WO2011110939A2

WO2011110939A2 - Pharmaceutical compositions of substituted benzhydrylpiperazines

Info

Publication number: WO2011110939A2
Application number: PCT/IB2011/000518
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi
Original assignee: Rubicon Research Pvt Ltd
Current assignee: Rubicon Research Pvt Ltd
Priority date: 2010-03-11
Filing date: 2011-03-11
Publication date: 2011-09-15
Anticipated expiration: 2012-09-11
Also published as: WO2011110939A3

Abstract

The present invention relates to pharmaceutical compositions for oral administration comprising substituted benzhydrylpiperazine, at least one cyclodextrin; and at least one polyol; wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex. Particularly the present invention relates to stable taste- masked compositions of cetirizine, its pharmaceutically acceptable salts, its enantiomers, or their pharmaceutically acceptable salts in the form of orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets, or the like.

Description

PHARMACEUTICAL COMPOSITIONS OF SUBSTITUTED

BENZHYDRYLPIPERAZINES

Field of the Invention

The present invention relates to pharmaceutical compositions of substituted benzhydrylpiperazines. More particularly, the present invention provides stable taste- masked compositions of cetirizine, its enantiomers, or their pharmaceutically acceptable salts. The compositions of the present invention are suitable for administration in the form of orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets, or the like that are stable and wherein the bitter taste of cetirizine, its enantiomers, or their pharmaceutically acceptable salts is masked providing palatable formulations.

Background of the Invention

An important therapeutic area in human health is the medicinal treatment of allergic conditions. Allergic reactions occur to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Immunologists separate allergic reactions into two main types: immediate hypersensitivity reactions, which are predominantly mast cell- mediated and occur within minutes of contact with allergen; and delayed hypersensitivity reactions, mediated by T cells (a type of white blood cells) and occurring hours to days after exposure. Normally, the immune system responds to foreign microorganisms or particles by producing specific proteins called antibodies. These antibodies are capable of binding to antigens, on the foreign particle. This reaction between antibody and antigen sets off a series of chemical reactions designed to protect the body from infection. Sometimes, this same series of reactions is triggered by harmless, everyday substances such as pollen, dust, and animal danders. When this occurs, an allergy develops against the offending substance (allergen.) Inhaled or ingested allergens usually cause immediate hypersensitivity reactions. It is characterized by excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as immunoglobulin type E (IgE), resulting in an extreme inflammatory response. Mast cells, one of the major players in allergic reactions, capture and display IgE antibody that binds to allergens. Within the mast cells are granules that contain a variety of potent chemicals, including histamine. When the allergens bind to IgE antibodies on the surface of mast cells, they spill the contents of their granules out onto neighboring cells, including blood vessels and nerve cells. Histamine binds to the surfaces of these other cells through special proteins called histamine receptors. Interaction of histamine with receptors on blood vessels dilates the blood vessels, causing the mucous membrane (tissue lining of the nose and airways) to swell and stimulates the glands in the nose and the respiratory passages to produce mucus (i.e., phlegm). Substances that make the musculature of the respiratory passages contract are also released along with histamine, leading to difficulty in breathing and an asthma attack may follow.

Common allergic reactions include eczema, hives, hay fever, asthma, allergic rhinitis, allergic sinusitis, allergic urticaria and the like. Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. The management of allergic reactions includes specific treatment aimed at removing the cause, blocking allergic reaction by immunotherapy, and symptomatic treatment with antihistamines, steroids or other oral medications.

Anti-histamines block H1 and/or H2 histamine receptors so that the histamine messages are not received. Selective H1 antagonists are useful to treat allergic reactions. A number ,of substances belonging to the family of substituted benzhydryl piperazines with useful antihistaminic properties have been disclosed in EP0058146. The active substances belonging to the family of substituted benzhydryl piperazines include [2-[4-[(4-chlorophenyl)- phenylmethyl]-1-piperazinyl]ethoxy]acetic acid (cetirizine), 2-[2-[4-[ (4-chlorophenyl) phenylmethyl]-1 -piperazinyl] ethoxy] ethanol (hydroxyzine), 2-[2-[4-bis (4-fluorophenyl) methyl]-1-piperazinyl] ethoxy] acetic acid (efletirizine), 1 -[(4-chlorophenyl) phenylmethyl]-4- [(3-methylphenyl)-methyl] piperazine (meclizine), or 1-[(4-tert-butylphenyl) methyl]-4-[(4- chlorophenyl) phenylmethyl] piperazine (buclizine), their optically active isomers, as well as their pharmaceutically acceptable salts.

Cetirizine (C21H25CIN2O₃) chemically known as [2-[4-[(4-chlorophenyl)-phenylmethyl]-1- piperazinyl]ethoxy]acetic acid or [2-[4-[(p-chloro-a-phenylbenzyl)-1-piperazinyl] ethoxy] acetic acid is a human metabolite of hydroxyzine. Cetirizine is useful as an antiallergen, spasmolytic, and a histamine H receptor antagonist and is generally non-sedating. It has been approved by USFDA for use in seasonal allergic rhinitis, perennial allergic rhinitis and chronic urticaria. It blocks the effect of histamines that are released by allergic reactions in the body which mitigates the ability of histamine to promote allergy symptoms. Cetirizine has an asymmetric center in the molecule, and thus may exist as enantiomers such as Levocetirizine. Levocetirizine is the active enantiomer of cetirizine. It is the L- enantiomer of the cetirizine racemate and is useful as an antiallergen, spasmolytic, and a histamine hVreceptor antagonist. Levocetirizine, like cetirizine, has a potential antiinflammatory effect in the treatment of allergic rhinitis with asthma. Levocetirizine is said to have a two fold higher affinity for human receptors than cetirizine and is also said to be rapidly and extensively absorbed. Substituted benzhydrylpiperazines, specifically cetirizine, its enantiomers, or their pharmaceutically acceptable salts exhibit a bitter taste with inherent unpleasant mouth feel. Many approaches have been attempted to mask the taste of orally administered cetirizine, its enantiomers, or their pharmaceutically acceptable salts. PCT Publication WO06061700A2 discloses resinates of cetirizine, or its salt or its enantiomers or salts of the enantiomers such as levocetirizine dihydrochloride to mask its bitter taste and fast disintegrating and or quick release pharmaceutical compositions comprising the said resinates. However the processes used for taste-masking with ion exchange resins may alter the stability and release characteristics of cetirizine/levocetirizine. U.S Patent Application 2006/0127479 provides a taste masked pharmaceutical composition comprising: (a) a core of cetirizine dihydrochloride; and (b) a coating applied to the surface of the core comprising a pharmaceutically acceptable cationic co-polymer based on mono- or dialkylaminoalkyl methacrylate and neutral acrylic or methacrylic esters. Cetirizine being an extremely bitter molecule, masking its taste demands very high polymer coating levels which may in turn increase the coating duration and also reduce the rate of release and moreover alter the stability of the drug. U.S Patent Application 2008/0241237A1 highlights a composition comprising taste-masked microparticles, each comprising: a) a core particle comprising cetirizine dihydrochloride; and b) a taste-masking layer comprising a water- insoluble polymer and a gastrosoluble polymer that substantially masks the taste of the bitter active. The water insoluble and gastrosoluble polymers of differing solubilities used require organic solvents for coating which are environmentally hazardous. U.S Patent Application 2007/0196483 discloses a pharmaceutical composition comprising multiparticulates comprising a core comprising cetirizine, a matrix material, and swelling agent and a coating surrounding the core selected from the group consisting of (i) a water-permeable, substantially drug-impermeable coating, and (ii) an anti-enteric coating. The system is highly complex and cumbersome. Moreover coating used to achieve taste masking results in reduced release rate of the drug with not more than 85% being released in 60 minutes. This is a very slow release profile as compared with other immediate release products available.

Thus, a number of different technologies have been employed acknowledging the fact that cetirizine, its enantiomers, or pharmaceutically acceptable salts thereof are extremely bitter and challenging molecules to work with, requiring special efforts for achieving both taste masking and acceptable in-vitro profiles. Taste masking of these bitter drugs has been carried out by using ion exchange resins or using combination of coating agents. Though, use of ion exchange resins and coating may achieve the desired taste masking in some cases, the processes employed for each are tedious, may involve use of organic solvents and may affect the stability and in-vitro dissolution of the formulations. A strong need thus exists for the development of compositions of cetirizine, its enantiomers, or their pharmaceutically acceptable salts that not only mask the bitter taste of drug but also provide desired drug release profile and bioavailability and improve the stability of the dosage forms. A yet another method for masking taste of bitter active ingredients is with the use of cyclodextrins. Cyclodextrins form complexes with the active in an aqueous environment that limit or reduce contact of uncomplexed drug with the taste buds; often providing improved taste over uncomplexed drug. In such a case masking of bitter taste of active results from the trapping of the active ingredient within cyclodextrin whereby the bitter tasting drug is not released while the dosage form is in the mouth.

In order to provide palatable formulations of cetirizine or levocetirizine many researchers have included cyclodextrins in their compositions. However some formulations as discussed beneath though based on use of cyclodextrins do not relate to incorporation of inclusion complexes thereof with the active. European Patent 0994710 B2 discloses pharmaceutical compositions for oral administration comprising a mixture of an active substance belonging to the family of substituted benzhydrylpiperazines and at least a cyclodextrin, wherein said mixture does not contain any inclusion complexes. These compositions are said to rely on in-situ formation of drug cyclodextrin complexes, which at times may not provide desired taste-masking. PCT Publication WO2006/01 1051 provides taste masking of pharmaceutical compositions of unpleasant-tasting drugs and cyclodextrin by forming a mixture of drug and cyclodextrin wherein the drug's dissolution rate has been retarded, or the cyclodextrin 's dissolution has been enhanced, or both. Manipulation of dissolution rates of active and cyclodextrin is said to provide effective in situ formation of complexes and taste-masking which in fact adds to the process steps making the process of manufacture cumbersome. U.S Patent Application 2010/0062061 discloses method of producing a tablet comprising cetirizine wherein an alkalizing agent is employed during the process of formation of cetirizine: beta cyclodextrin complex in order to reduce level of oxidative degradants.

Further, though cyclodextrins may be employed to taste-mask bitter actives their use is not always sufficient to obtain palatable pharmaceutical compositions. Good palatability usually further necessitates addition of polyols to the composition. Compounds like cetirizine in the presence of certain polyols, including mannitol, can result in undesired reaction products such as those disclosed in European Patent Application 081 1374 A1. The esterification side reaction is increased in the presence of water and/or by an increase of temperature. The presence of mannitol and other polyols may thus create a stability problem for cetirizine or levocetirizine. U.S Patent Application 2005/0038039 discloses that polyols with low molecular weight of less than 300 are very reactive towards compounds of the class of substituted benzhydrylpiperazines while those having molecular weight between 300 and 950 are reactive polyols. It has further been disclosed that reactive or very reactive polyols do not cause untolerable amounts of undesired reaction products with compounds of the class of substituted benzhydryl piperazines if the molar ratio between these polyols and the active does not exceed 10. The formulations provided therefore contain at least two separate formulations with a first formulation containing active such as cetirizine/levocetirizine and not containing polyols having molecular weight of less than 300 in a molar ratio between the polyol and active of above 10 and a second formulation containing one or more solid polyols with a molecular weight of less than 3000 and free of active. Many researchers employing cyclodextrins in cetirizine or levocetirizine formulations have therefore used various approaches to introduce polyols in their formulations in an attempt to further enhance palatability without affecting the stability of the formulation. European Patent 1494654 B1 relates to an oral palatable chewable tablet comprising cetirizine, a sweetener, a combination of a grape flavoring and a vanilla flavoring in a weight ratio from 4:1 to 2:1 , cyclodextrin, and additional excipients. Excipients having hydroxyl groups (e.g. mannitol) that are capable of forming esters with cetirizine are separated from the active to avoid formation of cetirizine esters and therefore the preferred dosage form provided in this case is a bi-layer chewable tablet where cetirizine is in a separate layer from sugars such as mannitol. PCT Publication WO2007/144902 discloses palatable chewable bilayer tablet comprising a first active formulation layer having effective ratio of water-soluble polymer and water-insoluble polymer, low molecular weight polyols with molecular weight less than 950 present in a molar ratio with active of more than 10 and other optional pharmaceutically acceptable excipients and a second inactive formulation layer having beta- cyclodextrin and other pharmaceutically acceptable excipients, wherein beta-cyclodextrin is not in intimate contact with cetirizine or its pharmaceutically acceptable salts of active formulation layer. The granules of active also comprising water soluble and insoluble polymer are prepared separately and blended with the granules of polyol to prepare the active formulation layer which is then formed into a bilayer tablet formulation along with inactive formulation layer thereby making the overall process tedious. PCT Publication WO2009/006898 discloses medicament containing chewing gum composition comprising gum base and inclusion complex of cyclodextrin and cetirizine that provides improved stability of said active. The composition is based on use of energy intensive spray drying process to prepare cyclodextrin inclusion complexes and involves the use of high temperatures which could be detrimental to the stability of the active. Further this process of preparation of the complex also demands the use of non-complex additives such as sodium citrate and carboxymethylcellulose that improve suspension homogeneity required for spray drying which introduces an additional step in the preparation process. Though the formulation with complex bound cetirizine is said to have improved stability in the presence of polyol such as sorbitol as compared to uncomplexed active, the stability studies indicate % total impurities for formulations with complexed active is high. Thus though attempts have been made in prior art to develop formulations of substituted benzhydrylpiperazines comprising cyclodextrin and polyols the processes employed for the preparation of such compositions have been either very tedious, energy intensive and stability impacting and or have involved preparation of formulations having special designs or prerequisites that tend to reduce the interaction between the active and polyols. A need thus exists for palatable stable formulations wherein the bitter taste of cetirizine, its enantiomers, or salts thereof is masked and the formulations are prepared by simple, conventional non-laborious processes that do not affect the stability of the active or generate any undesirable impurities during preparation or on storage, especially due to interaction of active with polyols. It is a challenging task to address this need and provide highly palatable compositions of cetirizine, its enantiomers, or their pharmaceutically acceptable salts without compromising on the in-vitro release, bioavailability and stability of the drug. The present inventors through thorough research have developed compositions of cetirizine, its enantiomers, or their pharmaceutically acceptable salts that are palatable, stable, incorporate both cyclodextrins and polyols and can be prepared by simple, non-tedious and cost-effective processes. The formulations of the present invention are suitable for administration in the form of orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets or the like wherein the bitter taste of the drug is masked providing palatable formulations and the desired stability and in-vitro dissolution is also achieved.

Summary of the Invention

The present invention relates to pharmaceutical compositions for oral administration comprising substituted benzhydrylpiperazine, at least one cyclodextrin; and at least one polyol; wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex. Particularly the present invention relates to stable taste- masked compositions of cetirizine, its pharmaceutically acceptable salts, its enantiomers, or their pharmaceutically acceptable salts in the form of orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets, or the like. Detailed Description of the Invention

Palatability and mouth feel are extremely important factors for achieving total compliance of patients who are being administered the unpleasant or disagreeable or objectionable tasting active pharmaceutical agent. Taste masking technologies are known. However, not all taste masking technologies can work with every drug. Taste masking technologies can, in certain instances, interfere with disintegration, provide inadequate taste masking for a given active, interfere with the bioavailability or pharmacokinetic properties of the drug relative to a swallow tablet or affect the stability of the active. Therefore, it becomes important to develop taste masking technology for an active agent that not only enhances the organoleptic properties of the dosage form containing the same, but also does not interfere with the in- vitro dissolution, bioavailability and stability of the drug.

The present inventors, after rigorous experimentation have developed palatable pharmaceutical formulations of substituted benzhydrylpiperazines wherein the bitter, unpleasant and otherwise undesirable taste of the active is masked by simple conventional processes without compromising on the stability or in-vitro release of the active. The compositions of the invention comprise one or more substituted benzhydrylpiperazines, at least one cyclodextrin and at least one polyol.

Substituted benzhydrylpiperazines employed in the compositions of the present invention include, but are not limited to cetirizine, levocetirizine, efletirizine, hydroxyzine, meclizine or buclizine, and the like, or combinations thereof; in the form of, but not limited to, a free base, a pharmaceutically acceptable salt, a prodrug, an active metabolite, a polymorph, a solvate, a hydrate, an enantiomer, an optical isomer, a tautomer, a racemic mixture or a derivative thereof. In one embodiment the compositions of the present invention comprise cetirizine in the form of, but not limited to, a free base, a pharmaceutically acceptable salt, a prodrug, an active metabolite, a polymorph, a solvate, a hydrate, an enantiomer, an optical isomer, a tautomer, a racemic mixture or derivative thereof.

"Cetirizine" as employed herein is intended to include not only the racemate of [2-[4-[(4 chlorophenyl) phenylmethyl] -l-piperazinyl]ethoxy]-acetic acid and its dihydrochloride salt which is well known as cetirizine dihydrochloride or cetirizine hydrochloride, but also includes, but is not limited to, the free compound, any other pharmaceutically acceptable salt thereof, a prodrug, an active metabolite, a polymorph, a solvate, a hydrate, an optical isomer, a tautomer, an enantiomer such as levocetirizine or dextrocetirizine or any pharmaceutically acceptable salt of the enantiomer, a racemic mixture or derivative thereof. Preferred acid addition salts, includes, but is not limited to, dihydrochloride, also referred to herein as the "hydrochloride". In one embodiment, the compositions of the present invention comprise cetirizine, or pharmaceutically acceptable salts thereof or its enantiomers or their pharmaceutically acceptable salts. In another embodiment, the compositions of the present invention comprise levocetirizine or their pharmaceutically acceptable salts.

Substituted benzhydrylpiperazines is employed in an amount effective for treatment of allergies like rhinitis, urticaria or allergic symptoms such as sneezing, itching, watery eyes, or runny nose. In one embodiment the concentration of substituted benzhydrylpiperazines in the formulation is from about 0.01 weight % to about 20 weight % based on the total weight of the composition. In another embodiment, the concentration of substituted benzhydrylpiperazines in the formulation is from about 1 weight % to about 10 weight % based on the total weight of the composition. The pharmaceutical composition for oral administration of the present invention comprises substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol. The bitter taste of substituted benzhydrylpiperazine in the formulation according to various embodiments of the present invention is masked by use of at least one cyclodextrin. Cyclodextrins are cyclic oligosaccharides formed from a-(1 , 4)-linked D-glucopyranose units, α, β and γ-cyclodextrins consist of six, seven and eight units respectively. The molecules have a toroidal shape, with a hydrophobic central cavity and a relatively hydrophilic outer surface. This structure enables cyclodextrins to bind appropriately sized non-polar guest molecules, or moieties of guest molecules, within the hydrophobic central cavity, to form clathrate complexes. In one embodiment the bitter taste of cetirizine, or pharmaceutically acceptable salts thereof or its enantiomers or their pharmaceutically acceptable salts is masked by use of at least one cyclodextrin. In another embodiment, the substituted benzhydrylpiperazine and cyclodextrin are present in the form of an inclusion complex. In a further embodiment, cetirizine, or pharmaceutically acceptable salts thereof or its enantiomers or their pharmaceutically acceptable salts and cyclodextrin are present in the form of an inclusion complex. In one embodiment, the pharmaceutical composition for oral administration of the present invention comprises substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol; wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex.

Suitable cyclodextrins for use in the compositions of the present invention include, but are not limited to, a-cyclodextrin, β-cyclodextrin, γ-cyclodextrins, or alkylated, hydroxyalkylated, esterified, glycosylated or substituted derivatives thereof; such as, but not limited to, (2,6-di- o-methyl)- -cyclodextrin (DIMEB), randomly methylated-p-cyclodextrin (RAMEB), hydroxypropyl- -cyclodextrin (ΗΡβΟϋ), hydroxyethyl- -cyclodextrin, dihydroxypropyl-β- cyclodextrin, methyl-p-cyclodextrin, sulfobutyl ether cyclodextrin (SBE-CD), glucosyl-a- cyclodextrin, glucosyl- -cyclodextrin, diglucosyl- -cyclodextrin, maltosyl-y-cyclodextrin, maltosyl-y-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-β cyclodextrin, maltotriosyl-v- cyclodextrin, dimaltosyl-p-cyclodextrin, and the like, or mixtures thereof such as, but not limited to, maltosyl-p-cyclodextrin/dimaltosyl- -cyclodextrin.

Cyclodextrin is employed in the compositions of the present invention in an amount of about 0.01 weight % to about 95 weight % by weight of the composition. In one embodiment, cyclodextrin is employed in the compositions of the present invention in an amount of about 0.1 weight % to about 90 weight % by weight of the composition. In another embodiment, cyclodextrin is employed in the compositions of the present invention in an amount of about 1 weight % to about 85 weight % by weight of the composition. In one embodiment, substituted benzhydrylpiperazine and cyclodextrin are present in a molar ratio of about 1 :15 to about 15: 1. In another embodiment, substituted benzhydrylpiperazine and cyclodextrin are present in a molar ratio of about 1 :10 to about 10:1. In a further embodiment, substituted benzhydrylpiperazine and cyclodextrin are present in a molar ratio of about 1 :5 to about 5: 1 . The complex of substituted benzhydrylpiperazine with cyclodextrin may be prepared by various methods such as, but not limited to, solution method, co-precipitation method, co- evaporation/solid dispersion method, neutralization method, slurry method, kneading method, or grinding method, and the like of combinations thereof. In one embodiment of the present invention, the complex of cyclodextrin and substituted benzhydrylpiperazine is prepared by preparing an aqueous solution containing the active and cyclodextrin in desired ratio. The inclusion complex of substituted benzhydrylpiperazine with cyclodextrin can be introduced in the compositions of the present invention in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like, or combinations thereof. In one embodiment of the present invention, substituted benzhydrylpiperazine -cyclodextrin complex can be loaded on an inert carrier before incorporation in the compositions of the present invention. The inert carrier such as, but not limited to, beads, pellets, spheres or similar particles that do not contain an active ingredient may be employed. Non-limiting examples of inert carriers include, but are not limited to, microcrystalline cellulose, sugar or silicon dioxide, and the like or combinations thereof.

The pharmaceutical compositions of the present invention in addition to substituted benzhydrylpiperazine and at least one cyclodextrin, comprise at least one polyol. Polyols are alcohols containing multiple hydroxyl groups. Suitable polyols for the compositions of the present invention include, but are not limited to, xylitol, mannitol, sorbitol, maltitol, erythritol, cellobiitol, cellotriitol, xylobiitol, xylotriitol, inulotriitol, maltotriitol, maltotetraitol, inulin, cyclodextrin or derivative thereof, or combination thereof. In one embodiment polyol is employed in the compositions of the present invention in an amount from about 1 % to about 95% by weight of the composition. In another embodiment polyol is employed in the compositions of the present invention in an amount from about 2% to about 90% by weight of the composition. In a further embodiment polyol is employed in the compositions of the present invention in an amount from about 5% to about 85% by weight of the composition. The molar ratio of polyol to active that may be employed in the compositions of the present invention is more than 1. In one embodiment, the molar ratio of polyol to active that may be employed in the compositions of the present invention is more than 5. In one embodiment, the molar ratio of polyol to active that may be employed in the compositions of the present invention is more than 10.

In one embodiment polyol is employed in the compositions of the present invention is a part of coprocessed excipient. In another embodiment polyol employed in the compositions of the present invention is a part of directly compressible coprocessed excipient. The coprocessing of polyol with other excipients may provide additional stability benefits due to alteration of pH at micro-level. PCT Application WO2007052289 that has been incorporated herein as a reference describes directly compressible coprocessed excipient comprising of at least one water soluble excipient and water insoluble inorganic excipient. The water insoluble inorganic excipient includes, but is not limited to, silicates such as, but not limited to, calcium silicate, magnesium aluminum silicate, magnesium metasilicate aluminate and the like; celluloses such as, but not limited to, microcrystalline cellulose, crystalline cellulose, cellulose derivatives, vinylpyrolidone derivatives, colloidal silicon dioxide and the like or combinations thereof. The water soluble excipient is a polyol. Examples thereof include, but are not limited to, sorbitol, glucose, dextrose, fructose, maltose, xylitol, lactose or mannitol. The water soluble and water insoluble excipients in the directly compressible coprocessed excipient can be in a ratio of water-soluble excipient to water insoluble excipient of from about 50:1 to about 1 :50. In one embodiment of the present invention, this ratio is about 30: 1 to about 1 :30. In a further embodiment of the present invention, this ratio is from about 20:1 to about 1 :20. In further embodiment, the polyol employed in the compositions of the present invention is present as a coprocessed excipient. In one embodiment, the coprocessed excipient comprises polyol and water insoluble inorganic agent. In another embodiment, polyol present is xylitol, mannitol, sorbitol, maltitol, erythritol, cellobiitol, cellotriitol, xylobiitol, xylotriitol, inulotriitol, maltotriitol, maltotetraitol, inulin, cyclodextrin or derivative thereof, or combination thereof. In one embodiment, polyol present is mannitol. In a further embodiment, the water insoluble inorganic agent is calcium silicate. In another embodiment, the composition of the present invention comprises mannitol as a part of coprocessed excipient with calcium silicate. In one embodiment polyol is employed in the compositions of the present invention as a part of directly compressible coprocessed excipient that is available commercially as PanExcea™ ODT from Avantor™ (formerly known as Mallinckrodt Baker), US comprising mannitol and calcium silicate. The amount of directly compressible coprocessed excipient employed in the stable palatable compositions of the present invention is about 5% to about 95 % by weight of the said dosage form.

The pharmaceutical compositions of the present invention for oral administration comprising substituted benhydrylpiperazine, at least one cyclodextrin and at least one polyol further comprise at least one pharmaceutically acceptable excipients such as, but not limited to, binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, viscosity builders, glidants, lubricants, solubilizers, stabilizers, pH modifier or buffers, antioxidants, sweeteners or flavors.

The compositions of the present invention include at least one disintegrant or superdisintegrant such as, but not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems and the like, or mixtures thereof. The amount of disintegrant or superdisintegrant employed in the composition is about 2% to about 30 % by weight of the said dosage form. Suitable binders employed in the compositions of the present invention include, but are not limited to, starch, pregelatinized starch, polyvinyl pyrrolidone, copovidone, cellulose derivatives, such as, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose and carboxymethyl cellulose and their salts or any combinations thereof. Suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, maltose, fructose, guar gum, magnesium hydroxide, dicalcium phosphate, and the like or any combinations thereof. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate and the like, or mixtures thereof. The compositions of the present invention may also include a glidant such as, but not limited to, colloidal silicon dioxide, silica gel, precipitated silica, and the like or combinations thereof. The said compositions may also include salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica and the like or combinations thereof. Suitable solubilizers include, but are not limited to cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and the like or mixtures thereof. The compositions of the present invention may also include stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like or mixtures thereof. Examples of surfactants that may be employed include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and the like or mixtures thereof. Souring agents include, but are not limited to, monosodium fumarate and/or citric acid and the like, or mixtures thereof. The compositions of the present invention may optionally include viscosity building agents such as, but not limited to, polyalkylene oxides; polyols; starch and starch-based polymers; chitosan; polysaccharide gums; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, coprocessed microcrystalline cellulose, methyl cellulose, polyacrylic acid, gum arabic, alginates, agar, guar gum, locust bean, carrageenan, tara, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, karaya, whelan, dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; carbopol, methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s; poly(N-vinyl lactams); polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; povidone, vinylpyrrolidone/vinyl acetate copolymer and polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, chitin, cyclodextrin, gelatin, polyvinyl alcohol and copolymers and the like, or mixtures thereof.

The compositions of the present invention may include one or more sweetening agents such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate and the like, or mixtures thereof. One or more flavors that may be incorporated include, but are not limited to, peppermint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, tutty frutty flavor, magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts and the like, or mixtures thereof. The compositions of the present invention may optionally comprise pH modifiers and/or antioxidants. Suitable pH-modifiers or buffers include, but are not limited to, acidulants and alkalizing agents which may be added to the compositions of the present invention to change or maintain pH (acidic, alkaline or pH neutral). Acidulants that may be employed include, but are not limited to, aliphatic or aromatic, saturated or unsaturated, monobasic acid (monocarboxylic acid), dibasic acid (dicarboxylic acid) or tribasic acid (tricarboxylic acid), with preference given to a compound having 2-10, preferably 2-6 carbon atoms. Non- limiting examples of the monobasic acid include, but are not limited to, saturated aliphatic monocarboxylic acids such as, but not limited to, acetic acid, propionic acid, lactic acid and valeric acid, and monobasic amino acids such as, but not limited to, glycine, alanine, valine, leucine and isoleucine, and the like or mixtures thereof. Non-limiting examples of the dibasic acid include, but are not limited to, saturated aliphatic dicarboxylic acids such as, but not limited to, oxalic acid, malonic acid, succinic acid, glutaric acid and adipic acid, unsaturated aliphatic dicarboxylic acids such as maleic acid and fumaric acid, aromatic dicarboxylic acids such as, but not limited to, phthalic acid, dibasic amino acids such as aspartic acid and glutamic acid, and hydroxy dibasic acids such as malic acid and tartaric acid, and the like or mixtures thereof. Non-limiting examples of the tribasic acid include, but are not limited to, hydroxy tribasic acids such as citric acid, and the like or mixtures thereof. Preferred are malic acid, tartaric acid, fumaric acid, maleic acid, aspartic acid and citric acid. Suitable alkalizing agents include but are not limited to alkali or alkaline-earth metal hydroxide, carbonate, bicarbonate, phosphate or borate salt, basic salt of a carboxylic acid or hydroxy carboxylic acid, and the like or mixtures thereof. Examples of suitable alkalizing agents, include but are not limited to, basic salt of fumaric acid, a basic salt of lactic acid, a basic salt of malic acid, a basic salt of citric acid, a basic salt of adipic acid, a basic salt of tartaric acid, a basic salt of propionic acid, and the like or combinations thereof. Antioxidants suitable for use in accordance with the present invention include, but not limited to, tocopherol, tocopherol acetate, tocopherol acid succinate, β-carotene, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, vitamin E, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6- di-tert-butylphenol, erythorbic acid, gum guaiac, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone and the like, including pharmaceutically acceptable salts and esters thereof or combinations thereof.

In a further embodiment the compositions of the present invention may optionally comprise at least one polymeric excipient and/or at least one non-polymeric excipient or combinations thereof. In one embodiment the compositions of the present invention may optionally comprise polymeric excipients such as, but are not limited to, methacrylic acid, a polymethacrylic acid copolymer, other polymethylmethacrylates, ethyl cellulose, polyvinylacetate aqueous dispersion (Kollicoat SR 30D), cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, copolymers of vinyl pyrrolidone, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxy ethylcellulose phthalate, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, methacrylic acid ^' methylmethacrylate copolymer and methacrylic acid ethylacrylate copolymer available under the brand name Eudragit® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethylacrylate methymethacrylate copolymer) or the like, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), poloxamer, hydroxypropyl cellulose (HPC), methylcellulose, guar gum, xanthan gum, gum arabic, or hydroxyethyl cellulose, or any combinations thereof.

In another embodiment the compositions of the present invention may optionally comprise non-polymeric excipients such as, but are not limited to, waxes, fatty acids and long chain monohydric alcohols. Waxes include, but are not limited to, Cutina (hydrogenated castor oil), Hydrobase (hydrogenated soybean oil), Castorwax (hydrogenated castor oil), Croduret (hydrogenated castor oil), Carbowax, Compritol (glyceryl behenate), Sterotex (hydrogenated cottonseed oil), Lubritab (hydrogenated cottonseed oil), Apifil (wax yellow), Akofine (hydrogenated cottonseed oil), Softtisan (hydrogenated palm oil), Hydrocote (hydrogenated soybean oil), Corona (lanolin), Gelucire (macrogolglycerides lauriques), Precirol (glyceryl palmitostearate), Emulcire (cetyl alcohol), Plurol diisostearique (polyglyceryl diisostearate), and Geleol (glyceryl stearate), and mixtures thereof. The fatty acids include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, hydrogenated cottonseed oil, stearic acid, and palmitic acid, and mixtures thereof. Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, and stearyl alcohol and mixtures thereof.

The compositions of the present invention may be in the form of, but not limited to, orally disintegrating, dispersible, chewable or effervescent tablets, sprinkle granules, quick melt wafers, lozenge, chewing gum, suspensions, syrups, dry suspensions or syrups for reconstitution, or the like. The compositions of the present invention are palatable and taste- masked.

The inclusion complex of substituted benzhydrylpiperazine, either in isolated form or in solution is suitable for preparation of and incorporation into various oral dosage forms including, but not limited to, orally disintegrating, dispersible, chewable or effervescent tablets, sprinkle granules, quick melt wafers, lozenge, chewing gum, suspensions, syrups, dry suspensions or syrups for reconstitution, or the like. These oral formulations may contain from about 1 % to about 95% of substituted benzhydrylpiperazine in the form of complex with cyclodextrin.

In one embodiment, the composition of the present invention is in the form of an orally disintegrating tablet. Orally disintegrating tablets (ODTs) disintegrate/dissolve in the mouth rapidly without administering extra water, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation. The orally disintegrating tablet compositions of the present invention dissolve or disintegrate in the oral cavity, preferably within about 60 seconds. The orally disintegrating tablet compositions comprising substituted benzhydrylpiperazine can be prepared by any of the known non limiting techniques such as, but not limited to, freeze-drying, molding and sublimation, compression, cotton candy process, mass extrusion, etc or use of specialized excipients such as effervescent couple, highly micronized agents, coprocessed excipients or the like. These orally disintegrating tablets comprise various pharmaceutically acceptable excipients as have been discussed above.

In another embodiment the composition of the present invention is in the form of a chewable tablet. Chewable tablets are taken slowly by chewing or sucking in the mouth, and enable substituted benzhydrylpiperazine contained therein to be orally administered without water. These chewable tablets comprise various pharmaceutically acceptable excipients as have been discussed above in addition to excipients which may be specifically employed for chewable tablets.

In yet another embodiment the composition of the present invention is in the form of an effervescent tablet intended to be dissolved or dispersed in water before administration and generally contain acid substances and carbonates or bicarbonates, which react rapidly in the presence of water releasing carbon dioxide. These tablets comprise various pharmaceutically acceptable excipients as have been discussed above. The effervescent tablets can comprise effervescent couples selected from, but not limited to, thermolabile gas generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.

In another embodiment, the composition of the present invention is in the form of dispersible tablets. Dispersible tablet refers to a tablet which disperses in aqueous phase, e.g. in water before administration. A water-dispersible tablet, according to the British Pharmacopoeia and European Pharmacopoeia, should meet the requirements of the test for dispersible tablets as regards dispersion time (< 3 minutes) and dispersion quality (i.e. to pass through a 710 im sieve). The dispersible tablet compositions of the present invention comprising substituted benzhydrylpiperazine can further comprise pharmaceutically acceptable excipients as disclosed above and one or more viscosity building agents or viscolizers. in one embodiment, the weight percent of the viscolizer in the dosage form is about 2 to about 75 weight percent. In another embodiment the weight percent of the viscolizer in the dosage form is about 10 to about 70 weight percent. In further embodiment the weight percent of the viscolizer in the dosage form is about 5 to about 50 weight percent. The viscolizers act to control sedimentation rate of dispersed active thereby producing homogeneous dispersions when the dispersible tablets are dispersed in water before administration thus ensuring substantially uniform dosing. They rapidly generate viscosity when the dispersible tablets come in contact with water, and a homogenous suspension is formed, which can be easily swallowed by children and the elderly, with minimal effect of the release properties of the biologically active ingredient.

The terms "tablet" and "tablet composition" are used synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/ melt granulation. In a still another embodiment, the compositions of the present invention can be in the form of, but not limited to, suspensions, syrups or dry suspensions or syrups for administration.

In one of the embodiments of the present invention, the composition may optionally be coated. Surface coating may be employed for aesthetic purposes or for dimensionally stabilizing the dosage form. The coating may be carried out using any conventional technique employing conventional ingredients suitable for enteral use. A surface coating can for example be in the form of film using conventional polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol polymethacrylates and the like. In another embodiment of the present invention the composition may optionally be coated with a functional coat. The coat can be employed using polymeric or non-polymeric excipients as described above either alone or in combination, along with plasticizers, colorants, opacifiers etc.

In one embodiment the process for preparation of the stable palatable pharmaceutical compositions of the present invention comprises:

a. complexing substituted benzhydrylpiperazine with at least one cyclodextrin; b. blending complexed substituted benzhydrylpiperazine of step (a) with other excipients, except lubricant, to form a uniform powder mix;

c. lubricating the powder mix of step (b); and

d. compressing the lubricated powder mix of step (c) into an orally disintegrating tablet or chewable tablet composition.

In another embodiment the process for preparation of the stable palatable pharmaceutical compositions of the present invention comprises:

a. complexing substituted benzhydrylpiperazine with at least one cyclodextrin in solution; b. granulating a part of pharmaceutically acceptable excipients using solution of step (a); c. drying and sizing the granulate of step (b) to form granules;

d. blending granules of step (c) with remaining excipients, except lubricant, to form a uniform powder mix;

e. lubricating the powder mix of step (d); and

f. compressing the lubricated powder mix of step (c) into an orally disintegrating tablet or chewable tablet composition.

The compositions of the present invention comprising cyclodextrins and polyols are so prepared by simple, conventional processes discussed in various embodiments above such that its in-vitro release and stability is not compromised.

The compositions of the present invention provide desired in-vitro release profile. In one embodiment the orally disintegrating or chewable tablets of the present invention release not less than 80% of substituted benzhydrylpiperazine within about sixty (60) minutes, when tested for dissolution in USP Apparatus II at 50 rpm with degassed water. In another embodiment the orally disintegrating or chewable tablets of the present invention release not less than 80% of substituted benzhydrylpiperazine within about thirty (30) minutes, when tested for dissolution in USP Apparatus II at 50 rpm with degassed water. The compositions of the present invention are stable. In one embodiment the composition of the present invention comprising substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol, wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex, has a total impurity content of not more than about 1 % by weight of the initial substituted benzhydrylpiperazine content after storage up to about 6 months at a temperature of about 40°C and 75% relative humidity. In another embodiment the compositions of the present invention comprising substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol, wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex, has a total impurity content of not more than about 0.5% by weight of the initial substituted benzhydrylpiperazine content after storage up to about 6 months at a temperature of about 40°C and 75% relative humidity.

In one embodiment the composition of the present invention comprising substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol, wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex, remain stable when stored for six (6) months at temperature 25C and 60% relative humidity with % total impurities not exceeding more than 1 %. In another embodiment the compositions of the present invention comprising substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol, wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex, remain stable when stored for six (6) months at temperature 25C and 60% relative humidity with % total impurities not exceeding more than 0.5%.

In one embodiment the various dosage forms as described in the present invention comprising taste masked cetirizine, its enantiomers, or their pharmaceutically acceptable salts are immediate release dosage forms that release the taste masked cetirizine instantly upon reaching either stomach or intestine. In another embodiment of the present invention, compositions comprising cetirizine in the form of complex with cyclodextrin release active in a controlled manner over a period of time, for example, from about 2 to about 24 hours. In such a formulation, complexed cetirizine may further comprise a polymeric and non- polymeric excipients or combinations thereof, as discussed above. The amount of such polymeric or non-polymeric excipient ensures desired controlled release of cetirizine. In another embodiment, the orally disintegrating tablets of the present invention, release in a controlled manner, not less than 75% of cetirizine, its enantiomers, or their pharmaceutically acceptable salts in twenty-four (24) hours when tested for dissolution in USP Apparatus II at 50 rpm with degassed water.

In a still further embodiment of the present invention the stable palatable compositions of the present invention may be adapted to deliver one more active agent in addition to substituted benzhydrylpiperazine. The additional active agent that may be delivered includes, but is not limited to, mefenamic acid, zileuton, zafirlukast, pridefine, probenecid, nalidixic acid, acrosoxacin, meluadrine, nardeterol, darbufelone, fluocinolone, oxaprozin, fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, pseudoephedrine, docebenone, piripost, montelukast, pranlukast, naproxen, phenylephrine, aspirin, acetaminophen, ketoprofen, ibuprofen, phenylpropanolamine, codeine, hydrocodone, dextromethorphan, guaifenesin, nefazodone, trazodone, nimesulide, ciclesonide, cromolyn, cromoglycate, lodoxamide tromethamine, nedocromil, olopatadine, pemirolast. ketorolac tromethamine, roflumilast, fluticasone, beclomethasone, budesonide, triamcinolone, and mometasone.

The present invention further provides method of treating allergies by administering to a patient in need thereof stable palatable formulations comprising substituted benzhydrylpiperazine, at least one cyclodextrin and at least one polyol. The present invention further provides method of treating allergies by administering to a patient in need thereof stable palatable formulations comprising cetirizine, its enantiomers, or their pharmaceutically acceptable salts, at least one cyclodextrin and at least one polyol.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art.

Examples

Example 1 : Orally disintegrating tablet formulation of levocetirizine di hydrochloride Table 1 : Composition of levocetirizine orally disintegrating tablet

Procedure: Hydroxy propyl β-cyclodextrin was dissolved in sufficient amount of hot purified water. Once the clear solution of hydroxy propyl β-cyclodextrin was achieved, levocetirizine dihydrochloride was added to it and stirred to ensure complex formation. Further clear solution of drug and hydroxy propyl β-cyclodextrin was used to granulate microcrystalline cellulose. Granules were then dried, sized and mixed with remaining ingredients, except lubricant and blended. Finally after lubrication the blend was compressed into tablets that had desired taste-masking, friability and disintegration time.

Hardness (N) 32-40

Friability (%) .0.23

Disintegration time (sec) 10-13

Disintegration time in oral cavity (sec) 50-60 seconds

Example 2: Orally disintegrating tablet formulation of levocetirizine dihydrochloride

Table 2: Composition of levocetirizine orally disintegrating tablet

Ingredients mg/tab Levocetirizine dihydrochloride 2.5

β-cyclodextrin, USP 18.5

Microcrystalline cellulose, USP 12

Lactose monohydrate, USP 15

PanExcea™ ODT 110

Crospovidone, USP/NF 35

Sucralose, USP 2

Acesulfame potassium, Ph. Eur 2

Peppermint flavor 1

Magnesium stearate, USP 2

Total 200

Procedure: β-cyclodextrin was dissolved in sufficient amount of hot purified water. Once the clear solution of β-cyclodextrin was achieved, levocetirizine dihydrochloride was added to it and stirred to ensure complex formation. Further clear solution of drug and β-cyclodextrin was used to granulate microcrystalline cellulose and lactose monohydrate. Granules were then dried, sized and mixed with remaining ingredients, except lubricant and blended. Finally after lubrication the blend was compressed into tablets that had desired taste-masking, friability and disintegration time. Example 3: Chewable tablet formulation of cetirizine dihydrochloride

Table 3: Composition of cetirizine chewable tablet

Ingredients mg/tab

Cetirizine dihydrochloride 10

β-cyclodextrin, USP 87

Mannitol, USP 155

Microcrystalline cellulose, USP 225

PanExcea™ ODT 140

Croscarmellose sodium, USP/NF 35

Sucralose, USP 8 Acesulfame potassium, Ph. Eur 9

Peppermint flavor 6

Sodium stearyl fumarate, USP 5

Total 680

Procedure: β-cyclodextrin was dissolved in sufficient amount of hot purified water. Once the clear solution of β-cyclodextrin was achieved, cetirizine dihydrochloride was added to it and stirred to ensure complex formation. Further clear solution of drug and β-cyclodextrin was used to granulate microcrystalline cellulose and mannitol. Granules were then dried, sized and then mixed with remaining ingredients, except lubricant and blended. Finally after lubrication the blend was compressed into tablets with desired taste-masking, friability and disintegration time. Example 4: Comparative evaluation of in-vitro dissolution of the tablets of the present invention and marketed formulation XYZAL®

The orally disintegrating tablets of levocetirizine of example 1 were subjected to dissolution study in degassed water using USP type II apparatus at 50 rpm.

Table 4: Comparative in-vitro dissolution data

The in-vitro release of composition of the present invention was found to be comparable to the marketed immediate release product of levocetirizine.

Example 5: Orally disintegrating tablet formulation of levocetirizine comprising active in an uncomplexed form with cyclodextrin Table 5: Composition of levocetirizine orally disintegrating tablet

Procedure: Hydroxy propyl β-cyclodextrin was physically blended with levocetirizine dihydrochloride. This blend was then mixed with remaining ingredients, except lubricant and blended. Finally after lubrication the blend was compressed into tablets.

Example 6: Stability Study

The formulation described in example 1 was put on stability along with formulation described in example 5 wherein inclusion complex of active and cyclodextrin was not prepared. Comparative RS (related substances) and % known impurities data for the two formulations is as depicted beneath:

Table 6: Comparative evaluation of stability data

Total Known Total Unknown Total

Storage Impurities (%) Impurities (%) Impurities

Pack

Conditions (%)

Ex.1 Ex. 5 Ex.1 Ex. 5 Ex.1 Ex. 5

Initial 0.10 0.06 ND^* 0.04 0.10 0.10

HDPE 1 M 40°C/75% RH 0.12 0.21 0.04 0.31 0.16 0.52 3M 40°C/75% RH 0.16 0.34 0.12 0.45 0.28 0.79

6M 40°C/75% RH 0.13 0.50 0.16 0.75 0.29 1.25

3M 25°C/60% RH 0.15 0.3 0.09 0.35 0.24 0.65

6M 25°C/60% RH 0.12 0.46 0.09 0.64 0.21 1.1

ND* indicates Not Detected

The stability data indicates that formulation of example 1 remained stable with %total impurities not exceeding 0.5% on storage at 25°C/60% RH and 40°C/75% RH for six months when compared to formulation of example 5 indicating that formulations of the present invention incorporating levocetirizine-cyclodextrin complexes are very stable even in the presence of polyols in their formulations. On contrary formulation of example 5 including physical blend of active and cyclodextrin are not stable in the presence of polyols in the formulation.

Example 7: Chewable tablet formulation of cetirizine dihydrochloride

Table 7: Composition of cetirizine chewable tablet

Ingredients mg/tab

Cetirizine dihydrochloride 10

β-cyclodextrin, USP 62

Pan Excea™ ODT 180

Microcrystalline cellulose, USPNF 1 18

Mannitol, USP 45

Croscarmellose sodium, USPNF 21

Sucralose, USPNF 4

Tutti frutti flavor 4

Citric acid anhydrous, USP 1

D&C Red 0.2

Sodium stearyl fumarate, USPNF 4.8

Total 450 Procedure: Cetirizine was complexed with β-cyclodextrin in presence of water. The complex was adsorbed onto PanExcea™ ODT and microcrystalline cellulose. The granules were mixed with remaining part of PanExcea™ ODT and other excipients except lubricant to form a blend. The final blend was then lubricated and compressed to form cetirizine chewable tablets.

In vitro dissolution study

In vitro dissolution study was carried out for chewable tablets of table 7 using USP type II apparatus in 900ml of degassed water at 50rpm. The dissolution profile is as tabulated beneath:

Stability study: The chewable tablets of table 7 of the present invention were put on stability for one month in HDPE containers and tested at 40°C and 75% RH. The % impurity data is as depicted beneath:

Table 8: Stability data of cetirizine hydrochloride chewable tablets of table 7

Total Known Total Unknown Total

Storage

Pack Impurities (%) Impurities (%) Impurities

Conditions

(%)

Initial 0.04 0.16 0.20

HDPE 1 M 40°C/75% RH 0.05 0.16 0.21 The stability data indicates that the composition of table 7 remained stable with % total impurities not exceeding 1 % on storage at 40°C/75% RH for a period of one month.

Example 8: Chewable tablet formulation of cetirizine dihydrochloride

Table 9: Composition of cetirizine chewable tablet

Procedure: Cetirizine was complexed with β-cyclodextrin in presence of water. The complex was adsorbed onto mannitol and microcrystalline cellulose. The granules were mixed with remaining excipients except lubricant to form a blend which was then lubricated and compressed to form cetirizine chewable tablets.

In vitro dissolution study

In vitro dissolution study was carried out for the chewable tablets of table 9 that were kept on stability for 1 month at 40°C/75% RH, using USP type II apparatus in 900ml of degassed water at 50rpm. The dissolution profile is as tabulated beneath: Time % Drug release

(mins)

5 84.7

10 93.1

15 95.1

20 96.0

30 96.8

45 97.6

Claims

1. A pharmaceutical composition for oral administration comprising:

substituted benzhydrylpiperazine,

at least one cyclodextrin, and

at least one polyol;

wherein the substituted benzhydrylpiperazine and the cyclodextrin are present in the form of an inclusion complex.

2. The composition of claim 1 , wherein the substituted benzhydrylpiperazine is cetirizine, levocetirizine, efletirizine, hydroxyzine, meclizine or buclizine.

3. The composition of claim 2, wherein the substituted benzhydrylpiperazine is in the form of a free base, a pharmaceutically acceptable salt, a prodrug, an active metabolite, a polymorph, a solvate, a hydrate, an enantiomer, an optical isomer, a tautomer, a racemic mixture or derivative thereof.

4. The composition of claim 1 , wherein the substituted benzhydrylpiperazine is cetirizine dihydrochloride.

5. The composition of claim 1 , wherein the substituted benzhydrylpiperazine is levocetirizine dihydrochloride.

6. The composition of claim 1 , wherein the cyclodextrin is a-cyclodextrin, β- cyclodextrin, γ-cyclodextrin, (2,6-di-o-methyl)-3-cyclodextrin, randomly methylated-β- cyclodextrin, hydroxypropyl^-cyclodextrin, hydroxyethyl^-cyclodextrin, dihydroxypropyl-p-cyclodextrin, methyl-p-cyclodextrin, sulfobutyl ether cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl- -cyclodextrin, maltosyl- γ-cyclodextrin, maltosyl-y-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-β cyclodextrin, maltotriosyl-Y-cyclodextrin, dimaltosyl-p-cyclodextrin, maltosyl-β- cyclodextrin/dimaltosyl^-cyclodextrin or derivative thereof, or a combination thereof.

7. The composition of claim 1 , wherein the molar ratio between the substituted benzhydrylpiperazine and the cyclodextrin is about 1 : 15 to about 15:1.

8. The composition of claim 1 , wherein the polyol is xylitol, mannitol, sorbitol, maltitol, erythritol, cellobiitol, cellotriitol, xylobiitol, xylotriitol, inulotriitol, maltotriitol, maltotetraitol, inulin, cyclodextrin or derivative thereof, or combination thereof.

9. The composition of claim 1 , wherein the polyol is present as a coprocessed excipient.

10. The composition of claim 9, wherein the coprocessed excipient comprises polyol and water insoluble inorganic agent.

1 1. The composition of claim 10, wherein the water insoluble inorganic agent is calcium silicate.

12. The composition of claim 10, wherein the polyol is xylitol, mannitol, sorbitol, maltitol, erythritol, cellobiitol, cellotriitol, xylobiitol, xylotriitol, inulotriitol, maltotriitol, maltotetraitol, inulin, cyclodextrin or derivative thereof, or combination thereof.

13. The composition of claim 12, wherein the polyol is mannitol.

14. The composition of claim 1 , wherein the molar ratio between the polyol and the substituted benzhydrylpiperazine is above about 1.

15. The composition of claim 1 , wherein the polyol is present in intimate contact with the inclusion complex.

16. The composition of claim 1 , wherein the composition further comprises at least pharmaceutically acceptable excipient.

17. The composition of claim 16, wherein the excipient is binder, disintegrant, superdisintegrant, diluent, salivating agent, surfactant, flavor, sweetener, colorant, diluent, souring agent, viscosity builder, glidant, lubricant, solubilizer, stabilizer, pH modifier, buffer, antioxidant, sweetener or flavor.

18. The composition of claim 1 , wherein the composition has a total impurity content of not more than about 1% by weight of the initial substituted benzhydrylpiperazine content after storage up to about 6 months at a temperature of about 40°C and 75% relative humidity.

19. The composition of claim 1 , wherein the composition has a total impurity content of not more than about 0.5% by weight of the initial substituted benzhydrylpiperazine content after storage up to about 6 months at a temperature of about 40°C and 75% relative humidity.

20. The composition of claim 1 , wherein the composition is taste-masked and palatable.

21. The composition of claim 1 , wherein the composition releases not less than 80% of substituted benzhydrylpiperazine within about 60 minutes.

22. The composition of claim 1 , wherein the composition is in the form of an orally disintegrating tablet, chewable tablet, bite-dispersion tablet, effervescent tablet, dispersible tablet, sprinkle granules, dry suspension or dry syrup for reconstitution, quick melt wafers, lozenge, or chewing gum.

23. The composition of claim 1 , wherein the composition further comprises an additional active agent.

24. The composition of claim 23, wherein the active agent is mefenamic acid, zileuton, zafirlukast, pridefine, probenecid, nalidixic acid, acrosoxacin, meluadrine, nardeterol, darbufelone, fluocinolone, oxaprozin, fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, pseudoephedrine, docebenone, piripost, montelukast, pranlukast, naproxen, phenylephrine, aspirin, acetaminophen, ketoprofen, ibuprofen, phenylpropanolamine, codeine, hydrocodone, dextromethorphan, guaifenesin, nefazodone, trazodone, nimesulide, ciclesonide, cromolyn, cromoglycate, lodoxamide tromethamine, nedocromil, olopatadine, pemirolast. ketorolac tromethamine, roflumilast, fluticasone, beclomethasone, budesonide, triamcinolone, or mometasone.