There are two types of widely used dosage forms for oral administration: tablets and capsules. However, such dosage forms have several disadvantages. For example, it is estimated that 50% of the population have problems swallowing tablets (see Seager in Journal of Pharmacy and Pharmacology, 50, pages 375-382, 1998). It is especially hard for aged persons to swallow tablets or capsules, or to medicate children who are unable or unwilling to swallow tablets or capsules. This leads to poor compliance, or even non-compliance with the treatment, and thus has a negative impact on the efficacy of the treatment.
In addition, many therapeutic agents are bitter. The bitter taste precludes the medication from being easily sprinkled onto foods such as applesauce, a commonly used method of administering medications to children. Conventional capsules or tablets are also inconvenient for patients who do not have ready access to drinking water or fluids.
Chewable tablets comprising taste-masked particles capable of being chewed without providing a bitter taste are known. However, a taste-masking coating which prevents release of a bitter-tasting drug in the oral cavity during chewing can also undesirably reduce the rate of drug release in the gastrointestinal tract. Furthermore, because of the rate reduction, the taste-masked drug product may no longer be bioequivalent to the reference listed immediate-release (IR) product.
Orally disintegrating tablet (ODT) dosage forms are also known, which rapidly dissolve or disintegrate in the oral cavity and hence can be taken without water. Ideally, an orally disintegrating tablet (ODT) formulation should rapidly disintegrate on contact with saliva in the oral cavity of the patient, should form a smooth, easy-to-swallow suspension containing taste-masked drug particles, provide a smooth mouthfeel leaving little or no aftertaste (i.e., little or minimal drug release with a non-gritty or non-chalky taste) until swallowed, and should provide rapid, substantially complete release upon arrival in the stomach. If conventional immediate-release tablet or capsule dosage forms are already approved, ODT dosage forms should also release the drug in a manner bioequivalent to the immediate-release drug product. However, it can be quite difficult to formulate ODT compositions which disintegrate rapidly with good organoleptic properties (e.g., little or no bitter taste) and still release the drug rapidly within the gastrointestinal tract.
Undesirable taste is one of several important formulation problems that are encountered in providing patient-friendly dosage forms such as oral disintegrating tablets. These patient-friendly dosage forms could significantly improve convenience and efficacy by enhancing compliance with the dosing regimen. The techniques most often employed for achieving effective taste-masking include various physical and chemical methods such as use of combinations of flavors and sweeteners, polymer coating, inclusion complex formation with cyclodextrins, mixing/treating with ion exchange resins, solubility limiting methods, liposomes, microemulsions and numbing of taste buds.
Much effort has been devoted to developing coating processes such as aqueous and non-aqueous coacervation, fluid-bed coating, etc., for coating bitter drug particles with polymers that are water-soluble, water-insoluble or soluble under alkaline pH conditions. The type and amount of coating applied depends on the physicochemical properties of the drug, especially its particle size, shape, aspect ratio, particle size distribution, solubility in neutral to saliva pH liquids, organoleptic properties (i.e., extent of bitterness), dose, and the dosage form application (e.g., chewable or ODT).
An undesirable consequence of taste-masking using a water-insoluble polymer is the generally slower release of the drug in the gastrointestinal tract. One approach for addressing this problem is described in U.S. patent application Ser. No. 11/213,266 filed Aug. 26, 2005 (U.S. Pub. No. 2006/0105038), the contents of which are hereby incorporated by reference. The '266 application discloses substituted benzhydrylpiperizines granulated in the presence of cellulose and cellulose derivatives, taste-masked by microencapsulation (coacervation) with a water-insoluble polymer in combination with a gastrosoluble organic or inorganic pore-former.
Cetirizine (C21H25ClN2O3), represented chemically as 2-[2-{4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl}ethoxy]acetic acid, belongs to a class of drugs known as substituted benzhydrylpiperazines which are reported to exhibit a bitter taste, as disclosed in EP 0 811 374. Cetirizine and its dihydrochloride salt are well known for their antihistamine properties. Cetirizine dihydrochloride is freely soluble in gastrointestinal fluids. Its high solubility together with its extremely bitter taste often results in poor compliance of the regimen. Chewable tablets have been developed for oral administration, especially for administering to children. However, cetirizine dihydrochloride taste-masked by complexation in cyclodextrin and conventional chewable tablet ingredients such as mannitol or sorbitol were required, from stability considerations, to be confined into two separate layers of a bi-layer tablet. By so doing, intimate contact between mannitol, the primary ingredient of the group of polyols widely used in conventional chewable tablets, and cetirizine, which is highly susceptible to degradation in the presence of polyols, is minimized. Substituted benzhydrylpiperazines, including cetirizine dihydrochloride, have been reported to interact with certain polyols including mannitol resulting in undesired reaction products. These reaction products are reported to increase in the presence of water and/or higher temperature.
EP 0 811 374 recommends not to use any of the polyols, especially those with a molecular weight of less than 900, particularly less than 300, in the dosage form and/or to coat the active with cellulosic or methamethacrylate polymers. The dosage form described therein as a preferred embodiment demonstrates the absence of palatability improving polyols, excepting a high molecular weight polyethylene glycol.
Chewable tablet formulations comprising cetirizine and palatable polyols have been described wherein these two components are present in two separate layers of a bi-layer tablet. Because of the instability of such formulations (presumably caused by the interaction of cetirizine and polyols), so far no orally disintegrating tablet (ODT) formulations of cetirizine are available even though ODT formulations have been developed and marketed for antihistamines of other chemical classes, such as loratidine. Thus there still exists an unmet need for substituted benzhydrylpiperazine-containing ODT compositions with improved long-term storage stability, and which provide plasma concentration profiles bioequivalent to existing conventional non-ODT dosage forms, while maintaining effective taste-masking properties and acceptable mouthfeel.