NZ747865B2 - Physiologically balanced injectable formulations of fosnetupitant - Google Patents
Physiologically balanced injectable formulations of fosnetupitant Download PDFInfo
- Publication number
- NZ747865B2 NZ747865B2 NZ747865A NZ74786517A NZ747865B2 NZ 747865 B2 NZ747865 B2 NZ 747865B2 NZ 747865 A NZ747865 A NZ 747865A NZ 74786517 A NZ74786517 A NZ 74786517A NZ 747865 B2 NZ747865 B2 NZ 747865B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- formulation
- fosnetupitant
- mannitol
- sodium hydroxide
- disodium edetate
- Prior art date
Links
- HZIYEEMJNBKMJH-UHFFFAOYSA-N [4-[5-[[2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl]-methylamino]-4-(2-methylphenyl)pyridin-2-yl]-1-methylpiperazin-1-ium-1-yl]methyl hydrogen phosphate Chemical compound C=1N=C(N2CC[N+](C)(COP(O)([O-])=O)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HZIYEEMJNBKMJH-UHFFFAOYSA-N 0.000 title claims abstract 17
- 229950010727 fosnetupitant Drugs 0.000 title claims abstract 16
- 239000007972 injectable composition Substances 0.000 title claims 2
- 238000009472 formulation Methods 0.000 claims abstract 29
- 239000000203 mixture Substances 0.000 claims abstract 29
- 150000003839 salts Chemical class 0.000 claims abstract 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 11
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 11
- 229930195725 Mannitol Natural products 0.000 claims 11
- 239000000594 mannitol Substances 0.000 claims 11
- 235000010355 mannitol Nutrition 0.000 claims 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical group Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 10
- 229960003359 palonosetron hydrochloride Drugs 0.000 claims 8
- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 claims 8
- 239000012458 free base Substances 0.000 claims 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 5
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229960002131 palonosetron Drugs 0.000 claims 2
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 claims 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 206010047700 Vomiting Diseases 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
Abstract
Injectable dosages and formulations of fosnetupitant and pharmaceutically acceptable salts thereof are provided that are efficacious, chemically stable and physiologically balanced for safety and efficacy.
Claims (28)
1. An injectable formulation of fosnetupitant, liquid or lyophilized, comprising: a) fosnetupitant or a pharmaceutically acceptable salt thereof; b) sodium hydroxide; c) disodium edetate; and d) mannitol.
2. The formulation of claim 1, further comprising palonosetron or a pharmaceutically acceptable salt thereof.
3. The formulation of claim 1 or claim 2, further comprising hydrochloric acid.
4. The formulation of any one of claims 1 to 3, wherein said fosnetupitant salt is a chloride hydrochloride salt of fosnetupitant.
5. The formulation of any one of claims 1 to 4, having a pH of from 7.0 to 10.
6. The formulation of any one of claims 1 to 5, having a pH of from 8.5 to 9.5.
7. The formulation of any one of claims 1 to 6, wherein said formulation is isotonic.
8. The formulation of any one of claims 1 to 7, as a water solution, comprising: a) from 2.3 to 30 mg/mL of fosnetupitant or a pharmaceutically acceptable salt thereof based on the weight of the free base; b) sodium hydroxide; c) disodium edetate; and d) mannitol.
9. The formulation of claim 8, further comprising from 5 to 50 µg/mL of palonosetron or a pharmaceutically acceptable salt thereof based on the weight of the free base.
10. The formulation of claim 8 or claim 9, further comprising hydrochloric acid.
11. The formulation of any one of claims 8 to 10, comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) sodium hydroxide; c) from 0.05 to 0.9 mg/mL of disodium edetate; and d) from 10 to 100 mg/mL of mannitol.
12. The formulation of claim 11, further comprising from 5 to 50 µg/mL of palonosetron hydrochloride based on the weight of the free base.
13. The formulation of claim 11 or claim 12, further comprising HCl q.s. to pH 7.0-10.0.
14. The formulation of any one of claims 8 to 10, comprising: a) from 5 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 µg/mL of palonosetron hydrochloride based on the weight of the free base; c) sodium hydroxide; 31 d) from 0.05 to 0.9 mg/mL of disodium edetate; e) HCl q.s. to pH 7.0-10.0; and f) from 10 to 100 mg/mL of mannitol.
15. The formulation of any one of claims 8 to 10, comprising: a) about 13.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 µg/mL of palonosetron hydrochloride; c) sodium hydroxide; d) about 0.16 mg/mL of disodium edetate; e) HCl q.s. to pH 7.0-10.0; and f) about 38 mg/mL of mannitol.
16. The formulation of any one of claims 8 to 10, comprising: a) about 26.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 28.08 µg/mL of palonosetron hydrochloride; c) sodium hydroxide; d) about 0.32 mg/mL of disodium edetate; e) HCl q.s. to pH 7.0-10.0; and f) about 25 mg/mL of mannitol.
17. The formulation of any one of claims 8 to 10, comprising: a) about 13 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 µg/mL of palonosetron hydrochloride; c) sodium hydroxide; d) about 0.16 mg/mL of disodium edetate; e) HCl q.s. to pH 8.5-9.5; and f) about 38 mg/mL of mannitol.
18. The formulation of any one of claims 1 to 7, in lyophilized form, comprising: a) from 2.3 to 30 mg/mL of fosnetupitant or a pharmaceutically acceptable salt thereof; b) sodium hydroxide; c) from 0.1 to 2.0 mg/mL of disodium edetate; and d) from 10 to 100 mg/mL of mannitol; based on reconstitution in a suitable water volume.
19. The formulation of claim 18, further comprising from 5 to 50 µg/mL of palonosetron hydrochloride based on the weight of the free base.
20. The formulation of claim 18 or claim 19, further comprising HCl q.s. to pH 7.0-10.0. 32
21. The formulation of any one of claims 18 to 20, comprising: a) from 2.3 to 30 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) from 5 to 50 µg/mL of palonosetron hydrochloride based on the weight of the free base; c) sodium hydroxide; d) from 0.1 to 2.0 mg/mL of disodium edetate; e) from 10 to 100 mg/mL of mannitol; and f) HCl q.s. to pH 7.0-10.0; based on reconstitution in a suitable water volume.
22. The formulation of any one of claims 18 to 20, comprising: a) about 13.0 mg/mL of the chloride hydrochloride salt of fosnetupitant; b) about 14.04 µg/mL of palonosetron hydrochloride based on the weight of the salt; c) sodium hydroxide; d) about 0.32 mg/mL of disodium edetate; and e) about 38 mg/mL of mannitol; based on reconstitution in a water volume of 20 mL.
23. The formulation of claim 22, further comprising HCl q.s. to pH 8.5-9.5.
24. The formulation of any one of claims 1 to 23, further comprising 0.9% wt. saline or 5% wt. glucose.
25. The formulation of any one of claims 1 to 24, in a sealed sterile vial.
26. The formulation of any one of claims 1 to 25, comprising approximately 260 mg of the chloride hydrochloride salt of fosnetupitant.
27. A method of manufacturing a formulation of any one of claims 1 to 26, comprising: a) admixing the chloride hydrochloride salt of fosnetupitant with sodium hydroxide in water at a basic pH to form a solution; b) reducing the pH of the solution to a basic pH by addition of one or more acidic pH adjusting agents; and c) admixing the solution with disodium edetate and mannitol.
28. Use of a formulation of any one of claims 1 to 26 in the manufacture of a medicament for treating emesis
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662345942P | 2016-06-06 | 2016-06-06 | |
| PCT/EP2017/063268 WO2017211663A1 (en) | 2016-06-06 | 2017-06-01 | Physiologically balanced injectable formulations of fosnetupitant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ747865A NZ747865A (en) | 2024-05-31 |
| NZ747865B2 true NZ747865B2 (en) | 2024-09-03 |
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