Pharmacokinetic analysis of sustained-release dosage forms of theophylline in humans: comparison of single and multiple dose studies

A pharmacokinetic analysis of two sustained-release dosage forms of theophylline (Theo-Dur and Theotrim) was carried out following single and multiple dose administrations of the two formulations in five healthy subjects. Despite the prolonged absorption after administration of the two sustained-release formulations, theoretical predictions of theophylline steady-state levels following multiple dosages based upon data obtained from the single dose study, correlated with the data of the multiple dose study. This study shows that the recommended dose and dosage regimen of new sustained-release formulations of theophylline can be based upon single dose studies. In the population studied, repetitive doses of 450 mg b.i.d. of Theo-Dur and Theotrim maintain steady-state concentrations of theophylline within the drug's therapeutic window.     

The rise and fall of serum theophylline concentration: a comparison of sustained-release formulations in volunteers with rapid theophylline clearance.

The pharmacokinetics of four sustained-release formulations of theophylline have been examined after single doses (Nuelin SA, Phyllocontin, Slo-phyllin and Theo-Dur) and at steady-state (Phyllocontin, Theo-Dur) in six healthy adult volunteers, selected because they all eliminated theophylline rapidly after an intravenous dose of aminophylline. After a single dose of Theo-Dur, the peak concentration of theophylline was smaller and occurred later than after single doses of Nuelin SA, Phyllocontin and Slo-phyllin, suggesting that absorption occurs over a longer period. The systemic availability of theophylline was virtually complete after all four formulations. After repeated 12-hourly dosing to steady-state, and adjustment of dose to achieve trough concentrations of between 5 and 10 mg l-1 (28-55 mumol l-1), theophylline concentration fluctuated to a significantly greater extent within a dose interval when the subjects were taking Phyllocontin than when they were taking Theo-Dur.     

Conversion from intravenous aminophylline to sustained-release theophylline: computer simulation versus in vivo results

The accuracy of computer-predicted theophylline serum concentrations compared with actual serum concentrations in patients whose drug therapy was being converted from aminophylline infusions to an oral sustained-release theophylline product (Theo-Dur) was measured. The SIMKIN computer program was used to simulate theophylline serum-concentration curves in nine patients receiving an initial dose of sustained-release theophylline at the time their maintenance aminophylline infusions were discontinued. The sustained-release theophylline doses were calculated using individual patient theophylline clearance values to produce mean theophylline serum concentrations in the normal therapeutic range. Pharmacokinetic variables used in the SIMKIN program were derived from individual patients' serum concentrations and average literature values. Theophylline serum concentrations were measured before the initial dose of the sustained-release product and periodically for 12 hours. Mean SIMKIN-predicted serum theophylline concentrations were within 10% of actual measurements 39% of the time, but data from individual patients varied considerably. Two patients had prolonged absorption lag times that could not be explained. Computer-simulation programs using population-based pharmacokinetic variables to predict theophylline serum concentrations must be tested against in vivo measurements to verify their accuracy.     

Zero-Order Release Formulation of Oxprenolol Hydrochloride with Swelling and Erosion Control

Zero-order release of oxprenolol hydrochloride was obtained by controlling the swelling and erosion of the matrix. This formulation involves only mixing of drug, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (Na CMC) at the ratio of 1:0.4:1.6, respectively, and compressing the mixture directly into tablets. The in vitro release pattern from this optimized matrix tablet was reproducible. Accelerated stability studies revealed that the optimized formulation remains stable for an approximately 2-year shelf life. This sustained-release (SR) tablet was evaluated in dogs, and for comparison a conventional (CV) formulation was also given at the same dose level. Plasma oxprenolol levels were monitored by a sensitive and specific high-performance liquid chromatographic (HPLC) method. Significant differences in the pharmacokinetic parameters, i.e., lower C _max, higher values of t _max, MRT, AUC, and plasma concentration at 24 hr, and nearly constant plasma levels over 12 hr, indicated that the SR matrix tablet is superior to the CV rapid-releasing formulation. The in vitro release parameters and in vivo pharmacokinetics correlated well.     

Characterization and evaluation of self-nanoemulsifying sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food effect

The purpose of this work was to develop self-nanomulsifying drug delivery systems (SNEDDS) in sustained-release pellets of ziprasidone to enhance the oral bioavailability and overcome the food effect of ziprasidone. Preformulation studies including screening of excipients for solubility and pseudo-ternary phase diagrams suggested the suitability of Capmul MCM as oil phase, Labrasol as surfactant, and PEG 400 as co-surfactant for preparation of self-nanoemulsifying formulations. Preliminary composition of the SNEDDS formulations were selected from the pseudo-ternary phase diagrams. The prepared ziprasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized ziprasidone-SNEDDS were used to prepare ziprasidone-SNEDDS sustained-release pellets via extrusion-spheronization method. The pellets were characterized for SEM, particle size, droplet size distribution and zeta potential. In vitro drug release studies indicated the ziprsidone-SNEDDS sustained-release pellets showed sustained release profiles with 90% released within 10?h. The ziprsidone-SNEDDS sustained-release pellets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation of Zeldox as a control. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolonged actions and enhanced bioavailability with no food effect was achieved simultaneously in ziprsidone-SNEDDS sustained-release pellets compared with Zeldox in fed state. The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment.     

Release and absorption characteristics of chlorphenesin carbamate sustained-release formulations: In vitro-in vivo and in vivo dog-human correlations

The bioavailability of chlorphenesin carbamate (CPC) in sustained-release (SR) formulations exhibiting different in vitro release characteristics in dogs and humans was examined using formulations tested previously in the in vitro dissolution method. The human-dog correlation of the bioavailability of SR formulations was examined under fasting conditions. Pharmacokinetic analysis using the Wagner-Nelson procedure revealed sustained-release absorption characteristics for the SR formulations, with the exception of the immediate-release (IR) formulation as control in dogs and humans. For each of the SR formulations tested, regression analysis results of the percentage of CPC absorbed in human against that in dogs, at corresponding times, indicated a high correlation. Moreover, the correlation of the dissolution rates and bioavailabilities of these formulations in humans was also examined. Although the in vitro CPC release profiles from the SR formulations were smooth and controlled, they were too rapid when compared with the in vivo human data. However, the rank order was exactly the same between in vivo and in vitro data, and a good relationship was found after time scaling of the release data. These data imply that the release characteristics of CPC after changing of the formulations could be evaluated using the in vitro dissolution method or dogs as an animal model in place of human studies.     

Theophylline absorption from sustained-release products: comparative steady-state bioavailability of once-daily Theo-Dur, Theo-24, and Uniphyl

Theophylline absorption from three sustained-release formulations was evaluated in 18 healthy men. First, a 600-mg oral dose of aminophylline, a rapidly absorbed formulation, was studied to confirm that theophylline clearance was in the expected range (mean +/- SD, 0.710 +/- 0.096 mL/min/kg), t1/2 = 6.9 +/- 1.1 hr. Then each of the three sustained-release formulations was given at one hour before breakfast for eight days to achieve steady state. Multiple blood samples were drawn on days 7 and 8 over two complete dosing intervals. After a six-day drug-free period each subject was crossed over to the next product. At steady state, mean fluctuations of serum theophylline levels were more than 200% with Theo-Dur (Key Pharmaceuticals, Miami, FL), more than 150% with Uniphyl (Purdue-Frederick, Norwalk, CT), and about 75% with Theo-24 (Searle Laboratories, Chicago, IL). Theophylline Cmax levels averaged 16.5 micrograms/mL after 900 mg Theo-Dur, with 8% exceeding 20 micrograms/mL. Despite these high peak levels, nearly half of the Cmin levels were below 5 micrograms/mL. Uniphyl administration resulted in three-fourths of trough levels to be at 5 micrograms/mL or lower. Peak levels from 800-mg daily doses of Uniphyl were also low, with 42% never reaching 10 micrograms/mL. With Theo-24 only 17% of trough levels were below 5 micrograms/mL, as compared to 47% with Theo-Dur and 72% with Uniphyl. The three products differed in the areas under the serum concentration-time curves (AUC), which reflect bioavailability. Theo-Dur AUC was nearly equivalent to that of rapidly absorbed aminophylline (when adjusted for dosage).(ABSTRACT TRUNCATED AT 250 WORDS)     

长效茶碱片的研究

本文研究了长效茶碱片(SRTT)的处方组成,制备工艺,溶出速率;并应用改进的紫外分光光度法测定了l2名健康受试者口服SRTT后的体内血药浓度,实验数据按单室模型用电子计算机进行处理得各药物动力学参数。SRTT单剂量给药(300 mg),3.8小时达有效血药浓度,可维持5μg/ml以上23小时;多剂量给药,3小时达有效血药浓度,至第三天已达稳态血药浓度13.78±0.47μg/ml。将SRTT与世界名牌产品Theo-Dur进行对照试验,表明两制剂为生物等效。本文采用脱卷积法计算体内外相关性,理论值与实测值基本相符。     

THEOPHYLLINE CONTROLLED-RELEASE FORMULATIONS: IN VIVO--IN VITRO CORRELATIONS

Four experimental controlled-release oral solid dosage formulations were developed and the in vitro dissolution characteristics of theophylline from these formulations were studied in USP apparatus I. Pharmacokinetic evaluation of these formulations was carried out in eight beagle dogs under fasting conditions. Theophylline in a 5% dextrose injection USP, oral solution, and Slo-Phyllin® were used as controls to estimate the in vivo dissolution of these four formulations in the GI tract. The percentage cumulative amounts of drug absorbed and the percentage cumulative amounts of drug released into the GI tract from these four controlled-release formulations were obtained by numerical deconvolution methods. The in vivo and in vitro dissolution data demonstrated good correlation indicating that in vitro dissolution tests can be used to optimize the further design of controlled drug release oral solid dosage formulations for theophylline.     

Pharmacokinetic evaluation in dogs of theophylline in a novel zero-order release core-in-cup tablet

A new core-in-cup tablet that is manufactured from a novel adjustable punch, has been formulated and evaluated for its ability to release with subsequent absorption of theophylline via a zero-order rate of absorption. The core-in-cup tablets were compared with core only tablets and immediate release capsules. Pharmacokinetic parameters used to test the effectiveness of the formulations included, elimination rate, rate and kinetic order of absorption, relative availability as compared with an immediate release capsule of pure theophylline, and percentage area under the curve fluctuation (%AUCF) at steady state. The correlation coefficient, Akaike's information criterion (AIC) and the F -ratio probability were used to test the applicability of a zero-order, first-order, or square root of time model, for the rate of release of theophylline from the core-in-cup and core only tablets. The zero-order rate model was most applicable to the core-in-cup tablet, whereas the square root of time release model was most applicable to the core only tablet. The average %AUCF for the core-in-cup tablet was 9.26±3.15 while that for the core only tablet was 16.19±2.37 (p =0.0545). The results of this study suggest that the core-in-cup tablet is a versatile zero-order release rate dosage form that are simple to produce. © 1998 John Wiley & Sons, Ltd.     

Correlation of in Vitro Release Rate and in Vivo Absorption Characteristics of Four Chlorpheniramine Maleate Extended-Release Formulations

An in vitro/in vivo correlation was established for four formulations of chlorpheniramine maleate (histamine, H₁-blocker) extended-release tablets exhibiting different in vitro release rate characteristics. In vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2, paddle stirrer at 50 rpm in 1000 ml of distilled water at 37.0 ± 0.5°C. Inspection of the individual and mean release rate data indicated that the in vitro release rate of chlorpheniramine maleate was consistent with the intended design of the four extended-release formulations. The in vivo bioavailability and pharmacokinetics of these formulations were evaluated in 24 healthy subjects under fasting conditions. Wagner Nelson analyses of the in vivo data revealed extended release absorption profiles for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a statistically significant correlation (r ² > 0.98, P < 0.001) for each formulation. Qualitative rank-order correlations were observed among all combinations of in vitro and in vivo parameters. These data support a Level A correlation between the in vitro release rate profiles and the in vivo absorption for chlorpheniramine maleate determined under fasting conditions.     

Clinical assessment of theophylline absorption from Theolair-SR and two other sustained-release formulations relative to a conventional formulation

In this single dose study with 8 subjects, the rate and extent of theophylline absorption from 3 sustained-release formulations (Theolair-SR tablet, Slo-phyllin Gyrocaps, and an experimental SR tablet) were compared to absorption from a conventional formulation (Theolair tablet) that has been shown to provide both prompt and complete absorption. Plasma theophylline level versus time profiles show that the rate of absorption from all 3 sustained-release formulations is slower than from the conventional tablet. In addition, the higher plasma levels at later times and the slower apparent plasma elimination rate of theophylline following the Theolair-SR tablet as compared to the conventional Theolair tablet indicate that drug absorption continues over a more prolonged period of time. Plasma AUC data indicate, with good assurance, that the extent of theophylline absorption is essentially complete from all 3 sustained-release formulations when compared to data for the conventional tablet. Statistical analyses with plasma AUC data indicate that the Theolair-SR tablet should provide both reliable and complete drug absorption. Projected plasma drug levels for multiple dosage regimens (simulated on the basis of the single dose data from this study) demonstrate that, even with a twice daily dosage regimen, the Theolair-SR tablet has acceptable sustained-release characteristics relative to the conventional Theolair tablet with 4 daily doses, and that the sustained-release properties compare favorably with those of Slo-phyllin Gyrocaps.     

Conversion from intravenous to sustained-release oral theophylline in pediatric patients with asthma

A method for converting pediatric patients from intravenous aminophylline to sustained-release oral theophylline was evaluated in eight asthmatic children. The administration of Theo-Dur tablets two hours before discontinuation of a continuous intravenous aminophylline infusion resulted in a peak rise of 5.6 +/- 3.0 micrograms/ml over steady-state serum theophylline concentrations. This method of conversion is acceptable in children with equivalent oral and intravenous doses of theophylline and serum theophylline concentrations less than 15 micrograms/ml. Children with steady-state theophylline concentrations greater than 15 micrograms/ml are likely to develop concentrations exceeding the therapeutic range using this conversion method.     

Comparison of two sustained-release theophylline preparations in adult patients with obstructive airways disease

The bioavailability profiles of two sustained-release oral theophylline preparations, Respbid and Theo-Dur, were compared in 19 adults with obstructive airways disease. Intravenous aminophylline was used as the reference standard. No significant differences were detected in fraction absorbed, peak-trough fluctuations, or time to peak concentrations.     

Imperatorin sustained-release tablets: <Emphasis Type="Italic">In Vitro</Emphasis> and pharmacokinetic studies

We prepared and evaluated imperatorin (IMP) sustained-release tablets. IMP is an active compound in Angelica dahuricae, a Chinese herbal medicine. We used different polymers, such as hydroxypropyl methylcellulose (HPMC K4M, K15M, and K100M), carbopol 934P, sodium carboxymethyl cellulose (CMC-Na), and their combinations to prepare the matrix tablets and achieve the desired sustained release profile. The in vitro release profiles of these formulations were examined and fit to various kinetic release models. We also tested the effects of polymer combination ratios on the in vitro release rate. In vivo studies were performed for the optimized formulation in six beagle dogs, and pharmacokinetic parameters were compared with plain IMP tablets. IMP sustained-release tablets exhibited a more sustained plasma concentration than the plain tablets, with a relative bioavailability of 127.25%. The in vitro releases rates and in vivo absorption correlated for the initial 8 hours. These results demonstrate that the sustained-release tablet system can effectively control the release of IMP.     

Evaluation of the absorption from some commercial enteric-release theophylline products

In a single-dose bioavailability study, Wales, Robinson, Columbia, and Choledyl (Warner/Chilcott) enteric-coated tablets all allowed a bioavailability of theophylline (99%±25%, 102%±23%,103%±18%, and 98%±15%;mean±SD, n=12) statistically indistinguishable from that of the standard uncoated tablet (Searle 200 mg aminophylline). Only the Wales and Choledyl tablets (7.6, 4.2 hr) could be shown (p<0.05) to generate a peak plasma theophylline concentration later than the standard (1.4 hr). All tablet brands demonstrated a significant lag time before appearance of theophylline in the plasma, and both Wales and Choledyl tablets also had a (t _peak -t _tag )statistically different from that of the standard. Despite misleading indications from the mean plasma profile (plasma concentrations at each sampling time averaged over all subjects), plasma data from the individual participants and in vitrodissolution data show that, while release of theophylline from the Wales tablet might be inordinately slow, this is not a sustained-release preparation. Of the enteric-coated tablets only the Columbia product allowed significant levels in the first sample after dosage. Five of the 18 Columbia doses gave rise to 40–99%of the peak concentration in the 1- hr sample. In vitro,it takes 39±14 min for 40% of the theophylline content of Columbia tablets to dissolve in simulated intestinal fluid. Surprisingly rapid delivery of an entericcoated tablet to the duodenum would appear to be required to allow a significant percentage of theophylline to be dissolved and absorbed before 1 hr. None of 12 Columbia tablets tested in vitro,however, allowed dissolution of more than 0.2% of their theophylline content during 1 hr immersion in simulated gastric fluid. Since once in intestinal fluid Columbia tablets appear to dissolve more rapidly than the other enteric products, it is not clear whether the five Columbia tablets in question had imperfections or whether, in fact, this tablet brand more closely than the others represents the ideal of immediate release once in the duodenum. Plasma samples should be taken as early as 15 min after dosage when evaluating the bioavailability of enteric release products.This work was supported by FDA Contract No. 223-74-3145. Data management and analysis were achieved largely by the NIH-sponsored PROPHET system (ref.Proc. Natl. Comput. Conf. Exposition 43:457, 1974). Dr. Guentert was assisted by the Swiss National Science Foundation.     

Formulation and in Vitro-in Vivo Evaluation of Sustained-Release Lithium Carbonate Tablets

The release of lithium carbonate incorporated into polymethylmethacrylate, poly vinyl chloride, hy-drogenated vegetable oil, and carbomer matrix tablets was studied in vitro. The formulation containing 10% carbomer showed a sustained-release profile comparable to that of a standard, commercially available, sustained-release preparation containing 400 mg lithium carbonate embedded in a composite material. In vivo the newly formulated and standard sustained-release lithium carbonate tablets were compared to an oral solution and conventional lithium carbonate tablets in 12 healthy subjects. These crossover studies showed that the sustained-release tablets produced a flatter serum concentration curve than the oral solution and conventional tablet, without loss of total bioavailability.     

A Floating Controlled-Release Drug Delivery System: In Vitro-in Vivo Evaluation

A novel floating controlled-release drug delivery system was formulated in an effort increase the gastric retention time of the dosage form and to control drug release. The buoyancy was attributed to air and oil entrapped in the agar gel network. A floating controlled-release 300-mg theophylline tablet having a density of 0.67 was prepared and compared in vitro and in vivo to Theo-dur. The in vitro release rate of the floating tablet was slower. In vivo scintigraphic studies for a floating and a heavy nonfloating tablet, under fasting and nonfasting conditions, showed that the presence of food significantly increased the gastric retention time for both tablets, and tablet density did not appear to make a difference in the gastric retention time. However, the positions of the floating and nonfloating tablets in the stomach were very different. Bioavailability studies in human volunteers under both fasting and nonfasting conditions showed results comparable to those with Theo-dur. The floating controlled-release theophylline tablet maintained constant theophylline levels of about 2 mg/mL for 24 hr, which may be attributable to the release from the agar gel matrix and the buoyancy of the tablet in the stomach.     

Comparison of inter- and intra-subject variation in oral absorption of theophylline from sustained-release products

A comparative study of inter- and intra-subject variation in the bioavailability of theophylline from two commercial sustained-release dosage forms (a beaded capsule and a tablet formulation) was performed in 12 healthy adult volunteers. The disposition kinetics of theophylline was characterized in each subject following a single 250 mg oral dose of a fully bioavailable liquid formulation. Duplicate single dose studies of each of the two sustained-release products were then performed on 4 separate occasions in a randomized crossover fashion. On the average, the extent of theophylline bioavailability from the two sustained-release dosage forms was equivalent and essentially complete as compared to that from the liquid formulation. Both sustained-release formulations exhibited reasonable consistency in the extent of bioavailability when tested on two different trial days in a given subject (the mean percentage difference in extent of absorption was 11.5 ± 8.3% for the beaded capsule and 11.8 ± 12.3% for the tablet). The rate of theophylline absorption from the beaded capsule formulation was more rapid than from the tablet formulation as indicated by an earlier time to reach peak serum concentration (6.0 ± 1.9 vs 8.9 ± 2.5 h). Individual time course of cumulative absorption from the sustained-release formulations was determined using the Wagner-Nelson procedure. The overall variability in the cumulative absorption profile was greater for the tablet as compared to the capsule formulation. More significant was the fact that within each subject the absorption profiles were less reproducible between trials with the tablet as compared to the capsule. Dose-to-dose variation in the release/absorption kinetics of theophylline from these sustained-release products may lead to unpredictable fluctuations in steady-state serum theophylline concentration-time profiles during chronic drug administration.     

Theophylline-Controlled Release Preparations and Fatty Food: An in Vitro Study Using the Rotating Dialysis Cell Method

The in vitro dissolution behavior of four controlled-release theophylline products was investigated utililzing the rotating dialysis cell method. The effects of pH, oil, and enzymes on the dissolution profiles were studied. The wide range of pH values and the content of oil and enzymes in the dissolution media in the dialysis cell, which functioned as an in vitro model, were simulated to mimic physiological changes due to food along the entire gastrointestinal tract. Treatment with oil affected the dissolution behavior of Uniphyl and especially Theo-Dur Sprinkle but had little or no effect on the dissolution profiles of Theo-Dur tablets and Theo-24 capsules. The in vitro observations of the oil effect were related to the food effect obtained from published in vivo studies. The rotating dialysis cell can be a useful tool in studying factors which may be responsible for dissolution-related food effects on the absorption of controlled-release products.