Sustained-release Theophylline Formulation Research Articles

Organic solution versus aqueous dispersion of Eudragit RS in preparation of sustained release microparticles of theophylline using spray drying

The aim of this study was to compare aqueous dispersion and organic solution of Eudragit RS in preparation of sustained release theophylline microparticles using spray drying technique. Spray dried samples (SD) with drug:polymer (D:P) ratios of 1:1, 1:2, 1:3 were prepared using aqueous dispersion (SDaq) or organic solutions of Eudragit RS in ethanol (SDor). Properties of spray dried samples including yield, particle morphology, size distribution and drug dissolution were examined. Differential scanning calorimetry (DSC) and FTIR studies were performed to track any polymorphic changes in drug and/or drug- polymer interaction respectively. The SD samples were compacted and the crushing strengths and release profiles of tablets were determined.The yields of samples were in the range of 33–74%. The yield was higher for SDaq samples, being higher at higher D:P ratios. The SDor samples were smaller in size. SEM images confirmed the formation of spherical particles with somehow different structures for SDaq or SDor samples. Tablets prepared from SDor samples exhibited the highest crushing strengths. In study on release profiles for uncompacted samples, SDor samples exhibited superior sustained release properties. The same results were observed for compacted SD samples. DSC studies showed no polymorphism in SD samples and FTIR analysis showed that there was not any interaction between drug and polymer.In conclusion spray dried samples prepared from organic solution of Eudragit RS had superior sustained release properties and have more potential for application in sustained release formulation of theophylline than aqueous dispersion of the polymer.

Preparation and evaluation of a sustained-release suspension containing theophylline microcapsules

A great effort has been devoted to the preparation of sustained-release formulations of theophylline to prevent large fluctuations of serum concentration and increasing the therapeutic efficacy followed by patient compliance. In the present study, microcapsules of theophylline with ethyl cellulose (EC) were prepared by emulsion-solvent evaporation method in different polymer to drug ratios. Size, morphology, drug loading and release behavior of microcapsules were also studied. Microcapsules were then formulated into suspensions to provide an oral liquid dosage form for drug and resulting suspensions were examined for stability and release characteristics in various storage times. Results showed that microcapsules prepared in drug to polymer ratio 1:1.4 by emulsifying polymer solution in liquid paraffin presented the sustained-release properties which met the United States Pharmacopeia (USP) (2007) requirements (t50% and t80% of these microparticles were 150 and 360 min, respectively). The suspensions prepared by these microcapsules were also stable in the study period and their release profiles were consistent to the original microcapsules. The results allow for the conclusion that the formulated suspension can be used as a sustained-release formulation for theophylline in treatment of obstructive pulmonary disorders. Key words: Theophylline, microencapsulation, suspension, sustained-release, ethyl cellulose.

Use of dika fat in the formulation of sustained release theophylline tablets and capsules

Sustained release theophylline tablets and capsules were prepared with dika fat, a solid vegetable oil extracted from the kernels of Irvingia gabonesis var gabonesis and var excelsia. Anhydrous theophylline was incorporated into dika fat by the fusion method. The in vitro release of the theophylline was monitored by the so-called half change dissolution method in stimulated gastric juice USP without pepsin and in stimulated intestinal juice without pancreatin, respectively. The USP XX paddle method was used. A level of sustained release was achieved over a 6-h period in both the tabletted and encapsulated dosage forms. The theophylline formulations containing dika fat, prepared in this study, exhibited dissolution profiles similar to those of Theo 24, Theodur and Respid, some commercial sustained release theophylline formulations.

Complex Interactions of Drugs, Nutrients

Complex Interactions of Drugs, Nutrients

Influence of Theophylline on Activated Lymphocytes and Eosinophils in Peripheral Blood and Sputum

The influence of a once-a-day sustained-release theophylline (Uniphyl) on lymphocytes and eosinophils in the peripheral blood and sputum of patients with bronchial asthma was investigated. The peripheral blood lymphocytes included CD4, CD8, CD25 and HLA-DR. The sputum lymphocytes and eosinophils included CD4, CD8, CD25 and HLA-DR, and EG2, respectively. The results revealed that theophylline administration did not affect the numbers of activated CD4 and CD8 T lymphocytes in peripheral blood. No significant change in the lymphocyte count was observed in sputum, but the eosinophil count in the sputum decreased significantly after theophylline administration. EG2-positive eosinophils also decreased in number. CD4+HLA-DR+ and CD4+CD25+ T lymphocytes were significantly decreased, whereas CD8+ T lymphocytes in the sputum were not significantly reduced in number. Respiratory function test showed that forced expiratory volume in 1 s was significantly increased after theophylline administration. The results suggest that a new once-a-day sustained-release theophylline formulation would be useful in the treatment of chronic respiratory tract inflammation.

Comparative Pharmacodynamic-Pharmacokinetic Correlation of Oral Sustained-Release Theophylline Formulation in Adult Asthmatics

A sustained-release formulation of theophylline with an innovative release mechanism was evaluated in adult asthmatics. The pharmacodynamics and pharmacokinetic behavior of this formulation was compared with a market formulation (Theobid®). The formulations, each containing 200 mg of anhydrous theophylline, were evaluated in six male subjects, 40–55 years of age, 151–169 cm in height, 41–60 kg in weight, who were nonsmokers with moderate chronic obstructive pulmonary disease (COPD); the study was a randomized, single-dose, open, complete crossover study with an interval of 1 week. Written consent was obtained from the patients prior to the trial. Plasma samples were obtained at 0, 1, 2, 4, 6, 8, 10, and 12 hr postadministration. Pulmonary functions were simultaneously recorded using an Erich Jaeger spirometer. Plasma theophylline assays were performed using high-performance thin-layer chromatography (HPTLC). Individual bioavailability parameters were obtained using the S-Inv computer program. Pharmacodynamic-pharmacokinetic correlation was studied using the Excel 95 version 7.0 Regression Statistics program. The test formulation (innovator) was found to be comparable with the marketed product with respect to tmax, t1/2 and Kel (p <. 05). A significant difference in the means of Cmax and AUC0–12 between the innovator and the market formulation indicated a superior extent of absorption from the innovator formulation. A good pharmacodynamic-pharmacokinetic correlation was observed when plasma theophylline concentration was compared with forced expiratory volume.

Comparative bioavailability of two sustained-release theophylline formulations in the dog

The kinetics of two sustained-release theophylline formulations, Theo-Dur®(Recordati, Milano, Italy) and Diffumal®(Malesci, Firenze, Italy) were studied in eight beagle dogs. In a first part of the study each animal was injected intravenously with aminophylline dihydrate, Aminomal®(Malesci, Firenze, Italy), in order to determine the absolute bioavailability of the two sustained-release theophylline formulations orally administered to the dogs in the second experimental phase, over a period of 9 days, following a balanced two-period cross-over design. Assays for theophylline were performed by high performance liquid chromatography and the pharmacokinetic analysis was performed using the non-compartmental method. The principle of superposition was then applied to predict multiple dose plasma concentrations from experimental single dose data. No significant differences between the two preparations were found with respect to the main pharmacokinetic parameters, showing that the two preparations are bioequivalent. The fact that the differences between experimental and predicted results were not statistically significant allows us to conclude that multiple dose steady state plasma theophylline concentration in the dog can be predicted from experimental single dose data. Furthermore, after repeated treatment, both Diffumal®and Theo-Dur®, given twice daily are able to maintain therapeutic (5–20 mg ml−1) plasma theophylline concentrations in the dog.

Effect of once daily and twice daily sustained release theophylline formulations on daytime variation of bronchial hyperresponsiveness in asthmatic patients.

BACKGROUND: Previous studies evaluating spirometric values and symptoms have shown that once daily theophylline administered in the evening produces greater stabilisation of the airway function in asthmatic patients than the...

Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the beagle dog.

Enrofloxacin, a quinolone antibiotic developed exclusively for use in animals, was investigated for its effects on the steady-state pharmacokinetics of theophylline in six healthy Beagle dogs. A sustained-release theophylline formulation was given alone (20 mg/kg per os twice daily at 12 h intervals) for 9 days and then co-administered with enrofloxacin (5 mg/kg i.v. once a day) for 5 days. Mean trough theophylline concentrations progressively and significantly increased during the five days of enrofloxacin co-administration. Theophylline clearance and concentration-time profile were significantly changed by enrofloxacin co-administration. No significant change was observed in enrofloxacin pharmacokinetics. The kinetic interaction between theophylline and enrofloxacin could be of clinical significance and may require plasma drug concentration monitoring and adjustment of theophylline dosage.

Effect of Three Different Doses of a Slow-Release Theophylline Formulation on Bronchial Response to Inhaled Methacholine in Asthmatic Patients

This study investigated whether or not a sustained release formulation of theophylline (SRT) at different dosages had any effect on bronchial hyperresponsiveness as measured by the methacholine challenge. On four separate occasions, 16 patients with mild asthma took either placebo or 300, 400, 500 mg of SRT twice a day. SRT had a slight bronchodilating effect that was not dose-related, but produced a dose-related decrease in the bronchial response to inhaled methacholine (r = 0.39, p = 0.007). This effect was present after all three treatment periods with the active drug when mean +/- SE theophylline serum concentrations of 10.3 +/- 0.7, 12.6 +/- 0.9 and 17.1 +/- 1.1 mg/l respectively were reached. A highly significant relationship between theophylline serum concentration and the degree of protection against methacholine bronchospasm was also found (r = 0.45, p = 0.001). It is concluded that oral theophylline does reduce bronchial hyperresponsiveness in a dose dependent fashion, this effect being present at all the serum concentrations within the normal range.

Pharmacokinetics and clinical effects in dogs of a sustained-release formulation of theophylline

Theophylline was administered orally in a sustained-release preparation at a dose rate of 20 mg/kg bodyweight to six beagle dogs. A mean (+/- se) maximum plasma concentration of 12.2 +/- 0.65 micrograms/ml was obtained 5.17 +/- 0.70 hours after administration and it was calculated to have a mean residence time of 9.09 hours. When given at 40 mg/kg bodyweight twice daily for five days the theophylline preparation was well tolerated, but, the dogs developed a marked tachycardia and hyperpnoea which were attributed to the high plasma concentrations (> 30 micrograms/ml) reached during this dosage regimen.

Development andIn-VitroEvaluation of a Multiparticulate Sustained Release Theophylline Formulation

AbstractA multiparticulate sustained release formulation of theophylline was developed and evaluated in-vitro. The formulation comprised spherical pellets of high drug loading, coated with a rate controlling membrane. The pellets were prepared using an extrusion spheronisation method, whilst coating was performed with an aqueous dispersion of ethylcellulose using a fluidized bed coating technique. When ethylcellulose was used alone as the coating polymer, the drug release profile was unsatisfactory, but could be improved by incorporating a coating additive. Several additives were evaluated and methylcellulose of high Viscosity grade was found most satisfactory. The in-vitro theophylline release was relatively linear and pH independent, and could be varied in a predictable manner by manipulating the coat thickness. In addition, when the coated pellets were subjected to additional thermal treatment, the drug release was stable after storage for one year.

ACTIVATED CHARCOAL FOR THE TREATMENT OF THEOPHYLLINE INTOXICATION

We roported two cases of theophylline intoxication in which activated charcoal was given as treatment, and we experimentally evaluated the theophylline absorbability of activated charcoal.Case 1: A 4 years and 6 months old boy had been given both of continuous intravenous infusion of aminophylline and oral sustained-release theophylline formulation by medication error. He had tremor and the peak serum theophylline level was 35.68μg/ml. Then he was given 0.5g/kg of activated charcoal orally. The elimination rate constant (Kel) was 0.158/h in the first 2.5 hours after the charcoal administration.Case 2: A 12 years and 6 months old girl took sustained-release theophylline formulation and felt discomfort after last medication. Serum theophylline level was 28.79μg/ml at 2.5 hours after the medication and the patient was given 0.5g/kg of activated charcoal orally. The elimination rate constant in the first 110 minutes was 0.148/h.In in vitro study, 7.4g of activated charcoal could absorb 1g of theophylline. Theophylline was absorbed immediately after the addition of activated charcoal. The amount of theophylline absorbed was the highest at pH5.

INTERPATIENT AND INTRAPATIENT VARIATION OF THEOPHYLLINE PHARMACOKINETICS

Data of serum theophylline levels from 60 asthmatic children receiving Round the Clock Therapy with sustained-release theophylline formulations were analyzed for 144 times, using microcomputer soft-ware “Theopredict-I”. As both of intrapatient variations of pharmacokinetic parameters and interpatient variations are very large, the result of a single analysis should not be used for the analysis with Baysian Method instead of population parameters generally used. Low levels of serum theophylline observed in night-time were considered to be the result of decreased absorbtion rate (AR) and increased clearance (CL) compared with those in day-time. The optimal doses calculated from the results of the analysis varied widely, suggesting that serum theophylline levels should be frequently monitored during the Round the Clock Therapy.AR of Theodur® Tab. were significantly small when compared with that of Theolong®, in cases of Children between 4-9 years of age, and these results suggests the Theodur Tab. are of more superior sustained-release property than the Theolong Gr..

Modified starches as hydrophilic matrices for controlled oral delivery III. Evaluation of sustained-release theophylline formulations based on thermal modified starch matrices in dogs

The sustained-release of theophylline from several thermal modified starch matrices was evaluated in dogs in comparison to the commercial formulation Theodur 300. Matrices formulated with starches containing 70% amylose revealed a minor shift in t max in comparison with a conventional tablet. The matrices containing amylose free starches showed t max values of ±4 h. Starch matrices containing 25% amylose demonstrated a good sustained-release performance, comparable to Theodur 300. The influence of the drug/starch ratio was investigated on two types of starches containing 25% amylose: drum dried corn starch and extruded corn starch. A starch/drug ratio between 50 50 and 70 30 showed no significant influence on the biopharmaceutical parameters investigated.

Pharmacokinetic evaluation of sustained release formulations of theophylline by analog hybrid simulation

Several new formulations of theophylline, loaded on polystyrene beads, were developed. Their sustained release performance was evaluated by in vitro dissolution test. Analog-hybrid simulation was carried out in order to evaluate the influence of some technological parameters on the pharmacokinetics of theophylline. Single- and multiple-phase processes of dissolution were proposed. Furthermore, predicted plasma levels in single- and multiple-dosage-regimen schemes were obtained. Formulations with a first-order release rate constant lower than 1.0 h −1 can be administered as a sustained release dosage form at 12-h intervals.

Twenty-four Hour Lung Function in Adult Patients with Asthma: Chronoptimized Theophylline Therapy Once-daily Dosing in the Evening versus Conventional Twice-daily Dosing

Many patients with asthma experience a worsening of symptoms at night and in the early morning, resulting in sleep disruption and possibly altered daily performance. A bronchodilator agent that exerts its maximal effect overnight to control nocturnal symptoms, without a worsening of the disease during the daytime, should improve the treatment of asthma. This investigation examined the efficacy and kinetics of a new chronotherapeutically optimized, sustained-release theophylline formulation administered once daily (OD) in the evening at 8:00 P.M. in comparison with a conventional sustained-release theophylline administered twice daily (TD) at 8:00 A.M. and at 8:00 P.M. in the same dose. After a theophylline clearance study to substantiate normal or slow metabolism of the drug, a dose-titration period, and a 24-h baseline spirometric study of patients not receiving any medication, participants were randomized to 7-day treatment phases with either OD or TD. Each outpatient segment of 6 days of OD and TD was followed by a 24-h inpatient study on Day 7 when serum drug level and spirometric (PEF, FEV1, and FEF25-75) parameters were obtained every 2 h. The conventional TD treatment was associated with a constant serum theophylline level over the 24 h. In contrast, the OD treatment was associated with larger peak-to-trough drug level fluctuation, with higher levels produced overnight and lower ones in the evening at the end of the dosing interval. Compared with the baseline references, both OD and TD significantly improved airflow over the entire 24 h and to a comparable extent. However, between 2:00 and 6:00 A.M., PEF and FEV1 were significantly greater with OD than with TD. The improvement in PEF and FEV1 at this time, because of OD, was correlated with the serum theophylline level. This was not the case for TD. The improvement in airflow over baseline values between 2:00 and 6:00 P.M. was not correlated with theophylline level with either treatment regime. Overall, the chronotherapeutically conceptualized OD treatment administered in the evening resulted in better airflow levels overnight than did the TD regime without loss of airflow in the afternoon.

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.

Comparison of a New Sustained-Release Theophylline Formulation (Theotrim) with a Reference Drug (Theodur) in the Steady State in Asthmatic Children

The bioequivalency of two sustained-release theophylline formulations (SRT), Theotrim and Theodur, was studied in the steady state in asthmatic children, using a double-blind crossover design. Ten children, aged 7–14 (mean 10.2) years, were treated for 2 weeks, with identical doses (mean 16 mg/kg•day) of either Theotrim or Theodur tablets. Each drug was given for 1 week in a randomized sequence. At the end of each week, a 12-hour serum theophylline concentration (STC) profile was performed and pharmacokinetic data of both drugs were compared. Peak STCs with Theotrim and Theodur were 17.1 ± 1.4 μg/ml (M ± SEM) and 16 ± 1 μg/ml (M ± SEM), respectively. Through STC were 8.9 ± 0.8 μg/ml (M ± SEM) with Theotrim compared with 9.4 ± 0.8 μg/ml (M ± SEM) with Theodur. Six patients had % fluctuation of STC < 100% with both Theotrim and Theodur, while the mean (±SEM) % fluctuation was 99(±17)% and 79(±15)% with Theotrim and Theodur, respectively. The area under the concentration curve (AUC) for 0–12 hours was 158.9 ± 13 (M ± SEM) μg/hr•ml for Theotrim, compared with 153.0 ± 10 (M ± SEM) μg/hr·ml for Theodur. The differences between all these pharmacokinetic parameters showed no statistical significance (p > 0.1). Likewise, there were no differences in the frequency of symptoms of asthma, requirement for additional bronchodilator medication, and theophylline side effects in the patients during the week of treatment with Theotrim compared with the other week when treated with Theodur. We conclude that in this group of asthmatic children, Theotrim proved to be bioequivalent to Theodur in the steady state and equally effective in the treatment of asthma.

Kinetic interaction between theophylline and a newly developed quinolone, NY-198.

The effect of a newly developed quinolone, NY-198, on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in six male healthy volunteers, in a crossover fashion. A sustained-release theophylline formulation (200 mg twice daily at 12 h intervals) was received as monotherapy or coadministration with NY-198 (200 mg twice daily at 12 h intervals). No significant change in the pharmacokinetic parameters of theophylline was observed during coadministration of NY-198. No significant change in urinary excretion of theophylline and its metabolites was also observed. These findings indicate that NY-198 does not influence the pharmacokinetics of theophylline and we can suggest that quinoline derivatives have less effect on theophylline disposition than 1,8-naphthyridine derivatives among quinolones.