Theophylline Capsules Research Articles

STUDI PELEPASAN TEOFILIN DARI CANGKANG KAPSUL ALGINAT-KITOSAN MENGGUNAKAN TRIPOLIFOSFAT SEBAGAI CROSSLINKER

The modified formulation provides a fairly effective way to overcome the problem of bioavailability and results in increasing drug reactions and minimizing fluctuations in blood levels during release. The crosslinker in this study is sodium tripolyphosphate (Na-TPP) which is considered the best binding agent and can produce prolonged drug release. The purpose of this study was to determine the profile of theophylline release from the capsule shell of the alginate-chitosan matrix combination using the crosslink method. The capsule shell was made with the ratio of the percentage of alginate ; chitosan; The TPP are F1 (2%; 2%; 4%) and F2 (4%; 2%; 4%). The difference in percentage is intended to determine the ratio of the most optimal levels of releasing theophylline. The results obtained showed that theophylline capsules from formulas F1 and F2 could release the drug slowly and for a long time to the artificial intestinal fluid pH 7.4 for 8 hours for formula F1 and for 12 hours for formula F2 with a cumulative percentage of release of 99.75%.

Preparation of Extended-Release Theophylline for Gastric Tube Administration Significantly Impairs Gradual Resorption

Background: Although Extended Release (ER) dosage forms are not suitable for administration via Nasogastric Tube (NGT), they are used in critically ill patients. The aim of this study is to compare pharmacokinetics of intact and crushed ER theophylline capsules and tablets. Methods: Open-label, randomized controlled trial with two parallel groups was conducted on 10 healthy volunteers. They were randomized into Theo plus® 300 (ER tablets) and Eupyllin CR N® 300 (capsules with ER pellets) group. Each group took the same drug orally twice-first prepared (for the NGT administration) by crushing and secondly as an intact dosage form. Theophylline serum levels were taken at baseline, 30 min, 60 min, 2 h, 4 h, 6 h, 9 h and 12 h after drug administration. maximum serum concentration (Cmax), time to reach Cmax (Tmax) and area under the serum concentration-time curves over 12 h (AUC12h) were calculated. Data are presented as mean ± SD. Results: Crushing increased Cmax in both Euphyllin (43.8 ± 6.5 vs. 26.5 ± 1.6 μmol/l; p<0.01) and Theoplus (45.2 ± 3.6 vs. 29.4 ± 4.8 μmol/l; p=0.013) groups. Tmax was significantly shorter after administration of crushed dosage forms in Euphyllin (0.9 ± 0.7 vs. 5.6 ± 0.9 h; p<0.001) and Theoplus (1.1 ± 0.5 vs. 9.6 ± 2.5 h; p<0.01) group. Concordantly, drug crushing augmented AUC12 h by 40% in both drugs. Conclusion: Crushing destroyed ER properties of theophylline tablets and capsules and their pharmacokinetic profiles were comparable with immediate release forms.

Fatty Acid and Water-Soluble Polymer-Based Controlled Release Drug Delivery System

Sustained release capsule formulations based on three components, drug, water-soluble polymer, and water-insoluble fatty acid, were developed. Theophylline, acetaminophen, and glipizide, representing a wide spectrum of aqueous solubility, were used as model drugs. Povidone and hydroxypropyl cellulose were selected as water-soluble polymers. Stearic acid and lauric acid were selected as water-insoluble fatty acids. Fatty acid, polymer, and drug mixture was filled into size #0 gelatin capsules and heated for 2 h at 50 °C. The drug particles were trapped into molten fatty acid and released at a controlled rate through pores created by the water-soluble polymer when capsules were exposed to an aqueous dissolution medium. Manipulation of the formulation components enabled release rates of glipizide and theophylline capsules to be similar to commercial Glucotrol XL tablets and Theo-24 capsules, respectively. The capsules also exhibited satisfactory dissolution stability after exposure to 30 °C/60% relative humidity (RH) in open Petri dishes and to 40 °C/75% RH in closed high-density polyethylene bottles. A computational fluid dynamic-based model was developed to quantitatively describe the drug transport in the capsule matrix and the drug release process. The simulation results showed a diffusion-controlled release mechanism from these capsules.

Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD

Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD. To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L). In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD. Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD. clinicaltrials.gov; Identifier NCT00241631.

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.

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Pharmacokinetics of an extended-release theophylline product in cats

To evaluate the pharmacokinetics of a brand of extended-release theophylline tablets and capsules in healthy cats. Randomized 3-way crossover study. 6 healthy cats. A single dose of aminophylline (10 mg/kg [4.5 mg/lb], IV), a 100-mg extended-release theophylline tablet, or a 125-mg extended-release theophylline capsule was administered to all cats. Plasma samples were collected via preplaced central catheters throughout a 36-hour period. Plasma samples were frozen until analyzed by use of a fluorescence polarization monoclonal immunoassay. All cats tolerated drug administration and plasma collection with no adverse effects. Peak concentrations were reached for both orally administered products between 8 and 12 hours after administration. Bioavailability was excellent. Plasma concentrations were within the human therapeutic concentration of 5 to 20 microg/mL. Daily administration of the brand of theophylline tablets and capsules used in this study at 15 mg/kg (6.8 mg/lb) and 19 mg/kg (8.6 mg/lb), respectively, maintained plasma concentrations within the desired therapeutic range in healthy cats.

Therapeutic comparison between low-dose sustained-release theophylline dry syrup and capsule in children with mild persistent asthma

Purpose : Theophylline has recently been reported to have concurrent anti-inflammatory effects at low therapeutic plasma concentrations which are below the doses at which significants, clinically useful bronchodilatation is evident. Sustained-release formulation in capsule and dry syrup forms were developed to reduce its adverse effects and improve its clinical effects. We compared the therapeutic effects of theophylline dry syrup and capsules in children with mild asthma. Methods : Ninety children with mild asthma were randomized to receive either theophylline dry syrup (n=44) or theophylline capsules (n=46); 4 mg per kilogram of body weight, twice a day, for 12 weeks. Baseline and serial measurements of daytime and nighttime asthma symptom score were performed. Compliance scores, drug swallowing scores, and drug usability scores were measured every 4 weeks. Each scoring was rated on a scale of 0-4. Serum theophylline concentration were measured at 4 and at 12 weeks. To examine the anti-inflammatory effect of theophylline on asthma, Serum eosinophilic cationic protein as a marker of airway inflammation caused by eosinophil was measured 12 weeks pre- and post-administration. Results : The daytime and nighttime asthma symptom scores of the two groups after 4 weeks significantly improved over the baseline score. Daytime and nighttime asthma symptom scores in the dry syrup group were statistically lower at all time points except for the nighttime symptom scores at 4 weeks. Compliance scores, drug swallowing scores, and drug usability scores in the dry syrup group were significantly higher at the end time point. Only in the dry syrup group was the serum ECP at the end time point statistically lower than baseline. Conclusion : Low-dose sustained-release theophylline may be safe and effective in bronchial asthma and this effect may be mediated by its anti-inflammatory action mechanisms. Especially, when used in children with asthma, dry syrup formulation is recommended because of its higher compliance than capsule formulation.

Microencapsulation of theophylline using ethylcellulose: In vitro drug release and kinetic modelling

This study details the process of coating theophylline with ethylcellulose using the coacervation technique of microencapsulation. Microencapsulation of the phylline not only renders it sustained-release, but also decreases its gastric irritation and masks the bitter taste (Lin and Yang 1987). The non-solvent addition method was chosen through a literature survey to ascertain various phases of the coacervate (Robinson 1989, Nixon and Wong 1990). A three-phase diagram was used to determine the optimum quantity of each component required. Steps were then carried out to optimize the production. Drug release rates of the prepared microcapsules were determined over 12-h cycles using the U.S.P. dissolution apparatus and the results obtained were compared with those of Knoll's (Germany) sustained-release theophylline capsules. Significant con trol over the rate of drug released from the developed dosage form was achieved during the experiment time (12 h). It is concluded that the method employed in this study could be effectively used in the preparation of sustained-release theophylline microcapsules capable of releasing their drug content for an extended period of time. Kinetic studies suggested that both the prepared microcapsules and Knoll's product followed Higuchi's model for drug release. Particle size and release data analysis from five consecutive batches prepared in the laboratory indicated suitable reproducibility of the coacervation process.

Comparison of inhaled salmeterol and individually dose-titrated slow-release theophylline in patients with reversible airway obstruction. European Study Group

The aim of this study was to compare the clinical efficacy of salmeterol versus theophylline in the treatment of moderate-to-severe asthma. One hundred and eighty nine asthmatic patients (forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) >50% of predicted) were randomized to receive either salmeterol dry powder, 50 microg b.i.d. via a Diskhaler (n=92) or dose-titrated slow-release theophylline capsules ("Theo-Dur") b.i.d. (n=97), in a double-blind, double-dummy, parallel group study for 4 weeks. Patients had previously been titrated with theophylline to a serum theophylline level of 10-20 microg x mL-1. The median percentage of nights with no asthma symptoms rose from 14% in both groups at baseline to 71% with salmeterol and to 46% with theophylline (p=0.044). There was also a significant increase for salmeterol in the median percentage of nights with no rescue salbutamol use (from 36 to 86%) compared with theophylline (from 71 to 78%; p=0.002). The mean morning PEF increased from 337 L x min-1 in the salmeterol group and 332 L x min-1 in the theophylline group to 372 and 357 L x min-1, respectively. No significant difference between the two treatments was observed for PEF, symptoms or additional salbutamol medication during the day. The incidence of gastrointestinal symptoms (gastric irritation, nausea and vomiting) was greater among patients receiving theophylline (11%) than with salmeterol (3%). These findings suggest that inhaled salmeterol is more effective in relieving symptoms of asthma, and better tolerated than theophylline in patients with moderate-to-severe asthma.

In vitro-in vivo correlation studies on a novel controlled release theophylline delivery system and on Theo-Dur tablets

A good correlation should be obtained between data derived from in vitro dissolution and bioavailability studies on drug delivery systems if bioavailability parameters are to be reliably predicted from the in vitro dissolution variables. This study compares the in vivo absorption with the in vitro dissolution profiles into various dissolution media of a novel controlled release theophylline capsule (Mintab) containing mini-matrices, and also those of Theo-Dur 300 mg tablets. Mintab displayed significant pharmacokinetic advantages over Theo-Dur. However, Theo-Dur demonstrated good in vitro-in vivo correlation, whereas Mintab showed poor correlation.

Comparative Pharmacokinetics of Morning and Evening Doses of Once-a-Day Theophylline Capsules

The objective of this study was to determine if the theophylline diurnal variation that has been observed primarily between morning and evening doses of twice-a-day products could be overcome by a once-a-day formulation. Eighteen healthy, nonsmoking, adult male subjects were given 900-mg theophylline doses as three 300-mg once-a-day theophylline capsules in the morning or evening for 5 days in a single-blind fashion. Matching placebo capsules were administered midway between each dose of active drug. Predose theophylline serum levels on day 3-6 were statistically equivalent within each treatment, indicating that approximate steady-state conditions were achieved by day 3. Mean serum level profiles over the 24-h interval following the active dose on day 5 were almost superimposable for the morning and evening treatments. All pharmacokinetic parameters were equivalent between the treatments, except for the time to peak serum level (Tmax), which was significantly shorter for the morning dose. Given the flatness of the serum level curves for both treatments, theTmaxdifference was judged to be clinically unimportant. A small peak-trough level fluctuation of about 50% was seen with each treatment. We conclude that by designing a dose form in which drug release was the rate-limiting step in drug absorption, the diurnal variation commonly associated with theophylline formulations may be eliminated.

A Novel Method for the Preparation of Controlled-Release Theophylline Capsules Coated with a Polyelectrolyte Complex of .KAPPA.-Carrageenan and Chitosan.

A novel method for the preparation of κ-carrageenan/chitosan polyelectrolyte complex (PEC) membrane capsules containing theophylline as a model drug was developed. The theophylline release from the capsules followed zero-order kinetics, and the release rates were independent of pH of the dissolution medium, suggesting that κ-carrageenan/chitosan PEC capsules could be a useful vehicle for controlled-release drug delivery.

Effect of helix characteristics on the dissolution rate of hard gelatin capsules

In a factorial experiment, the effect of the characteristics of the wire helix on the dissolution rate of theophylline capsules and on the reproducibility of the dissolution data has been investigated. The results support the ‘helix-envelope’ concept developed in this study. Thus, any change that favoured the ‘enveloping’ action of the helix, such as an increase in the number of turns and a decrease in the distance between the turns, decreased the dissolution rate of the capsules.

THE EFFECT OF SUSTAINED‐RELEASE THEOPHYLLINE IN NOCTURNAL ASTHMA

SUMMARY Nocturnal symptoms are common and often disabling in asthmatic subjects. Furthermore, they often persist, in spite of appropriate dosages of inhaled β2‐agonists and topical steroids. In such a clinical situation, theophylline preparations may have a therapeutic role. This double‐blind, placebo‐controlled, cross‐over trial was designed to evaluate the effectiveness of a twice‐daily Bioavail slow‐release theophylline capsule in a group of out‐patient asthmatics, with a history of nocturnal and/or early morning wheeze or chest tightness. Theophylline was initially prescribed and monitored in an ‘open’ phase to obtain the drug dosage required to achieve a serum level in the therapeutic range of 10‐20 mg/l. In the ten patients who completed the study, serum theophylline levels were stable throughout.During active treatment there was an improvement in morning peak expiratory flow rate (PEFR), and a reduction in measurements of diurnal variation. In addition, the bronchodilator response to an inhaled β2‐agonist was preserved. Bioavail theophylline has thus been shown to be an effective agent in the management of adults with nocturnal asthma.

Relationship of different serum levels of theophylline on methacholine sensitivity

With an increased awareness of the importance of bronchial hyperreactivity on the clinical state of asthma, efforts at establishing effective treatment for asthma have been aimed at trying to reduce the level of bronchial hyperreactivity. This study investigated whether or not theophylline at different serum concentrations had any effect on bronchial hyperreactivity, as measured by methacholine challenges. Twelve adult subjects with mild asthma participated. All subjects wre atopic and were nonsmokers. Subjects were studied on three separate occasions according to a double-blind, randomized, crossover study design with one of the following medications: two placebo capsules in the morning and evening, a placebo and 250 mg of sustained-release theophylline in the morning and evening, or two 250 mg sustained-release theophylline capsules each morning and evening. Subjects were administered their medication between 5 and 15 days before performing methacholine challenges in the morning at the presumed trough level, and in the afternoon at the presumed peak serum theophylline level. Despite statistically significant differences in the pulmonary function and theophylline levels between the two active dosages ( p < 0.05 for both), there was no difference in methacholine sensivity at the time of ingestion of the two dosage forms. There was also no correlation between a particular theophylline level and degree of methacholine sensitivity. It was concluded that, although theophylline has significant bronchodilator capability, it has little, if any, effect on bronchial hyperreactivity, as measured by methacholine challanges. Thus, other forms of long-term therapy should be used in reducing bronchial hyperreactivity.

Bioavailability of a new sustained‐release theophylline capsule in fasted and non‐fasted healthy subjects: Single and multiple dosing studies

Eighteen healthy, non-smoking, adult volunteers participated in single and multiple dose three-way crossover studies to evaluate a sustained-release, pellet-filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained-release capsule was investigated by administering 300 mg single doses of Austyn, with a high-fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p greater than 0.05) between the three regimens with respect to AUC0-infinity values (mg h l-1), (mean +/- SD); Elixophyllin fasting = 97.1 +/- 33.7, Austyn with food = 90.9 +/- 31.3, Austyn fasting = 91.2 +/- 33.8. Similarly, multiple dosing with rapid-release Nuelin tablets, Austyn capsules, and sustained-release Theo-Dur tablets demonstrated that there were no significant differences between regimens with respect to AUC0-24h, AUC0-12h, and AUC12-24h values calculated from the steady-state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady-state over the total blood sampling period was significantly less for treatment with the sustained-release capsule. Austyn, compared with the sustained-release tablet, Theo-Dur (Austyn = 36.7 +/- 13.7 per cent, Theo-Dur = 53.1 +/- 14.1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high-fat meal and with no evidence of dose dumping.

Sustained release properties of the once daily theophylline capsule euphylong as compared with theo-dur tablets

In a multiple dose cross-over experiment in 18 healthy male volunteers the sustained release properties and relative bioavailability of new once daily Euphylong 375 mg capsules (= A) were studied using twice daily Theo-Dur (= B) as reference. Theophylline was given over a period of 8 days: A once daily as a 750 mg dose at 20.00 h (with placebo at 08.00 h) and B twice daily as a 400 mg dose at 08.00 and 20.00 h. Plasma concentration-time profiles were evaluated on days 5 6 and 8 9 . Theophylline in plasma was measure by high-performance liquid chromatography (HPLC). Considerable sustained release properties for A were indicated by an extended shape of the plateau phase on days 5 6 and 8 9 , resulting in high T 75% values (11.0 h and 10.6 h). As to be expected, peak-to-trough fluctuations (defined as % PTF= 100 ( max − C min)/C av) on the two steady-state days with once daily A (% PTF: 104% and 108%) were significantly larger than fluctuations with twice daily B (52% and 53%). The two products were found to be bioequivalent although bioavailability of A was slightly lower on both days (85% and 90%). In conclusion, A was found to be of good sustained release quality. In once daily dosing it may occasionally (e.g. in fast metabolizers) be difficult to keep theophylline plasma concentrations within the therapeutic range during the 24-h dosing interval, although in asthmatic patients, who generally have slower elimination than healthy young adults, smaller peak-trough fluctuations can be anticipated.

The effect of food on the absorption of controlled-release theophylline in mini-swine.

The effect of differing fat contents of food on the bioavailability of theophylline following a 400-mg single dose of Theo-24 was studied in mini-swine. The pharmacokinetics of theophylline, following the intravenous administration of aminophylline equivalent to 5 mg/kg as a single dose, were also studied in the same animals. The terminal plasma half-life of theophylline following an i.v. dose was found to be approximately 24 hr. The volume of distribution, Vdext, and clearance following the i.v. dose were approximately 0.7 liter/kg and 0.023 liter/hr/kg, respectively. The terminal half-life of theophylline following the administration of theophylline capsules under fasting conditions was 21 hr. The average bioavailability under fasting conditions was approximately 80% compared to the i.v. dose. Food appeared to have decreased the rate of absorption but no significant effect on the extent of absorption.

Steady-state pharmacokinetics and effects of a new once-daily, slow-release theophylline capsule preparation in asthma.

Plasma and saliva theophylline concentrations were measured in 21 asthmatic subjects receiving chronic oral therapy with a new sustained-release theophylline capsule (K1B Riker) given as a once daily dose, after titration to achieve a before-dose concentration of 8 mg l-1 or greater, or to the maximum dose of 1200 mg of theophylline daily. Plasma concentrations rose from a mean +/- s.d. minimum concentration (Cmin) of 7.9 +/- 2.3 mg l-1 to a mean maximum of 13.6 +/- 3.3 mg l-1 at a median time of 10 h after dosing. Saliva theophylline concentrations were closely related to the plasma theophylline concentration both between and within subjects with a mean saliva to plasma concentration ratio between subjects (S/P ratio) of 0.62 (+/- 0.05) and a mean within subject coefficient of variation of 8.2% (+/- 4.5%). There was a significant but small (10%) change in the mean S/P ratio during the dosing interval. Peak expiratory flow rate (PEFR) changed slightly but significantly during the dosing interval but forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) did not. The drug was well tolerated at the dose used (600-1200 mg once daily).