C LINICAL ASPECTS OF ORALLY DISINTEGRATING TABLETS

ODTs are preferred for people suffering from dysphagia, nausea, vomiting or motion sickness and for hospitalized patients suffering from mental disorders, stroke, thyroid disorder, Parkinson‟s disease, multiple sclerosis and cerebral palsy (Badgujar and Mundada, 2011). Apart from the swallowing difficulties, this dosage form is appropriate for travelling people as well, since they can take their tablets even if they have no access to water.

These products/tablets are distinguished from conventional sublingual or buccal tablets where disintegration requires several minutes. ODTs have the ability to release the API at different locations of the gastrointestinal tract (GIT). Using this technology, it is possible to promote drug absorption through local oromucosal tissues, and through pre-gastric, gastric and post-gastric parts of the GIT (Pfister and Ghosh, 2005).

Dissolution of the portion of the drug in the saliva allows pre-gastric absorption, which causes faster onset of action and reduces first pass metabolism. The absorption through the buccal and the pharyngeal regions may have benefits in the case of drugs undergo high first-pass metabolism. Safety profiles could be also improved in the case of drugs producing toxic metabolites by hepatic or gastric biotransformation (Hirani et al., 2009).

Dissolved and swallowed fraction of drug can be absorbed in the conventional way.

However, the non-swallowed fraction can enter into epithelium, which is not keratinized in the soft palate, the sublingual, and the buccal regions endowing them with good permeability. Smaller molecules can get into the circulation directly while larger

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molecules get into the lymphatic system from the epithelium first (Dévay and Antal, 2009; Shojaei, 1998).

The administration of an ODT may not result inevitably in faster onset of the therapeutic effect, but it has several advantages over conventional tablets and could possess beneficial clinical, medical, technical, and marketing features. Usually ODTs are formulated as bioequivalent line extensions of existing products. In this case, it is necessary to provide drug absorption that is similar to the absorption of the drug of the conventional tablets. It causes financial difficulties for the manufacturer if an ODT fails bioequivalence tests due to the varying degrees of pre-gastric absorption for example.

The characteristics of the API greatly determine its sensitivity to the formulation. If it can be absorbed pre-gastric and is subject to high first-pass metabolism then the dissolved fraction from an ODT formulation may cause pharmacokinetic changes (Pfister and Ghosh).

3.1.1. Biopharmaceutical aspects of ODTs

Several clinical studies were conducted using ODT formulations due to the high versatility, patient compliance and convenience of the dosage form.

Proton pump inhibitors (PPIs) act through the long-lasting reduction of gastric acid production and are widely used in the treatment of several gastro-intestinal diseases, such as dyspepsia, gastroesophageal reflux and esophagitis. There is a great need to provide a convenient dosage form for patients suffering from excessive acid secretion due to the obvious swelling difficulties caused by these diseases. Lansoprazole was the first PPI formulated as orally disintegrating tablets. It was made up of enteric-coated microgranules of the drug and was compressed using a rapidly dispersing matrix.

Bioavailability studies showed that the formulation was comparable to lansoprazole capsules of 15 and 30 mg doses (Baldi and Malfertheiner, 2003).

In an another study, bioavailability of two dosing regimens of lansoprazole ODT was compared, i.e. administration of the tablet per os without water or dispersed in water and administered via nasogastric tube. There was no clinically significant difference between the two methods, because dispersing the tablet in water and administering via a nasogastric tube did not resulted in drastic pharmacokinetic

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changes. In conclusion, the formulation was stable with respect to the in vivo efficacy, which enables an important additional dosing option for the drug (Freston et al., 2004).

Selegiline is an irreversible inhibitor of the MAO-B enzyme. It has several beneficial clinical effects as an adjuvant to levodopa in the treatment of Parkinson‟s disease, e.g. reduction of the motor performance deterioration (Riederer and Lachenmayer, 2003). It was possible to avoid largely the gut and first-pass metabolism of the drug by the use of an ODT formulation, which enabled transbuccal absorption.

This formula allowed higher bioavailability and lowered the plasma concentration of harmful metabolites, such as the amphetamine (Lew, 2005; Clarke and Jankovic, 2006).

Ondansetron is an effective and well-tolerated antiemetic agent, which is useful for the prevention of the chemotherapy and radiotherapy induced emesis and nausea.

The use of ODTs is highly recommended in the case of such conditions. Freeze-dried ondansetron tablets were prepared and evaluated in two doses (8 and 16 mg). The preparations dispersed rapidly on the tongue without water and were effective to treat emesis and nausea in a placebo controlled clinical trial (LeBourgeois et al., 1999).

The onset of antidepressant efficacy of mirtazapine and sertraline were compared in a multinational, randomized, double-blind study. Mirtazapine was formulated as orally disintegrating tablet. The study was conducted for 8 weeks and mirtazapine was more effective after the first 2 weeks. After this time, there was no significant difference between the efficacies of the two medicaments. It was concluded, that the mirtazapine ODT had faster onset of action than sertraline and it was superior in convenience and compliance due to its modern dosage form (Behnke et al., 2003).

It is considered that the food has no effect on the bioavailability of the atypical antipsychotic drug clozapine. Bioavailability and pharmacokinetics of clozapine ODTs were investigated by healthy subjects in fasted and fed conditions in a clinical study.

Pharmacokinetic results demonstrated significant differences between fasted and fed conditions for both clozapine and the metabolite desmethylclozapine at various time points. The lower limits of the 90% confidence intervals (CI) for the geometric mean fed-to-fasted maximum plasma concentration (cmax) ratios were below the bioequivalence lower limit, 0.80. The mean c_max of both clozapine and the metabolite was decreased approximately by 20% when the formulations were administered after a high-fat/calorie breakfast. However, the 90% CIs for the fed-to-fasted ratios of the

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geometric means of the AUC values from time zero to infinity (AUC0-∞) were within the bioequivalence boundaries of 0.80-1.25. In conclusion, the coadministration of food was shown to decrease the rate of clozapine absorption but had no effect on the extent of clozapine absorption, therefore clozapine ODTs should be administered at least 1 hour before meals or after a light meal (Disanto and Golden, 2009).

Considering these examples, it can be seen that ODTs offer new opportunities for physicians and patients and their benefits include convenience but serious clinical possibilities, as well. Bioavailability studies are important in the field of this technology because the fast disintegration increase the number of the possible interactions between our system and the drug molecule.