DESC:FIELD OF THE INVENTION
This invention in general relates to a stable pharmaceutical composition comprising multiparticulate systems of solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. More particularly, the multiparticulate systems of solifenacin or its salts can be formulated into a rapidly disintegrating tablet dosage form or into a unit dosage form which can be dispensed in a sachet. The invention also provides a process for manufacturing such compositions.

BACKGROUND OF THE INVENTION

Solifenacin succinate is one of the muscarinic receptor antagonist developed for treating contraction of overactive bladder with associated problems such as increased urination frequency and urge incontinence. Chemically it is butanedioic acid, compounded with (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (1:1) having a molecular weight of 480.55.
Solifenacin succinate is represented by the following formula:

Solifenacin succinate is approved for oral administration as tablet dosage form in US under the tradename VESICARE®. Also, it is marketed as orally disintegrating tablet dosage form by Astellas Pharma in Japan under the tradename VESICARE® OD tablets.

The marketed composition of VESICARE® OD tablet contains Ethyl acrylate-methyl methacrylate copolymer, polyoxyethylene nonylphenyl ether, ammonioalkyl methacrylate copolymer, americium powder (candy powder), magnesium stearate, cellulose, sorbic acid, polysorbate 80, macrogol, D-mannitol, methyl cellulose, dihydrogen phosphate sodium and pH regulator. Vesicare® OD tablet 5 mg is orally administered to adults once a day. The dose may be increased or decreased according to age and symptoms, but the maximum daily dose should be up to 10 mg.
Pharmaceutical compositions exist to optimize the delivery of a pharmaceutical active to its site of release. Compliance has become a major problem, particularly for pediatric and geriatric patients or certain patients who already have difficulty in swallowing solid medications. Oral liquid formulations such as suspension pharmaceutical compositions have been developed as an alternative to tablets in order to circumvent this problem; however, suspensions are often thermodynamically unstable and may result in aggregation and sedimentation 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.
It is often desirable to have a tablet that disintegrates and disperses rapidly in the mouth without requiring water intake or a multiparticulate which can be sprinkled on food. Such tablets or multiparticulates are easier for the elderly and children who often have difficulty in swallowing capsules or tablets.
Patient convenience leads to compliance with the prescribed dosing regimen and, as a consequence, to enhanced therapeutic benefit. Orally disintegrating tablets and multiparticulates are a viable alternative for convenient administration of drugs to patients who have difficulty in swallowing.

US patent 6,017,927 assigned to Astellas Pharma discloses solifenacin succinate as product generically.

US patent 8,039,482 assigned to Astellas Pharma discloses a pharmaceutical composition of solifenacin or a salt thereof for use in a solid formulation containing crystalline and amorphous solifenacin together with an inhibitor of an amorphous preparation, wherein the inhibitor of an amorphous preparation is a substance having an ethylene oxide chain.

US patent 9,050,249 assigned to Astellas Pharma discloses an oral pharmaceutical composition in timed-release particle form as fast-disintegrating tablets. In this patent, inventors attempted to suppress the drug release for a specific time inside the oral cavity in order to mask the unpleasant taste of the drug and to prevent absorption of the drug in the oral cavity, further they attempted to quickly release the drug from the oral pharmaceutical composition in particle form in the gastrointestinal tract in order to attain pharmacological effects.

The prior art composition comprises particles that contain a drug at the core of the pharmaceutical composition in particle form, wherein the core is not pre-coated; a middle layer that contains two types of water-soluble components, an insolubilizer and an insolubilizing substance; and an outer layer for controlling water penetration that contains a water-insoluble substance, one more outer layer is coated over the middle layer to obtain a longer lag time and to suppress the initial drug release.

The above mentioned prior art attempted to develop orally timed release fast disintegrating tablet dosage form wherein the manufacturing processes are complicated, time consuming and costly. Moreover, control of the manufacturing process is difficult due to various challenges associated with drug layering and control of critical process parameters. Hence, there exists a need in the pharmaceutical art to develop a simple, reproducible and cost-effective manufacturing process for preparing stable timed release orally disintegrating tablet dosage form of solifenacin or its salts which offer desired technical attributes and also masks the bitter taste of the drug.
The inventors of the present invention developed a stable timed release orally disintegrating tablet with desirable pharmaceutical attributes prepared by a process which is simple, cost effective and reproducible.

SUMMARY OF THE INVENTION
The present invention relates to a multiparticulate (MUPs) based pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a process for preparing the same. The present invention also relates to a MUPs based pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof prepared by core coat system or hot melt extrusion process, wherein the composition is free of polyethylene glycol (PEG).

One embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof comprising:
a) an inert core coated with one or more water soluble polymer optionally having other pharmaceutically acceptable excipients
b) a drug layer comprising of solifenacin or its salt thereof and one or more water soluble polymer optionally having other pharmaceutically acceptable excipients, wherein the drug layer is substantially free of polyethylene glycol
c) an outer layer comprising a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof, one or more water soluble polymer and one or more pharmaceutically acceptable excipient wherein the drug layer is substantially free of polyethylene glycol
c) a middle layer comprising one or more water soluble polymers and is substantially free of insolubilizer
d) an outer layer comprising a pH-independent polymer and
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof, one or more water soluble polymer and an insolubilizer wherein the drug layer is substantially free of polyethylene glycol
c) an outer layer comprising of a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) a core comprising drug, an insolubilizer and one or more pharmaceutically acceptable excipients
b) a middle layer comprising one or more water soluble polymer and is substantially free of polyethylene glycol
c) an outer layer comprising a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
In yet another embodiment, the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof and one or more water soluble polymer, wherein the drug layer is substantially free of polyethylene glycol
c) a middle layer comprising one or more water soluble polymers and an insolubilizer, wherein the amount of insolubilizer is less than 20% in terms of the weight of the middle layer
d) an outer layer comprising a pH-independent polymer and
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
In another embodiment, the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) a core comprising solifenacin or its salts thereof and one or more pharmaceutically acceptable excipients, wherein said core is prepared by extrusion/ spheronization method, wherein the core is substantially free of polyethylene glycol
b) an outer layer comprising a pH-independent polymer and
c) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
Yet another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form is prepared by:
a) mixing solifenacin and one or more pharmaceutically acceptable water insoluble polymer with one or more suitable solvents to form a wet mass;
b) extruding the mass to obtain an extrudate
c) spheronizing the extrudate to obtain a plurality of spherical pellets; and
d) drying of the pellets, wherein the pellets are substantially free of polyethylene glycol
e) coating the pellets with pH independent polymer and
f) mixing extra granular excipients with the coated pellets for compressing the coated pellet into a tablet dosage form or for dispensing the coated granules into sachet.

The pH independent polymer in the above mentioned embodiment is used in an amount to mask the bitter taste of the drug and will not retard the release of the drug in the gastrointestinal tract. Extra granular excipients comprise of one or more diluents/fillers, binders, disintegrants, surfactants, stabilizers, water soluble polymers, water insoluble polymers, insolubilizers, antioxidants, pH modifiers, lubricants, glidants, flavouring agents, sweeteners and combinations thereof.

Yet another embodiment of the present invention relates to an orally disintegrating tablet comprising: a multiparticulate comprising solifenacin or its salts and one or more pharmaceutically acceptable excipient selected from diluents/fillers, binders, disintegrants, surfactants, stabilizers, water soluble polymers, water insoluble polymers, insolubilizers, antioxidants, pH modifiers, lubricants, glidants, flavouring agents and sweeteners which is prepared by extrusion/ spheronization method and the multiparticulate is substantially free of polyethylene glycol.

In an embodiment of the present invention relates to an orally disintegrating tablet comprises of a core comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and one or more pharmaceutically acceptable excipients, wherein said core is prepared by roller compaction method; wherein the one or more pharmaceutically acceptable excipient comprises of water insoluble polymer. Further comprising an outer layer of a pH-independent polymer and extra granular excipients for compressing the coated granules into a tablet dosage form.

In another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form wherein said composition is prepared by:
a) forming a blend of solifenacin or its salts thereof and one or more pharmaceutically acceptable water insoluble polymer
b) applying pressure to blend of step a) to form a compact, and milling the compact to form a granulate, wherein the granules are substantially free of polyethylene glycol; further comprising an outer layer of a pH-independent polymer and mixing extra granular excipients with coated granules for compressing the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprises:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof and a water soluble polymer, optionally having other pharmaceutically acceptable excipients, wherein the drug layer is substantially free of polyethylene glycol
c) a middle layer comprising one or more water insoluble polymers wherein the middle layer is substantially free of insolubilizer
d) an outer layer of pH independent polymer for masking the taste, wherein the ratio of the outer layer to core containing drug is less than 7.5% w/w or more than 20.0% w/w, preferably less than 6.0% w/w or more than 18.0% w/w based on the weight of outer layer
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Yet another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in the form of powder for oral suspension/solution.
Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in particle form having expected bulk density and tapped density.

Yet another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in particle form, wherein the composition exhibits an expected release profile.

In another embodiment, the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in particle form which is stable at 40 °C and 75% relative humidity at least for a period of about 3 months.

In further embodiment, the present invention includes method of using a MUPs based pharmaceutical composition of solifenacin or its salts in particle form in the treatment of urgency, urinary frequency and urinary incontinence in overactive bladder.

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 solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention includes, but is not limited to, pellets, beads, minitabs, particle form, spherules, granules, beadlets, microcapsules, millispheres, microspheres, tablets, orally disintegrating tablets or powder for oral suspension, powder for solution, capsules, sachets, and the like. Preferably, the pharmaceutical composition refers to particle form. More preferably, the pharmaceutical composition refers to an orally disintegrating tablets or powder for oral suspension, capsules, pellets, sachets, and the like.
The term “particle form” used herein refers to a plurality of discrete or aggregated particles, pellets, beads, spheroids, granules, spheres or mixture thereof, irrespective of their size, shape or morphology.
“Solifenacin” as used herein refers to the free acid form, its salts, esters, solvates, polymorphs, enantiomers or mixtures thereof. Preferably, the salt of solifenacin used here is solifenacin succinate.
The term “core” as used herein refers to pellets/spheres, granules comprising a drug, at least one or more pharmaceutically acceptable inert excipients.
The phrase “inert core,” as used herein, includes core that may be microcrystalline cellulose spheres, sugar spheres, non-pariel seeds, and water insoluble and non-swellable beads.
The “dry powder composition” or “unit dosage form” or “powder for oral suspension” can be in the form of powder, granules, pellets, bead, cores, spheroids or multiparticulates.
The phrase “MUPs based pharmaceutical composition,” as used herein, means that the drug will not be released in the mouth after disintegration, but will be released in the GI tract with the lag time of 2-20 minutes. Also the MUPs based composition is in the form of a tablet, capsule, orally disintegrating tablets, powder for oral suspension, dispersible tablets and the like.
The multiparticulates, pellets/spheres and granules can be dispensed in a sachet or bottle pack.
The term "excipient" means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like as known in the art. 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 present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
As used herein, the term "about" means ± approximately 10% of the indicated value.
The term “w/w” as used herein refers the total weight of the core or various layers of the composition.
The term “substantially free” as used herein refers to the amount which is in range from 0-5% w/w by total weight of composition, preferably less than 4%, less than 3 %, less than 2% and more preferably less than 1%.

The present invention relates to a multiparticulate (MUPs) based pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and a process for preparing the same. The present invention also relates to a MUPs based pharmaceutical composition comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof prepared by core coat system or hot melt extrusion process, wherein the composition is free of polyethylene glycol (PEG).

One embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof comprising:
a) an inert core coated with one or more water soluble polymer optionally having other pharmaceutically acceptable excipients
b) a drug layer comprising of solifenacin or its salt thereof and one or more water soluble polymer optionally having other pharmaceutically acceptable excipients, wherein the drug layer is substantially free of polyethylene glycol
c) an outer layer comprising a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof, one or more water soluble polymer and one or more pharmaceutically acceptable excipient wherein the drug layer is substantially free of polyethylene glycol
c) a middle layer comprising one or more water soluble polymers and is substantially free of insolubilizer
d) an outer layer comprising a pH-independent polymer and
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof, one or more water soluble polymer and an insolubilizer wherein the drug layer is substantially free of polyethylene glycol
c) an outer layer comprising of a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) a core comprising drug, an insolubilizer and one or more pharmaceutically acceptable excipients
b) a middle layer comprising one or more water soluble polymer and is substantially free of polyethylene glycol
c) an outer layer comprising a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
In yet another embodiment, the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof and one or more water soluble polymer, wherein the drug layer is substantially free of polyethylene glycol
c) a middle layer comprising one or more water soluble polymers and an insolubilizer, wherein the amount of insolubilizer is less than 20% in terms of the weight of the middle layer
d) an outer layer comprising a pH-independent polymer and
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
In another embodiment, the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising:
a) a core comprising solifenacin or its salts thereof and one or more pharmaceutically acceptable excipients, wherein said core is prepared by extrusion/ spheronization method, wherein the core is substantially free of polyethylene glycol
b) an outer layer comprising a pH-independent polymer and
c) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
Yet another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form is prepared by:
a) mixing solifenacin and one or more pharmaceutically acceptable water insoluble polymer with one or more suitable solvents to form a wet mass;
b) extruding the mass to obtain an extrudate
c) spheronizing the extrudate to obtain a plurality of spherical pellets; and
d) drying of the pellets, wherein the pellets are substantially free of polyethylene glycol
e) coating the pellets with pH independent polymer and
f) mixing extra granular excipients with the coated pellets for compressing the coated pellet into a tablet dosage form or for dispensing the coated granules into sachet.

The pH independent polymer in the above mentioned embodiment is used in an amount to mask the bitter taste of the drug and will not retard the release of the drug in the gastrointestinal tract. Extra granular excipients comprise of one or more diluents/fillers, binders, disintegrants, surfactants, stabilizers, water soluble polymers, water insoluble polymers, insolubilizers, antioxidants, pH modifiers, lubricants, glidants, flavouring agents, sweeteners or the like.

Yet another embodiment of the present invention relates to an orally disintegrating tablet comprising: a multiparticulate comprising solifenacin or its salts and one or more pharmaceutically acceptable excipient selected from diluents/fillers, binders, disintegrants, surfactants, stabilizers, water soluble polymers, water insoluble polymers, insolubilizers, antioxidants, pH modifiers, lubricants, glidants, flavouring agents and sweeteners which is prepared by extrusion/ spheronization method and the multiparticulate is substantially free of polyethylene glycol.

In an embodiment of the present invention relates to an orally disintegrating tablet comprises of a core comprising solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and one or more pharmaceutically acceptable excipients, wherein said core is prepared by roller compaction method; wherein the one or more pharmaceutically acceptable excipient comprises of water insoluble polymer. Further comprising an outer layer of a pH-independent polymer and extra granular excipients for compressing the coated granules into a tablet dosage form.

In another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form wherein said composition is prepared by:
a) forming a blend of solifenacin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and one or more pharmaceutically acceptable water insoluble polymer
b) applying pressure to blend of step a) to form a compact, and milling the compact to form a granulate, wherein the granules are substantially free of polyethylene glycol; further comprising an outer layer of a pH-independent polymer and mixing extra granular excipients with coated granules for compressing the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.
Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprises:
a) an inert core coated with one or more water soluble pharmaceutically acceptable polymers
b) a drug layer comprising solifenacin or its salts thereof and a water soluble polymer, optionally having other pharmaceutically acceptable excipients, wherein the drug layer is substantially free of polyethylene glycol
c) a middle layer comprising one or more water insoluble polymers wherein the middle layer is substantially free of insolubilizer
d) an outer layer of pH independent polymer for masking the taste, wherein the ratio of the outer layer to core containing drug is less than 7.5% w/w or more than 20.0% w/w, preferably less than 6.0% w/w or more than 18.0% w/w based on the weight of outer layer
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts thereof in particle form comprising
a) an inert core coated with one or more water soluble polymer optionally having one or more pharmaceutically acceptable excipients
b) a drug layer comprising solifenacin or its salts thereof and one or more water soluble polymer optionally having other pharmaceutically acceptable excipients and/or and an insolubilizer, wherein drug layer is substantially free of polyethylene glycol
c) optionally a middle layer comprising one or more water soluble polymers and is substantially free of insolubilizer
d) an outer layer comprises of a pH-independent polymer and
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

Yet another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in the form of powder for oral suspension/solution.

Another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in particle form having expected bulk density and tapped density.

Yet another embodiment of the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in particle form, wherein the composition exhibits an expected release profile.

In another embodiment, the present invention relates to a MUPs based pharmaceutical composition of solifenacin or its salts in particle form which is stable at 40 °C and 75% relative humidity at least for a period of about 3 months.

In further embodiment, the present invention includes method of using a MUPs based pharmaceutical composition of solifenacin or its salts in particle form in the treatment of urgency, urinary frequency and urinary incontinence in overactive bladder.

Another embodiment of the present invention includes the pharmaceutical compositions in particle form comprising solifenacin succinate prepared by using dry granulation, dry blending, extrusion spheronization or wet granulation process, fluidized bed coating of particle form or the like known in art. Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate, ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol, dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during process is water.
One embodiment of the invention encompasses the pharmaceutical compositions in particle form comprising solifenacin or its salts thereof and a pharmaceutically acceptable excipient selected from at least one of diluents/fillers, binders, disintegrants, surfactants, stabilizers, water soluble polymers, water insoluble polymers, insolubilizers, antioxidants, pH modifiers, lubricants, glidants, flavouring agents and sweeteners or the like.
In another embodiment, the present invention relates to the pharmaceutical composition comprising low amount of intermediate/ pH independent polymer coating as compared to amount used in conventional coatings, wherein the amount of coating comprises from 0.1% w/w to 5.0% w/w, preferably 0.1% w/w to 4.0% w/w of the composition.
Diluents or fillers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. Diluent may constitute from about 10% w/w to about 95% w/w of the total composition.
Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, microcrystalline cellulose, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch, pregelatinised starch, polyvinyl alcohol, or mixtures thereof. The binder may constitute from about 1% w/w to about 20% w/w of the total composition.

Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof.
Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available SEPITRAP® 80 or SEPITRAP® 4000 etc. The surfactant may constitute from about 0.1% w/w to about 5% w/w of the total composition.
The term disintegrant also includes superdisintegrant. The disintegrants used in the composition includes but not limited to, natural, modified or pre-gelatinized starch, carboxymethylcellulose, starch, crospovidone, microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and the like or mixtures thereof in the range of about 0.1 to 20 % w/w. Effervescent disintegrating systems can also be employed. A disintegrant may be employed singularly or more than one disintegrants may also be employed. Higher concentrations of disintegrants may as well be employed.
Alkaline agent may be used generally to provide a microenvironment of pH above 7 around the active ingredient but it also gives effervescence effect when come into contact with gastric juice. Suitable alkaline agents include, but are not limited to, pharmacologically alkali metal, alkaline earth metal or metal salts of weak acids such as sodium carbonate which can be anhydrous or hydrous, calcium carbonate and magnesium carbonate and the pharmacologically hydroxides and oxides of alkaline earth and earth metals such as magnesium hydroxide and magnesium oxide. The alkaline agent may constitute from about 0.1% w/w to about 10% w/w of the total composition.
Suitable sweeteners used according to present invention are selected from sucralose, aspartame, saccharin sodium and the like or mixtures thereof. Although concentrations lower than 0.1% w/w may be used, the sweetening agent when present in the concentration of 0.1 to 5% w/w, gives better results.
Suitable flavoring agents used according to present invention are selected from mint, orange, lemon, peppermint, vanilla, bubble gum, strawberry, cherry, caramel, raspberry, tutti-fruity, banana and the like or mixtures thereof. Flavoring agent is present in the concentration of 0.1-1.0 % w/w and is satisfactory. Although flavoring agent in lesser concentrations than 0.1 % w/w or in higher concentrations than l% w/w can be used, use of flavoring agent concentration in the vicinity of 0.4 % w/w gives better composition. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavour/s used.
In another embodiment, the MUPs based pharmaceutical composition of the present invention comprise of a particle form comprising solifenacin or its salts thereof from about 1 mg to about 100 mg in the formulation, preferably 1-50 mg, more preferably 1-20 mg.
Additional excipients such as film-forming polymers, plasticizers, antiadherents and opacifiers are used.
Examples of insolubilizers are sodium carbonate, potassium carbonate, monobasic sodium phosphate, dibasic potassium phosphate, dibasic sodium phosphate, sodium metaphosphate, trisodium phosphate, monobasic potassium phosphate, potassium bicarbonate, sodium bicarbonate, ammonium carbonate, sodium polyphosphate, sodium pyrophosphate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium sulfite, sodium bisulfite, sodium hydroxide, sodium citrate, dibasic sodium citrate, monosodium glutamate, arginine glutamate, disodium succinate, calcium acetate, glycine, alanine, sorbitol, xylitol, inositol, sucrose, glucose, and fructose, as well as hydrides thereof. Preferred examples are sodium carbonate, monobasic sodium phosphate, dibasic sodium phosphate, sodium citrate, and dibasic sodium citrate, as well as hydrates thereof. Combination of two or more of these insolubilizers can also be used if needed. The insolubilizer may constitute from 0-5 % w/w of the total composition.

Various water-soluble polymers are used in the composition. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. If desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking agents, and the like, wherein the water soluble polymer is present in an amount from about 1% to about 30% of the total weight of the coated granules or tablet dosage form.

Various water insoluble polymers/ polymers suitable for use in the present invention include, but are not limited to, all the pH independent polymers like various grades of Eudragit: Eudragit®RL PO, Eudragit®RL 100, Eudragit®RL 30D, Eudragit®RL 12, 5, Eudragit®NE 30 D, Eudragit®NE40 D, Eudragit®NM 30 D etc. Other water insoluble polymers/enteric polymers may be selected from cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), ethylcellulose (EC), polyvinyl acetate phthalate methylcellulose acetate phthalate (MCAP) and methacrylic acid copolymers or its derivatives. Methacrylic acid copolymers or its derivatives are available under various trade names such as EUDRAGIT®, Acryl-EZE®, Eastacryl®, and Kollicoat® from Evonik Industries, Colorcon, Eastman Chemical and BASF Fine Chemicals respectively. Preferably, enteric coating polymers suitable for use in the present invention are Eudragit S100, Eudragit L100, Poly(methacrylic acid-co-methyl methacrylate), Cellulose acetate trimellitate (CAT), Poly(vinyl acetate phthalate) (PVAP), Hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS).
The pH independent polymer is selected from methacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methylcellulose, xanthum gum, polyethylene oxide and carboxypolymethylene; wherein the pH independent polymer is present in an amount from about 1% to about 40% of the total weight of the coated granules or tablet dosage form.
In another embodiment the present invention includes particle form of solifenacin or its salts thereof, prepared as per 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 + (1/n)St=1n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 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 method for the preparation of pharmaceutical composition of solifenacin or its salts thereof. 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. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.

EXAMPLES
The following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature.
TABLE 1
Composition Example
I II III IV
S. No. Ingredients % w/w
A. Core
1. Inert spheres 5-70 5-70 5-70 5-80
B. Seal coat
2. HPMC 0.1-5 0.1-5 -- --
3. PVP -- -- 0.1-5 0.1-5
C. Drug layer
4. Solifenacin succinate 1-40 1-40 1-40 1-40
5. HPMC 1-5 -- 1-5 --
6. Ethyl cellulose -- 1-5 -- 1-5
7. Sodium bicarbonate 0-5 -- -- --
8. Sodium citrate -- -- 0-5 --
D. Middle layer
9. Eudragit 1-5
10. Hydroxypropyl methylcellulose -- 1-4 0-5 --
11. Sodium bicarbonate -- 0-5 -- --
12. Sodium citrate 0-5 -- -- --
13. Acetone q.s. q.s. -- --
14. Isopropyl alcohol -- -- q.s. --
15. Purified water q.s. q.s. q.s. --
16. Acetone: Isopropyl alcohol (1:1) -- -- -- --
E. Outer layer
17. Methacrylic acid copolymer 0.1-5 -- 0.1-5 --
18. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) -- 0.1-5 -- --
19. HPMC -- -- -- 0.1-5
20. Talc 1-5 1-5 1-4 1-6
21. Purified Water q.s. q.s. q.s. q.s.
F. Extragranular
22. Mannitol 20-50 15-40 -- --
23. Xylitol -- -- 15-45 --
24. Sucrose -- -- -- 5-30
25. Sucralose 0.5-2 -- -- 0.5-2
26. Aspartame -- 0.5-2 -- --
27. Sodium Saccharin -- -- 0.5-2 --
28. Flavoring agent 0.1-2 0.1-2 0.1-2 0.1-2
29. Talc 1-10 1-8 2-6 1-10
30. Magnesium stearate 0.5-5 1-3 0.5-2 1-5

Preferred method of manufacture: Fluidized-Bed Process
Example I, II and III can be dispensed as powder for oral suspension into a sachet.
Example I, II, III and IV can be compressed into orally disintegrating tablets.

We Claim:
1. A multiparticulate pharmaceutical composition of solifenacin or its salts thereof comprising
a) an inert core coated with one or more water soluble polymers optionally having one or more pharmaceutically acceptable excipients
b) a drug layer comprising solifenacin or its salts thereof and one or more water soluble polymers optionally having other pharmaceutically acceptable excipients and/or an insolubilizer, wherein drug layer is substantially free of polyethylene glycol
c) optionally a middle layer comprising one or more water soluble polymers and is substantially free of insolubilizer
d) an outer layer comprises of a pH-independent polymer and
e) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

2. The multiparticulate pharmaceutical composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from one or more diluents/fillers, binders, disintegrants, surfactants, stabilizers, water soluble polymers, water insoluble polymers, insolubilizers, antioxidants, pH modifiers, lubricants, glidants, flavouring agents, sweeteners and combinations thereof.

3. The multiparticulate pharmaceutical composition according to claim 1, wherein the pH independent polymer is selected from methacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methylcellulose, xanthum gum, polyethylene oxide and carboxypolymethylene.

4. The multiparticulate pharmaceutical composition according to claim 3, wherein the pH independent polymer is present in an amount from about 1% to about 40% of the total weight of the coated granules or tablet dosage form.

5. The multiparticulate pharmaceutical composition according to claim 1, wherein the water soluble polymer is selected from cellulose derivatives such as soluble alkyl or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum arabic,xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof.

6. The multiparticulate pharmaceutical composition according to claim 5, wherein the water soluble polymer is present in an amount from about 1% to about 30% of the total weight of the coated granules or tablet dosage form.

7. The multiparticulate pharmaceutical composition according to claim 1, wherein said composition contains solifenacin or its salts thereof in an amount from about 1 mg to about 20 mg.

8. The multiparticulate pharmaceutical composition according to claim 1, wherein the composition is an orally disintegrating tablet or powder for oral suspension.

9. A multiparticulate pharmaceutical composition of solifenacin or its salts in particle form comprising:
a) a core comprising solifenacin or its salts thereof, an insolubilizer and one or more pharmaceutically acceptable excipients
b) a middle layer comprising one or more water soluble polymer and is free of polyethylene glycol
c) an outer layer comprising a pH-independent polymer and
d) extra granular excipients to compress the coated granules into a tablet dosage form or for dispensing the coated granules into sachet.

10. A process for preparing a multiparticulate pharmaceutical composition of solifenacin or its salts thereof according to claim 1 comprises of:
a) coating an inert core with one or more water soluble polymer
b) layering an active layer on the surface of the inert core comprising solifenacin or its salts thereof and one or more water soluble polymer and
c) layering a polymeric layer over the active layer, wherein the polymeric layer comprises of a pH-independent polymer
d) mixing the extra granular excipients with multiparticulates of step (c)
e) compressing the coated granules into a tablet dosage form or dispensing the coated granules into sachet.