WO2024009319A1 - Liquid injectable compositions of trilaciclib - Google Patents

Liquid injectable compositions of trilaciclib Download PDF

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Publication number
WO2024009319A1
WO2024009319A1 PCT/IN2023/050647 IN2023050647W WO2024009319A1 WO 2024009319 A1 WO2024009319 A1 WO 2024009319A1 IN 2023050647 W IN2023050647 W IN 2023050647W WO 2024009319 A1 WO2024009319 A1 WO 2024009319A1
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WO
WIPO (PCT)
Prior art keywords
trilaciclib
liquid injectable
mixtures
solvent system
injectable composition
Prior art date
Application number
PCT/IN2023/050647
Other languages
French (fr)
Inventor
Raju KOTA
Kuldipgiri Rajendragiri GOSWAMI
Anil Kumar ARE
Mukesh Bothra
Original Assignee
Dr. Reddy's Laboratories Limited
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Publication of WO2024009319A1 publication Critical patent/WO2024009319A1/en

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    • 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
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to liquid injectable compositions of trilaciclib or pharmaceutical acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof.
  • Trilaciclib dihydrochloride is approved as CDK4 Kinase Inhibitor to decrease the incidence of chemotherapy -induced myelosuppression in adult patients when administered prior to a platinium/etoposide-containing regimen or topotecan-containing regimen for extensive- stage small cell lung cancer.
  • Trilaciclib dihydrochloride is structurally represented as
  • Trilaciclib is available in the US market with the Brand Name COSELA® and marketed by G1 Therapeutics as a sterile, preservative free, lyophilized cake in a single dose vial for intravenous infusion after reconstitution and dilution.
  • US Patent Nos. 8598186, 8598197, 9957276, 10189849, 10189850 & 10927120 describe trilaciclib and related compounds.
  • Each single dose vial of COSELA contains the equivalent of 300 mg of trilaciclib (provided as 349 mg of trilaciclib dihydrochloride) and the following inactive ingredients: citric acid monohydrate (75.6 mg) and mannitol (300 mg), hydrochloric acid and sodium hydroxide to adjust pH.
  • the lyophilized preparation needs reconstitution with 19.5 mL of 0.9% NaCl injection, USP OR 5% dextrose injection, USP using a sterile syringe to obtain a concentration of 15 mg/mL of trilaciclib.
  • the re-constituted solution can only be stored at 20°C to 25°C (68°F to 77°F) for up to 4 hours prior to transfer to the infusion bag.
  • US Patent No. 9,487,530 discloses one example of pharmaceutical composition that includes hydrochloride salt of trilaciclib in an aqueous system for intravenous use, wherein the aqueous solvent system comprises of hydroxypropyl-beta-cyclodextrin and dextrose along with hydrochloric acid /sodium hydroxide as pH adjusting agents.
  • US Patent No. 10,988,479 discloses morphic forms of trilaciclib free base that can be delivered as an IV solution from lyophilized formulations. Additionally, it discloses that trilaciclib has less solubility in water and further less soluble as the pH increases to 7.2-7.4. Further discloses the solubility studies conducted for dihydrochloride salt form of trilaciclib in various solvent systems. While, a thermodynamic solubility for different crystalline and amorphous dihydrochloride salt forms have been disclosed at a concentration of 30 mg/ml in aqueous system, there is no data given with commercial viability of trilaciclib in the aqueous system that can be directly administered to the patient.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid compositions are re-constituted from lyophilized forms of trilaciclib.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- dilute.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- use.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection.
  • Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the stable liquid injectable compositions are ready-to-dilute, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the stable liquid injectable compositions are ready-to-use, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof and wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of non-aqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, benzyl alcohol, glycerol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, wherein the solvent system comprises aqueous solvents or nonaqueous solvents or mixtures thereof and wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of nonaqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, benzyl alcohol, glycerol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof.
  • compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol.
  • compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol.
  • compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol.
  • compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benz
  • Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the non-aqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 25:1 to about 75:1.
  • Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the non-aqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 30:1 to about 50:1.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, about 1 mg /mL to about 150 mg/mL of solubilizer and a stabilizer.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, about 5 mg /mL to about 100 mg/mL of solubilizer and a stabilizer.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, solubilizer and about 1 mg /mL to about 150 mg/mL of stabilizer.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, solubilizer and about 5 mg /mL to about 100 mg/mL of stabilizer.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and a buffering agent.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer, a stabilizer and about 1 mg /mL to about 150 mg/mL of buffering agent.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer, a stabilizer and about 5 mg /mL to about 100 mg/mL of buffering agent.
  • a preferred embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from
  • Another preferred embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w
  • Another preferred embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • Another preferred embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85%
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid compositions are re-constituted from lyophilized forms of trilaciclib.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- dilute.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- use.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • liquid refers to either ready-to-dilute or ready-to-use or compositions obtained from re-constitution of lyophilized forms of trilacicib.
  • ready-to-dilute refers to a formulation which can be directly combined with a diluent (e.g., dextrose solution, saline solution, or any other infusion medium) and then administered to a patient.
  • a diluent e.g., dextrose solution, saline solution, or any other infusion medium
  • ready-to-use refers to any preparation of trilaciclib which can be administered to patient directly without any further dilution or processing.
  • composition and “formulation” refer to preparations comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof in a form suitable for administration to a human of a mammal.
  • solvent refers to an ingredient used for dissolving an ingredient.
  • stable refers to physical and chemical stability for commercially significant periods, such as atleast 3 months, 6 months, 1 year, or 2 years or 3 years, without significant physical stability (description, clarity etc.) and chemical degradation. Stable or stability may represent stability when stored at 2° C.-8 0 C. or at ambient conditions (e.g., 25° C.) or elevated temperatures (e.g., 40° C).
  • the present invention relates to the liquid injectable composition
  • the liquid injectable composition comprising from about O.lmg/mL to about 25 mg/mL of trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; preferably from about 0.5 mg/mL to about 15 mg/mL of trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
  • the non-aqueous solvents in the present invention include polar protic solvents and polar aprotic solvents or mixtures thereof.
  • the polar protic solvents are known in the art and include alkyl alcohols, for example ethanol, benzyl alcohol; alkyl glycols for example, ethylene glycol, propylene glycol; and butylene glycol; glycerol; polysorbates for examples TWEEN 20, TWEEN 40 and TWEEN 80; benzyl benzoate; polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, and polybutylene glycol or mixtures thereof.
  • the polar aprotic solvents are known in the art and include dimethyl acetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1, 4-dioxone, acetonitrile, dimethyl formamide, propylene carbonate, 1- methyl-2-pyrrolidione, 1, 3-dimethyl-2-imidazolidinone or mixtures thereof.
  • mixtures of polyalkylene glycols such as PEG 300, PEG 400 along with non-ionic liquid polymer of the alkyl aryl poly ether alcohol type such as Tyloxapol and other solvents such as ethanol, glycerol and castor oil may be used.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof and wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of non-aqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, glycerol, benzyl alcohol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof.
  • liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, wherein the solvent system comprises aqueous solvents or nonaqueous solvents or mixtures thereof and wherein the solvent system comprises about thereof.to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of non-aqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, benzyl alcohol, glycerol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof
  • aqueous solvents in the present invention include purified water, dextrose solution, saline solution.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v or preferably from about 70% w/v to about 85% w/v of propylene glycol.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 6.5% w/v to about 8.5% w/v or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70% w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70% w/v to about 85% w/v
  • the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about
  • the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof
  • the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
  • the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of
  • the present invention relate liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the nonaqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 25:1 to about 75:1.
  • the present invention relate liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the nonaqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 30:1 to about 50:1.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, about 1 mg /mL to about 150 mg/mL solubilizer and a stabilizer.
  • solvent system suitable for injection about 1 mg /mL to about 150 mg/mL solubilizer and a stabilizer.
  • the quantity varies depending on the nature of the solubilizer and the stabilizer used.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, about 5 mg /mL to about 100 mg/mL of solubilizer and a stabilizer.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer and about 1 mg /mL to about 150 mg/mL of stabilizer.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer and about 5 mg /mL to about 100 mg/mL of stabilizer.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, about 5 mg /mL to about 100 mg/mL solubilizer and a stabilizer
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and a buffering agent.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and about 1 mg /mL to about 150 mg/mL of buffering agent.
  • the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and about 5 mg /mL to about 100 mg/mL of buffering agent.
  • Solubilizers refers to any substance which enhances the solubility of the drug in the solvents. Solubilizers are selected from the group of carboxylic acids, castor oil, tromethamine, cyclodextrins such as beta cyclodextrin, etc.
  • carboxylic acid as used in some embodiments includes, without limitation thereto malic acid, tartaric acid, succinic acid, acetic acid and the like.
  • stabilizer identifies an agent which improves the composition physical and chemical stability for commercially significant periods, such as at least 3 months, 6 months, 1 year, or 2 years or 3 years, without significant physical instability (description, clarity etc.) and chemical degradation.
  • Stable or stability may represent stability when stored at 2° C.-8 0 C. or at ambient conditions (e.g., 25° C.) or elevated temperatures (e.g., 40° C).
  • Suitable stabilizers include but are not limited to include citric acid etc.
  • the stabilizer is present in the amount of about 5mg/mL to about 100 mg/mL.
  • a primary source of pH control can be buffer. Typically, a buffer is present as an acid or a base and its conjugate base or acid, respectively.
  • the buffering agent may comprise at least one buffering agent selected from the group consisting of citrate (sodium or potassium), sodium acetate, phosphate, malate, lactate, Tromethamine (Tris), hydrochloric acid, sodium hydroxide and mixtures thereof.
  • the most preferably used buffering agent is acetic acid.
  • the buffering agent may be present in an amount of about O.Olmg/mL to about 100 mg/mL. The amount of buffering agent used differs based on the buffering agent used in the composition.
  • the liquid injectable compositions of trilaciclib may optionally include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include any one or more of: one or more antibacterial preservatives, including one or more of phenyl mercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol; and tonicity contributors including one or more of sodium chloride, potassium chloride, and alkaline substances including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglumine and salts such as sodium chloride. Additionally, may include one or more chelating agents such as EDTA, tartaric acid etc.
  • the liquid injectable formulations of the present invention have sufficient stability to have utility as a pharmaceutical agent.
  • the formulation has both physical and chemical stability for commercially significant periods, such as at least 3 months, 6 months, 1 year, or 2 years or 3 years, without significant physical instability (description, clarity etc.) and chemical degradation.
  • Stable or stability may represent stability when stored at 2° C.-8 0 C. or at ambient conditions (e.g. 25° C.) or elevated temperatures (e.g. 40° C.). Percent degradation may be determined by analyzing for impurities by suitable analytical method such as HPLC.
  • Injectable formulations may take any route including intramuscular, intra-peritoneal, intravenous or subcutaneous administration. Preferred are intravenous route of administration for the composition of the present invention.
  • the present invention relates to the liquid injectable composition comprising trilaciclib; wherein the injectable composition is packaged in a container suitable for both single and multi-use.
  • the preferred containers include an ampoule, a vial, a pre-filled syringe, and intravenous bag.
  • Trilaciclib dihydrochloride solution of step 5 was filled into suitable vial, stoppered.
  • Vials prepared are stored at 2-8°C, 25 ⁇ 2°C and 60% relative humidity (RH), or at 40 ⁇ 2°C and 75% RH, for at least 3 months.
  • the contents of the initial and stored vials are analyzed for impurity content using suitable analytical method.
  • Example 1 Liquid injectable compositions of trilaciclib comprising non-aqueous solvents
  • Example 2 Liquid injectable compositions of trilaciclib comprising a mixture of aqueous and non-aqueous solvents
  • Trilaciclib was added to the solution of step 1 to form a white slurry.
  • step 4 The solution of step 4 was filtered through 0.45p filter followed by 0.22 p filer to get a sterile filtrate.
  • step 5 The solution of step 5 was filled into suitable vial, stoppered. 7.
  • Vials prepared are stored at 2-8°C, 25 ⁇ 2°C for at least 3 months. The contents of the initial and stored vials are analyzed for impurity content using suitable analytical method.
  • Example 4 As evident in Tables 1 & 2, the liquid injectable compositions of trilaciclib of Example 4 showed both physical stability (i.e., clear solution with no drug precipitation) and chemical stability for a period of 3 months. Total impurities of the compositions were found to be less than 1% in the similar time period.
  • Example 5 A fresh batch of example 4 was prepared with same manufacturing process and physical and chemical stability was evaluated at 25 ⁇ 2°C & 40°C respectively for a period of 1 month.
  • Table 3 represents the physical and chemical stability data of Example 5
  • liquid injectable compositions of trilaciclib of Example 5 showed both physical and chemical stability at i.e., TO, and when stored for 1 Month at 25 ⁇ 2°C & 40°C. Total impurities of the compositions were both the compositions were found to be less than 1%.
  • Trilaciclib base is equivalent to 349 mg of Trilaciclib Dihydrochloride **2% of Trilaciclib base is equivalent to 2.33% of Trilaciclib Dihydrochloride Manufacturing process for Example 6
  • Trilaciclib dihydrochloride was added to the solution of step 1 to form a slurry.
  • Trilaciclib dihydrochloride solution of step 5 was filled into suitable vial, stoppered.
  • the contents of the initial time period i.e., TO are analyzed for impurity content using suitable analytical method.
  • Table 4 represents the physical and chemical stability data of Example 6
  • liquid injectable compositions of trilaciclib of Example 6 showed both physical and chemical stability at i.e., TO. Total Impurities of both the compositions were found to be less than 1%.

Abstract

The present invention relates to liquid injectable compositions of trilaciclib or pharmaceutical acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof. More particularly, the present invention relates to liquid injectable compositions which are either ready-to-dilute or ready-to-use or reconstituted from lyophilized forms of trilaciclib and further comprise of aqueous solvents or non-aqueous solvents of mixtures thereof.

Description

LIQUID INJECTABLE COMPOSITIONS OF TRILACICLIB
CROSS REFERENCE
The application claims priority from Indian Patent Application No. 202241025607 filed on May 2, 2022.
TECHNICAL FIELD OF INVENTION
The present invention relates to liquid injectable compositions of trilaciclib or pharmaceutical acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof.
BACKGROUND OF THE INVENTION
Trilaciclib dihydrochloride is approved as CDK4 Kinase Inhibitor to decrease the incidence of chemotherapy -induced myelosuppression in adult patients when administered prior to a platinium/etoposide-containing regimen or topotecan-containing regimen for extensive- stage small cell lung cancer. Trilaciclib dihydrochloride is structurally represented as
Figure imgf000002_0001
Trilaciclib is available in the US market with the Brand Name COSELA® and marketed by G1 Therapeutics as a sterile, preservative free, lyophilized cake in a single dose vial for intravenous infusion after reconstitution and dilution. US Patent Nos. 8598186, 8598197, 9957276, 10189849, 10189850 & 10927120 describe trilaciclib and related compounds.
Each single dose vial of COSELA contains the equivalent of 300 mg of trilaciclib (provided as 349 mg of trilaciclib dihydrochloride) and the following inactive ingredients: citric acid monohydrate (75.6 mg) and mannitol (300 mg), hydrochloric acid and sodium hydroxide to adjust pH. The lyophilized preparation needs reconstitution with 19.5 mL of 0.9% NaCl injection, USP OR 5% dextrose injection, USP using a sterile syringe to obtain a concentration of 15 mg/mL of trilaciclib. Moreover, the re-constituted solution can only be stored at 20°C to 25°C (68°F to 77°F) for up to 4 hours prior to transfer to the infusion bag.
US Patent No. 9,487,530 discloses one example of pharmaceutical composition that includes hydrochloride salt of trilaciclib in an aqueous system for intravenous use, wherein the aqueous solvent system comprises of hydroxypropyl-beta-cyclodextrin and dextrose along with hydrochloric acid /sodium hydroxide as pH adjusting agents.
US Patent No. 10,988,479 discloses morphic forms of trilaciclib free base that can be delivered as an IV solution from lyophilized formulations. Additionally, it discloses that trilaciclib has less solubility in water and further less soluble as the pH increases to 7.2-7.4. Further discloses the solubility studies conducted for dihydrochloride salt form of trilaciclib in various solvent systems. While, a thermodynamic solubility for different crystalline and amorphous dihydrochloride salt forms have been disclosed at a concentration of 30 mg/ml in aqueous system, there is no data given with commercial viability of trilaciclib in the aqueous system that can be directly administered to the patient.
There exists a need to develop liquid, ready-to-dilute or ready-to-use compositions of trilaciclib or pharmaceutical acceptable salts or solvates thereof, for improved patient’s compliance.
SUMMARY OF INVENTION
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid compositions are re-constituted from lyophilized forms of trilaciclib.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- dilute.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- use.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection.
Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the stable liquid injectable compositions are ready-to-dilute, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
Another embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the stable liquid injectable compositions are ready-to-use, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof. Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof and wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of non-aqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, benzyl alcohol, glycerol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, wherein the solvent system comprises aqueous solvents or nonaqueous solvents or mixtures thereof and wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of nonaqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, benzyl alcohol, glycerol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the non-aqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 25:1 to about 75:1.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the non-aqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 30:1 to about 50:1.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, about 1 mg /mL to about 150 mg/mL of solubilizer and a stabilizer.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, about 5 mg /mL to about 100 mg/mL of solubilizer and a stabilizer.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, solubilizer and about 1 mg /mL to about 150 mg/mL of stabilizer.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, solubilizer and about 5 mg /mL to about 100 mg/mL of stabilizer.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and a buffering agent.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer, a stabilizer and about 1 mg /mL to about 150 mg/mL of buffering agent.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer, a stabilizer and about 5 mg /mL to about 100 mg/mL of buffering agent.
A preferred embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
Another preferred embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
Another preferred embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
Another preferred embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
Another preferred embodiment of the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid compositions are re-constituted from lyophilized forms of trilaciclib. The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- dilute.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to- use.
The present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
As used herein the term “liquid” refers to either ready-to-dilute or ready-to-use or compositions obtained from re-constitution of lyophilized forms of trilacicib.
As used herein the term “ready-to-dilute” refers to a formulation which can be directly combined with a diluent (e.g., dextrose solution, saline solution, or any other infusion medium) and then administered to a patient.
As used herein the term “ready-to-use” refers to any preparation of trilaciclib which can be administered to patient directly without any further dilution or processing.
As used herein, the terms “composition” and “formulation” refer to preparations comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof in a form suitable for administration to a human of a mammal.
The term “solvent” refers to an ingredient used for dissolving an ingredient.
As used herein, the term “stable” refer to physical and chemical stability for commercially significant periods, such as atleast 3 months, 6 months, 1 year, or 2 years or 3 years, without significant physical stability (description, clarity etc.) and chemical degradation. Stable or stability may represent stability when stored at 2° C.-80 C. or at ambient conditions (e.g., 25° C.) or elevated temperatures (e.g., 40° C).
According to another embodiment, the present invention relates to the liquid injectable composition comprising from about O.lmg/mL to about 25 mg/mL of trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; preferably from about 0.5 mg/mL to about 15 mg/mL of trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof. Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, and wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof.
The non-aqueous solvents in the present invention include polar protic solvents and polar aprotic solvents or mixtures thereof. The polar protic solvents are known in the art and include alkyl alcohols, for example ethanol, benzyl alcohol; alkyl glycols for example, ethylene glycol, propylene glycol; and butylene glycol; glycerol; polysorbates for examples TWEEN 20, TWEEN 40 and TWEEN 80; benzyl benzoate; polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, and polybutylene glycol or mixtures thereof. The polar aprotic solvents are known in the art and include dimethyl acetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1, 4-dioxone, acetonitrile, dimethyl formamide, propylene carbonate, 1- methyl-2-pyrrolidione, 1, 3-dimethyl-2-imidazolidinone or mixtures thereof. Preferably, mixtures of polyalkylene glycols such as PEG 300, PEG 400 along with non-ionic liquid polymer of the alkyl aryl poly ether alcohol type such as Tyloxapol and other solvents such as ethanol, glycerol and castor oil may be used.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof and wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of non-aqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, glycerol, benzyl alcohol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof.
Another embodiment of the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use, wherein the solvent system comprises aqueous solvents or nonaqueous solvents or mixtures thereof and wherein the solvent system comprises about thereof.to about 100% w/v of non-aqueous solvents, preferably from about 5% w/v to about 95% w/v of non-aqueous solvents and most preferably from about 10% w/v to about 90% w/v of non-aqueous solvents and wherein the non-aqueous solvent comprises propylene glycol, polyethylene glycol, benzyl alcohol, glycerol, castor oil, polysorbate, tyloxapol, ethanol or mixtures thereof
The aqueous solvents in the present invention include purified water, dextrose solution, saline solution.
According to a preferred embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v or preferably from about 70% w/v to about 85% w/v of propylene glycol.
According to another preferred embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 6.5% w/v to about 8.5% w/v or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol.
According to another preferred embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol.
According to another preferred embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof. According to another preferred embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
According to another preferred embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70% w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
According to another preferred embodiment, the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
According to another preferred embodiment, the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-dilute and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof
According to another preferred embodiment, the present invention relate to stable liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection, wherein the liquid injectable compositions are ready-to-use and wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol or mixtures thereof.
According to a further embodiment, the present invention relate liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the nonaqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 25:1 to about 75:1.
According to a further embodiment, the present invention relate liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, wherein the nonaqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 30:1 to about 50:1.
According to a further embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; and solvent system suitable for injection, about 1 mg /mL to about 150 mg/mL solubilizer and a stabilizer. The quantity varies depending on the nature of the solubilizer and the stabilizer used.
According to a further embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, about 5 mg /mL to about 100 mg/mL of solubilizer and a stabilizer.
According to another embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer and about 1 mg /mL to about 150 mg/mL of stabilizer.
According to further embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, solubilizer and about 5 mg /mL to about 100 mg/mL of stabilizer.
According to a further embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, about 5 mg /mL to about 100 mg/mL solubilizer and a stabilizer
According to another embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and a buffering agent.
According to further embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and about 1 mg /mL to about 150 mg/mL of buffering agent.
According to further embodiment, the present invention relate to liquid injectable compositions comprising trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof; solvent system suitable for injection, a solubilizer, a stabilizer and about 5 mg /mL to about 100 mg/mL of buffering agent.
The term “solubilizer” refers to any substance which enhances the solubility of the drug in the solvents. Solubilizers are selected from the group of carboxylic acids, castor oil, tromethamine, cyclodextrins such as beta cyclodextrin, etc.
The term “carboxylic acid” as used in some embodiments includes, without limitation thereto malic acid, tartaric acid, succinic acid, acetic acid and the like.
The term “stabilizer” identifies an agent which improves the composition physical and chemical stability for commercially significant periods, such as at least 3 months, 6 months, 1 year, or 2 years or 3 years, without significant physical instability (description, clarity etc.) and chemical degradation. Stable or stability may represent stability when stored at 2° C.-80 C. or at ambient conditions (e.g., 25° C.) or elevated temperatures (e.g., 40° C). Suitable stabilizers include but are not limited to include citric acid etc. The stabilizer is present in the amount of about 5mg/mL to about 100 mg/mL. A primary source of pH control can be buffer. Typically, a buffer is present as an acid or a base and its conjugate base or acid, respectively. According to the present disclosure the buffering agent may comprise at least one buffering agent selected from the group consisting of citrate (sodium or potassium), sodium acetate, phosphate, malate, lactate, Tromethamine (Tris), hydrochloric acid, sodium hydroxide and mixtures thereof. The most preferably used buffering agent is acetic acid. In certain embodiments the buffering agent may be present in an amount of about O.Olmg/mL to about 100 mg/mL. The amount of buffering agent used differs based on the buffering agent used in the composition.
The liquid injectable compositions of trilaciclib may optionally include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include any one or more of: one or more antibacterial preservatives, including one or more of phenyl mercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol; and tonicity contributors including one or more of sodium chloride, potassium chloride, and alkaline substances including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglumine and salts such as sodium chloride. Additionally, may include one or more chelating agents such as EDTA, tartaric acid etc.
The liquid injectable formulations of the present invention have sufficient stability to have utility as a pharmaceutical agent. Preferably, the formulation has both physical and chemical stability for commercially significant periods, such as at least 3 months, 6 months, 1 year, or 2 years or 3 years, without significant physical instability (description, clarity etc.) and chemical degradation. Stable or stability may represent stability when stored at 2° C.-80 C. or at ambient conditions (e.g. 25° C.) or elevated temperatures (e.g. 40° C.). Percent degradation may be determined by analyzing for impurities by suitable analytical method such as HPLC.
Injectable formulations may take any route including intramuscular, intra-peritoneal, intravenous or subcutaneous administration. Preferred are intravenous route of administration for the composition of the present invention.
According to a preferred embodiment, the present invention relates to the liquid injectable composition comprising trilaciclib; wherein the injectable composition is packaged in a container suitable for both single and multi-use. The preferred containers include an ampoule, a vial, a pre-filled syringe, and intravenous bag.
The following example further describes certain specific formulations (Examples 1-6) of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples and manufacturing are given by way of illustration only and are not intended to limit the scope of the invention in any manner. Manufacturing process for Examples 1-3
1. Required quantity of a suitable buffer was taken and dissolved in suitable solvent such as ethanol, or purified water to form the dissolved solution.
2. Trilaciclib was added to the solution of step 1.
3. Other suitable excipients such as solubilizers, buffering agents, antioxidants were added to the solution of step 2.
4. Trilaciclib solution of step 3 were purged with nitrogen.
5. The solution of trilaciclib of step 4 was filtered through 0.22p filter to get a sterile filtrate.
6. Trilaciclib dihydrochloride solution of step 5 was filled into suitable vial, stoppered.
7. Vials prepared are stored at 2-8°C, 25±2°C and 60% relative humidity (RH), or at 40±2°C and 75% RH, for at least 3 months. The contents of the initial and stored vials are analyzed for impurity content using suitable analytical method.
Example 1 Liquid injectable compositions of trilaciclib comprising non-aqueous solvents
Figure imgf000017_0001
*300 mg of Trilaciclib base is equivalent to 349 mg of Trilaciclib Dihydrochloride
Example 2 Liquid injectable compositions of trilaciclib comprising a mixture of aqueous and non-aqueous solvents
Figure imgf000018_0001
*300 mg of Trilaciclib base is equivalent to 349 mg of Trilaciclib Dihydrochloride Example 3: Liquid injectable compositions of trilaciclib comprising aqueous solvents
Figure imgf000019_0001
*300 mg of Trilaciclib base is equivalent to 349 mg of Trilaciclib Dihydrochloride
Example 4 & 5 Liquid ready-to-dilute injectable compositions of trilaciclib
Figure imgf000019_0002
*300 mg of Trilaciclib base is equivalent to 349 mg of Trilaciclib Dihydrochloride
Manufacturing process for Example 4
1. Required quantity of propylene glycol and benzyl alcohol was taken and stirred for 10 minutes.
2. Trilaciclib was added to the solution of step 1 to form a white slurry.
3. Required quantity of Hydrochloric acid was added to the slurry obtained in step 2 and stirred for 15 minutes to form a clear yellow solution.
4. Required quantity of glycerol was added to the solution of step 3 and stirred for 30 minutes or until a clear yellow solution is formed and made up the volume with glycerol.
5. The solution of step 4 was filtered through 0.45p filter followed by 0.22 p filer to get a sterile filtrate.
6. The solution of step 5 was filled into suitable vial, stoppered. 7. Vials prepared are stored at 2-8°C, 25±2°C for at least 3 months. The contents of the initial and stored vials are analyzed for impurity content using suitable analytical method.
Table 1 Physical stability data of Example 4
Figure imgf000020_0001
Table 2 Chemical stability data of Example 4
Figure imgf000020_0002
As evident in Tables 1 & 2, the liquid injectable compositions of trilaciclib of Example 4 showed both physical stability (i.e., clear solution with no drug precipitation) and chemical stability for a period of 3 months. Total impurities of the compositions were found to be less than 1% in the similar time period. Example 5: A fresh batch of example 4 was prepared with same manufacturing process and physical and chemical stability was evaluated at 25±2°C & 40°C respectively for a period of 1 month.
Table 3 represents the physical and chemical stability data of Example 5
Figure imgf000021_0001
As evident in Table 3, the liquid injectable compositions of trilaciclib of Example 5 showed both physical and chemical stability at i.e., TO, and when stored for 1 Month at 25±2°C & 40°C. Total impurities of the compositions were both the compositions were found to be less than 1%.
Example 6 Liquid ready-to-dilute injectable compositions of trilaciclib
Figure imgf000021_0002
*300 mg of Trilaciclib base is equivalent to 349 mg of Trilaciclib Dihydrochloride **2% of Trilaciclib base is equivalent to 2.33% of Trilaciclib Dihydrochloride Manufacturing process for Example 6
1. Required quantity of propylene glycol and benzyl alcohol was taken and stirred for 10 minutes.
2. Trilaciclib dihydrochloride was added to the solution of step 1 to form a slurry.
3. Required quantity of Hydrochloric acid was added to the slurry obtained in step 2 and stirred for 15 minutes.
4. Required quantity of Glycerol was added to the solution of step 3 and stirred for 30 minutes or until a clear yellow solution is formed, and volume make as per batch size.
5. The solution of Trilaciclib dihydrochloride of step 4 was filtered through 0.45p filter followed by 0.22 p filter to get a sterile filtrate.
6. Trilaciclib dihydrochloride solution of step 5 was filled into suitable vial, stoppered. The contents of the initial time period i.e., TO are analyzed for impurity content using suitable analytical method.
Table 4 represents the physical and chemical stability data of Example 6
Figure imgf000022_0001
As evident in Table 4, the liquid injectable compositions of trilaciclib of Example 6 showed both physical and chemical stability at i.e., TO. Total Impurities of both the compositions were found to be less than 1%.

Claims

We Claim: A liquid injectable composition comprising trilaciclib or its pharmaceutically acceptable salts hydrates, solvates, polymorphs, and mixtures thereof and solvent system suitable for injection. The liquid injectable composition of claim 1, wherein the solvent system comprises aqueous solvents or non-aqueous solvents or mixtures thereof. The liquid injectable composition of claim 2, wherein the solvent system comprises about 1% w/v to about 100% w/v of non-aqueous solvents. The liquid injectable composition of claim 3, wherein the non-aqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 25:1 to about 75:1. The liquid injectable composition of claim 3, wherein the non-aqueous solvents are mixed in a suitable ratio (w/w) with trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof from about 30:1 to about 50:1. The liquid injectable composition of claim 5, wherein the non-aqueous solvents are selected from propylene glycol, benzyl alcohol, ethanol, polyethylene glycol, glycerol, polysorbate 20, polysorbate 80, N, N-dimethylacetamide, N- methylpyrrolidone, dimethyl sulfoxide (DMSO), diethylene glycol or mixtures thereof. The liquid injectable composition of claim 6, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol or preferably from about 70%w/v to about 85% w/v of propylene glycol. The liquid injectable composition of claim 6, wherein the solvent system comprises from about 6.5% w/v to about 8.5% w/v of benzyl alcohol or preferably from about 7.0% w/v to about 8.0% w/v of benzyl alcohol. The liquid injectable composition of claim 6, wherein the solvent system comprises from about 13.3% w/v to about 33.3% w/v or preferably from about 15% w/v to about 25% w/v of glycerol. The liquid injectable composition of claim 6, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or mixtures thereof. The liquid injectable composition of claim 10, wherein the solvent system comprises from about 70% w/v to about 85% w/v of propylene glycol, from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 15% w/v to about 25% w/v of glycerol or mixtures thereof. The liquid injectable composition of claim 1, wherein the pharmaceutical acceptable salt of trilaciclib is trilaciclib dihyrochloride. The liquid injectable composition of claim 1, wherein the pharmaceutical acceptable hydrate of trilaciclib is trilaciclib dihyrochloride dihydrate. The liquid injectable composition of claim 1, wherein the concentration of trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof are in the range from about 0.1 mg/mL to about 25 mg/mL. The liquid injectable composition of claim 1, wherein the concentration of trilaciclib or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and mixtures thereof, are in the range from about 0.5 mg/mL to about 15 mg/mL. The liquid injectable composition of claim 10, wherein the composition is physically stable at 2°C-8°C for the period of atleast three months. The liquid injectable composition of claim 10, wherein the composition is physically stable at 25±2°C for the period of atleast three months. The liquid injectable composition of claim 16, wherein the composition contains no more than 1% total impurities upon storage for the period of at least three months. The liquid injectable composition of claim 17, wherein the composition contains no more than 1% total impurities upon storage for the period of three months. A method of preparing a liquid injectable composition comprising trilaciclib, wherein the said method comprises the steps of: a) Adding the required quantity of propylene glycol and benzyl alcohol and stirred. b) Adding the required quantity of trilaciclib in the solution obtained in step (a). c) Adding the required quantity of hydrochloric acid to the slurry obtained in step (b) to form a clear yellow solution. d) Adding the required quantity of glycerol to the solution obtained in step (c) to form a clear yellow solution. e) The solution obtained in step (d) was filtered through 0.45p filter followed by 0.22 p filer to get a sterile filtrate. he method of preparing a liquid injectable composition of claim 20, wherein the solvent system comprises from about 66% w/v to about 88% w/v of propylene glycol, from about 6.5% w/v to about 8.5% w/v of benzyl alcohol, from about 13.3% w/v to about 33.3% w/v or mixtures thereof. The method of preparing a liquid injectable composition of claim 21, wherein the solvent system comprises from about 70% w/v to about 85% w/v of propylene glycol, from about 7.0% w/v to about 8.0% w/v of benzyl alcohol, from about 15% w/v to about 25% w/v of glycerol or mixtures thereof. The liquid injectable composition of any preceding claim, wherein the preceding claim composition is re-constituted from lyophilized forms of trilaciclib. The liquid injectable composition of any preceding claim, wherein the preceding claim composition is ready-to-dilute. The liquid injectable composition of any preceding claim, wherein the preceding claim composition is ready-to-use. method for decreasing the incidence of chemotherapy -induced myelosuppression in adult patients when administered prior to a platinium/etoposide-containing regimen or topotecan- containing regimen for extensive- stage small cell lung cancer, wherein the method comprises of administering the liquid injectable composition of claim 1.
PCT/IN2023/050647 2022-07-02 2023-07-03 Liquid injectable compositions of trilaciclib WO2024009319A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257587A1 (en) * 2020-06-15 2021-12-23 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof
WO2022076779A1 (en) * 2020-10-08 2022-04-14 Teva Pharmaceuticals International Gmbh Solid state forms of trilaciclib and of trilaciclib salts

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021257587A1 (en) * 2020-06-15 2021-12-23 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof
WO2022076779A1 (en) * 2020-10-08 2022-04-14 Teva Pharmaceuticals International Gmbh Solid state forms of trilaciclib and of trilaciclib salts

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