The prevalence of overweight people in US has reached alarming levels. Also the proportion of children and adolescents who are overweight has tripled in the past three decades.
Obesity arises as a consequence of positive caloric balance. A comprehensive behavioral approach comprising a gradual increase of energy expenditure from exercise and an appropriate diet to decrease the caloric intake should be the more effective treatment of obesity.
However, this approach has a relatively low success rate. Consequently alternative forms of treatment, including surgery and/or medication, have been developed in an effort to increase the likelihood of achieving, and maintaining weight loss. In particular pharmacotherapy, in combination with intensive behavioral treatment, can lead to clinically significant decreases in body weight in obese population.
The FDA-approved weight-loss drugs are phentermine, sibutramine, orlistat and diethylpropion. Among them, phentermine is one of most efficient and safe in promoting weight loss especially when given along with recommendations for diet.
Phentermine is a sympathomimetic amine which first received approval from the FDA in 1959 as an appetite suppressant for the short-term treatment of exogenous obesity for patients with an initial body mass index ≧30 kg/m2, or ≧27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, hyperlipidemia).
Phentermine hydrochloride ({circumflex over (α)}, {circumflex over (α)}-dimethylphenethylamine hydrochloride) became available in the United States in the early seventies and is currently sold in several dosage form such as tablets, film coated tablets and capsules. Orally disintegrating tablets (ODT) which dissolve in the mouth for oral or sublingual administration are dosage forms particularly useful for patients with swallowing problems, for example children.
In particular, buccal tablets are intended for disintegrating in the mouth; the patient places them in the buccal cavity on the tongue or between cheeks and gums, thereby allowing a slow dissolution, which usually require 30-60 minutes (E. Rotteglia: “Compresse farmaceutiche” Societá Editoriale Farmaceutica, Milan, Italy, 1966).
On the contrary, sublingual tablets are intended to be placed under the tongue, where the active ingredient can be directly absorbed through the mucosa. These forms are provided with slow-disintegrating formulation as well (E. Rotteglia, ibid. and S. Casadio, Technologia Farmaceutica II Ed., Cisalpina Goliardica, Milan, Italy).
Orally disintegrating tablets with this kind of prolonged release are hardly suitable for formulating active ingredients, such as analgesics or anti inflammatory agents, which have to exert an immediate effect. Also, they are not always suitable for patients such as children or elderly people, and for the administration of active ingredients with an unpleasant taste because of the long stay in the mouth.
Sublingual tablets with a rapid dissolution profile can be prepared according to the Zydis® freeze-drying procedure. Zydis® is a registered trademark of R. P. Scherer Company (Manufacturing Chemist, February 1990). However, such formulations are very expensive and require sophisticated technologies and methods from the production point of view. These products are substantially freeze-dried products, the pharmaceutical formulation being therefore difficult to handle (due to its friability and fragility) and requiring specific packaging. A problem with freeze-dried sublingual tablet formulations is the impossibility to effect any taste-masking on the active ingredient.
WO088/08298 (Fuisz Technologies) discloses rapid-dissolution pharmaceutical composition in which the active ingredient is included in a water-soluble carrier obtained through a specific preparation process which requires a specific, expensive plant. Moreover, the resulting compositions exhibit friability problems and must always be handled and packed with particular precautions (use of dehydrating agents, humidity-tight packages, controlled-humidity work environmental and so on).
EP-A-494972 (Cima Labs Inc.) describes effervescent tablets suitable to the direct oral administration, i.e. without a previous development of the effervescence in water, consisting of microcapsules containing the active ingredients and an amount of effervescent agent sufficient to promote the release of microgranules when ingested and to give a “fizzing” sensation when in contact with the buccal mucosa of the patient.
In this case also, notwithstanding the presence of amounts of effervescent agent lower than in conventional formulations (60% by weight compared with the total composition) the typical cautions used for effervescent tablets should be taken.
Further drawbacks are the friability of the tablets and the use of microcapsules. In fact, the preparation technique described in EP-A-494972 does not foresee any wet granulation, i.e. using a solvent, but the direct mixing of the powder and its subsequent compression. Such a preparation technique yields tablets having friability values higher than those involving wet granulation of the mixture to be compressed.