In vivo evaluation of a theophylline oral controlled-release unit dosage form

A 200 mg controlled-release unit dosage form which was designed and developed showed desired in vitro release characteristics. This dosage form was subjected to in vivo studies (single and multiple p.o. dosing) in Beagle dogs with the aim of insuring the desired controlled-release performance in a biologic system. Using a parallel study design (intravenous, p.o. solution, p.o. controlled-release standard and p.o. controlled-release test dosage form), the dosage form index (DI), the fraction of drug absorbed (absolute bioavailability) (f) and the extent of (relative) bioavailability (EBA) of the experimental dosage form were determined.     

Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel

Summary The salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel have been compared. The bioadhesive tablet consisted of a mixture of thermally modified starch and 5% polyacrylic acid.Although the amount of drug administered via the bioadhesive tablet was sixfold lower than when the gel was used, the salivary miconazole levels were higher and remained above the MIC value ofCandida albicans for more than 10 hours. The mean adhesion time of the tablet was 586 min.The bioadhesive tablet appears to be a promising drug delivery system for the buccal administration of drugs for local therapy.     

Determination of ephedrine, theophylline and phenobarbital in a tablet dosage form by capillary electrophoresis

A capillary electrophoresis method was developed to separate and quantitate ephedrine (ED), theophylline (TP) and phenobarbital (PB) in a tablet dosage form. Tablets were ground and extracted with methanol using ultrasonication. Aliquots of standard stock solution were hydrodynamically injected for 5 s at the anodic end. Separation was performed on a fused silica capillary (72 cm x 50 microm i.d.; 50 cm to detector) at an applied voltage of 20 kV with a phosphate run buffer (pH 8.0, 50 mM). Analysis was performed at ambient temperature (23+/-1 degrees C) and the total run time was 9 min with detection at 220 nm. Calibration curves were prepared for ED, TP and PB with methyl p-hydroxy benzoate as internal standard. For each analyte, the correlation coefficients were >0.999 (n = 4). The RSD% of ten replicate injections for each analyte were <1%. The method was applied to the quantitation of ED, TP and PB in a commercial tablet dosage form.     

Determination of theophylline bioavailability using saliva theophylline concentrations

Substantial error occurs when individual saliva theophylline concentrations are used to predict serum theophylline concentrations. However, the use of saliva theophylline concentrations to determine product bioavailability has never been evaluated. Subjects in this study were 18 stable patients (20-51 yr) with a history of chronic obstructive pulmonary disease. Three preparations--a capsule (Elixophyllin 400 mg), elixir (Elixophyllin 373 mg), and tablet (Theolair 375 mg)--were administered in a randomized crossover design. Serum and saliva samples were obtained pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 8 hours after theophylline administration. The saliva AUC0-infinity and serum AUC0-infinity were highly associated for the elixir (r = 0.84) tablet (r = 0.89), and capsule (r = 0.89). The bioavailability of the tablet and capsule calculated from elixir saliva and elixir serum AUC0-infinity were not significantly different (p = 0.2). The bioavailability of the tablet calculated from saliva and serum was 93% and 102%, respectively. The bioavailability of the capsule calculated from saliva and serum was 113% and 102% respectively. Our data suggests that theophylline bioavailability can be reliably estimated from saliva theophylline concentrations. However, study designs that include larger sample sizes and more frequent sampling may be necessary when determining bioavailability from saliva.     

The interaction between chronic oral slow-release theophylline and single-dose intravenous erythromycin

1. Eight volunteers were each given 300mg of erythromycin lactobionate by i.v. infusion over 15 min in the presence and absence of chronic dosing with slow-release theophylline.

2. Pharmacokinetic profiles were obtained for theophylline in the presence and absence of erythromycin and for erythromycin in the presence and absence of theophylline.

3. A very small, clinically unimportant, but statistically significant increase occurred in mean (± S.E.M.) serum theophylline concentration from 4.9 ± 0.3 mg/1 to 5.2±0.3 mg/1 in the presence of erythromycin (P = < 0.01). The theophylline pharmacokinetic parameters did not change significantly.

4. The only changes in erythromycin pharmacokinetics were an increase in the renal excretion (0–12h) from 5.5±4.0 mg to 11.2±6.0 mg (P < 0.03) and an increase in renal clearance (0–2h) from 9.0±6.0 ml/min to 21.6±15 ml/min (P < 0.05) in the presence of theophylline.     

The interaction between chronic oral slow-release theophylline and single-dose intravenous erythromycin

Eight volunteers were each given 300 mg of erythromycin lactobionate by i.v. infusion over 15 min in the presence and absence of chronic dosing with slow-release theophylline. Pharmacokinetic profiles were obtained for theophylline in the presence and absence of erythromycin and for erythromycin in the presence and absence of theophylline. A very small, clinically unimportant, but statistically significant increase occurred in mean (+/- S.E.M.) serum theophylline concentration from 4.9 +/- 0.3 mg/l to 5.2 +/- 0.3 mg/l in the presence of erythromycin (P = less than 0.01). The theophylline pharmacokinetic parameters did not change significantly. The only changes in erythromycin pharmacokinetics were an increase in the renal excretion (0-12 h) from 5.5 +/- 4.0 mg to 11.2 +/- 6.0 mg (P less than 0.03) and an increase in renal clearance (0-2 h) from 9.0 +/- 6.0 ml/min to 21.6 +/- 15 ml/min (P less than 0.05) in the presence of theophylline.     

Formulation of an oral solid dosage form containing human interferon-alpha

The main objective of this study was to process the human alpha-interferon for the solid dosage form. The first step was the preparation of the intermediate product for the tablet making. Fluid bed apparatus with top spray method was applied for the layering of powdered cellulose with human alpha-interferon solutions. The intermediate product was compressed into tablet and an enteric solvent coating of the tablets was made in a fluid bed apparatus with Wurster method. The physical parameters were detected. These fitted the Ph. Eur. and the mechanical properties of the tablets were appropriate for coating in fluid bed apparatus. The tablets agree with the requirements of Ph. Eur. and the active agent was not dissolved in gastric juice. An animal test was also performed. The human alpha-interferon in the blood of the animals was detected with ELISA method. The human alpha-interferon specific kit was used. The active ingredient dissolved from the tablets was absorbed from the ileum. The solid dosage form containing human alpha-interferon was prepared; this can make oral application of human alpha-interferon possible.     

Comparative pharmacokinetic analysis of a novel sustained-release dosage form of theophylline in humans

Summary The pharmacokinetics and relative bioavailability of theophylline from a new sustained-release formulation (Theotard^®) and from a standard sustained-release formulation (Theo-Dur^®) were compared in 6 healthy, adult, male volunteers. After a single oral dose of 300 mg Theotard, a mean maximal plasma concentration (Cb_max of 3.49±1.05 mg/l was obtained after 8 h (t_max). After an identical dose of Theo-Dur, a peak plasma concentration of 4.68±1.33 mg/l was obtained after 6.33 h. The mean relative bioavailability of theophylline from Theotard was 1.02±0.16 relative to that of Theo-Dur. In 5 of the volunteers the Theotard formulation exhibited a more prolonged and uniform absorption rate and yielded more sustained plasma levels.     

Plasma theophylline concentrations following the oral administration of microcrystalline theophylline and a new sustained-release theophylline preparation to normal subjects

Summary Plasma theophylline concentrations have been measured in 14 normal subjects following the oral administration of a microcrystalline theophylline preparation (MT) 187.5 mg every 6 h and a sustained-release theophylline preparation (SRT) 375 mg every 12 h for 5 days. During the 5 days, blood samples were drawn before and 2 h after each morning dose with MT, and before and 4.5 h after each morning dose of SRT. On days 1 and 5, more frequent samples were taken during the dose interval. With both preparations, steady-state plasma concentrations were achieved by the third day. The trough levels were significantly higher with SRT than with MT on days 3 and 4, and the levels at 4.5 h after SRT were significantly higher than those measured 2 h after MT on days 3, 4 and 5. Over the terminal 3 days of the study, mean theophylline concentrations with SRT ranged between 11.2 and 15.5 µg/ml at measured trough and peak times, whereas the mean trough levels with MT were always below 10 µg/ml. With adjustment for the dosage differences, the mean ratio of the areas under the plasma concentration/time curves for the final dosage interval for the two formulations (AUC_SRT/AUC_MT) was 1.29±0.56, suggesting that the SRT preparation was well absorbed. The mean steady-state plasma theophylline concentrations (AUC/dose interval) on day 5 were 11.5±4.7 µg/ml with MT and 13.7±5.7 µg/ml with SRT. Nine subjects experienced a total of 35 side-effects whilst taking MT, compared with 10 subjects complaining of 23 side-effects on SRT. These results indicate that, in normal subjects, SRT 375 mg every 12 h exhibited satisfactory sustained-release properties and achieved adequate mean plasma theophylline concentrations during chronic administration. It produced higher plasma levels and a lower incidence of side-effects than the same daily dose of MT.     

Use of extrusion-spheronization to develop an improved oral dosage form of indomethacin

Two new pelletized formulations of indomethacin were developed and compared against pellets from the proprietary product, Indocid-R. Extensive dissolution testing involving pH-shift and topographical profiling showed that the new product containing polyvinylpyrrolidone had slightly faster in vitro release than the commercial product, but surprisingly the other new product containing sodium lauryl sulphate had reduced drug release. The cause of the anomalous result was shown by solubility studies and scanning electron microscopy to be related to the ability of the wetting agent to promote fragmentation of the microcrystalline cellulose used as spheronization aid into small crystallites, retarding drug release. The two new products had improved sphericity compared to the proprietary product when examined by image analysis. However, on in vivo testing in dogs, the new product containing sodium lauryl sulphate had the highest bioavailability of the three preparations examined due to its effect as a penetration enhancer.     

Plasma thiamine concentrations after intramuscular and oral multiple dosage regimens in healthy men

Summary A novel liquid chromatographic method for the determination of thiamine in plasma has been developed and has been used to study plasma thiamine concentrations after multiple dosage regimens for 11 days. The method involves purification, concentration and analytical separation of thiochrome on-line, using a switching column system.Ten healthy men were given 500 mg thiamine i.m. once a day (Group 1) and ten were given 250 mg p.o. every 12 h (Group 2). The times to reach steady state (7 and 5.6 days for Groups 1 and 2, respectively) were not different (P>0.05). The mean elimination half-life was 1.8 days. The mean minimum steady-state concentration after the oral regimen (23 g·l^–1) was 78% of that after the intramuscular regime (29 g·l^–1).     

In vivo efficacy of a novel double liposome as an oral dosage form of salmon calcitonin

A simple method for the preparation of the inner liposomes for double liposomes (DL) was developed. The encapsulation efficiency of erythrosine in liposomes prepared by this new method is superior to that of the previous method because of the concentration of the drug in the lipid membrane. To evaluate the usefulness of DL prepared by the glass‐filter method modified in this study as an oral dosage form of salmon calcitonin (SCT), a suspension of liposomes containing SCT was administered to rats at a dose of 10 μg SCT/kg. Each type of DL showed better efficacy than its inner liposomes alone. The decrease in plasma calcium level was dependent on the electrical charge and particle size of the inner liposomes. The hypocalcemic efficacy of DL encapsulating SCT‐loading cationic liposomes relative to that after subcutaneous administration of SCT at a dose of 1 μg/kg was 6.47%, which was the largest value obtained. These results indicated that not only the particle size but also the electrical charge of inner liposomes affect intestinal absorption. This study verified that the efficacy was increased because of the decrease in diameter of the inner liposomes and the use of lipid with a positive charge. These findings concluded that DL might be useful as an oral dosage form of SCT. Drug Dev. Res. 58:253–257, 2003. © 2003 Wiley‐Liss, Inc.     

Evaluation of passively absorbed saliva for determination of oral slow-release theophylline bioavailability in children

Assessment in young children of the bioavailability of slow-release theophylline formulations is hampered by the requirement for frequent blood sampling. Calculations of bioavailability from serial serum and passively absorbed saliva samples were therefore compared in six 9- to 12-year-old asthmatic children receiving multiple doses of Theo-Dur Sprinkle every 12 hours, using Theo-Dur tablets, a previously characterized formulation, as a reference. Results indicated 85 +/- 5 percent and 82 +/- 8 percent (mean +/- SEM) relative bioavailability based on serum and salivary measurements, respectively. Correlation coefficient for serum and passively absorbed saliva bioavailabilities was 0.90. Passively absorbed saliva provides an acceptably accurate, noninvasive method for theophylline bioavailability assessment and may be a useful alternative for bioavailability studies in young children.     

In vitro-in vivo correlation and dissolution studies with oral theophylline dosage forms

The dissolution rates of theophylline from six commercially available products (three uncoated and three sustained-release formulations) were determined in distilled water using the USP and rotating-filter dissolution apparatus. The effect of pH on the dissolution of these products was also examined by both methods. In addition, the effect of stirring rate on the dissolution of theophylline from these products was studied using the rotating-filter apparatus. The data obtained under all conditions were reproducible and well-described by a first-order equation. There was no significant difference between the percent of labeled content dissolved in 30 min (D30) and in 60 min (D60) obtained by the USP method and those obtained by the rotating-filter apparatus. The product-to-product variation in D30 and D60 was significant (p less than 0.001) for both the sustained-release and uncoated dosage forms. The pH of the dissolution fluid had a significant effect on the dissolution of theophylline from the products. The data obtained from the dissolution and absolute bioavailability studies in the rabbit were subjected to linear least-squares regression analysis, and good correlations were obtained between the dose-normalized peak serum level, time-to-peak, percent of the dose absorbed at 1 h and at 6 h, or the dose-normalized area under the curve from t = 0 to t = 00 and from t = 0 to t = 6 h and D30, D60, or the rate constant for dissolution. The linear relationship assumed for two of the products was used to predict bioavailability parameters from dissolution variables. The values predicted by this method were not statistically different from the actual values of these parameters.     

Formulation development of an oral dosage form for an hiv protease inhibitor,AG1284

Several preformulation characteristics of a series of novel HIV protease inhibitors were examined as a prelude to expedient oral dosage form development. Initial studies indicated that these compounds were orally bioavailable in rats (≤ 39%), but chemically unstable at low pH. AG1284 was selected as the lead compound from the series for further preclinical development based on its relatively high oral bioavailability and stability. The pH-rate profiles of AG1284 indicated a first-order degradative loss of a dimethylbenzyl group under acidic conditions. Concentrated solutions of an amorphous form prepared in various pharmaceutical solvents exhibited precipitation on standing. The precipitate was identified as crystalline AG1284 by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and polarized light/hot stage microscopy, and its solubility in water proved to be much lower than that of the amorphous form. Oral administration in dogs of a solid blend of AG1284 with polyethylene glycol 3350 (PEG 3350) in enteric-coated hard gelatin capsules did not yield any detectable AG1284 levels in plasma. When dosed in a propylene glycol/water (60/40) solution at 50 mg/kg to rats, oral bioavailability and C_max were 39% and 2.8 μg/ml, respectively. When delivered in a lyophilizable emulsion to rats at 100 mg/kg, oral bioavailability and C_max were 31% and 3.0 μg/ml, respectively. The lyophilized product could be reconstituted with WFI to regenerate an emulsion.     

Plasma concentrations of isosorbide dinitrate and its metabolites after chronic high oral dosage in man

1 We have previously reported that vasodilator headache due to isosorbide dinitrate (ISDN) can be circumvented by using small 'priming' doses for an induction period of 1-2 weeks, after which it is possible to increase to dose rapidly to 360-720 mg, daily without recurrence of headache and without toxicity. The present study corroborates this earlier finding. 2. Chronic oral administration of doses of ISDN of this order of magnitude results in prolonged high plasma concentrations of the parent compound, as well as higher levels of the metabolites 2-ISMN and 5-ISMN. 3. It is our thesis that chronic high oral dosage of ISDN saturates the intrahepatic biotransformation process, and allows high concentrations of ISDN and its metabolites to enter the systemic circulation.     

Activity and pharmacokinetics of a new oral dosage form of soluble ibuprofen.

The pharmacokinetics and the relative bioavailability of a soluble granular form (sachets) of a pharmaceutical formulation containing ibuprofen (CAS 15687-27-1) and 1-arginine were investigated in healthy volunteers. Two granular dosage forms were evaluated, 200 and 400 mg, in comparison with the commercial equivalents (tablets). After the oral administration of both granular dosage forms, a quicker absorption and a significantly higher plasma bioavailability of ibuprofen in the first hour following the treatment than after tablets administration were observed. The mean values of peak plasma concentration (microgram/ml) were 26.1 and 56.4 after treatment with 200 and 400 mg sachets respectively vs. 16.3 and 43.0 after treatment with 200 and 400 mg tablets. The mean values of peak time were 16.9 and 24.4 min after treatment with 200 and 400 mg sachets respectively vs. 90.0 and 63.7 min after treatment with 200 and 400 mg tablets. The shortening in the absorption time and the increase in the plasma concentrations did not involve a quicker drug elimination nor cause any changes in the bioavailability (mean values of the relative bioavailability indexes of 0.98 for 200 mg dosage form and 1.02 for the 400 mg one). The analgesic activity of soluble ibuprofen 400 mg was compared with that of ibuprofen 400 mg tablets in patients with osteo-articular pain, according to a single dose, double-blind cross-over balanced design. The results showed that the soluble granular form is able to determine an analgesic effect significantly quicker and higher than that of tablets.