DESC:FIELD OF THE INVENTION

The present invention relates to taste masked oral liquid composition of Solifenacin. More particularly, the present invention relates to an oral suspension comprising resinate complex of solifenacin or a pharmaceutically acceptable salt thereof prepared by admixing palatable ingredients of differential polarities.

BACKGROUND OF THE INVENTION
Solifenacin is a muscarinic receptor antagonist disclosed in U.S. Patent No. 6,017,927. Chemically, solifenacin succinate is butanedioic acid, compounded with (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)­ iso-quinolinecarboxylate having the following structural formula:

Solifenacin succinate is commercially available in US as 5 mg/5 ml (1 mg/ml) oral suspension from Astellas Pharmaceuticals, under the trade name VESICARE LSTM for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged 2 years. Solifenacin is also available as 5 mg & 10 mg tablets under the trade name VESICARE® for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.
International Application Publication No. WO2008128028 describes stable composition containing the amorphous form of solifenacin, and a process of manufacturing the composition. Also describes premix compositions comprising solifenacin or its salts and a resin.

European Patent Application No. EP2500013A describes a stable pharmaceutical composition comprising crystalline solifenacin and excipient granules.

U.S. Patent No. US9918970 describes suspension for oral administration comprising a complex of solifenacin or a pharmaceutically acceptable salt thereof and polacrilin potassium in 1:2 to 1:4 ratio.

It is known that solifenacin or its salts have a bitter and astringent taste particularly in liquid dosage form. Accordingly, there is a need to develop compositions with high level of convenience, which can mask the bitterness, and astringency of the pharmaceutical ingredient.

SUMMARY OF THE INVENTION
The present invention relates to taste masked oral liquid composition of Solifenacin. Further, the invention relates to an oral suspension comprising resinate complex of solifenacin or a pharmaceutically acceptable salt thereof prepared by admixing palatable ingredients of differential polarities.
In one embodiment, the present invention provides taste masked oral liquid composition comprising: resinate complex of solifenacin or a pharmaceutically acceptable salt thereof and one or more of suspending agent, neutralizing agent, corrigent, flavoring agent, coloring agent, anti-foaming agent, antioxidant, preservative and the like or mixtures thereof.
In another embodiment, the present invention provides taste masked oral liquid composition comprising solifenacin succinate, ion-exchange resin and 0.2 to 0.6% simethicone, wherein the ratio of solifenacin succinate to ion-exchange resin is from 1:0.2 to 1:1.0.
In another embodiment, the present invention provides taste masked oral liquid composition of solifenacin succinate containing less than 1% of para hydroxy benzoic acid impurity.
In another embodiment, the present invention provides process for preparing a taste-masked pharmaceutical composition comprising the steps of:
a) forming a complex of solifenacin with the ion-exchange resin;
b) forming a hydrated polymeric phase comprising water and one or more of suspending agent, neutralizing agent, corrigent, flavoring agent, coloring agent, anti-foaming agent, antioxidant, preservative and the like or mixtures thereof;
c) forming an oil phase comprising one or more of propylene glycol, vitamin E TPGS, 0.2 to 0.6% simethicone and sesame oil/ olive oil; and
d) admixing of above to yield final composition.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “resinate complex” includes complex formed between solifenacin and ion-exchange resin, where a drug ion and an inorganic ion are exchanged.
The present invention relates to a taste masked oral suspension comprising resinate complex of solifenacin or a pharmaceutically acceptable salt thereof prepared by admixing palatable ingredients of differential polarities.
The present invention further relates to a taste masked oral liquid composition comprising solifenacin succinate, ion-exchange resin and 0.2 to 0.6% simethicone, wherein the ratio of solifenacin succinate to ion-exchange resin is from 1:0.2 to 1:1.0.
Pharmaceutical composition of the present invention is formulated into the taste masked suspension.
The concentration of solifenacin succinate present in oral suspension composition ranges from 0.05 mg/mL to 10 mg/mL, preferably, from 0.1 to 0.3 mg/mL.
The taste masked oral suspension of solifenacin succinate contains less than 1% of para hydroxy benzoic acid impurity.
The ion exchange resin contains acidic or basic functional groups and has the ability to exchange counter-ions with aqueous solutions surrounding them. When a drug is loaded onto or released from a resin, a drug ion and an inorganic ion are exchanged. This property allows drugs to be loaded onto resins and then be released in vivo by the salts present in gastrointestinal fluids. The ion exchange resin can form a complex with solifenacin, thereby reducing the bitterness and astringency derived from solifenacin and forming a pharmaceutically acceptable pharmaceutical composition. Examples of cationic exchange resin or anionic exchange resin include a cross-linked polymer of methacrylic acid and divinylbenzene (polacrilin potassium NF), a cross-linked polymer of styrenesulfonic acid and divinylbenzene (sodium polystyrene sulfonate USP), and a cross-linked polymer of methacrylic acid and divinylbenzene (Polacrilex Resin). As still another embodiment, Amberlite (registered trademark) IRP88 can be exemplified. As the ion exchange resin can be used alone or two or more kinds can be used appropriately in combination in suitable amounts.
The concentration of ion exchange resin in the present oral liquid composition ranges from 0.1 mg/mL to 50 mg/mL.
The ratio of solifenacin succinate to ion-exchange resin in the present oral liquid composition is from 1:0.2 to about 1:1.
The amount of simethicone in the present oral liquid composition is from 0.2% to 0.6%, preferably from 0.3% to 0.5%.
Simethicone when used at relatively higher concentration of 0.2% to 0.4%, it can be expected to have sturdy arrangement of oleaginous structures in presence of compatible hydrotropes across the hydrophilic phase. Uniform localization of solifenacin, at solubilized (uncomplexed) or dispersed (complexed) state, across high polar to least polar region of such sturdy lamellar structure thereby resulting into ease in resuspendability. Thus, with an added advantage of improved palatability & masking of objectionable taste attainable by efficient processability of simethicone when properly emulsified with aqueous components under the impact high shear mixing. This mechanism of taste masking is in assimilation to utilizing solifenacin succinate complexed with resin polacrillin potassium.
The present invention further relates to a taste masked oral suspension comprising solifenacin succinate and polacrilin potassium in a ratio of 1:0.2 to 1:1, wherein the oral suspension contains less than 1% para hydroxy benzoic acid impurity.
Oral liquid composition of solifenacin succinate as per the present invention contains less than 1% of para hydroxy benzoic acid impurity after storage for 7 days at 60ºC.
Oral liquid composition of solifenacin succinate as per the present invention contains less than 1% of para hydroxy benzoic acid impurity after storage for 3 months at 25ºC.
Pharmaceutical composition of the present invention comprises one or more of the following: suspending agent, neutralizing agent, corrigent, flavoring agent, coloring agent, anti-foaming agent, antioxidant, Hydrotropes, preservative and the like or mixtures thereof.
Pharmaceutical composition of the present invention comprises one or more of the carbomers selected from carbomer Homopolymer Type A, Carbomer Homopolymer Type B, carbopol 71G, 971P or 974P, Carbomer 934, Carbomer 934P, Carbomer 940, or Carbomer 941.
Neutralizing agents according to the present invention include but are not limited to sodium hydroxide, sodium carbonate, ammonia.
Corrigent according to the present invention include but are not limited a sugar or a sugar alcohol such as sucrose, fructose, lactose, sorbitol, mannitol, xylitol, erythritol, or trehalose; or a sweetening agent such as stevia, aspartame, acesulfame potassium, sucralose, neotame, advantame or saccharin or mixtures thereof.
Flavoring agents according to the present invention include but are not limited to cherry, maple, pineapple, orange, raspberry, banana-vanilla, butterscotch, coconut-custard, fruit-cinnamon, strawberry, vanilla and lemon-lime.
Antioxidants according to the present invention include but are not limited to ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E TPGS (D-a-tocopheryl polyethylene glycol 1000 succinate) and the like for chemical stability.
Hydrotropes according the present invention are relatively innocuous compounds include but are not limited to a compound that solubilizes hydrophobic compounds in aqueous solutions. Typically, hydrotropes consist of a hydrophilic part and a hydrophobic part (similar to surfactants), but the hydrophobic part is generally too small to cause spontaneous self-aggregation. Hydrotropes which can be used in the compositions of the present invention selected from a mono fatty acid ester of polyoxyethylene (20) sorbitan, (for example, polyoxyethylene (20) sorbitan monooleate (Tween® 80 or Polysorbate 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tweens® 20)) and the like), polyoxyethylene castor oil derivatives (such as polyoxyethyleneglycerol triricinoleate, polyoxyl 35 castor oil, polyoxyethyleneglycerol oxystearate, polyethyleneglycol 60 castor oil, caprylocaproyl poloxyglycerides and the like, block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropylene glycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 338, Poloxamer® 407, and the like. A preferred pharmaceutically acceptable hydrotrope is polyoxyethylene (20) sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monooleate (Tween® 80 or Polysorbate 80).
Preservatives according to the present invention include but are not limited to sodium benzoate, potassium sorbate, methyl paraben, propyl paraben and sodium citrate.
Pharmaceutical composition of the present invention also comprises coloring agent, anti-foaming agent, hydrotropes, propylene glycol, olive oil/ sesame oil.
The present invention also relates to process for preparing a taste-masked liquid composition comprising the steps of:
a) forming a complex of solifenacin with the ion-exchange resin;
b) forming a hydrated polymeric phase comprises water and one or more of suspending agent, neutralizing agent, sweetening agent, flavoring agent, coloring agent, anti-foaming agent, preservative and the like or mixtures thereof;
c) forming an oil phase comprises one or more of propylene glycol, vitamin E TPGS, 0.2% to 0.6% simethicone, polysorbate 80 and sesame oil/ olive oil; and
d) admixing of above to yield final composition.

The invention is further exemplified with following examples and is not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1: Solifenacin suspension composition

S. No Ingredients with Brand name mg/mL % w/v
1. Methyl Paraben 1.60 0.160
2. Propyl Paraben 0.20 0.020
3. Carbomer homopolymer type B, USP-NF
(Carbopol 974P) 2.00 0.200
4. Xylitol 150.00 15.000
5. Acesulfame Potassium 0.51 0.051
6. Sodium hydroxide (Pellets Extra Pure) 0.08 0.008
7. Purified Water 450.00 45.000
8 Vitamin E TPGS 3.00 0.300
9. Polysorbate 80 1.00 0.100
10. Simethicone 4.00 0.400
11. Propylene Glycol 20.00 2.000
12. Purified Water (for rinsing) (Part-II) 100.00 10.000
13. Solifenacin Succinate 1.00 0.100
14. Polacrilin Potassium 1.00 0.100
15. Purified Water (Part-III) 25.00 2.500
16. Purified Water (for rinsing) (Part-IV) 125.00 12.500
17. Orange flavor (Orange Flavor 501071 AP0551) 1.00 0.100
18. Purified Water (Part-V) 25.00 2.500
19. Purified Water (for rinsing) (Part-VI) 75.00 7.500
20. Sodium hydroxide (Pellets Extra Pure) 0.35 0.035
21. Purified Water (Part-VII) q.s to 1mL --

Brief manufacturing procedure:

1. Take part quantity of purified water (Part I) in a vessel and heat it. Add methylparaben and propylparaben and stir to get clear solution.

2. Disperse dispensed quantity of Carbomer homopolymer type B to aqueous bulk of step 1. Stir appropriately to swell the polymer.

3. Transfer xylitol to bulk solution of step 2 under stirring.

4. Transfer weighed quantity of Acesulfame Potassium to the step 3 under continuous stirring.

5. Add weighed quantity of Sodium Hydroxide (0.08 mg/mL) as 10%w/w solution to the bulk of step 5 under stirring at medium shear.

6. Take dispensed quantity of butylated hydroxytoluene, propylene glycol, simethicone, polysorbate 80, vitamin E TPGS in a separate container and stir to mix well.

7. Transfer the bulk of step 6 to step 5 under continuous stirring for the formation of homogeneous bulk.

8. Take weighed quantity of purified water and add accurately weighed quantity of Solifenacin Succinate under continuous stirring.

9. Transfer weighed quantity of polacrilin potassium to step 9 and stir well for 15 min for the formation of Solifenacin Succinate and polacrilin potassium complex.

10. Add complex of step 10 to homogeneous bulk of step 7 for the formation of homogenous dispersion.

11. Add weighed quantity of flavor to purified water, stir well and add to the step 10 dispersion.

12. Adjust the pH of the dispersion to 5.5-6.0 with sodium hydroxide.

13. Finally make up the above dispersion to required volume with purified water (if required) and mix well.

Impurity Profile:
Vesicare Suspension Test product
Initial 60°C / 3 days 60°C / 7 days Initial 60°C / 3 days 60°C / 7 days
Para-hydroxy benzoic acid 0.98 1.96 2.75 0.02 0.28 0.5
Related compound-03 0.03 0.05 0.06 0 0.08 0.09
Any individual unspecified degradation product 0.06 0.08 0.1 0.07 0.08 0.08
Total unknown Impurities 0.11 0.16 0.2 0.11 0.13 0.13
Total Impurities 0.14 0.21 0.26 0.16 0.22 0.21

Further, solifenacin suspension prepared as per Example 1 was stored at 25°C. Para-hydroxy benzoic acid impurity was found to be less than 1% after storage for 3 months at 250C.

Example 2: Solifenacin suspension composition

S.No. Ingredients mg/5ml
1 Solifenacin Succinate 5
2 Polacrilin Potassium 7.5
3 Methyl Paraben 8
4 Propyl Paraben 1
5 Butylated hydroxyl toluene 0.5
6 Propylene Glycol 250
7 Simethicone 15
8 Carbomer homopolymer type B (Carbopol 974P) 5
9 Xylitol 300
10 Acesulfame Potassium 2.55
11 Natural Orange Flavour 2
12 Sodium hydroxide (4% aq. solution) Qs to pH 5.5 to 6.5
13 Purified Water Qs to 5ml
14 Vitamin E TPGS 20
15 Sesame Oil/ Olive Oil 200

Brief manufacturing procedure:

1. Take part quantity of purified water (Part I) in a vessel and heat it. Add methylparaben and propylparaben and stir to get clear solution.
2. Transfer xylitol to bulk solution of step 1. Stir well to dissolve xylitol.
3. Cool bulk solution of step 2.
4. Disperse dispensed quantity of Carbomer homopolymer type B to aqueous bulk of step 3. Stir appropriately to swell the polymer.
5. Take part quantity of purified water (Part II) in a suitable vessel. Dissolve acesulfame potassium in purified water.
6. Add bulk solution of step 5 to polymeric solution of step 4 & stir appropriately (treated as aqueous phase).
7. Take part quantity of purified water (Part III) in a suitable vessel. Intimately mix solifenacin and polacrilin potassium together under slow stirring in this part quantity of purified water. Mix sufficiently to allow drug-resinate complex to form (Note: Drug-resinate complex formation can be adjudged visually as by change in original appearance of polacrilin potassium after appropriate mixing).
8. Take dispensed quantity of butylated hydroxytoluene, propylene glycol, simethicone, vitamin E TPGS and sesame oil/ olive oil in a separate container and stir to mix well (treated as oil phase).
9. Agitate under moderate to high shear oil phase bulk of step 8 with hydrated polymeric phase bulk of step 6 for about 15-30 minutes to yield emulsified white to off white dispersion.
10. If required adjust pH to 5-7 (target pH 6) of bulk of step 9 using suitable molar concentration of sodium hydroxide solution.
11. Add drug-resinate complex bulk of step 7 to bulk of step 10 followed by addition of dispensed quantity of orange flavour. Mix well under continuous slow to moderate stirring. End point of mixing bulk is adjudged as homogenous dispersion.
12. Finally make up the above dispersion to required volume with purified water (if required) and mix well.
13. Bulk ready for filling in requisite bottles.
,CLAIMS:We Claim:
1. A taste masked oral liquid composition comprising solifenacin succinate, ion-exchange resin and 0.2 to 0.6% simethicone, wherein the ratio of solifenacin succinate to ion-exchange resin is from 1:0.2 to 1:1.0.

2. The composition of claim 1, wherein the concentration of solifenacin succinate is from 0.1 to 0.3.

3. The composition of claim 1, comprise Para-hydroxy benzoic acid impurity in an amount of less than 1% after storage for 3 months at 250C.

4. The composition of claim 1, wherein the solifenacin is complexed with the ion-exchange resin in an aqueous medium.

5. The composition of claim 1, wherein the ion-exchange resin is polacrilin potassium, sodium polystyrene sulfonate or polacrilex resin.

6. The composition of claim 1, further comprise one or more pharmaceutically acceptable excipients selected from carbomers, suspending agents, sweeteners, flavors, colorants, anti-foaming agent, antioxidant and preservatives.

7. Process for preparing a taste-masked liquid composition comprising the steps of: a) forming a complex of solifenacin with the polacrilin potassium in an aqueous medium;
b) forming a hydrated polymeric phase comprises water and one or more of suspending agent, neutralizing agent, sweetening agent, flavoring agent, coloring agent, anti-foaming agent, antioxidant, preservative and the like or mixtures thereof;
c) forming an oleaginous phase comprises one or more of propylene glycol, 0.2 to 0.6% simethicone, polysorbate 80, vitamin E TPGS and sesame oil/ olive oil;
d) mixing of step (c) with step (b) to yield emulsified dispersion and
e) mixing of step (a) with step (d) to yield final composition

8. The composition of claim 1, is in the form of suspension.

Dated this Third (3rd) day of June 2020

Signature: ----------------------------------------------------------
Name: CH. SURYANARAYANA
DGM - IPM
HETERO LABS LIMITED