured before and after the SO 2 challenge and on a different day before and after an air exposure. After exposure to SO 2, average values of FEV 1 dropped 16% after placebo treatment and 7% after theophylline treatment. The corresponding percentages for R T were a 37% increase after placebo and a 7% increase after theophylline treatment. Analysis of variance demonstrated a significant difference between the SO 2-induced decrease in FEV 1 and increase in R T after SR theophylline treatment compared with that of placebo treatment. Thus, we conclude that SR theophylline tablets, taken at this concentration for 1 week, mitigate SO 2-induced bronchoconstriction.

Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients

Recently, it has become evident that some quinolones affect the processing of theophylline in the human system. The effect of a new quinolone, sparfloxacin, on the pharmacokinetics and metabolism of theophylline was investigated in six asthmatic patients receiving chronic theophylline therapy (a sustained-release theophylline tablet formulation of 200 to 300 mg twice daily at 12-h intervals). To these patients, sparfloxacin (200 mg once daily) was coadministered for 1 week. Plasma and urine samples were analyzed by high-performance liquid chromatography for theophylline and its metabolites. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of sparfloxacin were compared. The total body clearance of theophylline after coadministration of sparfloxacin, 42.81 +/- 6.64 ml/h/kg (mean +/- standard error of the mean), was not significantly different from that after the administration of theophylline alone, 47.11 +/- 7.61 ml/h/kg. Also, no significant change in the urinary excretion of theophylline and its metabolites was observed for subjects receiving or not receiving sparfloxacin. These findings indicate that a once-daily dose of 200 mg of sparfloxacin has no significant effect on the pharmacokinetics and metabolism of theophylline and that it would be safe to coadminister this quinolone to asthmatic patients receiving chronic theophylline therapy.

Scintigraphic study of the gastro-intestinal transit of a sustained release theophylline tablet. II. Administration in non-fasting state

Abstract The gastro-intestinal transit of a sustained release theophylline tablet labelled with a gamma-emitting radionuclide has been studied in human subjects. Gastric emptying was monitored using a gamma camera. Fasting conditions have been previously described, characterised by a 72±25 min (mean±S.D.) gastro-duodenal transit time. In the same volunteers, after a high fat breakfast, the tablets entered into the duodenum 258±75 min (mean±S.D.) after intake. However, the amounts of theophylline absorbed were similar between the two treatments, assuming that, in spite of the transit time increase, theophylline release is not affected by simultaneous intake of a heavy meal.

The effect of raising gastric pH with ranitidine on the absorption and elimination of theophylline from a sustained-release theophylline tablet.

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2-2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 x 100-mg immediate-release tablets, (b) 2 x 300-mg sustained-release theophylline tablets, and (c) 2 x 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P greater than 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.

Inhibition of Natural Killer Cell Activity by Oral Administration of Theophylline

Asthmatic patients have a low incidence of malignancies, and this is possibly due to higher NK cell activity in this population. Because theophylline is used widely in this population, we evaluated the influence of theophylline on NK cell activity in vitro and in vivo. The NK cell activity was significantly inhibited by direct addition of concentrations of aminophylline that exceeded 5 x 10(-5) M. To test whether such an effect can be observed in vivo, we administered one sustained-release tablet of theophylline (400 to 500 mg twice daily) to five normal volunteers for seven days. Significant inhibition of NK activity was noted after administration (mean percentage of inhibition, 41.3 percent), but the serum concentrations observed gave a mean value of 2 x 10(-5) M, which was lower than that yielding the same degree of inhibition by direct addition in vitro (about 20 x 10(-5) M). These results suggest that long-term theophylline therapy may inhibit NK cell activity, and thus more information would be needed to determine the position of such therapy in the management of asthmatic patients.

Effect of mequitazine on the pharmacokinetics of theophylline in asthmatic patients

The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200-400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.

Pharmacokinetic disposition of an immediate-release aminophylline and a sustained-release theophylline formulation in the horse.

The pharmacokinetic disposition of theophylline was determined by high-performance liquid chromatographic analysis of plasma samples from six healthy, adult horses following the administration of intravenous aminophylline (dosed at 9.94 mg/kg as theophylline), immediate-release aminophylline tablets (dosed at 9.94 mg/kg as theophylline), and sustained-release theophylline tablets (dosed at 20 mg/kg). The elimination rate constant (lambda z), apparent volume of distribution (Vz), and clearance (Cl) determined by compartmental analysis of the intravenous data were 0.07 +/- 0.01 h-1, 0.80 +/- 0.06 l/kg, and 0.06 +/- 0.01 l/kg/h (mean +/- SD), respectively. Mean residence time determined by statistical moment theory of the oral data was different (P less than 0.05) for the immediate-release aminophylline (13.8 +/- 2.8 h) and sustained-release theophylline (18.2 +/- 2.3 h) formulation. Immediate-release aminophylline tablets quickly achieved peak theophylline plasma concentration of 11.51 +/- 1.4 micrograms/ml at 1.6 +/- 0.6 h while the sustained-release theophylline tablets were more slowly absorbed and achieved peak theophylline concentrations of 17.20 +/- 1.3 micrograms/ml at 7.3 +/- 1.0 h. Absolute bioavailability was 87% for the immediate-release and 97% for the sustained-release formulation. Using the principle of superposition, a loading dose of 20 mg/kg of the sustained-release formulation followed by maintenance doses of 15 mg/kg every 24 h was predicted to achieve trough-peak theophylline plasma concentrations between 6 and 17 micrograms/ml.

Scintigraphic study of the gastro-intestinal transit and correlations with the drug absorption kinetics of a sustained release theophylline tablet: I. Administration in fasting state

After the administration to six fasting volunteers of a slow-release theophylline tablet containing [ 99mTc]diethylenetriamine pentaacetic acid (DTPA) as a labelled tracer, absorption data were compared with in vitro dissolution kinetics. The absorption data and the in vitro release kinetics were correlated with total gastro-intestinal tract transit time.

市販テオドール５０ｍｇ錠の溶出挙動

Dissolution behavior of a newly designed, commercially available sustained-release tablet of theophylline containing 50mg (Theodur® 50) was measured according to the J. P. X dissolution test procedures in pH 1.2, 6.8, and pH1.2 adding 0.25% Tween 80 solutions.The following results were obtained: The release from Theodur® 50 was pH-independent, but was much affected by wet and rotating velocity of dissolution test.The required time for 50% dissolution at 100rpm was about 2 times as large as at 200rpm.

Absorption inhibition and enhancement of elimination of sustained-release theophylline tablets by oral activated charcoal

The effect of orally administered activated charcoal (OAC) on the first 12 hours of absorption and elimination of sustained-release theophylline tablets (SRT) was investigated in 20 normal children ages 8 to 18 years. The theophylline absorption-elimination characteristic of all subjects was determined after ingestion of 10 mg/kg SRT. Blood for theophylline was sampled at 0, two, four, six, eight, ten, 12, and 24 hours. After a 72-hour theophylline washout period, the subjects were assigned randomly to one of four study groups and received 10 mg/kg SRT. OAC then was given as a single dose one hour later to Group 1 subjects. Group 2 subjects took four doses of OAC at three-hour intervals beginning at one hour after SRT dosing. Group 3 subjects also received four doses of OAC at three-hour intervals with the first dose given three hours after SRT; Group 4 subjects received three doses at similar intervals with the first dose administered six hours after SRT dosing. OAC administration reduced the 12-hour area under the concentration time curve for theophylline (AUC) by 61% in Group 1, by 68% in Group 2, by 37% in Group 3, and by 18% in Group 4. The differences in AUC between treated and untreated subjects were significant at P less than .01 for Group 1, at P less than .001 for Group 2, at P less than .02 for Group 3, and not significant for Group 4. These data indicate that early OAC administration can inhibit SRT absorption significantly and enhance elimination of previously absorbed theophylline.

Studies on the absorption kinetics of theophylline in the steady state, following multiple oral dosing of a sustained-release theophylline tablet formation to asthmatic patients.

Studies on the absorption kinetics of theophylline in the steady state, following multiple oral dosing of a sustained-release theophylline tablet formation to asthmatic patients.

Food and a sustained release theophylline tablet on chronic dosing: bioavailability, peak-trough and trough-trough differences.

The bioavailability of theophylline and the serum concentration fluctuations after administration of a sustained release tablet (Theograd 250 mg, one tablet twice daily) were studied in the steady state in six volunteers. On postprandial administration of the 250 mg tablets the bioavailability was 89 +/- 16%. Good sustained release properties were obtained provided that the tablets were taken after a meal; Cmax was 7.9 +/- 2.0 mg X 1(-1), tmax was 5.3 +/- 1.6 h, the peak-trough difference was 2.3 +/- 0.6 mg X 1(-1) and the serum concentration fluctuation was accounted for 42.8 +/- 11.2%. It was shown that on postprandial administration the mean serum concentration-time profile could be successfully calculated by means of multiple dose projection from single dose data. However, when the a.m. dose was given on an empty stomach and the p.m. dose 3 h after a meal, it appeared not to be possible to use the single diurnal dose data for calculation of the steady state serum concentration-time profile: the experimentally observed a.m. trough levels were significantly higher than the p.m. trough values and also the observed mean serum concentration was significantly higher than the calculated level. The possible causes for this discrepancy are extensively discussed.

Evaluation of a sustained-release theophylline tablet in young asthmatics.

A sustained-release theophylline (SRT) tablet was evaluated in 15 children with moderately severe asthma between the ages of 3 and 5 years (4.2 +/- 0.83 years). They received a mean daily dose of 20.4 mg/kg given q12h for 3 or more weeks with daily symptom scores and twice daily peak flow rates (PFR) measured. Serum theophylline levels (STL) were then obtained at 0, 1, 2, 4, 6, 8, 10, and 12 hr (eight children had 24-hr samples obtained), along with PFRs every 3 hr. The mean peak STL (x +/- SD) was 16.6 +/- 4.4 and the trough was 5.9 +/- 2.8, with a peak-trough difference of 10.6 +/- 3.9. The average time to peak level was 3.9 hr. The mean +/- SD clearance was 1.42 +/- 0.63 ml/kg per min and the apparent T1/2 was 5.11 +/- 1.34 hr. The average weekly morning PFR for the 3-week period ranged from 116.8 +/- 41.2 to 127.4 +/- 37.4 L/min, and the evening PFT ranged from 126.5 +/- 38.4 to 137.0 +/- 40.9 L/min. In conclusion, the SRT tablet is effective in treating many young asthmatics on a 12-hr dosage schedule. For some children who experience excessive peak-trough differences, an 8-hr dosage schedule may be indicated.

Serum theophylline levels in young children receiving a sustained-release theophylline tablet.

This study indicates that a sustained-release tablet may be used in certain young children on an every-12-hr dosing schedule with acceptable serum theophylline fluctuation. Many young children are able to swallow the tablet and dosing increments are convenient.