DESC:FIELD OF THE INVENTION

The present invention relates to pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients. It further relates to process for making such composition and its use for treatment of chronic obstructive pulmonary disease (COPD).

BACKGROUND OF THE INVENTION

Revefenacin is a long-acting muscarinic receptor antagonist (LAMA) developed as an inhalation solution for administration via a standard jet nebulizer at a proposed dose of 175 mcg/3mL once daily. Revefenacin is commercially marketed under brand name of YUPELRI® and is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). The chemical name for revefenacin is 1-(2-{4­[(4-carbamoylpiperidin-1-yl)methyl]-N-methylbenzamido}ethyl)piperidin-4-yl N-({1,1’­biphenyl}-2-yl)carbamate; its structural formula is:

U.S. Patent No. 8,541,451 B2 discloses crystalline Form III and IV of revefenacin and process of preparation thereof. U.S. Patent No. 9,249,099 B2 discloses crystalline Form I and II of revefenacin and process of preparation thereof.

U.S. Patent No. 7,288,657 B2 discloses aqueous aerosol revefenacin formulation for use in a nebulizer which is prepared by dissolving drug in sodium chloride solution acidified with citric acid. The pH of the solution is adjusted with addition of sodium hydroxide.

U.S. Patent No. 7,700,777 B2 discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline salt of revefenacin and phosphoric acid.

U.S. Patent Publication No. 2020/0069667 A1 generically discloses an aqueous solution of revefenacin or a pharmaceutically acceptable salt comprising sodium chloride, citric acid and sodium citrate.

There always exists a need to develop an alternate pharmaceutical composition, and present invention is focussed towards the development of a stable pharmaceutical composition of revefenacin or its pharmaceutically acceptable salt thereof which is reproducible at large scale production.
SUMMARY OF THE INVENTION

According to main aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group comprising tonicity agent, buffering agent, pH adjusting agent, vehicle and/or combinations thereof.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and atleast one buffering agent, wherein said buffering agent is sodium chloride and citric acid.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and atleast one buffering agent, wherein said buffering agent is acetic acid and sodium acetate.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and atleast one buffering agent, wherein said buffering agent is citric acid and sodium citrate.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared by a process comprising the steps:
a. dissolving revefenacin, buffering agent and/or tonicity agent in water;
b. optionally adjusting the pH of solution;
c. filtering the solution and filling in suitable container.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared by a process comprising the steps:
a. transferring water to manufacturing vessel;
b. dissolving tonicity agent in water of step (a) to get a solution;
c. dissolving buffering agent in the solution of step (b);
d. optionally adjusting pH of the solution of step (c);
e. dissolving revefenacin in the solution of step (d);
f. optionally adjusting pH of the solution of step (e);
g. making final volume upto 100% with water to get a bulk solution;
h. filtering the bulk solution of step (g);
i. filling the solution of step (h) into container; and
j. optionally, sterilising by steam sterilisation.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically-acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition is having a pH in a range of about 3.0 to about 8.0.

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients which is useful for treatment of chronic obstructive pulmonary disease (COPD).

According to another aspect, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients which is useful for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

According to another aspect, the present invention provides a process for preparing pharmaceutical composition using crystalline Form I or Form II of revefenacin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition of revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

Revefenacin as used herein, includes and is not limited to, pharmaceutically acceptable salts, hydrates, solvates, and polymorphic forms (crystalline or amorphous), and derivatives thereof. All stereoisomers which may exist due to asymmetric carbons on the R substituents of the compound, including enantiomeric and diasteromeric forms, are contemplated within the scope of this invention. Further, it also includes their enantiomeric pure forms or their racemic mixtures.

The term “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like.

As used herein the term “about” in reference to a numerical value means that variations of 10% above or below the numerical value are within the range ascribed to the specified value.

According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition comprises from about 0.02 mg/mL to about 0.1 mg/mL of revefenacin or pharmaceutically acceptable salts thereof.

According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition comprises about 0.058 mg/mL of revefenacin or pharmaceutically acceptable salts thereof.

According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition is suitable for inhalation. The pharmaceutical compositions can be in a form suitable for inhalation administration such as a sterile solution or suspension.

According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of aqueous inhalation solution.

According to another embodiment of the present invention, the pharmaceutical composition may be in the form of a unit dose formulation or multi dose formulation.

According to another embodiment of the present invention, the pharmaceutical composition is sterilized using filtration (0.2µm filter) or steam sterilization/autoclaving.

According to another embodiment of the present invention, the pharmaceutical composition is terminally sterilized using steam sterilization/autoclaving.

According to another embodiment of the present invention, the container can be sterilized using any of the known sterilization method which includes, but is not limited to, autoclaving/steam sterilization, dry heat sterilization, ethylene oxide (ETO) and radiation (gamma and E-beam) sterilization.

According to another embodiment of the present invention, the pharmaceutical composition is filled into sterile container under aseptic conditions.

According to another embodiment of the present invention, the pharmaceutical compositions of this invention are suitable for inhaled administration and will be in the form of an aerosol or a powder. The pharmaceutical compositions of this invention are generally administered using well-known delivery devices, such as a nebulizer inhaler, a metered-dose inhaler (MDI), a dry powder inhaler (DPI) or a similar delivery device.

According to another embodiment of the present invention, the pharmaceutical composition is filled into a single-dose container or multi-dose container.

According to another embodiment of the present invention, the pharmaceutical composition may be provided in a vial, ampoule, or bottle, or for instance in the form of prefilled single-use cartridges which are emptied into the reservoir of the inhalation device prior to an inhalation treatment.

According to another embodiment of the present invention, the pharmaceutical composition is free from preservatives.

According to another embodiment of the present invention, the pharmaceutical composition is in the form of ready to use composition.

According to another embodiment of the present invention, there is provided a process for preparing pharmaceutical composition using crystalline Form I or Form II of revefenacin.

According to another embodiment of the present invention, the pharmaceutical composition has a pH in the range of about 3 to about 8. Preferably, the pharmaceutical composition has a pH of about 5.

According to another embodiment of the present invention, the pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group comprising tonicity agent, buffering agent, pH adjusting agent, vehicle and/or combinations thereof.

Suitable tonicity agents include, but are not limited to, propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, lactose, sucrose, mannose, sodium phosphate, sodium bicarbonate, an amino acid and the like and/or mixtures thereof. The tonicity agent is present in the composition in an amount in the range of about 0.1 to about 5.0% w/v of the composition. Preferably, the tonicity agent is present in the composition in an amount in the range of about 0.1 to about 2.0 % w/v of the composition.

Suitable buffering agents include, but are not limited to, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, lactic acid, tartaric acid, potassium phosphate, sodium succinate, sodium chloride, ammonium bicarbonate, carbonates, monobasic sodium phosphate, dibasic sodium phosphate, potassium metaphosphate, sodium tartrate and sodium citrate, and the like and mixtures thereof. Buffers are used in the present compositions to adjust the pH in a range of about 3 to about 8. Preferably, the pharmaceutical composition has a pH of about 5. The buffering agent is present in the composition in an amount in the range of about 0.0001 to about 1.5% w/v of the composition.

Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, citric acid, hydrochloric acid, sulphuric acid, nitric acid, acetic acid, phosphoric acid, fumaric acid, ascorbic acid, nitric acid, tartaric acid, maleic acid, succinic acid, ammonia solution, ammonium carbonate, sodium borate, sodium carbonate, triethanolamine and trolamine. A pH adjusting agent is present in the composition in an amount to adjust the pH of the composition in a range of about 3.0 to about 8.0.

Suitable vehicles include aqueous or non-aqueous solvent. The composition can be formulated with one or a mixture of more than one pharmaceutically acceptable solvent and is selected from, but not limited to, water, glycerol, propylene glycol, polyethylene glycol, polypropylene glycol, ethyl alcohol, isopropyl alcohol, mineral oil, peanut oil, and corn oil. Preferably, the solvent is water in the form of purified water or water for injection.

The pharmaceutical composition as per the present invention may contain preservative. Suitable preservatives include, but are not limited to, benzalkonium chloride, benzyl alcohol, chlorobutanol and/or mixtures thereof.

The pharmaceutical composition as per the present invention may contain chelating agent. Suitable chelating agents include, but are not limited to, citric acid, ethylenediamine tetraacetic acid (EDTA), or its salt.

Accordingly, in one embodiment, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared by process comprising the steps:
a. dissolving revefenacin, buffering agent and/or tonicity agent in water;
b. optionally adjusting the pH of solution;
c. filtering the solution and filling in suitable container.

According to another embodiment, the present invention provides a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared by process comprising the steps:
a. transferring water to manufacturing vessel;
b. dissolving tonicity agent in water of step (a) to get a solution;
c. dissolving buffering agent in the solution of step (b);
d. optionally adjusting pH of the solution of step (c);
e. dissolving revefenacin in the solution of step (d);
f. optionally adjusting pH of the solution of step (e);
g. making final volume upto 100% with water to get a bulk solution;
h. filtering the bulk solution of step (g);
i. filling the solution of step (h) into container; and
j. optionally, sterilising by steam sterilisation.

According to another embodiment, the pharmaceutical composition as per the present invention is useful for treating bronchoconstrictive disorder which is selected from the group comprising bronchospasm in adults, adolescents, children 6 years of age and older with reversible obstructive airway disease, asthma, pediatric asthma, bronchial asthma, allergic asthma, occupational asthma, aspirin sensitive asthma, exercise, induced asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis and emphysema.

According to another embodiment, the pharmaceutical composition as per the present invention is useful for the maintenance treatment of patients with COPD.

According to another embodiment, the pharmaceutical composition as per the present invention are stable when stored at 40°C and 75% relative humidity for 6 months.

According to another embodiment, the present invention relates to a pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein the composition optionally comprises one or more additional therapeutic agents. Alternatively, the pharmaceutical composition of the present invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don't limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 27.00
Glacial Acetic acid 0.1152
Sodium acetate trihydrate 1.500
Hydrochloric Acid q.s to adjust pH 5.0
Sodium Hydroxide q.s to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:
1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Sodium acetate trihydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained.
4. Glacial acetic acid was added to the solution of step 3 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
5. pH (pH-5.00) of the solution of step 4 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
6. Revefenacin was added to the solution of step 5 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
7. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
8. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
9. Bulk solution of step 8 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
10. Filtered solution of step 9 was filled into suitable container and stored at labelled storage condition.

Example 2
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 23.55
Glacial Acetic acid 0.150
Sodium acetate trihydrate 2.000
Hydrochloric Acid q.s to adjust pH 5.0
Sodium Hydroxide q.s to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:
1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Sodium acetate trihydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained.
4. Glacial acetic acid was added to the solution of step 3 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
5. pH (pH-5.00) of the solution of step 4 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
6. Revefenacin was added to the solution of step 5 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
7. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
8. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
9. Bulk solution of step 8 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
10. Filtered solution of step 9 was filled into suitable container and stored at labelled storage condition.

Example 3
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 25.00
Glacial Acetic acid 0.160
Sodium acetate trihydrate 1.75
Hydrochloric Acid q.s to adjust pH 5.0
Sodium Hydroxide q.s to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:
1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Sodium acetate trihydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained.
4. Glacial acetic acid was added to the solution of step 3 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
5. pH (pH-5.00) of the solution of step 4 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
6. Revefenacin was added to the solution of step 5 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
7. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
8. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
9. Bulk solution of step 8 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
10. Filtered solution of step 9 was filled into suitable container and stored at labelled storage condition.

Example 4
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 27.00
Sodium Citrate dihydrate 12.00
Citric acid monohydrate 4.05
Hydrochloric Acid q.s. to adjust pH 5.0
Sodium Hydroxide q.s. to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:

1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Sodium citrate dihydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained.
4. Citric acid monohydrate was added to the solution of step 3 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
5. pH (pH-5.00) of the solution of step 4 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
6. Revefenacin was added to the solution of step 5 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
7. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
8. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
9. Bulk solution of step 8 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
10. Filtered solution of step 9 was filled into suitable container and stored at labelled storage condition.

Example 5
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 27.00
Sodium Citrate dihydrate 6.00
Citric acid monohydrate 2.02
Hydrochloric Acid q.s. to adjust pH 5.0
Sodium Hydroxide q.s. to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:
1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Sodium citrate dihydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
4. Citric acid monohydrate was added to the solution of step 3 followed by stirring for 10 minutes or till the time clear solution is obtained.
5. pH (pH-5.00) of the solution of step 4 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
6. Revefenacin was added to the solution of step 5 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
7. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
8. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
9. Bulk solution of step 8 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
10. Filtered solution of step 9 was filled into suitable container and stored at labelled storage condition.

Example 6
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 25.80
Sodium Citrate dihydrate 9.00
Citric acid monohydrate 3.04
Hydrochloric Acid q.s. to adjust pH 5.0
Sodium Hydroxide q.s. to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:
1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Sodium citrate dihydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained. . pH was checked and recorded.
4. Citric acid monohydrate was added to the solution of step 3 followed by stirring for 10 minutes or till the time clear solution is obtained
5. pH (pH-5.00) of the solution of step 4 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
6. Revefenacin was added to the solution of step 5 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
7. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
8. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
9. Bulk solution of step 8 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
10. Filtered solution of step 9 was filled into suitable container and stored at labelled storage condition.

Example 7
Ingredients mg/3mL
Revefenacin 0.175
Sodium Chloride 27.00
Citric acid monohydrate 6.00
Sodium Hydroxide q.s. to adjust pH 5.0
Hydrochloric Acid q.s. to adjust pH 5.0
Water for Injection q.s. to 3 mL

Process:

1. 100 % WFI required to the desired batch Size was collected, from that 90 % of WFI was transferred to manufacturing S.S vessel.
2. Sodium chloride was added to the above 90% collected WFI followed by stirring for 10 minutes or till the time clear solution is obtained.
3. Citric acid monohydrate was added to the solution of step 2 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
4. pH (pH-5.00) of the solution of step 3 if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
5. Revefenacin was added to the solution of step 4 followed by stirring for 10 minutes or till the time clear solution is obtained. pH was checked and recorded.
6. pH (pH-5.00) was adjusted if required was adjusted using Hydrochloric Acid/Sodium Hydroxide.
7. Volume was made to 100% with water for injection and pH was checked followed by stirring for 10 minutes or till the time clear solution is obtained
8. Bulk solution of step 7 was sterilized using 0.22 µm filter under Nitrogen pressure and collected in SS316L sterile holding tank.
9. Filtered solution of step 8 was filled into suitable container and stored at labelled storage condition.

CLAIMS:WE CLAIM:

1. A pharmaceutical composition comprising revefenacin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from a group comprising tonicity agent, buffering agent, vehicle, pH adjusting agent and/or combinations thereof.

2. The pharmaceutical composition as claimed in claim 1, wherein buffering agent is selected from the group comprising acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, lactic acid, tartaric acid, potassium phosphate, sodium succinate, sodium chloride, ammonium bicarbonate, carbonates, monobasic sodium phosphate, dibasic sodium phosphate, potassium metaphosphate, sodium tartrate and sodium citrate, and the like and mixtures thereof and is present in the range of about 0.0001 to about 1.5% w/v of the composition.

3. The pharmaceutical composition as claimed in claim 1, wherein the buffering agent is sodium chloride and citric acid.

4. The pharmaceutical composition as claimed in claim 1, wherein the buffering agent is acetic acid and sodium acetate.

5. The pharmaceutical composition as claimed in claim 1, wherein the buffering agent is citric acid and sodium citrate

6. The pharmaceutical composition as claimed in claim 1, wherein tonicity agent is selected from the group comprising, propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, lactose, sucrose, mannose, sodium phosphate, sodium bicarbonate, an amino acid and the like and/or mixtures thereof and is present in the range of about 0.1 to about 5.0% w/v of the composition

7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises:
0.175 mg revefenacin or its pharmaceutically acceptable salt;
23.0-28.0 mg sodium chloride;
4.0-12.0 mg sodium citrate dihydrate;
1.0-5.0 mg of citric acid monohydrate;
sodium hydroxide and/or hydrochloric acid, and
water for injection q.s. to 3mL.

8. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises:
0.175 mg revefenacin or its pharmaceutically acceptable salt;
23.0-28.0 mg sodium chloride;
0.05-0.5 mg of acetic acid;
0.1-3.0 mg of sodium acetate trihydrate;
sodium hydroxide and/or hydrochloric acid, and
water for injection q.s. to 3mL.

9. The pharmaceutical composition as claimed in claim 1, wherein in said pharmaceutical composition is stable at 40° C and 75% relative humidity for 6 months

10. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical
composition comprises:
0.175 mg revefenacin or its pharmaceutically acceptable salt;
23.0-28.0 mg sodium chloride;
1.0-8.0 mg of citric acid monohydrate;
sodium hydroxide and/or hydrochloric acid, and
water for injection q.s. to 3mL.