FIELD OF THE INVENTION

The present invention relates to an oral pharmaceutical composition of solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient(s). More particularly, the pharmaceutical composition is a ready to use oral suspension or a powder for reconstitution dosage form. The invention also provides a process for manufacturing such compositions and their use for the treatment of neurogenic detrusor over-activity and overactive bladder.
BACKGROUND OF THE INVENTION
Solifenacin succinate is a muscarinic receptor antagonist developed for the treatment of overactive bladder. Chemically it is butanedioic acid, compounded with (1S)-(3R)-l-azabicyclo[2.2.2]oct-3-yl3,4-dihydro-l-phenyl-2(lH)-isoquinoline carboxylate (1:1) having a molecular weight of 480.55.
Solifenacin succinate is represented by the following formula:
O
Solifenacin succinate is approved for oral administration as tablet and suspension dosage forms in USA under the tradenames Vesicare® and Vesicare LS™. It is also marketed as an orally disintegrating tablet dosage form by Astellas Pharma in Japan under the tradename Vesicare® OD.
The marketed composition of Vesicare LS™ suspension contains polacrilin potassium, methylparaben, propylparaben, propylene glycol, simethicone emulsion 30%, carbomer homopolymer Type B, xylitol, acesulfame potassium, natural orange flavor, sodium hydroxide, and purified water. Vesicare LS™ suspension 1 mg/ml is orally administered to pediatric patients aged 2 years and older once a day. The dose may be

increased or decreased according to the patient body weight, but the maximum daily dose should not exceed 10 mg.
US patent 6,017,927 assigned to Astellas Pharma discloses solifenacin succinate product generically.
US patent 9,918,970 assigned to Astellas Pharma discloses liquid pharmaceutical composition of solifenacin comprising a complex between solifenacin or a pharmaceutically acceptable salt thereof and an ion exchange resin, and acrylic based polymer like carbomer homopolymer type B as an essential excipient to get suspension with desired technical attributes.
Oral liquid formulations such as suspension have been developed as an alternative to tablets in order to circumvent problems like: a) dysphagia and b) to facilitate patient compliance in patients having swallowing issues with tablets and capsule dosage form; however, suspensions are often thermodynamically unstable and may result in aggregation and sedimentation of the suspended particles during storage. Problems are often encountered because the accuracy of the dose depends on the even distribution of particles in the suspensions at the time the preparations are administered to the patients.
To overcome restrictive formulation approaches disclosed in prior arts, the present inventors have surprisingly found that it is possible to develop an alternate oral suspension dosage form of solifenacin having improved physical and chemical properties with desired technical attributes for use by patients having difficulties in swallowing tablets. The dosage form as per present invention is expected to be stable, easily pourable with good viscosity, palatable, homogenous and free of undesirable impurities.

SUMMARY OF THE INVENTION
It is an object of the present invention to develop a pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipients and/or carrier and process for its preparation.
Another object of the present invention is to develop an immediate release pharmaceutical composition in the form of a liquid suspension and powder for suspension comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient and/or carrier and process for their preparation.
Another object of the present invention is to develop an immediate release pharmaceutical composition of solifenacin in the form of a ready to use suspension or dry powder for suspension which can be sprinkled on applesauce, chocolate syrup, j elly or soft foods or can be suspended in water or pharmaceutically acceptable carrier and is suitable for administration to pediatric patients.
Another object of the present invention is to provide an oral pharmaceutical composition in the form of a ready to use suspension or powder for suspension comprising solifenacin or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipients and/or carrier including a thickening agent/viscosity agent, taste masking agents, disintegrants, antioxidants, anticaking agent, antifoaming agent, pH adjusting agent, coloring agent, sweetening agent, flavoring agent, solubilizer/wetting agent, buffer, diluent and preservative.
Yet another object of the present invention is to develop a suspension comprising solifenacin or its pharmaceutically acceptable esters, salts, solvates, polymorphs,

enantiomers or mixtures thereof by a manufacturing process which is consistent and feasible for industrial production, while maintaining stability, palatability, easily pourable with good viscosity, palatable, homogenous and free of undesirable impurities, and acceptable content uniformity and pharmaceutical equivalence to the reference formulation(s). The following embodiments further generically describe the objects of the present invention in accordance with the best mode of practice, however, disclosed invention is not restricted to the particular embodiments hereinafter described.
DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term "composition", as in pharmaceutical composition, is intended to encompass a drug product comprising an active or its pharmaceutically acceptable salts or derivatives thereof, and the other inert ingredient(s) (i.e., pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with "formulations" and "dosage forms". Pharmaceutical compositions of the invention include, but are not limited to, ready to use suspension, powder for oral suspension, multiparticulates, pellets, beads, spherules, beadlets, microcapsules, millispheres, microspheres, powder, granules, spheroids and the like, filled in a bottle, capsule or sachet, or compressed into tablets. Preferably, the pharmaceutical composition refers to powder, granules, pellets, multiparticulates and the like, filled into capsules or sachets and ready to use suspension.
The term "core" as used herein refers to pellets, spheres, granules, beads, microspheres, spherules, beadlets, microcapsules, multiparticulates, millispheres, powder and the like comprising at least one or more excipients selected from diluent, binder, disintegrant, lubricant, glidant, surfactant, wetting agent, solubilizer, stabilizer, sweetener, flavoring

agent, coloring agent, carrier and taste masking agents and one or more active pharmaceutical ingredients (API).
The term "excipient" means a pharmacologically inactive component such as a diluent, binder, disintegrant, antioxidant, lubricant, glidant, surfactant, wetting agent, solubilizer, stabilizer, suspending agent, anticaking agent, antifoaming agent, sweetener, flavoring agent, coloring agent, carrier and one or more taste masking agent or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of the present invention. Further, the excipient may be in the form of powders or in the form of a dispersion. Combinations of excipients performing the same function may be used to achieve desired formulation characteristics.
Viscosity agents, thickening agents and suspending agents are synonymous and are used interchangeably throughout the specification.
As used herein, the term "about" means ± approximately 20% of the indicated value, such that "about 10 percent" indicates approximately 8 to 12 percent. The term "w/w" as used herein refers the total weight of the composition.
The term "stable" refers to the compositions of the present invention, wherein substantially no analogues or degradation product of Active Pharmaceutical Ingredient (API) is generated during storage of the dosage form for at least 3 months, preferably for at least 6 months. The stability of the solid oral composition may be evaluated at "long term" conditions 25°C/60% RH, at intermediate conditions 30°C/65% RH, at "accelerated conditions" 40°C/75% RH, in the final container or pack either measured

as the assay or drop in dissolution. Stability testing may be conducted according to the current ICH and FDA guidelines.
As used herein, the term "immediate release" refers to pharmaceutical compositions that release at least 75% of the active ingredient within a small period of time, typically less than 30 minutes.
The blending amount ratios, [X/(Y+Z)], are calculated from the amounts of thickening agent/suspending agent is '"X", Drug- solifenacin or a pharmaceutical^ acceptable salt thereof is "Y", and Taste masking agent is "Z".
As used herein, the term "ready to use suspension" means a preconstituted suspension which can be administered as such. The "powder for suspension" or "dry suspension" needs to be reconstituted with a liquid carrier to form a suspension.
The term "taste masked pharmaceutical composition" as used herein refers to coated drug particles, inclusion complexes of drug using cyclodextrins, drug resin complexes and other processes known in the art.
The term "composite" as used herein refers to the drug and at least one or more taste masking agents present in close proximity of each other. Also refers to the drug resin complex, drug cyclodextrin complex, polymer coated drug particles and the like. It is a challenge to mask the bitter taste of drugs in the development of most oral formulations. It is also necessary to choose the masking process which involves the minimum number of excipients, minimum processing steps, is rapid and easy to prepare, can be carried out at room temperature, is of low cost, and is environmental friendly. Various methods have been reported to achieve taste masking of bitter drugs, i.e., polymer coating, ion-exchange resins, spray-or freeze-drying, complexation, congealing with lipids, making multiple emulsions, liposomes, microcapsules, or

polymeric membranes. Inventors of the present invention developed taste masking with polymer coating technique using various grades of Eudragit®, complexation technique using ion exchange resins, solid dispersion using various carriers and cyclodextrin derivatives.
Ion-exchange resins (IERs) are cross-linked, water-insoluble, high molecular-weight polyelectrolytes that can reversibly exchange their mobile ions of equal charge with the surrounding medium stoichiometrically. Since most drugs have ionic sites in their molecule, the resin's charge provides a means to loosely bind such drugs. This complex prevents the drug release in the saliva, thus resulting in taste masking; however, it is weak enough to be broken down by hydrochloric acid present in the stomach. Thus, the drug resin complex is absolutely tasteless, and its bioavailability remains unaffected. A critical factor to prepare a Drug-Resin complex (DRC) is the choice of the right IER. Solifenacin contains an exchangeable secondary amine moiety i.e. cationic center. Therefore, cation exchange resins were selected for the complex formation. Weak cation acid ion exchange resins such as Indion 204, Indion 214, polacrillin potassium as well as a strong cation acid resin such as PuroliteClOOCaMR, Amberlite IRP-69 and Dowex-50 are tested in order to form the DRC.
Polymer coating of drug is another approach used for taste masking, polymers like, methyl methacrylates copolymers are used. The inventors of the present invention have found that these polymers are more effective in preventing the perception of taste of solifenacin (as it is bitter and has astringent taste) as compared to other taste masking techniques. Unlike conventional polymer coatings such as ethyl cellulose known for their properties of providing a dissolution barrier, the methyl methacrylates copolymers have proven to be superior for their taste masking properties when used in a specific ratio.

The present invention is directed to a suspension dosage form, suitable for use as a liquid suspension or sprinkled on to the food or beverages for administration to a subject in need thereof which comprises solifenacin or its pharmaceutically acceptable salts. The suspension dosage form is capable of masking the taste of the drug and also provides patient compliance, especially for pediatric population.
A first aspect of the present invention relates to an immediate release suspension dosage form comprising:
a) a composite comprising solifenacin or a pharmaceutically acceptable salt thereof and a taste masking agent selected from ion exchange resins, cyclodextrins, ammonioalkyl methacrylate copolymers;
b) a suspending agent selected from xanthan gum, carrageenan, hydroxylpropylmethyl cellulose, microcrystalline cellulose, mixture of crystalline cellulose/carmellose sodium (Avicel RC-591); pullulan, dextrin, pectin, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate and mixtures thereof and
wherein the ratio of solifenacin: taste masking agent ranges from 0.1:10 to about 10:0.1 by weight.
A second aspect of the present invention relates to an immediate release suspension
dosage form comprising:
a) a composite comprising solifenacin or a pharmaceutically acceptable salt thereof and a taste masking agent selected from ion exchange resins, cyclodextrins, ammonioalkyl methacrylate copolymers; b) a suspending agent selected from xanthan gum, carrageenan, hydroxylpropylmethyl cellulose, microcrystalline cellulose, mixture of crystalline cellulose/carmellose sodium (Avicel RC-591), pullulan, dextrin, pectin, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate and mixtures thereof and

wherein the ratio of solifenacin: taste masking agent ranges from 0.1:10 to about 10:0.1 by weight and the composition is free of carbomers.
A third aspect of the present invention relates to an immediate release suspension dosage form, wherein the blending amount ratio by weight of the suspending agent to solifenacin or its salt thereof and taste masking agent is less than 1.
A fourth aspect of the present invention relates to an immediate release suspension dosage form, comprising solifenacin or its salt thereof from about 0.1 mg/mL to about 10 mg/mL wherein the pH of the composition is from 4.0 to 8.0 and viscosity from 100-1200 cps.
A fifth aspect of the present invention relates to an immediate release suspension dosage form, wherein the dosage form comprises one or more pharmaceutically acceptable excipients selected from the group comprising diluents, preservatives, antioxidants, antifoaming agents, pH adjusting agents, anticaking agents, surfactants, coloring agents, sweetening agents and flavoring agents.
A sixth aspect of the present invention relates to an immediate release suspension dosage form, wherein the pharmaceutically acceptable carrier is selected from aqueous and non-aqueous carrier.
A seventh aspect of the present invention relates to an immediate release suspension dosage form, wherein the suspending agent comprises xanthan gum or Avicel RC-591 from about 0.1 to 10% w/w and the diluent comprises sugar or sugar alcohol from about
30 to 80% w/w.
An eighth aspect of the present invention relates to an immediate release suspension dosage form, wherein the taste masking agent is selected from cyclodextrins like SBE7-

P-CD, P-cyclodextrin, y-cyclodextrin or hydroxypropyl P-cyclodextrin or mixtures thereof, ion exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as Purolite, Amberlite IRP-69, Amberlite IRP-88, polacrillin potassium and Dowex-50, methyl methacrylates copolymers such as Eudragit RS, Eudragit RL, EPO, Eudragit RSI00, Eudragit RL100, cellulose esters such as cellulose acetate and cellulose propionate, cellulose acetate phthalate, and hydroxypropylmethyl cellulose phthalate, veegum, bentonite, silica gel, silicates, ethyl cellulose, hydroxyl methyl propyl cellulose, carrageenan, alginates, sweeteners, flavors and combinations thereof.
A ninth aspect of the present invention relates to an immediate release suspension dosage form, wherein the composition comprises:
a) a composite comprising solifenacin or a pharmaceutically acceptable salt thereof from about 0.01-10% w/w;
b) taste masking agent selected from cyclodextrins or ion exchange resins is from about 0.1-10% w/w;
c) a suspending agent selected from xanthan gum and Avicel RC-591 is from about 0.1-20% w/w;
d) one or more diluents and/or sweetening agents selected from sugars and sugar alcohols is from about 10-90% w/w;
e) one or more preservative is from about 0.01-2% w/w;
f) one or more antifoaming agents is from about 0. l-5%w/w;
g) one or more pH adjusting agents to maintain the pH of the composition in the range of about 4.0 to about 8.0 is from about 0.1-5% w/w;
and a pharmaceutically acceptable liquid carrier; wherein the blending amount ratio by weight of the suspending agent to solifenacin or a pharmaceutically acceptable salt thereof and taste masking agent is less than 1 and the composition is free of carbomers.
A tenth aspect of the present invention relates to an immediate release suspension dosage form, wherein the suspension dosage form is provided in a kit comprising: (a)

an immediate release oral pharmaceutical suspension dosage form comprising solifenacin or its salt thereof with one or more pharmaceutically acceptable excipients and/or carrier; (b) a dispensing and/or dosing syringe or a measuring cup for administering the composition; and (c) optionally, instructions for preparation and use.
An eleventh aspect of the present invention relates to an immediate release suspension dosage form, wherein the suspension dosage form comprising a composite of solifenacin or a pharmaceutically acceptable salt thereof and an ion exchange resins, wherein the process comprises the following steps:
a) weighed quantity of resin dispersed into distilled water under continuous stirring for 30-60 minutes for swelling of resin
b) adding weighed quantity of drug into the dispersion of step a) under continuous stirring for 2-4 hours at 37 °C to form a composite
c) separating the drug resin composite by filtration
d) washing the drug resin composite of step c) with distilled water to remove the free drug and other ions
e) drying the drug resin composite of step d) at 40 °C.
A twelfth aspect of the present invention relates to an immediate release suspension dosage form, wherein the suspension dosage form comprising a composite of solifenacin or a pharmaceutically acceptable salt thereof coated with polymer, wherein the process comprises the following steps: dissolving methylmethacrylate polymers / cyclodextrin and drug in a solvent,
a) adding one or more excipients to the suspension of step a),
b) spray drying the suspension of step b) at an inlet air temperature of less than
55° C.

Another aspect of the present invention relates to an immediate release suspension dosage form of solifenacin or its pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients prepared by a process comprising the following steps:
a) preparing a composite by dissolving/dispersing one or more taste masking agent in a portion of water and/or liquid carrier and dispersing solifenacin or its pharmaceutically acceptable salts to form a dispersion
b) mixing suspending agent and one or more pharmaceutically acceptable excipients in another portion of water;
c) adding the mixture of step b) to the dispersion of step a);
d) optionally adding one or more pharmaceutically acceptable excipients to the dispersion of step c); and
e) optionally homogenizing the mixture of step d) to form a suspension.
An aspect of the present invention relates to an immediate release suspension dosage form, wherein the composition is packed in a packaging material selected from the group consisting of a bottle, sachet, foil, pouch, capsule, and container.
In accordance with another aspect of the present invention, there is provided a ready to use stable liquid suspension comprising solifenacin or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof and at least one or more pharmaceutically acceptable excipient and/or carrier including a suspending agent, taste masking agent, antioxidant, anticaking agent, antifoaming agent, pH adjusting agent, coloring agent, sweetening agent, flavouring agent, solubilizer/wetting agent, buffer, diluent, preservative.
In another aspect of the present invention, there is provided a process for the preparation of a ready to use liquid suspension of solifenacin or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof,

comprising combining various components using conventional equipment such as overhead stirrers, ultrasonifiers, mills, homogenizers operating at an RPM range of about 100-8000 RPM, or as per requirement, manufacturing and heating tank with or without vacuum application assembly known in the art or industry practice. Different orders of adding components to the stirrer can be employed. This can be followed by addition of liquid carrier (such as aqueous and/or non-aqueous), suspending agent, sweetening agent, taste masking agent and the like. The pH of the suspension is adjusted to desired value using buffering agents as needed.
In still another aspect of the present invention, there is provided a process for the preparation of a dry powder for suspension composition of solifenacin or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, which is suitable for suspension in water and/or water miscible suitable solvents to form an orally administrable product which comprises admixing, at ambient temperature and humidity conditions. The process for preparing the powder for suspension is selected from blending, direct compression, dry granulation, wet granulation, extrusion-spheronization, drug layering, coating, spray drying and hot melt extrusion. Solifenacin granules with substantially dry pharmaceutically acceptable excipients selected from the group consisting of suspending agents, viscosity enhancers/Viscosity agent, coating agents, preservatives, flavouring agents, sweeteners, lubricants, wetting agents, surfactants, buffering agents, and diluents to form a dry admixture, and transferring the dry admixture to a sealable storage container.
Another aspect of the present invention relates to an immediate release suspension dosage form comprising solifenacin or their pharmaceutically acceptable salts, wherein the dose of solifenacin is about 0.1 mg to about 20 mg. Preferably, the dose of solifenacin is about 0.5 mg to about 10 mg, more preferably, the dose of solifenacin is about 0.5 mg to about 2 mg. Preferably, the salt of solifenacin is solifenacin succinate.

Yet another aspect of the present invention relates to an immediate release suspension dosage form comprising solifenacin or their pharmaceutically acceptable salts, wherein the formulation exhibits a desired release profile.
Yet another aspect of the present invention relates to an immediate release suspension dosage form comprising solifenacin or their pharmaceutically acceptable salts, which is stable at 40°C and 75% ± 5% relative humidity at least for a period of about 1 month.
In accordance with still another embodiment of the present invention, there is provided an immediate release suspension dosage form comprising solifenacin or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, in an amount of about 0.01% to about 90% by weight wherein, the composition exhibits desirable technical attributes like pourability, viscosity, dissolution, stability, re-suspendability and re-dispersibility and a process for preparing the same.
Yet another aspect of the present invention relates to an immediate release suspension dosage form comprising solifenacin or their pharmaceutically acceptable salts, used in the treatment of neurogenic detrusor over-activity in pediatric patients aged 2 years and older and various other indications.
Carrier/vehicle/solvents used in the suspension of the present invention include aqueous and non-aqueous carrier but are not limited to water, alcohol, polyethylene glycol, propylene glycol or glycerin, buffers, oil, or combinations thereof. Oils include peanut oil, soy bean oil, corn oil, sesame oil, cottonseed oil, acetylated glycerides, ethyl oleate, mineral oil, fatty acid esters, mono- or di- fatty acid esters of polyethylene glycols, or glyceryl mono-oleate. Particularly, the suspensions are aqueous based. By "aqueous carrier" is meant a suspension comprising water, or a combination of water and a water-miscible organic solvent or solvents. Water-miscible solvents include but

are not limited to propylene glycol, polyethylene glycol and ethanol. By "non-aqueous carrier" is meant a suspension in which the carrier does not include water. The carrier can also include one more pharmaceutically acceptable excipients which can be in dissolved or dispersed form. The carrier is present in an amount from about 30 w/w % to about 95 w/w %, particularly from about 50 w/w % to about 95 w/w %.
Various useful viscosity agents/ thickening agent/suspending agent include, but are not limited to, gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth; celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (Avicel® RC); polyvinylpyrrolidone; alginic acid; alginate; sodium alginate; bentonite; maltodextrin; polyvinyl alcohol; colloidal silicon dioxide, propylene carbonate; propylene glycol; sodium starch glycolate; starch etc. The viscosity agents are present in an amount of about 0.05% to about 20% w/w of the composition. Particularly, the viscosity agents are present in an amount of about 0.1 % to about 10% w/w of the composition. More particularly, the viscosity agents are present in an amount of about 0.1% to about 5% w/w of the composition.
The suspension is easily pourable and when shaken has a viscosity in the range of 100 to 5000 cP at 25° C. Particularly, the viscosity is in the range of 100 to 2500 cP at 25°C. More particularly, the viscosity is in the range of 100 to 1500 cP at 25° C.
The term "shaken" as used herein refers to shaken prior to use, e.g. by a patient, e.g. vigorously shaken, e.g. by hand, e.g. for 5 to 40 seconds. The viscosity can be measured by using as suitable instrument such as Brookfield viscometer, Haake VT 550 viscometer at room temperature (25° C).

Diluents or fillers or liquid vehicles are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to sucrose, sugar alcohol like sorbitol, xylitol, erythritol, mannitol; starch, pregelatinized starch, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystalline cellulose, cellulose acetate, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polydextrose, sodium alginate, sodium chloride and or mixtures thereof. The diluents may be present in an amount of about 2% w/w to about 90% w/w, preferably from about 5% w/w to about 70% w/w and more preferably from about 5% w/w to about 60% w/w.
Surfactants or surface-active agents or wetting agents improve wettability of the dosage form and/or enhance its dissolution. Few active ingredients are fluffy in nature and not suspend properly. Those type of active ingredients usually float on the surface of the vehicle/ solvent used in the suspension. Surfactants or surface-active agents or wetting agents contemplated in the present invention include, but are not limited to, anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. For example, polyethylene glycol stearates, poloxamer, polysorbates, sodium lauryl sulfate, dimethicone and simethicone, etc. The surfactant or wetting agents may be present in an amount of about 0.1% w/w to about 10% w/w, preferably from about 1% w/w to about 5% w/w and more preferably from about 0.5 % w/w to about 2% w/w.
Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabi sulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated

hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and the like. In particular, the preservative is selected from benzoic acid and its salts and parabens. The preservative may be present in an amount of about 0.01% w/w to about 5% w/w, preferably from about 0.05% w/w to about 2% w/w.
Anticaking agent helps to re-suspend the ingredients suspended in the formulation. Generally, suspension formulations contain micronized particles of active ingredients and inactive ingredients, which settle at the bottom of the container and form a thin hard cake, which is not easily re-suspendable after shaking. Anticaking agent helps to improve the re-suspendability of the formulation. Various useful Anticaking agents include, but are not limited to, colloidal silica and/or colloidal silicon dioxide, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate or the like. The anticaking agent may be present in an amount of about 0.01% w/w to about 5% w/w, preferably from about 0.05% w/w to about 2% w/w.
Various useful antioxidants include, but are not limited to, ascorbic acid, tert-butylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a-tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate.
Various useful sweetening agents include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium, aspartame. Sugar or a sugar alcohol can also act as filler. The sweetening agent may be present in an amount of about 1%> w/w to about 70% w/w, preferably from about 1% w/w to about 50% w/w and more preferably from about 1% w/w to about 30% w/w.

Various useful flavoring agents according to the present invention include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, pineapple, apricot, bubblegum flavor and combinations thereof. Preferably, wild cherry, walnut, chocolate, pineapple, apricot, anise, banana and orange. The flavoring agent may be present in an amount of about 5% w/w or less, 2% w/w or less, 1% w/w or less, 0.5% w/w or less, 0.2% w/w or less. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavor(s) used.
Suitable coloring agents according to the present invention are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents, natural coloring agents, natural juice concentrates, pigments such as iron oxide, titanium dioxide, and zinc oxide, and combinations thereof. The coloring agent may be present in an amount of about 0.1% w/w to about 2% w/w, preferably from about 0.1% w/w to about 1.0% w/w.
Various useful isotonizing agent include, but are not limited to, sodium chloride, mannitol, D-sorbitol, glucose, glycerin or the like.
Various useful pH adjusting agent or buffering agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate.
Various taste masking agents according to the present invention include, but are not limited to, water soluble and/or insoluble polymeric excipients, water insoluble non-polymeric excipients, adsorbent, carbomer, alkali metal chlorides or an alkaline earth

metal chlorides or a derivative, Cyclodextrin derivatives such as SBE7-P-CD, P-cyclodextrin, y-cyclodextrin or hydroxypropyl P-cyclodextrin or mixtures thereof; ion exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as PuroliteClOOCaMR, Amberlite IRP-69, Amberlite IRP-88 and Dowex-50, methyl methacrylates copolymers such as Eudragit RS, Eudragit RL, Eudragit RSI00, Eudragit RL100, EPO or the same polymers in aqueous solution like "Eudragit RS30D" or "Eudragit ROOD", Eudragit RSPO and RLPO, cellulose esters such as cellulose acetate and cellulose propionate, polymers that dissolve at acidic or alkaline pH such as Eudragit E, cellulose acetate phthalate, and hydroxypropylmethyl cellulose phthalate or combinations thereof. The taste masking agents may be present in an amount of about amount of about 0.1% w/w to about 60%w/w, preferably from about 5.0% w/w to about 50%) w/w.
Taste masking of the pharmaceutically active ingredient may be performed by the processes selected from suspending, dissolving, or dispersing the pharmaceutically active ingredient in a solution or dispersion of polymer coating material and spray drying, fluid-bed coating, simple or complex coacervation, coevaporation, co-grinding, melt dispersion and emulsion-solvent evaporation techniques and so on.
The polymer coated drug powder or the drug resin complex can be applied for the preparation of both ready to use suspensions or reconstitutable powders, i.e., dry powder drug products that are reconstituted as suspensions in a liquid vehicle such as water before usage or sprinkled on food beverages before administration. The reconstitutable powders have a long shelf life and the suspensions, once reconstituted, have adequate taste masking.
The pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE)

bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like. The glass or plastic bottle is provided with a child proof closure. The package can include a syringe (marked in mL) for ease of dosing.
The container such as bottle has a fill volume of, e.g., from about 50 mL to about 500 mL comprising solifenacin suspension. Pack chosen are made of material which is non-reactive with the suspension and suspension powder for reconstitution. Containers for use in the storage of the oral suspensions may be used to administer a multiple dose of solifenacin.
Another aspect of the present invention includes particle size of free drug particulate form of solifenacin or their pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the particle diameter at 90% cumulative volume (d9o) is less than about 200 um, preferably less than 100 um. Particle diameter at X% cumulative particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like.
In yet another aspect of the invention, the taste masked pharmaceutical composition of solifenacin or its pharmaceutically acceptable salts, In-Vitro taste-masking efficiency study will be done using electronic tongue system (E-tongue), optimization of drug:resin ratio and drug: cyclodextrin ratio will be done based on various parameters.
The pharmaceutical oral dosage form prepared according to the present invention can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is

released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
f2= 50 • log {[1 + (l/n)£t=in(Rt- Tt)2]"0-5 • 100} Two dissolution profiles are considered similar when the h value is equal to or greater than 50.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the methods for the preparation and testing of the pharmaceutical compositions. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The following examples are set out to illustrate the invention and do not limit the scope of the present invention.
EXAMPLES
The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting to the scope of the present invention.
Pharmaceutical composition of solifenacin suspension may be prepared by using quantitative formula as given in Table 1 and 2:

TABLE 1: Taste masked drug composites

Components Example 1 Example 2 Example 3 Example 4 Example 5

Quantity % w/w
Solifenacin succinate 0.01-5 0.1-5 0.01-2 0.01-1 0.1-4
(3-CD 1.0-20 — ~ ~ ~
SBE7-P-CD ~ 1.0-40 ~ ~ ~
EudragitLlOO — — 1.0-30
Polacrillin Potassium ~ ~ ~ 1.0-50 ~
Amberlite IRP-69 ~ ~ ~ ~ 1.0-40
Purified water/Hydro alcoholic solvent q.s q.s q.s q.s q.s
The drug resin composites can be prepared using the standard reported methods.
TABLE 2: Ready to use oral suspension

Components Role of excipients Example 6 Example 7 Example 8

Quantity % w/w
Taste masked drug composite Active 0.1-10 0.1-5 1-10
Sorbitol/xylitol Diluent/Filler 10-50 30-45 35-70
Propylene glycol Solvent 5-15 10-15 0-15
Polysorbate 80 Surfactant 0.1-5 — —
Poloxamer Surfactant — 1-5 —
AvicelRC-591 Suspending agent 0.1-10 — —
Xanthan Gum Suspending agent — 0.1-3.0 —
Hypromellose 2208 (Methocel K4M) Suspending agent — — 0.1-10
Methyl paraben Preservative 0.1-1.0 0.1-0.5 0.1-1.0
Propyl paraben Preservative 0.1-1.0 0.1-0.5 0.1-1.0
Citric acid pH adjusting agent 0.1-5.0 0.1-3.0 0.1-2.0
Sucralose Sweetening agents 0.1-5.0 — 0.1-10
Aspartame Sweetening agents — 0.1-10 —
Simethicone Antifoaming agent 0-20 0-20 0-20
Orange flavor Flavoring agent 0.1-2 — 0.1-2
Strawberry flavor Flavoring agent — 0.1-2 —
Purified water Carrier/vehicle q.s. q.s. q.s.

TABLE 3: Suspension powder for reconstitution

Components Example 9 Example 10 Example 11

Quantity % w/w
Taste masked dmg composite 0.1-10 0.1-5 1-10
Sucrose 10-50 30-45 35-70
Polysorbate 80 1-5 — 1.5
Avicel RC-591 0.1-10 0.1-3.0 —
Xanthan Gum — — 0.1-10
Monosodium dibasic phosphate anhydrous 0.1-5 0.1-2 0.1-3
Methyl paraben 0.1-1.0 0.1-0.5 0.1-1.0
Propyl paraben 0.1-1.0 0.1-0.5 0.1-1.0
Citric acid 0.1-5.0 0.1-3.0 0.1-2.0
Sodium saccharin 0.1-5.0 — 0.1-10
Aspartame — 0.1-10 —
Silicon dioxide 0-20 0-20 0-20
Flavoring agents 0.1-2 0.1-2 0.1-2

WE CLAIM:

1. An immediate release suspension dosage form comprising:
a) a composite comprising solifenacin or a pharmaceutically acceptable salt thereof and a taste masking agent selected from ion exchange resins, cyclodextrins, ammonioalkyl methacrylate copolymers; and
b) a suspending agent selected from xanthan gum, carrageenan, hydroxylpropylmethyl cellulose, microcrystalline cellulose, pullulan, dextrin, pectin, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate and mixtures thereof and
wherein the blending amount ratio by weight of the suspending agent to solifenacin or its salt thereof and taste masking agent is less than 1.
2. The immediate release suspension dosage form as claimed in claim 1, wherein the ratio of solifenacin: taste masking agent ranges from 0.1:10 to about 10:0.1 by weight.
3. The immediate release suspension dosage form as claimed in claim 1, comprising solifenacin or its salt thereof from about 0.1 mg/mL to about 10 mg/mL wherein the pH of the composition is from 4.0 to 8.0 and viscosity from 100-1200 cps.
4. The immediate release suspension dosage form as claimed in claim 1, wherein the dosage form comprises one or more pharmaceutically acceptable excipients selected from the group comprising diluents, preservatives, antioxidants, carrier, antifoaming agents, pH adjusting agents, anticaking agents, surfactants, coloring agents, sweetening agents and flavoring agents.

5. The immediate release suspension dosage form as claimed in claim 4, wherein the pharmaceutical^ acceptable carrier is selected from aqueous and non¬aqueous carrier.
6. The immediate release suspension dosage form as claimed in claim 1, wherein the suspending agent is present from about 0.1 to 10% w/w.
7. The immediate release suspension dosage form as claimed in claim 1, wherein taste masking agent is selected from cyclodextrins like SBE7-P-CD, P-cyclodextrin, y-cyclodextrin or hydroxypropyl P-cyclodextrin or mixtures thereof, ion exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as Purolite, Amberlite IRP-69, Amberlite IRP-88, polacrillin potassium and Dowex-50, methyl methacrylates copolymers such as Eudragit RS, Eudragit RL, EPO, Eudragit RSI00, Eudragit RL100, cellulose esters such as cellulose acetate and cellulose propionate, cellulose acetate phthalate, and hydroxypropylmethyl cellulose phthalate; veegum, bentonite, silica gel, silicates, ethyl cellulose, hydroxyl methyl propyl cellulose, carrageenan, alginates, sweeteners, flavors and combinations thereof.
8. The immediate release suspension dosage form as claimed in claim 1, wherein the composition comprises:

a) a composite comprising solifenacin or a pharmaceutically acceptable salt thereof is from about 0.01-10% w/w;
b) taste masking agent selected from cyclodextrins or ion exchange resins is from about 0.1-10%) w/w;
c) a suspending agent from about 0.1-20% w/w;
d) one or more diluents and/or sweetening agents selected from sugars and sugar alcohols is from about 10-90%> w/w;
e) one or more preservative from about 0.01-2%> w/w;

f) one or more antifoaming agents from about 0. l-5%w/w;
g) one or more pH adjusting agents to maintain the pH of the composition in the range of about 4.0 to about 8.0 from about 0.1-5% w/w;
and a pharmaceutically acceptable liquid carrier; wherein the blending amount ratio by weight of the suspending agent to solifenacin or a pharmaceutically acceptable salt thereof and taste masking agent is less than 1.
9. The immediate release suspension dosage form as claimed in claim 1, wherein
the suspension dosage form is provided in a kit comprising: (a) an immediate
release oral pharmaceutical suspension dosage form comprising solifenacin or its
salt thereof with one or more pharmaceutically acceptable excipients and/or
carrier; (b) a dispensing and/or dosing syringe or a measuring cup for
administering the composition; and (c) optionally, instructions for preparation
and use.
10. An immediate release suspension dosage form prepared by a process
comprising the following steps:
a) preparing a composite by dissolving / dispersing one or more taste masking agent in a portion of water and/or liquid carrier and dispersing solifenacin or its pharmaceutically acceptable salts to form a dispersion;
b) mixing suspending agent and one or more pharmaceutically acceptable excipients in another portion of water;
c) adding the mixture of step b) to the dispersion of step a);
d) optionally adding one or more pharmaceutically acceptable excipients to the final dispersion of step c); and
e) optionally homogenizing the mixture of step d) to form a suspension.