FIELD OF THE INVENTION

The present invention is directed to a stable pharmaceutical composition containing antiemetic agents selected from 5-HT3 antagonist, neurokinin 1 (NK1) receptor antagonist or a combination thereof.

BACKGROUND OF THE INVENTION

Palonosetron (5-HT3 antagonist) and its combination with Fosnetupitant (neurokinin 1 (NK1) receptor antagonist) has been approved by US FDA under the brand name of AKYNZEO for preventing Chemotherapy-Induced Nausea and Vomiting (CINV).

Palonosetron .HC1 (I) is chemically known as (3aS)-2-[(S)-l-Azabicyclo [2.2.2] oct-3-yl]-2,3,3a,4,5,6-hexahydro-l-oxo-lH-benz[de]isoquinoline hydrochloride
Fosnetupitant chloride hydrochloride (II) is chemically known as 2-(3,5-bistrifluoromethylphenyl)-N-methyl-N-[6-(4-methyl-4-0-methylene-phosphate piperazinium-1 -yl)4-o-tolyl-pyridin-3-yl]-isobutyramide chloride hydrochloride.
U.S Pat. No. 10,624,911 describes a liquid and lyophilized pharmaceutical composition containing Fosnetupitant and Palonosetron. The patent specifically describes a liquid formulation comprising Fosnetupitant, Palonosetron.HCl, EDTA, mannitol, sodium hydroxide, HC1 and water for injection. The patent also specifically describes a lyophilized composition comprising the said ingredients but the solvent water for injection is removed during the lyophilisation.

US FDA package insert of AKYNZEO describes that the concentrated solution containing Palonosetron and Fosnetupitant is diluted with a diluent, 5% dextrose or 0.9% sodium chloride, for administration. Similarly, the lyophilized powder is reconstituted followed by diluted for administration. It also mentions that these diluted solutions should be administered within 24 hours. The diluted solution is stored at room temperature.

There is a need in the art to provide a stable injectable pharmaceutical ■ composition comprising 5-HT3 antagonist and neurokinin 1 (NK1) receptor antagonist and a process for preparation thereof.

SUMMARY OF THE INVENTION

An embodiment of the present invention provides a stable injectable pharmaceutical composition comprising;

a) 5-HTj antagonist,

b) Neurokinin 1 (NK1) receptor antagonist and

c) Iodide.

Still an another embodiment of the present invention provides a stable injectable pharmaceutical composition comprising;

a) Palonosetron or its pharmaceutically acceptable salt,

b) Fosnetupitant or its pharmaceutically acceptable salt and

c) Iodide.

Another embodiment of the present invention provides a stable injectable pharmaceutical formulation comprising;
a) 5-HT3 antagonist,

b) Neurokinin 1 (NK1) receptor antagonist,

c) Iodide and

d) Isotonicity agent.

Still an another embodiment of the present invention provides a stable injectable pharmaceutical composition comprising;

a) Palonosetron or its pharmaceutically acceptable salt,

b) Fosnetupitant or its pharmaceutically acceptable salt,

c) Iodide and

d) Isotonicity agent which is selected from sodium chloride, dextrose, mannitol, sorbitol or a combination thereof.

Still another embodiment of the present invention provides a process for preparation of a stable pharmaceutical composition of 5-HT3 antagonist, neurokinin 1 (NK1) receptor antagonist or a combination thereof and iodide.

DETAILED DESCRIPTION OF THE INVENTION

5-HT3 antagonists are a class of medicines that are used for the prevention and treatment of nausea and vomiting, particularly that caused by chemotherapy, radiation therapy, or postoperatively.

Neurokinin-1 (NK1) receptor antagonists are used for prevention of acute and delayed nausea and vomiting. The NK1 receptor antagonist competitively binds to the NK1 receptor, which blocks the binding of substance P and prevents the emetic signal being transmitted.

NK1 receptor antagonists has been approved for use in conjunction with 5-HT3-receptor antagonists and corticosteroids to augment their antiemetic activity.

Within the context of the present invention, the term “ready-to-use” or “RTU” as used herein refers to a pharmaceutical composition that is stable and is not reconstituted from a lyophilizate. In certain embodiments, for example, the ready-to-use pharmaceutical composition is an injectable composition that is premixed
and suitable for administration to a patient without dilution. The term “RTU” encompasses within its scope, parenteral compositions that are stable and must not be diluted from a concentrated, liquid solution just prior to use. The term “RTU” also encompasses formulations that are premixed. As used herein the terms “premix” or “premixed” refer to a pharmaceutical composition, which does not require reconstitution or dilution prior to administration to a patient, e.g., suitable for parenteral administration. In certain embodiments, the compositions of the present invention are “ready to use” upon removing the compositions from a sealed container or vessel.

In certain embodiment, the pharmaceutical composition such as concentrated solution and diluted solution of the present invention involves water for injection as a vehicle. It may also contain any other pharmaceutically acceptable solvent in combination with water. The pharmaceutically acceptable solvent is selected from alcohol, amide, sulfoxide and the like.

One embodiment of the present invention provides a stable injectable pharmaceutical composition comprising;

a) 5tHTj antagonist,

b) Neurokinin 1 (NK1) receptor antagonist and

c) Iodide.

The stable injectable formulation according to the present invention is available in the following forms such as lyophilized powder form, a concentrated solution for dilution for injection or a diluted solution for direct administration. The lyophilized powder form is reconstituted followed by diluted using a suitable diluent selected from 5% dextrose, 0.9% sodium chloride, mannitol etc for administration. The concentrated solution is diluted using a suitable diluent selected from 5% dextrose, 0.9% sodium chloride, mannitol etc for administration.
5-HT3-receptor is selected Palonosetron, Ondansetron, Granisetron or its pharmaceutically acceptable salt; preferably Palonosetron or its hydrochloride salt.

Neurokinin-1 (NK1) receptor antagonist is selected from Aprepitant,

Fosaprepitant, Rolapitant, 'Neupitant, Fosnetupitant or a pharmaceutically acceptable salt thereof; preferably Fosnetupitant or its chloride hydrochloride salt.

The concentration of Fosnetupitant or a pharmaceutically acceptable salt thereof, based on the weight of the free base is in the range of about 1 mg/ ml to 50 mg/ ml and Palonosetron or a pharmaceutically acceptable salt thereof, based on the weight of the free base is in the range of about 1 meg/ ml to 50 meg/ ml.

The pharmaceutical composition according to the present invention contains Iodide which is added into the formulation separately or it is obtained from the input active pharmaceutical ingredient Palonosetron or Fosnetupitant. In case of separate addition of iodide then sodium iodide or potassium iodide is added into the formulation.

An effective amount of iodide is required to present in the formulation to control the formation of impurity. Specifically, the presence of iodide controls the formation of Palonosetron or its salt related impurity. More specifically, the presence of iodide controls formation of impurity-A of Palonosetron or its salt (III). The amount of iodide present in the formulation is about 1000 ppm, about 900 ppm, about 800 ppm, about 700 ppm, about 600 ppm, about 500 ppm, about 400 ppm, about 300 ppm, about 200 ppm, about 100 ppm, about 50 ppm, about 25 ppm, about 10 ppm, about 5 ppm or about 2 ppm.
The formulation may contain pH adjusting agents. The pH adjusting agent is selected from alkalizing agent and acidifying agent. The alkalizing agent is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, diethanolamine, monoethanolamine, potassium bicarbonate, sodium citrate, potassium citrate, sodium bicarbonate, sodium carbonate, sodium borate, dimeglumine, tris (hydroxymethyl) aminomethane, and triethanolamine. The acidifying agent is selected from adipic acid, ammonium chloride, citric acid monohydrate, glacial acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, as well as edetic acid and its various salts. The alkalizing agent and/ or acidifying agent is used to adjust the pH of the composition in the range of about 7 to 10; preferably about 8.5-9.5. The pH adjusting agent may also act as a solubilizing agent for the active ingredients used in the formulation.

The pharmaceutical composition may additionally contain a “tonicity modifier” that can be used to adjust the tonicity of the formulation. Suitable tonicity modifiers include glycerine, lactose, mannitol, dextrose, sodium chloride, sodium sulphate, sorbitol, trehalose and others known to those of ordinary skill in the art. In one embodiment, the tonicity of the liquid formulation approximates that of the tonicity of blood or plasma. The tonicity agent may be used alone or in a combination with other tonicity agent. Tonicity agent according to the present invention is preferably selected from sodium chloride, dextrose, mannitol, sorbitol, lactose or a combination thereof.

The present invention provides a composition that may optionally comprise one or more preservatives. The term “preservative” refers to a substance present in a composition which can, at least in part, prevent and/or reduce decomposition of the composition. In some embodiments, the preservative may prevent and/or reduce decomposition of the composition by microbial growth in the composition. Preferably, the preservative is pharmaceutically acceptable.

The present invention provides a composition that may contain one or more of bulking agents. In various embodiments, the bulking agent comprises mannitol,
sorbitol, polyvinylpyrrolidone (PVP), sucrose, lactose, cellulose, or glycine. A preferred bulking agent is mannitol. In various embodiments, the bulking agent also functions as a tonicity agent, and is preferably present in an amount sufficient to render the formulation isotonic.

The present invention provides a composition that may contain one or more of chelating agents. In various embodiments, the chelating agent is selected from ethylene diamine tetra acetic acid (EDTA) or its salts, acetic acid, citric acid, tartaric acid and the like. A preferred chelating agent is EDTA or its salts such as disodium and tetra sodium.

In certain embodiments, the pharmaceutical composition of the present invention is stored in a container which is compatible with the formulation. The container is a vial, pre-filled syringe, bag (e.g., an infusion bag or a pouch), bottle, or ampoule. In certain non-limiting embodiments, the polymeric container or vessel includes flexible polymeric containers such as bags, e.g., infusion bags or pouches.

The formulations of the present invention may be sterilized using methods known to the skilled artisan. Non-limiting examples of sterilization techniques include filtration through a bacterial-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating. In certain non-limiting embodiments, the pharmaceutical compositions of the present application are sterilized by filtration.

Another embodiment of the present invention provides a stable injectable pharmaceutical formulation comprising;

a) 5-HTi antagonist, ■

b) Neurokinin 1 (NK1) receptor antagonist,

c) Iodide and

d) Isotonicity agent.

The stable injectable formulation according to the present invention is available in the following forms such as lyophilized powder form, a concentrated solution fordilution for injection or diluted solution for direct administration. The lyophilized powder form is reconstituted followed by diluted using a suitable diluent selected from 5% dextrose, 0.9% sodium chloride, mannitol etc for administration. The concentrated solution is diluted using a suitable diluent selected from dextrose, sodium chloride, mannitol etc for administration.

5-HT3-receptor is selected Palonosetron, Ondansetron, Granisetron or its pharmaceutically acceptable salt; preferably Palonosetron or its hydrochloride salt.

Neurokinin-1 (NK1) receptor antagonist is selected from Aprepitant, Fosaprepitant, Rolapitant, Neupitant, Fosnetupitant or a pharmaceutically acceptable salt thereof; preferably Fosnetupitant or its chloride hydrochloride salt.

The concentration of Fosnetupitant or a pharmaceutically acceptable salt thereof, based on the weight of the free base is in the range of about 1 mg/ ml to 50 mg/ ml and Palonosetron or a pharmaceutically acceptable salt thereof, based on the weight of the free base is in the range of about 1 meg/ ml to 50 meg/ ml.

The pharmaceutical composition according to the present invention contains Iodide which is added into the formulation separately or it is obtained from the input active pharmaceutical ingredient Palonosetron or Fosnetupitant. In case of separate addition of iodide then sodium iodide or potassium iodide is added into the formulation.

An effective amount of iodide is required to present in the formulation to control the formation of impurity. Specifically, the presence of iodide controls the formation of Palonosetron or its salt related impurity. More specifically, the presence of iodide controls formation of impurity-A of Palonosetron or its salt. The amount of iodide present in the formulation is about 1000 ppm, about 900 ppm, about 800 ppm, about 700 ppm, about 600 ppm, about 500 ppm, about 400 ppm, about 300 ppm, about 200 ppm, about 100 ppm, about 50 ppm, about 25 ppm, about 10 ppm, about 5 ppm or about 2 ppm.
The formulation may contain pH adjusting agents. The pH adjusting agent is selected from alkalizing agent and acidifying agent. The alkalizing agent is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, diethanolamine, monoethanolamine, potassium bicarbonate, sodium citrate, potassium citrate, sodium bicarbonate, sodium carbonate, sodium borate, dimeglumine, tris (hydroxymethyl) aminomethane, and triethanolamine. The acidifying agent is selected from adipic acid, ammonium chloride, citric acid monohydrate, glacial acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, as well as edetic acid and its various salts. The alkalizing agent and/ or acidifying agent is used to adjust the pH of the liquid composition in the range,of about 7 to 10; preferably about 8.5 to 9.5. The pH adjusting agent may also act as a solubilizing agent for the active ingredients used in the formulation.

The present invention provides a composition that may optionally comprise one or more preservatives. The term “preservative” refers to a substance present in a composition which can, at least in part, prevent and/or reduce decomposition of the composition. In some embodiments, the preservative may prevent and/or reduce decomposition of the composition by microbial growth in the composition. Preferably, the preservative is pharmaceutically acceptable.

The present invention provides a composition that may contain one or more of bulking agents. In various embodiments, the bulking agent comprises mannitol, sorbitol, polyvinylpyrrolidone (PVP), sucrose, lactose, cellulose, or glycine. A preferred bulking agent is mannitol. In various embodiments, the bulking agent also functions as a tonicity agent, and is preferably present in an amount sufficient to render the formulation isotonic.

The present invention provides a composition that may contain one or more of chelating agents. In various embodiments, the chelating agent is selected from ethylene diamine tetra acetic acid (EDTA) or its salts, acetic acid, citric acid, tartaric acid and the like. A preferred chelating agent is EDTA or its salts such as disodium and tetra sodium.
The pharmaceutical composition may additionally contain a “tonicity modifier” that can be used to adjust the tonicity of the formulation. Suitable tonicity modifiers include glycerine, lactose, mannitol, dextrose, sodium chloride, sodium sulphate, sorbitol, trehalose and others known to those of ordinary skill in the art. In one embodiment, the tonicity of the liquid formulation approximates that of the tonicity of blood or plasma. The tonicity agent may be used alone or in a combination with other tonicity agent. Tonicity agent according to the present invention is preferably selected from sodium chloride, dextrose, mannitol, sorbitol, lactose or a combination thereof.

In certain embodiments, the container is a vial, pre-filled syringe, bag (e.g., an infusion bag or a pouch), bottle, or ampoule. In certain non-limiting embodiments, the polymeric container or vessel includes flexible polymeric containers such as bags, e.g., infusion bags or pouches.

The formulations of the present invention may be sterilized using methods known to the skilled artisan. Non-limiting examples of sterilization techniques include filtration through a bacterial-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, and heating. In certain non-limiting embodiments, the pharmaceutical compositions of the present application are sterilized by filtration.

Another embodiment of the present invention provides a stable liquid pharmaceutical composition comprising;

a) Palonosetron HC1,

b) Fosnetupitant chloride hydrochloride,

c) Ededate disodium,

d) Mannitol,

e) Iodide,

f) Sodium hydroxide,

g) HC1 and

h) WFI.
Wherein the composition contains less than about 12% of total impurities when stored at 25±5°C for three months.

It is surprisingly found that the presence of iodide controls the formation of impurities in the liquid composition. Specifically, the presence of iodide controls the formation of Palonosetron or its salt related impurities. More specifically, the presence of iodide controls formation of impurity-A of Palonosetron or its salt. Iodide is added into the formulation separately or it is obtained from the input active pharmaceutical ingredient Palonosetron or Fosnetupitant. In case of separate addition of iodide then sodium iodide or potassium iodide is added into the formulation.

An effective amount of iodide is required to present in the formulation to control the formation of Palonosetron or its salt related impurity. The amount of iodide present in the formulation is about 1000 ppm, about 900 ppm, about 800 ppm, about 700 ppm, about 600 ppm, about 500 ppm, about 400 ppm, about 300 ppm, about 200 ppm, about 100 ppm, about 50 ppm, about 25 ppm, about 10 ppm, about 5 ppm or about 2 ppm.

Another embodiment of the present invention provides a stable ready to use liquid pharmaceutical composition comprising;

a) Palonosetron Hydrochloride,

b) Fosnetupitant chloride hydrochloride,

c) Edetate disodium,

d) Tonicity modifier selected from mannitol, sodium chloride, dextrose or a combination thereof,

e) Iodide,

f) Sodium hydroxide,

g) Hydrochloric acid and

h) WFI.

The stable pharmaceutical composition according to the present invention is ready to administer to the patient for preventing acute and chronic Chemotherapy-Induced Nausea and Vomiting (CINV).
The pharmaceutical composition of the invention is administered as an intravenous bolus injection or infusion, intramuscular and subcutaneous injection.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
About 80% of water for injection was added into the manufacturing vessel under nitrogen purging at 20-25“c. Sodium hydroxide was added and mixed until a clear solution was formed. Fosnetupitant chloride hydrochloride was added over a period of 30 minutes and mixed until complete dissolution and the solution was maintained between 8.5 and 9 using sodium hydroxide. A required quantity of sodium iodide solution (prepared by dissolving a required quantity of sodium
iodide in water) was added into the solution and dissolved. Mannitol and Edetate disodium dihydrate were added to the mixing vessel and stirred until complete dissolution. pH of the solution was adjusted to 8.75 ± 0.25 using sodium hydroxide solution/ 0.5 N Hydrochloric acid solution. Palonosetron HC1 was added to the mixing vessel and mixed until complete dissolution. pH of the solution was adjusted to 8.75 ± 0.25 using 0.5 N sodium hydroxide solution/ 0.5 N Hydrochloric acid solution. A sufficient quantity of water was added to make up the final volume. The final solution was filtered through 0.2 pm PES capsule filter and the filtrate was filled into Type I glass vial.
Manufacturing Process:

1. A required quantity of 0.5 N sodium hydroxide was added into a compounding vessel containing water for injection (70% of the batch size), stirred until complete dissolution.

2. Dispensed quantity of Fosnetupitant chloride HC1 was added into the above solution obtained in step 1 and stirred until complete dissolution.

3. pH of the solution obtained in step 2 was adjusted to 9.0-10.0 using 0.5N NaOH.

4. Dispensed quantity of mannitol was added into the above solution in step 3 and stirred until complete dissolution.

5. Dispensed quantity of edetate disodium dihydrate was added into the above solution in step 4 and stirred well until complete dissolution. pH of the solution was adjusted to 9.0 using 0.5N NaOH

6. A required quantity of Palonosetron hydrochloride solution (prepared by dissolving Palonosetron HC1 in water) was added into the solution obtained in step 5 and stirred until complete dissolution. pH of the solution was adjusted to 9.0 using 0.5N NaOH

7. A required quantity of Sodium iodide was added ((prepared by dissolving a required quantity of sodium iodide in water)

8. The volume was made up to 100% of the batch size with a required quantity of Water for Injection. The final pH of the solution was adjusted to 8.9.

9. The solution obtained in step 8 was filtered through 0.22p sterile filter.

10. The filtered solution was filled into a suitable vial and stoppered and stored at 25±5°C/ 60% relative humidity (RH) and 40°C/75%RH. The contents of the initial and stored vials were analyzed for impurity content using suitable HPLC method and shown in Table 2. 7093232941
Manufacturing Process:

1. A required quantity of 0.5 N sodium hydroxide was added into a compounding vessel containing water for injection (70% of the batch size), stirred until complete dissolution.

2. Dispensed quantity of Fosnetupitant chloride HCL was added into the above solution obtained in step 1 and stirred until complete dissolution.

3. pH of the solution obtained in step 2 was adjusted to 9.0-10.0 using 0.5N NaOH.

4. Dispensed quantity of mannitol was added into the above solution in step 3 and stirred until complete dissolution.

5. Dispensed quantity of Edetate disodium dihydrate was added into the above solution in step 4 and stirred well until complete dissolution. pH of the solution was adjusted to 9.0 using 0.5N NaOH

6. A required quantity of Palonosetron hydrochloride solution (prepared by dissolving Palonosetron HC1 in water) was added into the solution obtained in step 5 and stirred until complete dissolution. pH of the solution was adjusted to 9.0 using 0.5N NaOH

7. A required quantity of Sodium iodide was added (prepared by dissolving a required quantity of sodium iodide in water).

8. To the above solution obtained in step 6 added dispensed quantity of dextrose monohydrate and stirred until complete dissolution. The pH of the solution was adjusted to 8.8 using 0.5N NaOH

9. The volume was made up to 100% of the batch size with a required quantity of Water for Injection. The final pH of the solution was adjusted to around 9.0.

10. The solution obtained in step 8 was filtered through 0.22p sterile filter.
11. The filtered solution was filled into a suitable vial and stoppered and stored at 25±5°C/ 60% relative humidity (RH) and 40°C/75%RH. The contents of the initial and stored vials were analyzed for impurity content using suitable HPLC method and shown in Table 3.
Manufacturing Process:

1. A required quantity of 0.5 N sodium hydroxide was added into a compounding vessel containing water for injection (70% of the batch size), stirred until complete dissolution.

2. Dispensed quantity of Fosnetupitant chloride HCL was added into the above solution obtained in step 1 and stirred until complete dissolution.

3. pH of the solution obtained in step 2 was adjusted to 9.0-10.0 using 0.5N NaOH.

4. Dispensed quantity of mannitol was added into the above solution in step 3 and stirred until complete dissolution.

5. Dispensed quantity of Edetate disodium dihydrate was added into the above solution in step 4 and stirred well until complete dissolution. pH of the solution was adjusted to 9.0 using 0.5N NaOH

6. A required quantity of Palonosetron hydrochloride solution (prepared by dissolving Palonosetron HC1 in water) was added into the solution obtained in step 5 and stirred until complete dissolution. pH of the solution was adjusted to 9.0 using 0.5N NaOH

7. A required quantity of Sodium iodide was added (prepared by dissolving a required quantity of sodium iodide in water).

8. To the above solution obtained in step 6 added dispensed quantity of sodium chloride and stirred until complete dissolution. The pH of the solution was adjusted to 8.8 using the 0.5N NaOH

9. The volume was made up to 100% of the batch size with a required quantity of Water for Injection. The final pH of the solution was adjusted to 9.0.

10. The solution obtained in step 8 was filtered through 0.22p sterile filter.
11. The filtered solution was filled into a suitable vial and stoppered and stored at 25±5°C/ 60% relative humidity (RH) and 40°C/75%RH. The contents of the initial and stored vials were analyzed for impurity content using suitable HPLC method and shown in Table 4.