Varying efficacy of superdisintegrants in orally disintegrating tablets among different manufacturers.

PURPOSE: The main objective of the present study was to develop an orally disintegrating tablet formulation of domperidone and to study the functionality differences of superdisintegrants each obtained from two different sources on the tablet properties. METHODS: Domperidone tablets were formulated with different superdisintegrants by direct compression. The effect of the type of superdisintegrant, its concentration and source was studied by measuring the in-vitro disintegration time, wetting time, water absorption ratios, drug release by dissolution and in-vivo oral disintegration time. RESULTS: Tablets prepared with crospovidone had lower disintegration times than tablets prepared from sodium starchglycolate and croscarmellose sodium. Formulations prepared with Polyplasdone XL, Ac-Di-Sol, and Explotab (D series) were better than formulations prepared with superdisintegrants obtained from other sources (DL series) which had longer disintegration times and lower water uptake ratios. The in-vivo disintegration time of formulation D-106 containing polyplasdone XL was significantly lower than that of the marketed formulation Domel-MT. CONCLUSIONS: The results from this study suggest that disintegration of orally disintegrating tablets is dependent on the nature of superdisintegrant, concentration in the formulation and its source. Even though a superdisintegrant meets USP standards there can be a variance among manufacturers in terms of performance. This is not only limited to in-vitro studies but carries over to disintegration times in the human population.

Development of domperidone bilayered matrix type transdermal patches: physicochemical, in vitro and ex vivo characterization.

BACKGROUND AND THE PURPOSE OF THE STUDY: Domperidone (DOM) is a dopamine- receptor (D(2)) antagonist, which is widely used in the treatment of motion-sickness. The pharmacokinetic parameters make DOM a suitable candidate for transdermal delivery. The purpose of the present investigation was to develop transdermal delivery systems for DOM and to evaluate their physicochemical characteristics, in vitro release an ex vivo permeation through rat abdominal skin and their mechanical properties. METHODS: Bilayered matrix type transdermal drug delivery systems (TDDS) of DOM were prepared by film casting technique using hydroxypropyl methyl cellulose as primary and Eudragit RL 100 as secondary layers. Brij-35 was incorporated as a solubilizer, d-limonene and propylene glycol were employed as permeation enhancer and plasticizer respectively. The prepared TDDS were extensively evaluated for in vitro release, moisture absorption, moisture content, water vapor transmission, ex vivo permeation through rat abdominal skin, mechanical properties and stability studies. The physicochemical interaction between DOM and polymers were investigated by Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FTIR). RESULTS: All the formulations exhibited satisfactory physicochemical and mechanical characteristics. The optimized formulation F6 showed maximum cumulative percentage of drug release (90.7%), permeation (6806.64 µg) in 24 hrs, flux (86.02 µg /hr/cm(2)) and permeation coefficient of 0.86x10(-2) cm/hr. Values of tensile strength (4.34 kg/mm(2)) and elastic modulus (5.89 kg/cm(2)) revealed that formulation F6 was strong but not brittle. DSC and FTIR studies showed no evidence of interaction between the drug and polymers. A shelf life of 2 years is predicted for the TDDS. CONCLUSIONS: Domperidone bilayered matrix type transdermal therapeutic systems could be prepared with the required flux and suitable mechanical properties.

Effect of various cytochrome P450 3A and P-glycoprotein modulators on the biliary clearance of bromosulphaphthalein in male wistar rats.

The main aim of this study was to investigate the effect of various selective cytochrome P4503A (CYP3A) and/or P-glycoprotein (P-gp) modulators on biliary clearance of bromosulphaphthalein (BSP) in male albino wistar rats. Male albino wistar rats were divided into different groups, treated with CYP3A and P-gp modulators and BSP was administered intravenously (bolus or infusion) to each treated group. BSP in serum and bile samples was analyzed using spectrophotometric analysis at 580 nm. There was a statistically significant (p < 0.05) increase in serum BSP levels with CYP3A and P-gp substrates and/or inhibitors, cyclosporine-A, nitrendipine, quinidine, indinavir, daxorubicin, etoposide and erythromycin by 27%, 35%, 32%, 12%, 5%, 22%, and 106%, respectively. There was a slight increase (4%, p > 0.05) observed in serum BSP levels in the presence of ketoconazole, whereas CYP3A and P-gp inducers, rifampicin and sodium butyrate significantly (p < 0,05) decreased the serum BSP levels by 30% and 14% respectively, when compared to control group after 62 min of BSP i.v. bolus administration. In BSP infusion studies, Cyclosporine A, nitrendipine, quinidine, indinavir, ketoconazole, doxorubicin, etoposide, and erythromycin significantly decreased the bile BSP levels by 23%, 22%, 17%, 59%, 3%, 15%, 10%, 29%, respectively. Upon 60 min of BSP infusion, rifampicin and sodium butyrate significantly (p < 0.05) increased bile BSP levels by 33% and 25%, respectively. Finally, we observed that the P-gp and CYP3A inducers significantly decreased the total serum BSP levels and increased the total biliary levels of BSP, this could be by inducing P-gp in biliary canalicular membrane in male wistar rats. P-gp and CYP3A inhibitors and substrates significantly increased the total serum BSP levels and reduced the biliary excretion of BSP by inhibiting P-gp in biliary pathway. There was no significant difference observed between inhibitors and substrates of P-gp on BSP disposition. We suggest that the biliary transport of BSP could be useful as a simple and economical in vivo screening model for identifying P-gp and CYP3A substrates and/or inhibitors and/or inducers in wistar rats.

Time-dependent influence of pentoxifylline on the pharmacokinetics of orally administered carbamazepine in human subjects.

The time-dependent influence of pentoxifylline (PTX) on the pharmacokinetics of carbamazepine (CBZ) was studied after single-dose oral administration of 100 mg CBZ either alone or in combination with 400 mg PTX at 10:00 and 22:00 h. Serum samples were collected at predetermined time intervals and analysed for unchanged CBZ using high-performance liquid chromatography. The pharmacokinetic parameters of CBZ were calculated using the model-independent method. PTX reduced the rate (Tmax, 8.58 +/- 2.64 vs 5.66 +/- 1.44 h; K(a); 0.47 +/- 0.14 vs 0.72 +/- 0.19 h(-1)), but not the extent of CBZ absorption at 22:00 h treatment. However, such a change was not observed for 10:00 h treatment. No significant changes were observed in other pharmacokinetic parameters of CBZ under the influence of PTX for both 10:00 h as well as 22:00 h treatments. The clinical significance of the time-dependent influence of PTX on the rate of absorption of CBZ will be revealed upon extension of the study to patients.