DESC:TECHNICAL FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical liquid composition for oral administration comprising solifenacin or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the active ingredient has an average particle size of not more than 20 microns. It further relates to a stable pharmaceutical liquid compositions comprising a complex between solifenacin or its pharmaceutically acceptable salt thereof and ion exchange resin complexing agent, and a suspending agent.

BACKGROUND OF THE INVENTION
Solifenacin is a competitive muscarinic receptor antagonist which is selective for the M3 receptor of muscarinic receptor subtypes. Its binding to the muscarinic receptor modulates cholinergically mediated functions including the contraction of smooth muscle and, in particular, relaxes smooth muscle tone in the urinary bladder. It causes significant reduction in urgency incontinence episodes and improves urodynamic parameters in patients with neurogenic detrusor overactivity (NDO).
Chemically, solifenacin is (1S)-(3R)-1-azabicyclo [2.2.2] oct-3-yl3, 4-dihydro-1-phenyl-2(1H)iso-quinolinecarboxylate. It has the following structure:

Solifenacin is disclosed in U.S. Pat. Nos. 6,017,927 and 6,174,896. Solifenacin succinate is commercially available as film-coated tablets and as oral suspension under the brand name VESICARE®. It is indicated for symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder.
Liquid formulations are suitable for administration to patients who are unable to take solid dosage form (critically ill patients, children, elderly, patients suffering from dysphagia) or patients who are either unwilling or unable to swallow tablets or capsules. There exists a need in the art to develop alternate liquid compositions of solifenacin.
It is known that solifenacin and a salt thereof has very high solubility in various solvents and very strong bitterness and astringency. Therefore, in order to develop an oral liquid formulation, there is a need to mask the bitterness and astringency.
PCT Publication No. WO 2011/145642 discloses pharmaceutical suspension containing a complex between solifenacin or a pharmaceutically acceptable salt thereof and an ion exchange resin (polacrilin potassium), and an acrylic based polymer (carbomer Homopolymer Type B). It discloses that acrylic based polymers are necessary to obtain suspension with good dispersion stability. The alkaline agents are required to neutralize Carbomer Homopolymer B to cause gelation.
PCT Publication No. WO 2018/154495 discloses an oral solution of muscarinic receptor antagonist that is free from allergic preservatives. The flavored liquid solution masks the bitter taste of anti-muscarinic agent.
PCT Publication No. WO 2005/092889 discloses that if the amorphous content of solifenacin in the composition becomes greater, the amount of degradation product in the composition increases and exceeds 0.4% limit, and the composition becomes unstable. It further discloses a solid formulation comprising solifenacin or salts thereof and an inhibitor of the amorphous preparation wherein the amorphous content is within a range (i.e. not more than 77%) with no influence on product stability.
PCT Publication No. WO 2009/012987 discloses a stable pharmaceutical composition comprising solifenacin or a pharmaceutically acceptable salt thereof in amorphous form and a stabilizer. The amorphous solifenacin or salt thereof is stabilized by the stabilizer.
It is known in general, that a drug substance in an amorphous state has a characteristic that it is easily decomposed and deteriorates in stability as compared with a crystalline state. However, amorphous form has higher bioavailability and is therefore desirable. The solubility of amorphous state is high and the absorption speed in the stomach and intestine is superior compared to the crystalline state.
The inventors of the present invention have developed a stable oral suspension composition of solifenacin or pharmaceutically acceptable salt, comprising a complex between solifenacin or its pharmaceutically acceptable salt thereof and ion exchange resin complexing agent, and a suspending agent other than acrylic based polymer. The suspension of present invention has good dispersion stability and re-suspendability without the use of any acrylic based polymers. Further the suspension of present invention has less than 0.5% w/w of solifenacin N-oxide as impurity during storage for 12 months and shows good dissolution release profile.

SUMMARY OF THE INVENTION
The present invention relates to a stable pharmaceutical suspension composition for oral administration comprising solifenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

In one embodiment, wherein the solifenacin or its pharmaceutically acceptable salt has the average particle size (D50) of not more than 20 microns.
In another embodiment, D90 particle size of solifenacin or its pharmaceutically acceptable salt is not more than 50 microns.
In another embodiment, D10 particle size of solifenacin or its pharmaceutically acceptable salt is not more than 10 microns.
In another embodiment, the solifenacin or a pharmaceutically acceptable salt thereof is solifenacin succinate.
In another embodiment, the solifenacin or a pharmaceutically acceptable salt thereof is present in the liquid suspension as a complex with an ion exchange resin.
In another embodiment, the pharmaceutical liquid suspension contains polacrilin potassium as an ion exchange resin complexing agent.
In another embodiment, the pharmaceutically acceptable excipients include, but are not limited to complexing agent, suspending agent, sweetening agent, preservative, antifoaming agent, viscosity modifier, buffering agent (pH modifier), flavoring agent and a solvent.
In another embodiment, the solvent used for formulating a suspension is an aqueous solvent.
In another embodiment, the pharmaceutical liquid suspension contains blend of microcrystalline cellulose and carboxymethyl cellulose (Avicel®RC-591) as a suspending agent.
In another embodiment, the pharmaceutical liquid suspension contains carboxymethyl cellulose sodium as a viscosity modifier.
In another embodiment, the buffering agent present in the pharmaceutical liquid suspension acts as a pH modifier.
In another embodiment, the pharmaceutical liquid suspension of the present invention does not contain any acrylic based polymer.
In another embodiment, the pharmaceutical liquid suspension of the present invention does not contain acesulfame potassium.
In another embodiment, the pH of the pharmaceutical liquid suspension is from about 3.0 to about 7.0, preferably from 3.5 to about 6.5, more preferably about 5.0.
In another embodiment, the pharmaceutical liquid suspension has viscosity of from about 10 cPs to about 500 cPs, preferably from 30cPs to 300 cPs, more preferably from 30 cPs to 130 cPs, when the viscosity is determined at 25°C using a rotational viscometer at 180 rpm.
In another embodiment, the concentration of solifenacin succinate in the pharmaceutical liquid suspension is from about 1mg/ml to about 10mg/ml.
In another embodiment, the concentration of solifenacin succinate in the pharmaceutical liquid suspension is 1mg/ml.
In another aspect of the present invention, there is provided a stable pharmaceutical liquid suspension for oral administration comprising a complex between solifenacin succinate and a ion exchange resin complexing agent and a suspending agent, wherein the composition does not contain Carbomer polymer.
In another embodiment of the above aspect, the suspending agent is a cellulose derivative polymer.
In one embodiment of the above aspect, the stable liquid suspension comprising complex between solifenacin succinate and polacrilin potassium, and blend of microcrystalline cellulose and carboxymethyl cellulose (Avicel RC®591).
In another aspect of the present invention, there is provided a stable pharmaceutical liquid suspension for oral administration comprising a complex between solifenacin succinate and polacrilin potassium, and a blend of microcrystalline cellulose and carboxymethyl cellulose (Avicel RC®591), wherein the composition is free of Carbomer polymer.
In another embodiment, the weight ratio of solifenacin to polacrilin potassium in the pharmaceutical liquid suspension is from about 1:1 to about 1:5.
In another embodiment, the weight ratio of solifenacin to cellulosic polymer in the pharmaceutical liquid suspension is from about 1:1 to about 1:50,preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.

In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising a complex containing:
a) solifenacin succinate as an active agent in an amount of about 0.1-5% w/w;
b) Polacrilin potassium as complexing agent in an amount of about 0.5-10% w/w; and
c) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent in an amount of about 1-20% w/w
wherein the ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:10 to 1:30 or from about 1:12 to 1:20.

In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising a complex containing-
a) Solifenacin succinate as an active agent in an amount of about 0.5-1% w/w;
b) Polacrilin potassium as a complexing agent in an amount of about 1-2% w/w; and
c) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent in an amount of about 5-15% w/w
wherein the ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:10 to 1:30 or from about 1:12 to 1:20.

In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising:
a) complex containing solifenacin succinate and polacrilin potassium ;
b) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent;
c) carboxymethyl cellulose sodium as a viscosity modifier; and
d) pharmaceutically acceptable excipients selected from group of sweetening agent, buffering agent, a preservative, antifoaming agent, flavouring agent and a pharmaceutically acceptable liquid carrier (solvent)
wherein the ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:10 to 1:30 or from about 1:12 to 1:20.

In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising:
a) complex containing solifenacin or pharmaceutical salt thereof and polacrilin potassium
b) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent;
c) carboxymethylcellulose sodium as a viscosity modifier;
d) sucralose and xylitol as sweetening agents; and
e) citric acid monohydrate as buffering agent.
wherein the ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:10 to 1:30 or from about 1:12 to 1:20.

In another aspect of the present invention, there is provided a process of preparing a pharmaceutical liquid suspension for oral administration comprising:
(a) Preparing a drug solution by forming a complex between solifenacin and polacrilin potassium.
(b) Preparing a suspension by dispersing blend of microcrystalline cellulose and carboxymethyl cellulose in water followed by addition of aqueous solution of sodium carboxymethyl cellulose, optionally with pharmaceutically acceptable excipients.
(c) Mixing drug solution obtained in step (a) with suspension system of step (b) to form a stable liquid suspension.

In another aspect of present invention, the aforementioned pharmaceutical liquid suspension composition is used for the treatment of urge incontinence or symptoms associated with overactive bladder syndrome.

In another aspect of the invention, the suspension composition contains less than 0.5% w/w of Solifenacin N-oxide as an impurity upon storage for atleast 3 month at 25°C/60%RH.
In another aspect of the invention, the suspension composition contains less than 0.5% w/w of Solifenacin N-oxide as an impurity upon storage for atleast 3 month at 40°C/75%RH.
In another embodiment, the pharmaceutical composition of the present invention wherein 85% or more of solifenacin is release in 15 minutes in a dissolution test described in the United States Pharmacopeia and performed by the paddle method at a paddle speed of 50 rpm using 900 mL of 0.1N HCl as a fluid for the dissolution test and 5 mL of the suspension as described in the present invention.

DETAILED DESCRIPTION OF THE INVENTION

There is provided a pharmaceutical liquid formulation for oral administration comprising therapeutically effective amount of solifenacin or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The active ingredient used for formulating suspension may be either crystalline or amorphous form and has average particle size (D50) of not more than 20 microns. However, during manufacturing process, solifenacin particles form a complex with the ion exchange resin complexing agent and are thus present in substantially dissolved form in the liquid suspension.
In particular, the present invention relates to a stable liquid suspension for oral administration comprising solifenacin succinate, polacrilin potassium as complexing agent, and blend of microcrystalline cellulose and carboxymethyl cellulose sodium (Avicel RC®591) as suspending agent, and one or more pharmaceutically acceptable excipients.
As used herein, a “therapeutically effective amount” is a sufficient amount to provide a therapeutic benefit for the treatment or management of the disease or to delay or minimize symptoms associated with the disease.
The term "pharmaceutically acceptable", as used herein, refers to a compound that is not biologically or otherwise undesirable, i.e., the compound may be incorporated into a pharmaceutical formulation of the invention and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
As used herein, the term “about”, as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term “stable,” as used herein, refers to chemical stability, wherein not more than 1.5% w/w of total related substances are formed on storage at 25°C and 60% relative humidity (RH) or at 40°C and 75% relative humidity (RH) for a period of at least three months to the extent necessary for the sale and use of the composition. Also, the formulation should be physically stable without any visible phase separation of contents when stored at ambient or accelerated conditions for a period of at least three months.
The term “solifenacin,” as used herein, refers to solifenacin and pharmaceutically acceptable salts and derivatives thereof. The term "derivative" of solifenacin includes solifenacin base or salts, enantiomers, analogs, hydrates, solvates, polymorphs, prodrugs, esters, amides, or active metabolites thereof. The pharmaceutically acceptable salts of solifenacin include but are not limited to acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; or with an organic acid such as acetic acid, succinic acid, formic acid, propionic acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, fumaric acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc. In particular the pharmaceutical liquid suspension of the present invention comprises solifenacin succinate. In some embodiments, the solifenacin or its salt is present in a concentration of about 0.1mg/ml to about 30mg/ml, about 0.5mg/ml to about 20mg/ml, about 1mg/ml to about 10mg/ml in the liquid suspension. In some embodiments, the solifenacin or its salt is present in a concentration of about 0.1mg/ml , about 0.2mg/ml, about 0.5mg/ml, about 1mg/ml, about 1.5mg/ml, about 2mg/ml, about 3mg/ml, about 4mg/ml, about 5mg/ml, or about 10mg/ml in the liquid suspension. The solifenacin or salts thereof used for the preparation of the pharmaceutical composition of the present invention is present in crystalline form. Preferably, PXRD pattern exhibit peaks at about 3.7°, 14.2° and 21.0° ± 0.2° 2?. During the manufacturing process, the crystalline form of solifenacin or salts thereof forms a complex with complexing agent and may present in the dissolved form in complex.
The term “pharmaceutically acceptable excipients”, as used herein, includes excipients that may be added to the solifenacin liquid composition. Examples of suitable pharmaceutically acceptable excipients include, but are not limited to complexing agent, suspending agent, sweetening agent, preservative, antifoaming agent, buffering agent, auxiliary suspending agent, flavouring agent, solvent, coloring agent, humectant, antioxidant and mixture thereof.
Examples of complexing agents include, but are not limited to, ion exchange resins, EDTA or cyclodextrin or derivative thereof. An ion-exchange resin having the polymeric matrix with an anionic functional group is a cation exchange resin and that having a cationic functional group is an anionic exchange resin. Examples of cationic exchange resins useful for present invention include, but are not limited to, polacrilin potassium, sodium polystyrene sulfonate, and polacrilex resin. Solifenacin forms a complex with cationic exchange resin, thereby reducing the bitterness and astringency of solifenacin. The complex when dried and analyzed for PXRD is found to be amorphous. Preferred cationic exchange resin is polacrilin potassium NF which is a cross-linked polymer of methacrylic acid and divinylbenzene wherein a weakly acidic salt is formed from a carboxylic acid functional group of the methacrylic acid and potassium (product name: Amberlite (registered trademark) IRP88, Dow Chemical Company).The ion exchange resin is present in an amount of about 0.1 to about 50 %w/w, preferably about 0.5 to about 10 %w/w, more preferably about 0.5 to about 5 %w/w, most preferably about 1 to about 2 %w/w. The ratio by weight of solifenacin to polacrilin potassium is from 1:1 to 1:5.
The suspending agent used for formulating liquid suspension of the present invention provides uniform dispersion of complex particles of solifenacin or its salt and polacrilin potassium in the suspension. Examples of suspending agent include, but are not limited to, cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; and mixtures thereof. The preferred suspending agent is co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium (available under the brand names Avicel RC-501, Avicel RC-581, Avicel RC-591, and Avicel CL-611). Examples of auxiliary suspending agent include, but are not limited to, methyl cellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and combinations thereof. The suspending agent can be present in any concentration that promotes the formation of a stable suspension, typically 1% to 30% by weight of the composition. Preferably, the suspending agent concentration is between 1% to 30%, more preferably 5% to 15% by weight of the composition. When the auxiliary suspending agent is used, it is used in an amount of about 0.05-10 %, preferably about 0.1-3% by weight of the suspension. The weight ratio of solifenacin to suspending agent in the pharmaceutical liquid suspension is from about 1:1 to about 1:30 or preferably from about 1:10 to about 1:30 or more preferably from about 1:12 to about 1:20.
The amount of the cellulose derivative polymer is not particularly limited as long as the amount permits the reduction in precipitation of the drug-ion exchange resin complex in the suspension. Specifically, the blending amount of co-processed spray dried forms of microcrystalline cellulose and Carboxymethyl cellulose Sodium (available under the brand names Avicel RC-501, Avicel RC-581, Avicel RC-591, and Avicel CL-611) is, as one embodiment for example, about 5 mg/mL or more and about 50 mg/mL or less, as another embodiment, it is about 10 mg/mL or more and about 30 mg/mL or less, as still another embodiment, it is about 12 mg/mL or more and about 20 mg/mL or less, although it is suitably determined according to the amount of the drug or ion exchange resin, the type of polymer, the pH, or the like.
Examples of sweetening agents include, but are not limited to, aspartame, acesulfame potassium, sucralose, neotame, or saccharin; sugar or a sugar alcohol such as sucrose, fructose, lactose, sorbitol, mannitol, xylitol, erythritol, or trehalose; and mixture thereof. Preferably, the sweetening agent used in the present invention is sucralose and a sugar alcohol. The amount of the sweetening agent in the composition of the present invention is usually 0.1 to 90% by weight, preferably 0.1 to 80% by weight, more preferably 0.1 to 75% by weight based on the total weight of the suspension for oral administration. In one of the embodiments, the liquid composition does not contain acesulfame potassium.
Examples of preservatives include, but are not limited to, methyl parahydroxy benzoate, ethyl parahydroxy benzoate, propyl parahydroxybenzoate, butyl parahydroxy benzoate, benzoic acid, benzyl alcohol, sorbic acid, acetic acid, or a salt thereof. The amount of the preservative in the composition of the present invention is usually 0.01 to 10% by weight, preferably 0.1 to 2.0% by weight.
Examples of antifoaming agents include, but are not limited to, simethicone, dimethicone, or the like. The amount of the antifoaming agent in the composition of the present invention is usually 0.01 to 10% by weight, preferably 0.1 to 1.0% by weight.
Examples of buffering agents (pH modifier) include, but are not limited to, citric acid, citric acid monohydrate, phosphoric acid, boric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid, or a salt thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, or a salt thereof, magnesium oxide, zinc oxide, magnesium hydroxide, or a salt thereof. The amount of the buffering agent in the composition of the present invention is usually 0.1 to 10% by weight, preferably 0.5 to 2.0% by weight.
Examples of flavouring agent include, but are not limited to, lemon, lemon lime, orange, menthol, strawberry, banana, raspberry, or bubble gum flavor.
Examples of solvents include, but are not limited to, glycerin, propylene glycol, water or the like.
COMPOSITIONS OF THE INVENTION
There is provided a stable pharmaceutical liquid suspension for oral administration comprising a complex between solifenacin succinate and ion exchange complexing agent and a suspending agent, wherein the composition does not contain acrylic based polymer.
A stable pharmaceutical liquid suspension for oral administration comprising a complex between solifenacin succinate and ion exchange complexing agent and a suspending agent, wherein the composition does not contain Carbomer polymer.
The pharmaceutical liquid suspension contains polacrilin potassium as an ion exchange resin complexing agent.
The suspending agent as used in the present invention is a cellulose derivative polymer selected from group of co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and microcrystalline cellulose and its salts/derivatives.
The invention provides a stable pharmaceutical liquid suspension for oral administration comprising a complex between solifenacin succinate and polacrilin potassium, and a blend of microcrystalline cellulose and carboxymethyl cellulose, wherein the composition is free of acrylic based polymer.
The invention provides a stable pharmaceutical liquid suspension for oral administration comprising a complex between solifenacin succinate and polacrilin potassium, and a blend of microcrystalline cellulose and carboxymethyl cellulose, wherein the composition is free of Carbomer polymer.
The weight ratio of solifenacin to polacrilin potassium in the pharmaceutical liquid suspension is from about 1:1 to about 1:5.
The weight ratio of solifenacin to cellulosic polymer in the pharmaceutical liquid suspension is from about 1:1 to about 1:50, preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.
Most preferably, the weight ratio of solifenacin to cellulosic polymer in the pharmaceutical liquid suspension is 1:13.5
The pH of the pharmaceutical liquid suspension is from about 3.0 to about 7.0, preferably from about 3.5 to about 6.5, more preferably about 5.0.
The pharmaceutical liquid suspension has viscosity of from about 10 cPs to about 500 cPs, preferably from about 30 cPs to about 300 cPs, more preferably from about 30 cPs to about 130 cPs, when the viscosity is determined at 25°C using a rotational viscometer at 180 rpm.
The pharmaceutical suspension composition of the present invention does not contain any alkaline agent.
There is provided an aqueous pharmaceutical liquid suspension for oral administration comprising a complex containing:
a) solifenacin succinate as an active agent in an amount of about 0.1-5% w/w;
b) Polacrilin potassium as complexing agent in an amount of about 0.5-10% w/w; and
c) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent in an amount of about 1-20% w/w
wherein the weight ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:1 to about 1:50, preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.
In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising a complex containing-
a) Solifenacin succinate as an active agent in an amount of about 0.5-1% w/w;
b) Polacrilin potassium as a complexing agent in an amount of about 1-2% w/w; and
c) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent in an amount of about 5-15% w/w
wherein the weight ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:1 to about 1:50, preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.
In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising:
a) complex containing solifenacin succinate and polacrilin potassium ;
b) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent;
c) carboxymethyl cellulose sodium as a viscosity modifier; and
d) pharmaceutically acceptable excipients selected from group of sweetening agent, buffering agent, a preservative, antifoaming agent, flavouring agent and a pharmaceutically acceptable liquid carrier (solvent).
wherein the weight ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:1 to about 1:50, preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.
In another aspect of the present invention, there is provided an aqueous pharmaceutical liquid suspension for oral administration comprising:
a) complex containing solifenacin or pharmaceutical salt thereof and polacrilin potassium
b) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent;
c) carboxymethyl cellulose sodium as a viscosity modifier;
d) sucralose and xylitol as sweetening agents; and
e) citric acid monohydrate as buffering agent.
wherein the ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:1 to about 1:50, preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.
Most preferably, the weight ratio of solifenacin to cellulosic polymer in the pharmaceutical liquid suspension is 1:13.5
The advantage of the present invention is that the suspension composition contains less than 0.5% w/w of Solifenacin N-oxide as an impurity upon storage for atleast 3 month at 25°C/60%RH.
Another advantage of the present invention is that no sedimentation is observed in the suspension composition when exposed to stability conditions.
In another embodiment, the suspension composition contains less than 0.5% w/w of Solifenacin N-oxide as an impurity upon storage for atleast 3 months at 40°C/75%RH.
The suspension composition of the present invention contains less than 0.5% w/w of Solifenacin N-oxide as an impurity upon storage for 12 month at 25°C/60%RH.
Another advantage of the invention is to provide a pharmaceutical composition wherein 85% or more of solifenacin is released in 15 minutes in a dissolution test described in the United States Pharmacopeia and performed by the paddle method at a paddle speed of 50 rpm using 900 mL of 0.1N HCl as a fluid for the dissolution test and 5 mL of the suspension as described in the present invention.
The invention also illustrates a detailed process of preparing stable suspension composition of solifenacin comprising the steps of:
(a) dissolving solifenacin in a solvent,
(b) forming a complex between solifenacin and polacrilin potassium at desired pH, and
(c) preparing a suspension (suspension liquid).
Drug solution step: The drug is dissolved in a water-soluble solvent capable of dissolving the drug, whereby a drug solution is obtained. As the water-soluble solvent, water or an aqueous solution of an organic solvent capable of being arbitrarily dissolved in water such as a monohydric alcohol (such as methyl alcohol, ethyl alcohol, or isopropanol) or a ketone (such as acetone or methyl ethyl ketone), glycerin, propylene glycol, or the like can be exemplified.
Formation of complex between solifenacin and polacrilin potassium: Polacrilin Potassium is added to the drug solution under stirring to form a complex.
Formation of suspension: The blend of microcrystalline cellulose and sodium carboxymethylcellulose is hydrated in an aqueous liquid to form a first liquid admixture. The viscosity modifier is added to a liquid to form a second liquid admixture. The first and second liquid admixtures are combined to form the suspending system. Other pharmaceutical excipients like preservatives and sweetening agents are added to the solvent to form a solution which is added to the suspending system followed by addition of the solution of solifenacin complex, further followed by addition of flavor and antifoaming agent to form the pharmaceutical liquid suspension.
The pharmaceutical liquid suspension of the present invention is an immediate release composition. It may be modified by adding controlled release excipients to obtain a controlled release composition.
The pharmaceutical liquid composition of the present invention is administered once, twice or three times over a 24hour period. The composition of the present invention is administered with or without food. Preferable, it is administered once daily without food. The maximum daily dose of solifenacin succinate administered to patient is 10 mg / day. The pharmaceutical liquid suspension comprising solifenacin may be administered in combination with other therapeutic agents
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLES
Reference Example:
Table 1:
Sr. No. Components Batch No. T896/1/08-18/031
mg/mL
1 Solifenacin Succinate 1.00
2 Polacrilin Potassium 2.00
3 Carbopol 974P 3.00
4 Xylitol (Xylisorb 300) 100.00
5 Acesulfame Potassium (SweetACE) 1.00
6 Methyl Parahydroxybenzoate 1.60
7 Propyl Parahydroxybenzoate 0.20
8 Propylene glycol 20.00
9 Simethicone emulsion 30% 0.50
10 Orange 501071 AP 0551 1.00
11 Sodium hydroxide solution 4% 0.014
12 Purified water Qs

The impurity level of Solifenacin N-Oxide, dissolution and assay were measured for the reference example at initial time point & on stability. The data is given in Table 2-
Table 2:
Parameters 25°/60%RH 40°/75%RH, 6M
Solifenacin N-Oxide Impurity 0.03% 0.57%
Dissolution at 30 minutes 92% 90%
Assay 99.3% 101.9%

Test Examples 1-5
Table 3: Compositions of Test Example 1-5
S. No. Ingredients mg/ml
1 2 3 4 5
1 Solifenacin Succinate 1 1 1 1 1
2 Polacrilin potassium 2 2 2 2 2
3 Microcrystalline cellulose/ Carmellose Sodium 11.5 11.5 15.5 15.5 13.5
4 Propylene Glycol 15 25 15 25 20
5 Carmellose Sodium 3 1 3 1 2
6 Xylitol 100 100 100 100 100
7 Sucralose 1 1 1 1 1
8 Orange flavour 1 1 1 1 1
9 Simethicone emulsion 30% 1 1 1 1 1
10 Methylparaben 1.6 1.6 1.6 1.6 1.6
11 Propylparaben 0.2 0.2 0.2 0.2 0.2
12 Citric acid monohydrate 1.66 1.66 1.66 1.66 1.66
13 Purified water Qs Qs Qs Qs Qs

Manufacturing Process:
1. Solifenacin Succinate is dissolved in water under stirring followed by addition of Polacrilin Potassium under stirring.
2. Blend of microcrystalline cellulose and carboxymethyl cellulose (Avicel RC 591) is dispersed in water and homogenized.
3. Sodium Carboxymethylcellulose is dissolved in water.
4. Propylene glycol and water was heated up to 70-80°C.
5. Methyl paraben and Propyl paraben are dissolved in step 4 solution under stirring.
6. Xylitol and Sucralose were added to step 5 solution under stirring.
7. Step 3 solution is added in step 2 under stirring.
8. Step 6 solution is added to Step 7 solution under stirring.
9. Step 1 solution is added to Step 8 solution under stirring.
10. Orange flavour is added to step 9 dispersion under stirring.
11. Simethicone emulsion 30% and citric Acid were added to step 10 dispersion under stirring.
12. Makeup the volume with water to achieve desired dilution.
13. Step 12 dispersion is stirred and purged with nitrogen.
14. Step 13 dispersion is filtered using filtration assembly.
15. Step 14 dispersion is filled with volume of 150mL in PET amber bottle.

Example 6: The viscosity, dissolution and uniformity drug content are measured for the test example 1-5. The viscosity is measured at 25°C using rotational viscometer (Brookfield Viscometer, Spindle No. 31) at 180 RPM for 5 minutes. The dissolution are carried out in a dissolution test described in the United States Pharmacopeia and performed by the paddle method at a paddle speed of 50 rpm using 900 mL of 0.1N HCl as a fluid. The data is given in Table 4-
Table 4: The viscosity, dissolution and uniformity drug content for the test example 1-5
Examples Viscosity Dissolution at 30 min Uniformity Drug conc. (AV)
Example 1 83.0 cps 91% 3.0
Example 2 63.5 cps 91% 3.1
Example 3 91.6 cps 88% 5.5
Example 4 52.2 cps 94% 2.8
Example 5 72.8 cps 92% 3.6

Example 7: The Stability data of Example 5 is given in Table No. 5
Table 5:
Parameters Initial 25°C/60%RH, 6M 40°C/75%RH, 6M 25°C/60%RH, 12M
Viscosity 72.8 cps 69.8 cps 47.8 cps 78.3 cps
Dissolution (30 Min.) 92% 96% 94% 98 %
Solifenacin N-Oxide impurity Not Detected 0.09% 0.13% 0.13 %
Assay 99.4% 100.0% 102.5% 100.9 %

Example 8: The sedimentation data of Example 5 is given in Table No. 6
Table 6:
Test Specification Condition
Initial 40°C/75%RH 6 Months 25°C/60%RH, 6 Months
Sedimentation rate Not more than 1 mL of clear liquid is found Not more than 1 mL of clear liquid found Not more than 1 mL of clear liquid found Not more than 1 mL of clear liquid found

Example 9: The complete dissolution profile of Example 5 is given in table 7. The dissolution test as described in Example 6.

Table 7: The dissolution profile of test example 5 at initial and on stability.
Time points % Release
Initial 25°C/60% RH, 6M 40°C/75%RH, 6M 25°C/60% RH, 12M
15 minutes 89 90 91 93
20 minutes 90 93 92 98
30 minutes 92 96 94 98
45 minutes 93 97 96 99

The final optimized composition were selected on the basis of following characteristics i.e. viscosity, dissolution and uniformity of dosage unit. Among Test examples 1-5, Example 5 is selected and further considered for stability study. From the above results, it can be seen that the liquid suspension composition (Example 5, Table 4-6) of the present invention has less than 0.5%w/w of Solifenacin N-Oxide as impurity during storage in comparison with the reference composition (Reference Example, Table 1-2) comprising of acrylic based polymer.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:We claim
1. A stable pharmaceutical liquid suspension composition for oral administration comprising solifenacin or its pharmaceutically acceptable salt, polacrilin potassium as a complexing agent, cellulose derivatives as a suspending agent and optionally one or more pharmaceutically acceptable excipients, wherein said composition does not contain any acrylic based polymer and wherein the said composition has pH in the range of about 3.0 to 6.0, preferably about 5.

2. The pharmaceutical liquid suspension according to claim 1, wherein the suspending agent is blend of microcrystalline cellulose and carboxymethyl cellulose sodium.

3. The pharmaceutical liquid suspension according to claim 1, wherein the viscosity of said liquid suspension is from about 30 cPs to about 130 cPs, when the viscosity is determined at 25°C using a rotational viscometer at 180 rpm.

4. The pharmaceutical liquid suspension according to claim 1, wherein the weight ratio of solifenacin to suspending agent is from about 1:1 to about 1:50, preferably from about 1:10 to about 1:30, more preferably from about 1:12 to about 1:20.

5. The pharmaceutical liquid suspension for oral administration comprising:
a) a complex containing solifenacin succinate and polacrilin potassium ;
b) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent;
c) carboxymethyl cellulose sodium as a viscosity modifier; and
d) optionally pharmaceutically acceptable excipients selected from group of sweetening agent, buffering agent, a preservative, antifoaming agent, flavoring agent and a pharmaceutically acceptable liquid carrier
wherein the weight ratio of solifenacin to blend of microcrystalline cellulose and carboxymethyl cellulose is from about 1:10 to about 1:30 or from about 1:12 to about 1:20 and the weight ratio of solifenacin to polacrilin potassium is from about 1:1 to about 1:5.

6. The pharmaceutical liquid suspension as claimed in claim 1-5, wherein the said composition is free from alkaline agent and acesulfame potassium.

7. The pharmaceutical liquid suspension as claimed in claim 1-5, wherein 85% or more amount of solifenacin is released in 15 minutes in a dissolution test performed by the paddle method at 50 rpm speed using 900ml of 0.1N HCl as dissolution medium.

8. The pharmaceutical liquid suspension for oral administration according to claim 5 comprising:
a) A complex containing solifenacin or pharmaceutical salt thereof in an amount of about 0.5-1% w/w and polacrilin potassium in an amount of about 1-2% w/w;
b) blend of microcrystalline cellulose and carboxymethyl cellulose as a suspending agent in an amount of about 5-15% w/w;
c) carboxymethylcellulose sodium as a viscosity modifier in amount of about 0.1-3% w/w;
d) sucralose and xylitol as sweetening agents in an amount of about 0.1-80% w/w;
e) citric acid monohydrate as buffering agent in an amount of 0.5-2% w/w;
wherein 85% or more amount of solifenacin is released in 15 minutes in a dissolution test performed by the paddle method at 50 rpm speed using 900ml of 0.1N HCl as dissolution medium.

9. The pharmaceutical liquid suspension as claimed in claim 1-8, wherein the said composition contains less than 0.5% w/w of solifenacin N-oxide as impurity during storage upto 12 months.

10. A process of preparing a pharmaceutical liquid suspension for oral administration as claimed in claim 1-9 comprising:
(a) Preparing a drug solution by forming a complex between solifenacin and polacrilin potassium.
(b) Preparing a suspension by dispersing blend of microcrystalline cellulose and carboxymethyl cellulose in water followed by addition of aqueous solution of sodium carboxymethyl cellulose, optionally with pharmaceutically acceptable excipients.
(c) Mixing drug solution obtained in step (a) with suspension system of step (b) to form a stable liquid suspension.

Dated this 21st day of November 2020.

Signature…(Digitally signed)
Dr. Pramod Sagar
Deputy General Manager