WO2016059593A1 - Stable injectable composition of protein drugs and process for its preparation - Google Patents

Stable injectable composition of protein drugs and process for its preparation Download PDF

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Publication number
WO2016059593A1
WO2016059593A1 PCT/IB2015/057927 IB2015057927W WO2016059593A1 WO 2016059593 A1 WO2016059593 A1 WO 2016059593A1 IB 2015057927 W IB2015057927 W IB 2015057927W WO 2016059593 A1 WO2016059593 A1 WO 2016059593A1
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WIPO (PCT)
Prior art keywords
injectable composition
solution
protein drug
solvent
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2015/057927
Other languages
French (fr)
Inventor
Vandana SONAVARIA
Kamal Kumar Upadhyay
Pratikkumar PATEL
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Piramal Enterprises Limited
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Publication of WO2016059593A1 publication Critical patent/WO2016059593A1/en

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Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A61K38/166—Streptokinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2257—Prolactin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21073—Serine endopeptidases (3.4.21) u-Plasminogen activator (3.4.21.73), i.e. urokinase

Definitions

  • the present invention relates to a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; and processes for its preparation.
  • proteins are larger and more complex than the traditional small molecule drugs
  • the composition of protein drugs poses certain problems.
  • Parenteral compositions of proteins have been mostly attained in aqueous solutions.
  • proteins are not completely stable and have limited solubility in aqueous solutions. Further, they are prone to aggregation and precipitation. It is reported that proteins can undergo several degradation mechanisms i.e. chemical instability (reactions that involve specific residues which results in a change in the primary structure of the protein) and physical instability (partial unfolding, conformation changes, adsorption, dissociation and aggregation).
  • Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange. Physical instability can result from denaturation, aggregation, precipitation or adsorption. Due to the stability problem of many proteins in aqueous solutions, these are commonly formulated as a solid by lyophilization and reconstituted with a sterile diluent prior to administration.
  • Urokinase which is commercially available as KinlyticTM (Microbix Biosystems), is a sterile lyophilized white powder containing 250,000 international units urokinase per vial, mannitol (25 mg/vial), albumin (Human) (250 mg/vial), and sodium chloride (50 mg/vial).
  • Urokinase is a thrombolytic agent that works by dissolving blood clots;
  • Protein C Concentrate Human
  • Ceprotin ® is a natural protein that is made in the liver and is present in the blood.
  • Ceprotin ® is used to treat patients with severe congenital protein C deficiency for the prevention and treatment of: venous thrombosis (blood clot in the vein), and purpura fulminans (blood spots, bruising and discoloring to skin as a result of clotting of small blood vessels in the skin); and (iii) Coagulation Factor IX (Recombinant), commercially available as AlprolixTM, is a Fc Fusion Protein.
  • AlprolixTM is a sterile, non-pyrogenic, preservative-free, white to off-white, lyophilized powder to cake for reconstitution with the provided diluent, for intravenous injection and is indicated in adults and children with hemophilia B (congenital Factor IX deficiency) for control and prevention of bleeding episodes in perioperative management, and in routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
  • hemophilia B congenital Factor IX deficiency
  • compositions including lyophilized compositions for protein drugs are known in the art.
  • US4244943 discloses a method for preparing a stable urokinase injection by lyophilization of urokinase which comprises lyophilizing an aqueous solution containing urokinase, human serum albumin and one or more amino acid compounds selected from polar amino acids and salt thereof.
  • WO 97/04801 disclosed lyophilized compositions that can be reconstituted to generate high protein-concentration liquid compositions without apparent loss of stability. However, the potential issues associated with the high viscosity of the reconstituted compositions are not addressed.
  • compositions of protein drugs are primarily in the form of aqueous or lyophilized compositions.
  • the problem that is encountered during reconstitution of protein composition is the aggregation of proteins. Therefore, it is desirable to develop a stable, ready-to-use composition for proteinsto overcome stability problem.
  • inventors of the present invention have done extensive research and conducted several experiments to develop a stable and ready-to-use injectable composition of therapeutic proteins, without a need to reconstitute with water prior to administration, thereby rendering the composition according to the present invention an easy-to-use injectable composition.
  • the inventors have also provided a simple and cost-effective process for the preparation of stable and ready-to-use injectable composition of proteins.
  • the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the non-aqueous solvent used consists of a primary non-aqueous solvent and optionally one or more secondary non-aqueous co-solvent(s).
  • the present invention provides a process for the preparation of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof.
  • the present invention provides a method for treating or preventing one or more diseases, disorders or conditions, comprising administering to a subject in need thereof; a stable and ready-to-use injectable composition of the present invention in an amount effective to treat or prevent the conditions, diseases or disorders.
  • the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co- crystal thereof; for the manufacture of a medicament for use in the treatment or prevention of one or more diseases, conditions or disorders.
  • the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co- crystal thereof; for use in the treatment of a subject having one or more diseases, conditions or disorders.
  • the present invention provides a pharmaceutical kit comprising: (a) an injectable composition comprising a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water; optionally a polyol and a pH adjusting agent; and (b) optionally a package insert comprising instructions for using the said injectable composition.
  • the term “about” means approximately and in the context of numerical values the term “about” can be construed to estimate a value that is +10% of the value or range recited.
  • the term “stable” as used herein in reference to the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; means that the said composition does not exhibit appreciable degradation upon storage over a set time limit, at a set temperature, and at an identified pH; or within the context of the present invention the term “stable” as used herein in reference to the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; means that the said composition exhibit a chromatographic purity, where in the impurities identified are within the acceptable limit.
  • the term “sterile composition” means one in which essentially all forms of microbial life have been destroyed by an appreciable amount to meet the sterilization criteria outlined in the US Pharmacopeia.
  • the term "ready-to-use” or "RTU” as used herein in reference to the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; is a injectable composition that is stable and is not reconstituted from a lyophilizate.
  • RTU also encompasses within its scope, a injectable composition that is stable and has been diluted from a concentrated, liquid solution just prior to use.
  • solvent system refers to a non-aqueous solvent or a combination of a non-aqueous solvent with water.
  • non-aqueous solvent means a non-polar solvent which contain bonds between atoms of similar electronegativity like carbon and hydrogen by which they lack partial charges and do not contain hydrogen attached to oxygen or nitrogen so that they are unable to form hydrogen bonds with themselves.
  • solvents are selected from the group but not limited to ethylene glycol, polyethylene glycols (PEGs), propylene glycol (PG), dipropylene glycol tripropylene glycol, polyvinylpyrrolidone (PVP), methoxy propylene glycol (MPEG), glycerol and glycofurol or a mixture thereof.
  • the term "has not been reconstituted from a lyophilizate” means that a solid has not been dissolved or suspended.
  • pharmaceutically acceptable excipient means a diluent, carrier, or composition auxiliary, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent (e.g. protein drug) to the target site without affecting the therapeutic activity of the said active agent.
  • a therapeutically active agent e.g. protein drug
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt(s)” means salt(s) of protein drug(s), which can be prepared by treating the protein drug(s) with an appropriate acid or a base.
  • pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium salts or inorganic base salt.
  • pharmaceutically acceptable organic base addition salts include, but are not limited to, those derived from organic bases such as lysine, arginine, guanidine, and the like.
  • Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like, as well as the salts derived from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid,
  • co-crystal refers to a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule.
  • co-crystal encompasses within its scope many types of compounds, including hydrates, solvates and clathrates.
  • composition refers to a unit dose or a multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention.
  • composition refers to a unit dose or a multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention.
  • composition refers to a unit dose or a multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention.
  • the terms “composition”, “injectable compositions” and “stable and ready-to-use injectable composition” are used interchangeably.
  • the active pharmaceutical ingredient is a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof.
  • polyol refers to an alcohol containing multilple hydroxyl groups.
  • Polyols may comprise, but are not limited to, glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
  • the term "pH" is a measure of hydrogen ion concentration, as commonly used in the art. Customarily the pH provides a measure on a scale from 0 to 14 of the acidity or alkalinity of a solution.
  • the pH of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof, of the present invention is between about 2.0 and about 13.0.
  • pH adjusting agent or “pH adjusting agents” as used herein, includes a substance that adjusts the pH of pharmaceutical compositions to intended pH.
  • the pH adjusting agents may include pharmaceutically acceptable acids, bases, or buffering agents.
  • the acids may include, but are not limited to, one or more inorganic mineral acids such as citric, fumaric, gluconic, lactic, malic, metatartaric, tartaric, ascorbic and benzene sulphonic acid and the like.
  • the pH adjusting agent may be a base or a buffering agent.
  • the bases may be one or more inorganic bases or organic bases, including, but not limited to, alkaline carbonate, alkaline bicarbonate, alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metal hydroxide or amine.
  • the inorganic or organic base may be an alkaline hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide or the like; an alkaline carbonate such as calcium carbonate, sodium carbonate or the like; or an alkaline bicarbonate such as sodium bicarbonate or the like; the organic base may also be sodium acetate.
  • the buffering agent can be, but is not limited to an alkali metal salt of an amino acid, aluminum hydroxide, aluminum magnesium hydroxide, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartarate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartarate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium
  • a relative pH has been measured in case of a non-aqueous composition because it is difficult to measure the absolute pH of a non-aqueous solution due to lack of hydrogen ion activity or concentration. Further, the pH of the composition may vary depending upon the type of instrument and dilution media.
  • protein drug or “protein drug(s)” refers to hormones, enzymes and/or antibodies that are naturally occurring, recombinant or chemically synthesized large biological molecules or macromolecules comprising a plurality of natural or modified amino acids residues bound together by amide (CONH) linkages.
  • protein drug(s) is used herein interchangeably with the terms “therapeutic protein(s)” and “protein(s)”.
  • the length of proteins may extend from 51 amino acids up to several thousand amino acids. If the proteins on hydrolysis yield only amino acids, they are called as simple proteins and if, the proteins on hydrolysis yield amino acids and additional products, they are called as conjugated proteins.
  • Proteins due to action of heat, enzymes, or chemical reagents are called as derived proteins. Protein are also classified according to shape and solubility as fibrous proteins, globular proteins and membrane proteins. In the context of the present invention, proteins can be classified according to biological function such as hormone, enzyme, transport, storage, contractile, structural, protection or antibody.
  • Representative examples of protein drugs include, but are not limited to, urokinase, streptokinase, prolactin and a combination thereof. Combinations of protein drugs with other drugs such as peptides, small molecules and the like are also encompassed within the scope of the present invention.
  • peptide drug refers to synthetic or biological compounds (and salts thereof) containing short chains of amino acids bound together by amide (CONH) linkages that have demonstrated or potential use in treating, preventing, or ameliorating one or more diseases, disorders, or conditions in a subject in need thereof.
  • the peptide drugs are short chains of amino acid monomers containing up to 50 amino acids bound together by amide (CONH) linkages and have a molecular weight of less than approximately 5000 Daltons.
  • small molecule drug or “small molecule drug(s)” refers to therapeutically active compounds (and/or salts thereof) having molecular weight of less than about 3000 Daltons, that can bring about a desired and/or beneficial therapeutic effect on a subject in need thereof.
  • ADCs are type of biconjugates.
  • a bioconjugate is a compound in which two molecules are attached with a stable chemical link, at least one of which is a biomolecule; for example, a conjugate of a xenobiotic with some groups such as glutathione, sulfate or glucuronic acid.
  • ADCs are complex molecules composed of an antibody (a whole monoclonal antibody or an antibody fragment such as a single-chain variable fragment) linked, via a stable, chemical, linker with labile bonds, to a biological active cytotoxic (anticancer) payload or drug.
  • absolute alcohol refers to ethanol containing from about 98.0 to 99.8 v/v/ % of ethanol and from about 0.2 to 2.0 v/v % of water.
  • the term “subject” refers to an animal, preferably a mammal, and most preferably a human.
  • the term “mammal” is used interchangeably with the term “patient” or “subject”.
  • the phrase "a subject in need thereof means a subject (patient) in need of the treatment of a disease or disorder for which a protein drug can be suitably used.
  • injectable composition :
  • the inventors of the present invention have done extensive research and conducted several experiments to develop a stable injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof, which can be prepared in a solubilized and stable form suitable for ready-to-use injection.
  • RTU composition has enhanced patient compliance and also provides a more stable, safe and effective composition when compared to currently marketed lyophilized compositions.
  • the injectable composition of the present invention can be used for a wide variety of protein drug(s).
  • the present invention relates to a stable and ready-to- use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • a solvent system comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water
  • the protein drug is a simple protein or a conjugated protein.
  • the protein drug includes, but is not limited to, an enzyme, hormone or an antibody.
  • the protein drug is an enzyme selected from: urokinase, streptokinase, kallikrein, pancreatic RNAase, platelet activating factor acetyl hydrolase, tissue plasminogen activator (TPA) or Superoxide dismutase (SOD).
  • the protein drug is a hormone selected from insulin, gastrin prolactin, adrenocorticotropic hormone (ACTH), growth hormone (GH), thrombopoietin, obesity protein (leptin), Granulocyte colony-stimulating factor (G-CSF), Fibroblast growth factors (FGF), Insulin-like growth factors (IGF), Macrophage colony stimulating factor (M-CSF), Thyroid stimulating hormone (TSH), Luteinizing hormone (LH), Follicle stimulating hormone (FSH), Human chorionic gonadotropin (HCG) or Vascular endothelial growth factor (VEGF).
  • ACTH adrenocorticotropic hormone
  • GH growth hormone
  • thrombopoietin obesity protein
  • obesity protein lactin
  • G-CSF Granulocyte colony-stimulating factor
  • FGF Fibroblast growth factors
  • IGF Insulin-like growth factors
  • M-CSF Macrophage colony stimulating factor
  • Thyroid stimulating hormone T
  • the protein is a therapeutic agent that provides protection against diseases or other conditions, referred to as protection drug, which is selected from Osteoprotegerin (OPG), Alpha interferon, Beta interferon, Gamma interferon, Interleukin 2, Granulocyte macrophage colony stimulating factor (GM-CSF), Coagulation Factor IX, Tumor necrosis factor (TNF), Factor VII, Factor VIII, Factor IX, Colony stimulating growth factors (CSFs), Macrophage colony stimulating factor (M- CSF), Neurotrophic growth factor (NGF) or tumor necrosis factor binding protein (TNFbp).
  • OPG Osteoprotegerin
  • Alpha interferon Alpha interferon
  • Beta interferon Gamma interferon
  • Interleukin 2 Granulocyte macrophage colony stimulating factor
  • Coagulation Factor IX Coagulation Factor IX
  • TNF Tumor necrosis factor
  • TNF Tumor necrosis factor
  • CSFs Macrophage colon
  • the protein is selected from kerantinocyte growth factor (KGF), Platelet-derived growth factor (PDGF), Bone morphogenetic protein (BMP) or Stem cell factor (SCF).
  • KGF kerantinocyte growth factor
  • PDGF Platelet-derived growth factor
  • BMP Bone morphogenetic protein
  • SCF Stem cell factor
  • the protein drug is selected from urokinase, streptokinase, prolactin or a combination thereof.
  • the injectable composition contains a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 5000 IU to about 1000000 IU.
  • the injectable composition contains a protein drug at a concentration in the range of about 50000 IU to about 500000 IU.
  • the solvent system comprises 100 % of a non-aqueous solvent or a combination of non-aqueous solvent and water in a ratio ranging from about 95:5 to about 99:1.
  • the non-aqueous solvent system comprises 100% primary nonaqueous solvent; or in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in a ratio ranging from about 99:1 to about 50:50.
  • the non-aqueous solvent system comprises 100% primary nonaqueous solvent.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio ranging from about 99:1 to about 50:50.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in the ratio of 90: 10.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in the ratio of 85: 15.
  • the solvent system comprises one or more solvent selected from the group consisting of ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol, polyethylene glycol, methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the primary non-aqueous solvent contained in the solvent system is selected from the group consisting of but not limited to ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol and polyethylene glycol or a mixture thereof.
  • the primary non-aqueous solvent is propylene glycol.
  • the optional secondary non-aqueous co-solvent(s) contained in the solvent system is a (Ci-C3)alkyl alcohol selected from the group consisting of but not limited to methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the optional secondary non-aqueous co-solvent(s) contained in the solvent system is isopropyl alcohol, ethanol or an absolute alcohol or a combination thereof.
  • the optional secondary non-aqueous co-solvent contained in the solvent system is ethanol.
  • the optional secondary non-aqueous co-solvent contained in the solvent system is absolute alcohol.
  • the optional secondary non-aqueous co-solvent contained in the solvent system is isopropyl alcohol.
  • the optional secondary non-aqueous co-solvent(s) contained in the solvent system is a combination of ethanol/absolute alcohol and isopropyl alcohol.
  • the polyol is selected from a group consisting of but not limited to glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
  • the polyol is in the range of about 0.01% to about 10% of the total injectable composition of the protein drug.
  • the polyol is sorbitol or racemic salts or isomers thereof. In an embodiment, the polyol is D-sorbitol.
  • the solvent system contains propylene glycol and ethanol. In an embodiment, the solvent system contains propylene glycol and absolute alcohol.
  • the solvent system contains propylene glycol and isopropyl alcohol.
  • the non-aqueous solvent system comprises 100% propylene glycol; or in the non-aqueous solvent system, the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in a ratio ranging from about 99: 1 to about 50:50.
  • the non-aqueous solvent system comprises 100% propylene glycol.
  • the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio ranging from about 99: 1 to about 50:50.
  • the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 99:1 , 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
  • solvent system consisting propylene glycol and ethanol/ absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 90:10.
  • solvent system consisting propylene glycol and ethanol/ absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 85:15.
  • the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
  • the pH of the ready-to-use protein drug injectable composition of the present invention is between about 2.0 and about 13.0.
  • the pH of the ready-to-use protein drug injectable composition of the present invention is between about 4.0 and about 13.0.
  • the pH of the ready-to-use protein drug injectable composition of the present invention is between about 6.0 and about 13.0.
  • the present invention relates to a process for the preparation of a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of: a) dissolving a pH adjusting agent in a solvent system consisting of primary nonaqueous solvent and optionally water to obtain a first solution by stirring the solution at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes and allowing the solution to attain the temperature of 2°C to room temperature;
  • step (c) adding the first solution of step (a) to the second solution of step (b) under constant stirring to obtain a third solution;
  • step (d) dispersing the protein drug in the third solution of step (c) to obtain a solution; e) optionally filtering the solution of step (d) to obtain a clear solution; and f) filling the clear solution of step (e) into a container to obtain a preparation in a ready-to-use form.
  • the present invention relates to a process for the preparation of a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of: a) dissolving polyol in secondary non-aqueous solvent to obtain a first solution by stirring the solution at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes and allowing the solution to attain the temperature of 2°C to room temperature;
  • step (b) adding protein drug to the first solution of step (a);
  • step (b) adding primary non-aqueous solvent, pH adjusting agent and optionally water to the solution obtained in step (b) to produce a solution;
  • step (c) optionally filtering the solution of step (c) one or more times to obtain a clear solution
  • the present invention relates to a process for the preparation of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (a) allowing the resulting first solution of step (a) to attain a temperature of 2°C to room temperature;
  • step (c) optionally adding polyol to the first solution of step (b) under constant stirring until the polyol dissolves, to obtain a second solution;
  • step (c) optionally adding a secondary non-aqueous co-solvent to the second solution of step (c) under constant stirring for 5 minutes to 10 minutes to obtain a third solution;
  • step (e) adding protein drug to the third solution of step (d) and allowing to disperse to obtain a solution;
  • step (e) optionally filtering the solution as obtained in step (e) one or more times to obtain a clear solution
  • step (f) filling the clear solution of step (f) in suitable containers to obtain a composition in a ready-to-use form
  • the present invention relates to a process for the preparation of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (a) dissolving polyol and pH adjusting agent in primary non-aqueous solvent and optionally water to obtain a solution by stirring the resulting mixture at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes to obtain a first solution; b) allowing the resulting first solution of step (a) to attain a temperature of 2°C to room temperature;
  • step (c) optionally adding a secondary non-aqueous solvent to the first solution of step (b) under constant stirring for 5 minutes to 10 minutes to obtain a second solution; d) adding protein drug to the second solution of step (c) and allowing to disperse to obtain a solution;
  • step (d) optionally filtering the solution of step (d) one or more times to obtain a clear solution
  • step (e) filling the clear solution of step (e) in suitable containers to obtain a composition in a ready-to-use form.
  • the said protein drug in the process for the preparation of the injectable composition of the protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the said protein drug is as described above in one or more embodiments of the invention.
  • the solvent system comprises 100 % of a non-aqueous solvent or a combination of non-aqueous solvent and water in a ratio ranging from about 95:5 to about 99:1.
  • the nonaqueous solvent system comprises 100% primary non-aqueous solvent; or in the nonaqueous solvent system, the primary non-aqueous solvent and the secondary nonaqueous co-solvent can be used in a ratio ranging from about 99:1 to about 50:50.
  • the nonaqueous solvent system comprises 100% primary non-aqueous solvent.
  • the primary non-aqueous solvent and the secondary non- aqueous co-solvent in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the nonaqueous solvent system, can be used in a ratio ranging from about 99: 1 to about 50:50.
  • the primary non-aqueous solvent and the secondary nonaqueous co-solvent in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non- aqueous solvent system, can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
  • the primary non-aqueous solvent and the secondary non-aqueous co- solvent(s) can be used in the ratio of 90:10.
  • the primary non-aqueous solvent and the secondary non-aqueous co- solvent(s) can be used in the ratio of 85:15.
  • the primary non-aqueous solvent contained in the solvent system is selected from the group consisting of but not limited to ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol, and polyethylene glycol or a mixture thereof.
  • the primary non-aqueous solvent is propylene glycol.
  • the secondary non-aqueous co-solvent(s) is a (C 1 -C 3 )alkyl alcohol selected from the group consisting of but not limited to methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the secondary non-aqueous co-solvent(s) is isopropyl alcohol; ethanol or absolute alcohol; or a combination thereof.
  • the secondary non-aqueous co-solvent in another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent is ethanol. In another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent is absolute alcohol.
  • the secondary non-aqueous co-solvent is isopropyl alcohol.
  • the secondary non-aqueous co-solvent is a combination of ethanol/absolute alcohol and isopropyl alcohol.
  • the polyol is selected from a group consisting of glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
  • the polyol in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; is in the range of about 0.01% to about 10% of the total injectable composition of the protein drug.
  • the polyol in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the polyol is sorbitol or racemic salts or isomers thereof.
  • the polyol is D-sorbitol.
  • the nonaqueous solvent system comprises 100% propylene glycol.
  • the solvent system comprises propylene glycol and ethanol. In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the solvent system comprises propylene glycol and absolute alcohol.
  • the nonaqueous solvent system comprises propylene glycol and isopropyl alcohol.
  • the nonaqueous solvent system comprises 100% propylene glycol; or in the non-aqueous solvent system, the propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in a ratio ranging from about 99:1 to about 50:50.
  • the nonaqueous solvent system comprises 100% propylene glycol.
  • propylene glycol and ethanol/absolute alcohol can be used in the ratio ranging from about 99:1 to about 50:50.
  • propylene glycol and ethanol/absolute alcohol in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
  • propylene glycol and ethanol/absolute alcohol can be used in the ratio of 90: 10.
  • propylene glycol and ethanol/absolute alcohol can be used in the ratio of 85 : 15.
  • the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
  • the pH of the ready-to-use protein drug injectable composition obtained by the process as described above is between about 2.0 and about 13.0.
  • the pH of the ready-to-use protein drug injectable composition obtained by the process as described above is between about 4.0 and about 13.0.
  • the pH of the ready-to-use protein drug injectable composition obtained by the process as described above is between about 6.0 and about 13.0.
  • the present invention relates to use of the stable and ready-to-use composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; for the manufacture of a medicament for treating or preventing one or more diseases, conditions or disorders; wherein the said injectable composition is as described in one or more embodiments of the present invention as described herein above.
  • the present invention relates to a method of treating or preventing one or more diseases, conditions or disorders comprising administering to a subject in need thereof; a therapeutically effective amount of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition is as described in one or more embodiments of the present invention as described herein above.
  • the diseases, disorders or conditions for the treatment or prevention of which the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; of the present invention include, but are not limited to, metabolic disorders, autoimmune disorders, cardiovascular diseases, respiratory diseases, thyroid diseases, hormonal diseases, neurodegenerative diseases, bacterial infections, viral infections, fungal infections, renal diseases, hepatobiliary diseases, venereal diseases, platelet aggregation, inflammatory diseases, cancers, transplantation complications due to rejection reactions, graft rejection and hepatic diseases.
  • the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof can be packaged in a suitable container depending upon the composition and the method of administration of the composition.
  • suitable containers known to a person skilled in the art include vials, ampoules and infusion bag.
  • the present invention provides a pharmaceutical kit comprising the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said composition comprises of the protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; a solvent system comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water; optionally, a polyol; and a pH adjusting agent.
  • the kit may further comprise a package insert, including information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings.
  • the kit may further contain optional materials for storing and/or administering the drug, for example, an infusion bag as well as instructions for storage and use.
  • the stable and ready-to-use injectable composition of a protein drug of the present invention can be delivered to the subject intravenously.
  • Methods of delivering the RTU injectable composition intravenously are well known in the art.
  • the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof can be delivered to the subject by infusion.
  • the injectable dosage form may be delivered intravenously through infusion.
  • step (d) Urokinase was then added to the solution of step (c) to obtain another solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence for 30- 120 minutes to obtain a clear solution,
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • Urokinase was then added to the solution of step (1) to obtain another solution.
  • IN sodium hydroxide was added to said solution.
  • step (d) The solution obtained in step (d) was subjected to turbulence to obtain a clear solution.
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • Urokinase was then added to the solution of step (c) to obtain another solution.
  • IN sodium hydroxide and water was added to said solution.
  • step (d) The solution obtained in step (d) was subjected to turbulenceto obtain a clear solution.
  • step (e) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
  • step (b) Sodium hydroxide was dissolved in a solution obtained in the step (a) by heating at 50°C for 60 minutes and cooling to a temperature of 2°C to 8°C.
  • step (c) The solution obtained in step (c) was added to the solution obtained in (b).
  • Urokinase was then added to the solution obtained in step (d) to obtain a solution.
  • step (f) The clear liquid concentrate obtained in step (f) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.

Abstract

The present invention relates to a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; and processes for its preparation. It is not required to reconstitute the injectable composition of the protein drug with water prior to administration, thereby rendering it an easy-to-use injectable composition.

Description

STABLE INJECTABLE COMPOSITION OF PROTEIN DRUGS AND PROCESS
FOR ITS PREPARATION
Field of the Invention
The present invention relates to a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; and processes for its preparation.
Background of the invention
Recent advances in pharmaceutical biotechnology have led proteins to successfully emerge as potential drug candidates for the treatment of patients suffering from various diseases such as cancers, cardiovascular diseases, metabolic disorders such as diabetes, inflammatory disorders, immune disorders, bacterial infections, viral infections, and other diseases. In fact, more than 100 modified therapeutic proteins are approved for clinical use in the European Union and the USA with 2010 sales of US$108 billion (Methods Mol. Biol. 2012; 899: 1-26).
Considering that proteins are larger and more complex than the traditional small molecule drugs, the composition of protein drugs poses certain problems. Currently, most of the commercially available protein drugs are administered parenterally, because oral administration is limited due to enzymatic degradation. Parenteral compositions of proteins have been mostly attained in aqueous solutions. However, proteins are not completely stable and have limited solubility in aqueous solutions. Further, they are prone to aggregation and precipitation. It is reported that proteins can undergo several degradation mechanisms i.e. chemical instability (reactions that involve specific residues which results in a change in the primary structure of the protein) and physical instability (partial unfolding, conformation changes, adsorption, dissociation and aggregation). Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange. Physical instability can result from denaturation, aggregation, precipitation or adsorption. Due to the stability problem of many proteins in aqueous solutions, these are commonly formulated as a solid by lyophilization and reconstituted with a sterile diluent prior to administration. Representative examples of protein drugs that are marketed as lyophilized powder for injection include : (i) Urokinase, which is commercially available as Kinlytic™ (Microbix Biosystems), is a sterile lyophilized white powder containing 250,000 international units urokinase per vial, mannitol (25 mg/vial), albumin (Human) (250 mg/vial), and sodium chloride (50 mg/vial). Urokinase is a thrombolytic agent that works by dissolving blood clots; (ii) Protein C Concentrate (Human), commercially available as Ceprotin®, is a natural protein that is made in the liver and is present in the blood. Ceprotin® is used to treat patients with severe congenital protein C deficiency for the prevention and treatment of: venous thrombosis (blood clot in the vein), and purpura fulminans (blood spots, bruising and discoloring to skin as a result of clotting of small blood vessels in the skin); and (iii) Coagulation Factor IX (Recombinant), commercially available as Alprolix™, is a Fc Fusion Protein. Alprolix™ is a sterile, non-pyrogenic, preservative-free, white to off-white, lyophilized powder to cake for reconstitution with the provided diluent, for intravenous injection and is indicated in adults and children with hemophilia B (congenital Factor IX deficiency) for control and prevention of bleeding episodes in perioperative management, and in routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
Compositions including lyophilized compositions for protein drugs are known in the art. US4244943 discloses a method for preparing a stable urokinase injection by lyophilization of urokinase which comprises lyophilizing an aqueous solution containing urokinase, human serum albumin and one or more amino acid compounds selected from polar amino acids and salt thereof.
WO 97/04801 disclosed lyophilized compositions that can be reconstituted to generate high protein-concentration liquid compositions without apparent loss of stability. However, the potential issues associated with the high viscosity of the reconstituted compositions are not addressed.
From the above discussion it is apparent that currently marketed compositions of protein drugs are primarily in the form of aqueous or lyophilized compositions. However, the problem that is encountered during reconstitution of protein composition is the aggregation of proteins. Therefore, it is desirable to develop a stable, ready-to-use composition for proteinsto overcome stability problem.
Thus, there exists a need for the development of a new or an improved composition for therapeutic proteins that would prevent degradation, yet increase solubility and stability of the proteins. Moreover, there is a need to provide a stable and ready-to-use injectable composition of therapeutic proteins to improve patient compliance.
In consideration of the need as indicated above, inventors of the present invention have done extensive research and conducted several experiments to develop a stable and ready-to-use injectable composition of therapeutic proteins, without a need to reconstitute with water prior to administration, thereby rendering the composition according to the present invention an easy-to-use injectable composition. The inventors have also provided a simple and cost-effective process for the preparation of stable and ready-to-use injectable composition of proteins.
Summary of the invention
In one aspect, the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
(i) a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof;
(ϋ) a solvent system;
(iii) optionally a polyol; and
(iv) a pH adjusting agent.
In one aspect, the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
(i) a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof;
(ϋ) a solvent system comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water;
(iii) optionally a polyol; and
(iv) a pH adjusting agent. In one aspect, the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the non-aqueous solvent used consists of a primary non-aqueous solvent and optionally one or more secondary non-aqueous co-solvent(s).
In another aspect, the present invention provides a process for the preparation of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof.
In further aspect, the present invention provides a method for treating or preventing one or more diseases, disorders or conditions, comprising administering to a subject in need thereof; a stable and ready-to-use injectable composition of the present invention in an amount effective to treat or prevent the conditions, diseases or disorders.
In another aspect, the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co- crystal thereof; for the manufacture of a medicament for use in the treatment or prevention of one or more diseases, conditions or disorders.
In another aspect, the present invention provides a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co- crystal thereof; for use in the treatment of a subject having one or more diseases, conditions or disorders.
In still further aspect, the present invention provides a pharmaceutical kit comprising: (a) an injectable composition comprising a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water; optionally a polyol and a pH adjusting agent; and (b) optionally a package insert comprising instructions for using the said injectable composition.
These and other aspects and advantages of the present invention will be apparent to those skilled in the art from the following description.
Detailed Description of the Invention
It should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. One skilled in the art, based upon the definitions herein, may utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Unless otherwise defined, all the terms used herein, including the technical and scientific terms, have the meaning as that generally understood by one of ordinary skill in the art to which the present invention relates.
Definitions:
For the purpose of the disclosure, listed below are definitions of various terms used to describe the present invention. Unless otherwise indicated, these definitions apply to the terms as they are used throughout the specification and the appended claims, either individually or as part of a larger group. They should not be interpreted in the literal sense. They are not general definitions and are relevant only for this application.
It should be noted that, as used in this specification and the appended claims, the singular forms "a" "an" and "the" include plural referents unless the content clearly dictates otherwise.
It should be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
As used herein, the term "about" means approximately and in the context of numerical values the term "about" can be construed to estimate a value that is +10% of the value or range recited.
Within the context of the present invention the term "stable" as used herein in reference to the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; means that the said composition does not exhibit appreciable degradation upon storage over a set time limit, at a set temperature, and at an identified pH; or within the context of the present invention the term "stable" as used herein in reference to the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; means that the said composition exhibit a chromatographic purity, where in the impurities identified are within the acceptable limit. Within the context of the present invention, the term "sterile composition" means one in which essentially all forms of microbial life have been destroyed by an appreciable amount to meet the sterilization criteria outlined in the US Pharmacopeia.
Within the context of the present invention, the term "ready-to-use" or "RTU" as used herein in reference to the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; is a injectable composition that is stable and is not reconstituted from a lyophilizate. The term "RTU" also encompasses within its scope, a injectable composition that is stable and has been diluted from a concentrated, liquid solution just prior to use.
In the context of the invention the term "solvent system" refers to a non-aqueous solvent or a combination of a non-aqueous solvent with water.
The term "non-aqueous solvent" means a non-polar solvent which contain bonds between atoms of similar electronegativity like carbon and hydrogen by which they lack partial charges and do not contain hydrogen attached to oxygen or nitrogen so that they are unable to form hydrogen bonds with themselves. Examples of solvents are selected from the group but not limited to ethylene glycol, polyethylene glycols (PEGs), propylene glycol (PG), dipropylene glycol tripropylene glycol, polyvinylpyrrolidone (PVP), methoxy propylene glycol (MPEG), glycerol and glycofurol or a mixture thereof.
As used herein, the term "has not been reconstituted from a lyophilizate" means that a solid has not been dissolved or suspended.
The term "pharmaceutically acceptable excipient" as used herein means a diluent, carrier, or composition auxiliary, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent (e.g. protein drug) to the target site without affecting the therapeutic activity of the said active agent.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt(s)" means salt(s) of protein drug(s), which can be prepared by treating the protein drug(s) with an appropriate acid or a base. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium salts or inorganic base salt. Examples of pharmaceutically acceptable organic base addition salts include, but are not limited to, those derived from organic bases such as lysine, arginine, guanidine, and the like. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like, as well as the salts derived from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
The term "co-crystal" refers to a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule. The term co-crystal" encompasses within its scope many types of compounds, including hydrates, solvates and clathrates.
The term "composition" or "injectable composition" refers to a unit dose or a multi dose of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, which can be prepared by the processes described in one or more embodiments of the present invention. In the context of the present invention, the terms "composition", "injectable compositions" and "stable and ready-to-use injectable composition" are used interchangeably. In the case of the injectable composition of the present invention, the active pharmaceutical ingredient is a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof.
The term "polyol" as used herein, refers to an alcohol containing multilple hydroxyl groups. Polyols may comprise, but are not limited to, glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
The term "stirring" encompasses within its scope, sonication or turbulence or agitation by other means. Therefore the term "stirring" can be interchangeably used with the terms "sonication", "turbulence" or "agitation".
As used herein, the term "pH" is a measure of hydrogen ion concentration, as commonly used in the art. Customarily the pH provides a measure on a scale from 0 to 14 of the acidity or alkalinity of a solution. In the context of the present invention, the pH of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof, of the present invention is between about 2.0 and about 13.0.
The term "pH adjusting agent" or "pH adjusting agents" as used herein, includes a substance that adjusts the pH of pharmaceutical compositions to intended pH. Customarily, the pH adjusting agents may include pharmaceutically acceptable acids, bases, or buffering agents. For example, the acids may include, but are not limited to, one or more inorganic mineral acids such as citric, fumaric, gluconic, lactic, malic, metatartaric, tartaric, ascorbic and benzene sulphonic acid and the like. In the context of the present invention, the pH adjusting agent may be a base or a buffering agent. The bases may be one or more inorganic bases or organic bases, including, but not limited to, alkaline carbonate, alkaline bicarbonate, alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metal hydroxide or amine. For example, the inorganic or organic base may be an alkaline hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide or the like; an alkaline carbonate such as calcium carbonate, sodium carbonate or the like; or an alkaline bicarbonate such as sodium bicarbonate or the like; the organic base may also be sodium acetate. The buffering agent can be, but is not limited to an alkali metal salt of an amino acid, aluminum hydroxide, aluminum magnesium hydroxide, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartarate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartarate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartarate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartarate, sodium tripolyphosphate, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, or a mixture thereof. A relative pH has been measured in case of a non-aqueous composition because it is difficult to measure the absolute pH of a non-aqueous solution due to lack of hydrogen ion activity or concentration. Further, the pH of the composition may vary depending upon the type of instrument and dilution media.
Within the context of the present invention and as used herein the term "protein drug" or "protein drug(s)" refers to hormones, enzymes and/or antibodies that are naturally occurring, recombinant or chemically synthesized large biological molecules or macromolecules comprising a plurality of natural or modified amino acids residues bound together by amide (CONH) linkages. The term "protein drug(s)" is used herein interchangeably with the terms "therapeutic protein(s)" and "protein(s)". The length of proteins may extend from 51 amino acids up to several thousand amino acids. If the proteins on hydrolysis yield only amino acids, they are called as simple proteins and if, the proteins on hydrolysis yield amino acids and additional products, they are called as conjugated proteins. Derivatives of proteins due to action of heat, enzymes, or chemical reagents are called as derived proteins. Protein are also classified according to shape and solubility as fibrous proteins, globular proteins and membrane proteins. In the context of the present invention, proteins can be classified according to biological function such as hormone, enzyme, transport, storage, contractile, structural, protection or antibody. Representative examples of protein drugs include, but are not limited to, urokinase, streptokinase, prolactin and a combination thereof. Combinations of protein drugs with other drugs such as peptides, small molecules and the like are also encompassed within the scope of the present invention. Within the context of the present invention and as used herein, the term "peptide drug" or "peptide drug(s)" refers to synthetic or biological compounds (and salts thereof) containing short chains of amino acids bound together by amide (CONH) linkages that have demonstrated or potential use in treating, preventing, or ameliorating one or more diseases, disorders, or conditions in a subject in need thereof. Typically, the peptide drugs are short chains of amino acid monomers containing up to 50 amino acids bound together by amide (CONH) linkages and have a molecular weight of less than approximately 5000 Daltons. Within the context of the present invention and as used herein the term "small molecule drug" or "small molecule drug(s)" refers to therapeutically active compounds (and/or salts thereof) having molecular weight of less than about 3000 Daltons, that can bring about a desired and/or beneficial therapeutic effect on a subject in need thereof.
Antibody drug conjugates (ADC) are encompassed within the scope of the present invention. ADCs are type of biconjugates. A bioconjugate is a compound in which two molecules are attached with a stable chemical link, at least one of which is a biomolecule; for example, a conjugate of a xenobiotic with some groups such as glutathione, sulfate or glucuronic acid. ADCs are complex molecules composed of an antibody (a whole monoclonal antibody or an antibody fragment such as a single-chain variable fragment) linked, via a stable, chemical, linker with labile bonds, to a biological active cytotoxic (anticancer) payload or drug.
As used herein, the term "absolute alcohol" refers to ethanol containing from about 98.0 to 99.8 v/v/ % of ethanol and from about 0.2 to 2.0 v/v % of water.
Within the context of the present invention and as used herein the term "subject" refers to an animal, preferably a mammal, and most preferably a human. In the context of the present invention, the term "mammal" is used interchangeably with the term "patient" or "subject". In the context of the present invention the phrase "a subject in need thereof means a subject (patient) in need of the treatment of a disease or disorder for which a protein drug can be suitably used. Injectable composition:
As discussed herein above, the inventors of the present invention have done extensive research and conducted several experiments to develop a stable injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof, which can be prepared in a solubilized and stable form suitable for ready-to-use injection.
Further, being a RTU composition, it has enhanced patient compliance and also provides a more stable, safe and effective composition when compared to currently marketed lyophilized compositions.
In respect of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; of the present invention, there is no requirement of reconstituting the composition with water prior to its administration, thus eliminating tedious task of reconstitution step in aseptic area, thereby providing an easy-to-use injectable composition.
The injectable composition of the present invention can be used for a wide variety of protein drug(s).
Accordingly, in one aspect, the present invention relates to a stable and ready-to- use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
(i) a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof;
(ii) a solvent system comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water;
(iii) optionally a polyol; and
(iv) a pH adjusting agent. In an embodiment, the protein drug is a simple protein or a conjugated protein.
In an embodiment, the protein drug includes, but is not limited to, an enzyme, hormone or an antibody.
In an embodiment, the protein drug is an enzyme selected from: urokinase, streptokinase, kallikrein, pancreatic RNAase, platelet activating factor acetyl hydrolase, tissue plasminogen activator (TPA) or Superoxide dismutase (SOD).
In an embodiment, the protein drug is a hormone selected from insulin, gastrin prolactin, adrenocorticotropic hormone (ACTH), growth hormone (GH), thrombopoietin, obesity protein (leptin), Granulocyte colony-stimulating factor (G-CSF), Fibroblast growth factors (FGF), Insulin-like growth factors (IGF), Macrophage colony stimulating factor (M-CSF), Thyroid stimulating hormone (TSH), Luteinizing hormone (LH), Follicle stimulating hormone (FSH), Human chorionic gonadotropin (HCG) or Vascular endothelial growth factor (VEGF).
In an embodiment, the protein is a therapeutic agent that provides protection against diseases or other conditions, referred to as protection drug, which is selected from Osteoprotegerin (OPG), Alpha interferon, Beta interferon, Gamma interferon, Interleukin 2, Granulocyte macrophage colony stimulating factor (GM-CSF), Coagulation Factor IX, Tumor necrosis factor (TNF), Factor VII, Factor VIII, Factor IX, Colony stimulating growth factors (CSFs), Macrophage colony stimulating factor (M- CSF), Neurotrophic growth factor (NGF) or tumor necrosis factor binding protein (TNFbp).
In an embodiment, the protein is selected from kerantinocyte growth factor (KGF), Platelet-derived growth factor (PDGF), Bone morphogenetic protein (BMP) or Stem cell factor (SCF).
In an embodiment, the protein drug is selected from urokinase, streptokinase, prolactin or a combination thereof.
In an embodiment, the injectable composition contains a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 5000 IU to about 1000000 IU.
In an embodiment, the injectable composition contains a protein drug at a concentration in the range of about 50000 IU to about 500000 IU.
In an embodiment, the solvent system comprises 100 % of a non-aqueous solvent or a combination of non-aqueous solvent and water in a ratio ranging from about 95:5 to about 99:1.
In an embodiment, the non-aqueous solvent system comprises 100% primary nonaqueous solvent; or in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in a ratio ranging from about 99:1 to about 50:50.
In an embodiment, the non-aqueous solvent system comprises 100% primary nonaqueous solvent.
In an embodiment, in the solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio ranging from about 99:1 to about 50:50.
In an embodiment, in the solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent(s) can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
In an embodiment, in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in the ratio of 90: 10.
In an embodiment, in the non-aqueous solvent system, the primary non-aqueous solvent and the secondary non-aqueous co-solvent can be used in the ratio of 85: 15. In an embodiment, the solvent system comprises one or more solvent selected from the group consisting of ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol, polyethylene glycol, methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
In an embodiment, the primary non-aqueous solvent contained in the solvent system is selected from the group consisting of but not limited to ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol and polyethylene glycol or a mixture thereof.
In an embodiment, the primary non-aqueous solvent is propylene glycol.
In an embodiment, the optional secondary non-aqueous co-solvent(s) contained in the solvent system is a (Ci-C3)alkyl alcohol selected from the group consisting of but not limited to methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
In an embodiment, the optional secondary non-aqueous co-solvent(s) contained in the solvent system is isopropyl alcohol, ethanol or an absolute alcohol or a combination thereof.
In an embodiment, the optional secondary non-aqueous co-solvent contained in the solvent system is ethanol.
In another embodiment, the optional secondary non-aqueous co-solvent contained in the solvent system is absolute alcohol.
In another embodiment, the optional secondary non-aqueous co-solvent contained in the solvent system is isopropyl alcohol.
In another embodiment, the optional secondary non-aqueous co-solvent(s) contained in the solvent system is a combination of ethanol/absolute alcohol and isopropyl alcohol.
In an embodiment, the polyol is selected from a group consisting of but not limited to glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
In an embodiment, the polyol is in the range of about 0.01% to about 10% of the total injectable composition of the protein drug.
In an embodiment, the polyol is sorbitol or racemic salts or isomers thereof. In an embodiment, the polyol is D-sorbitol.
In an embodiment, the solvent system contains propylene glycol and ethanol. In an embodiment, the solvent system contains propylene glycol and absolute alcohol.
In an embodiment, the solvent system contains propylene glycol and isopropyl alcohol.
In an embodiment, the non-aqueous solvent system comprises 100% propylene glycol; or in the non-aqueous solvent system, the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in a ratio ranging from about 99: 1 to about 50:50.
In an embodiment, the non-aqueous solvent system comprises 100% propylene glycol.
In an embodiment, in the non-aqueous solvent system, the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio ranging from about 99: 1 to about 50:50.
In an embodiment, in the non-aqueous solvent system, the propylene glycol and the ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 99:1 , 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
In an embodiment, solvent system consisting propylene glycol and ethanol/ absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 90:10.
In an embodiment, solvent system consisting propylene glycol and ethanol/ absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 85:15.
In another embodiment, the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
In another embodiment, the pH of the ready-to-use protein drug injectable composition of the present invention is between about 2.0 and about 13.0.
In another embodiment, the pH of the ready-to-use protein drug injectable composition of the present invention is between about 4.0 and about 13.0.
In another embodiment, the pH of the ready-to-use protein drug injectable composition of the present invention is between about 6.0 and about 13.0. Process for the preparation of injectable composition:
In an aspect, the present invention relates to a process for the preparation of a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of: a) dissolving a pH adjusting agent in a solvent system consisting of primary nonaqueous solvent and optionally water to obtain a first solution by stirring the solution at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes and allowing the solution to attain the temperature of 2°C to room temperature;
b) optionally adding polyol to the secondary non-aqueous solvent under constant stirring until the polyol dissolves to obtain a second solution;
c) adding the first solution of step (a) to the second solution of step (b) under constant stirring to obtain a third solution;
d) dispersing the protein drug in the third solution of step (c) to obtain a solution; e) optionally filtering the solution of step (d) to obtain a clear solution; and f) filling the clear solution of step (e) into a container to obtain a preparation in a ready-to-use form.
In an aspect, the present invention relates to a process for the preparation of a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of: a) dissolving polyol in secondary non-aqueous solvent to obtain a first solution by stirring the solution at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes and allowing the solution to attain the temperature of 2°C to room temperature;
b) adding protein drug to the first solution of step (a);
c) adding primary non-aqueous solvent, pH adjusting agent and optionally water to the solution obtained in step (b) to produce a solution;
d) optionally filtering the solution of step (c) one or more times to obtain a clear solution; and
e) filling the clear solution of step (d) into a container to obtain a composition in a ready-to-use form In an embodiment, the present invention relates to a process for the preparation of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
a) dissolving a pH adjusting agent in a solvent system consisting of a primary nonaqueous solvent and optionally water to obtain a mixture and stirring the resulting mixture at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes to obtain a first solution;
b) allowing the resulting first solution of step (a) to attain a temperature of 2°C to room temperature;
c) optionally adding polyol to the first solution of step (b) under constant stirring until the polyol dissolves, to obtain a second solution;
d) optionally adding a secondary non-aqueous co-solvent to the second solution of step (c) under constant stirring for 5 minutes to 10 minutes to obtain a third solution;
e) adding protein drug to the third solution of step (d) and allowing to disperse to obtain a solution;
f) optionally filtering the solution as obtained in step (e) one or more times to obtain a clear solution; and
g) filling the clear solution of step (f) in suitable containers to obtain a composition in a ready-to-use form
In an embodiment, the present invention relates to a process for the preparation of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
a) dissolving polyol and pH adjusting agent in primary non-aqueous solvent and optionally water to obtain a solution by stirring the resulting mixture at a temperature ranging from 2°C to 60°C over a period of 30 minutes to 120 minutes to obtain a first solution; b) allowing the resulting first solution of step (a) to attain a temperature of 2°C to room temperature;
c) optionally adding a secondary non-aqueous solvent to the first solution of step (b) under constant stirring for 5 minutes to 10 minutes to obtain a second solution; d) adding protein drug to the second solution of step (c) and allowing to disperse to obtain a solution;
e) optionally filtering the solution of step (d) one or more times to obtain a clear solution; and
f) filling the clear solution of step (e) in suitable containers to obtain a composition in a ready-to-use form.
In an embodiment, in the process for the preparation of the injectable composition of the protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the said protein drug is as described above in one or more embodiments of the invention.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the solvent system comprises 100 % of a non-aqueous solvent or a combination of non-aqueous solvent and water in a ratio ranging from about 95:5 to about 99:1.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the nonaqueous solvent system comprises 100% primary non-aqueous solvent; or in the nonaqueous solvent system, the primary non-aqueous solvent and the secondary nonaqueous co-solvent can be used in a ratio ranging from about 99:1 to about 50:50.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the nonaqueous solvent system comprises 100% primary non-aqueous solvent.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the nonaqueous solvent system, the primary non-aqueous solvent and the secondary non- aqueous co-solvent can be used in a ratio ranging from about 99: 1 to about 50:50.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non- aqueous solvent system, the primary non-aqueous solvent and the secondary nonaqueous co-solvent can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, the primary non-aqueous solvent and the secondary non-aqueous co- solvent(s) can be used in the ratio of 90:10.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, the primary non-aqueous solvent and the secondary non-aqueous co- solvent(s) can be used in the ratio of 85:15.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the primary non-aqueous solvent contained in the solvent system is selected from the group consisting of but not limited to ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol, and polyethylene glycol or a mixture thereof.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the primary non-aqueous solvent is propylene glycol.
In another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent(s) is a (C1-C3)alkyl alcohol selected from the group consisting of but not limited to methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
In another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent(s) is isopropyl alcohol; ethanol or absolute alcohol; or a combination thereof.
In another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent is ethanol. In another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent is absolute alcohol.
In another embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent is isopropyl alcohol.
In another embodiment, in the process for the preparation of the injectable composition a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the secondary non-aqueous co-solvent is a combination of ethanol/absolute alcohol and isopropyl alcohol.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the polyol is selected from a group consisting of glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the polyol is in the range of about 0.01% to about 10% of the total injectable composition of the protein drug.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the polyol is sorbitol or racemic salts or isomers thereof.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the polyol is D-sorbitol.
In an embodiment, in the process for the preparation of the injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; the nonaqueous solvent system comprises 100% propylene glycol.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the solvent system comprises propylene glycol and ethanol. In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the solvent system comprises propylene glycol and absolute alcohol.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the nonaqueous solvent system comprises propylene glycol and isopropyl alcohol.
In an embc>diment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the nonaqueous solvent system comprises 100% propylene glycol; or in the non-aqueous solvent system, the propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in a ratio ranging from about 99:1 to about 50:50.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the nonaqueous solvent system comprises 100% propylene glycol.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio ranging from about 99:1 to about 50:50.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 99:1, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40 or 50:50.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 90: 10.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the solvent system, propylene glycol and ethanol/absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 85 : 15.
In an embodiment, in the process for the preparation of the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
In another embodiment, the pH of the ready-to-use protein drug injectable composition obtained by the process as described above is between about 2.0 and about 13.0.
In another embodiment, the pH of the ready-to-use protein drug injectable composition obtained by the process as described above is between about 4.0 and about 13.0.
In another embodiment, the pH of the ready-to-use protein drug injectable composition obtained by the process as described above is between about 6.0 and about 13.0.
Method of use of the injectable composition:
In an aspect, the present invention relates to use of the stable and ready-to-use composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; for the manufacture of a medicament for treating or preventing one or more diseases, conditions or disorders; wherein the said injectable composition is as described in one or more embodiments of the present invention as described herein above.
In an aspect, the present invention relates to a method of treating or preventing one or more diseases, conditions or disorders comprising administering to a subject in need thereof; a therapeutically effective amount of the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition is as described in one or more embodiments of the present invention as described herein above.
In an embodiment, the diseases, disorders or conditions for the treatment or prevention of which the injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; of the present invention can be used, include, but are not limited to, metabolic disorders, autoimmune disorders, cardiovascular diseases, respiratory diseases, thyroid diseases, hormonal diseases, neurodegenerative diseases, bacterial infections, viral infections, fungal infections, renal diseases, hepatobiliary diseases, venereal diseases, platelet aggregation, inflammatory diseases, cancers, transplantation complications due to rejection reactions, graft rejection and hepatic diseases.
In another embodiment, the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; can be packaged in a suitable container depending upon the composition and the method of administration of the composition. Suitable containers known to a person skilled in the art include vials, ampoules and infusion bag.
In another embodiment, the present invention provides a pharmaceutical kit comprising the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said composition comprises of the protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; a solvent system comprising of a non-aqueous solvent or a combination of a non-aqueous solvent with water; optionally, a polyol; and a pH adjusting agent. The kit may further comprise a package insert, including information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings. The kit may further contain optional materials for storing and/or administering the drug, for example, an infusion bag as well as instructions for storage and use.
In another embodiment, the stable and ready-to-use injectable composition of a protein drug of the present invention; can be delivered to the subject intravenously. Methods of delivering the RTU injectable composition intravenously are well known in the art.
In another embodiment, the stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; can be delivered to the subject by infusion. For example, the injectable dosage form may be delivered intravenously through infusion.
It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit the scope of the present invention Examples
Example 1:
The injectable composition of urokinase (RTU)
Figure imgf000024_0001
Procedure:
a) Sorbitol was dissolved in ethanol to obtain a solution.
b) Propylene glycol was then dissolved in the solution obtained in the step (a).
c) Sodium hydroxide was dissolved in a solution obtained in the step (b) by heating at 50°C for 60 minutes and cooling to a temperature of 2°C to 8°C.
d) Urokinase was then added to the solution of step (c) to obtain another solution. e) The solution obtained in step (d) was subjected to turbulence for 30- 120 minutes to obtain a clear solution,
f) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
Example 2:
The injectable composition of urokinase (RTU)
Figure imgf000024_0002
Procedure:
a) Propylene glycol was taken in a glass bottle /stainless steel (SS) container.
b) Sorbitol was dissolved in ethanol to obtain a solution.
c) Propylene glycol was then dissolved in the solution obtained in the step (b).
d) Urokinase was then added to the solution of step (1) to obtain another solution. IN sodium hydroxide was added to said solution.
e) The solution obtained in step (d) was subjected to turbulence to obtain a clear solution.
f) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
Stability Studies (Example 2):
Figure imgf000025_0001
M - Months
Results of the stability studies performed for ready to use injectable urokinase composition mentioned according to Example 2 demonstrates that the composition exhibited stability upto 1 month.
* Similar results were obtained using Bradford protein assay methods.
Example 3:
The injectable composition of urokinase (RTU)
Figure imgf000026_0001
Procedure:
a) Propylene glycol was taken in a glass bottle / SS container.
b) 12mM sorbitol was dissolved in ethanol to obtain a solution.
c) Propylene glycol was then dissolved in the solution obtained in the step (b).
d) Urokinase was then added to the solution of step (c) to obtain another solution. IN sodium hydroxide and water was added to said solution.
e) The solution obtained in step (d) was subjected to turbulenceto obtain a clear solution.
f) The clear liquid concentrate obtained in step (e) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
Stability Studies (Example 3):
Figure imgf000026_0002
M - Months
Results of the stability studies performed for ready to use injectable Urokinase composition mentioned according to Example 3 demonstrates that the composition exhibited stability upto 1 month.
* Similar results were obtained using Bradford protein assay methods. Example 4
The injectable composition of urokinase (RTU)
Figure imgf000027_0001
Procedure:
a) Propylene glycol was taken in a glass bottle / SS container.
b) Sodium hydroxide was dissolved in a solution obtained in the step (a) by heating at 50°C for 60 minutes and cooling to a temperature of 2°C to 8°C.
c) 12mM sorbitol was dissolved in ethanol to obtain a solution.
d) The solution obtained in step (c) was added to the solution obtained in (b).
e) Urokinase was then added to the solution obtained in step (d) to obtain a solution. f) The solution obtained in step (e) was subjected to turbulence to obtain a clear solution.
g) The clear liquid concentrate obtained in step (f) was filled in siliconised / non- siliconised vial and stoppered with Teflon coated rubber stoppers with nitrogen headspace to obtain a composition in a ready-to-use form.
Stability Studies (Example 4):
Figure imgf000027_0002
M - Months
Results of the stability studies performed for ready to use injectable urokinase composition mentioned according to Example 4 demonstrates that the composition exhibited stability upto 1 month.
* Similar results were obtained using Bradford protein assay methods.

Claims

We Claim:
1. A stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof comprising:
(i) a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof;
(ii) a solvent system;
(iii) optionally a polyol; and
(iv) a pH adjusting agent.
2. The injectable composition according to claim 1, wherein the protein drug is selected from urokinase, streptokinase, prolactin or a combination thereof.
3. The injectable composition according to claim 1, wherein the protein drug is a bioconjugate.
4. The injectable composition according to claim 1, wherein the solvent system comprises of a non-aqueous solvent or a combination of a non-aqueous solvent with water.
The injectable composition according to claim 4, wherein the solvent system comprises of 100 % non-aqueous solvent or a combination of a non-aqueous solvent with water in the ratio ranging from 95:5 to 99:1.
The injectable composition according to claim 4, wherein the non-aqueous solvent used consists of a primary non-aqueous solvent and optionally one or more secondary non-aqueous co-solvent(s).
The injectable composition according to claim 6, wherein the primary nonaqueous solvent is selected from the group consisting of ethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, glycerol and polyethylene glycol or a mixture thereof.
8. The injectable composition according to claim 6, wherein the secondary nonaqueous co-solvent is a (C1-C3)alkyl alcohol selected from the group consisting of methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol); or a mixture thereof.
9. The injectable composition according to claim 1, wherein the polyol is selected from a group consisting of glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, or a combination thereof.
10. The injectable composition according to claim 1, wherein the pH adjusting agent is selected from pharmaceutically acceptable acids, bases, or buffering agents.
11. The injectable composition according to claim 1, wherein the said composition contains the said protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; in a concentration in the range of about 5000 IU to about 1000000 IU.
12. The injectable composition according to claim 6, wherein the said injectable composition contains the primary non-aqueous solvent and the secondary non- aqueous co-solvent in the ratio ranging from about 99:1 to about 50:50.
13. The injectable composition according to claim 1, wherein the polyol is in the range of about 0.01% to about 10% of the total injectable composition of the protein drug.
14. The injectable composition according to claim 1, wherein the pH is between about 2.0 to about 13.0.
15. A process for the preparation of a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; comprising the steps of: a) dissolving a pH adjusting agent in a solvent system consisting of primary nonaqueous solvent and optionally water to obtain a first solution;
b) optionally adding polyol to the secondary non-aqueous solvent under constant stirring until the polyol dissolves to obtain a second solution;
c) adding the first solution of step (a) to the second solution of step (b) under constant stirring to obtain a third solution;
d) dispersing the protein drug in the third solution of step (c) to obtain a solution; e) optionally filtering the solution of step (d) to obtain a clear solution; and f) filling the clear solution of step (e) into a container to obtain a preparation in a ready-to-use form.
16. A process for the preparation of a stable and ready-to-use injectable composition of a protein drug or a pharmaceutically acceptable salt or a co-crystal thereof; comprising the steps of:
a) dissolving polyol in secondary non-aqueous solvent to obtain a first solution; b) adding protein drug to the first solution of step (a);
c) adding primary non-aqueous solvent, pH adjusting agent and optionally water to the solution obtained in step (b) to produce a solution;
d) optionally filtering the solution of step (c) one or more times to obtain a clear solution; and
e) filling the clear solution of step (d) into a container to obtain a composition in a ready-to-use form.
PCT/IB2015/057927 2014-10-16 2015-10-15 Stable injectable composition of protein drugs and process for its preparation WO2016059593A1 (en)

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CN113164390A (en) * 2018-10-09 2021-07-23 达特·特兰 Compositions and methods for enhancing systemic delivery, tolerability and efficacy of cationic macrocyclic peptides
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