WO2016059592A1 - Stable injectable composition of peptide drugs and process for its preparation - Google Patents

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

Info

Publication number
WO2016059592A1
WO2016059592A1 PCT/IB2015/057926 IB2015057926W WO2016059592A1 WO 2016059592 A1 WO2016059592 A1 WO 2016059592A1 IB 2015057926 W IB2015057926 W IB 2015057926W WO 2016059592 A1 WO2016059592 A1 WO 2016059592A1
Authority
WO
WIPO (PCT)
Prior art keywords
injectable composition
solution
aqueous solvent
peptide drug
aqueous
Prior art date
Application number
PCT/IB2015/057926
Other languages
English (en)
French (fr)
Inventor
Vandana SONAVARIA
Kamal Kumar Upadhyay
Pratikkumar PATEL
Original Assignee
Piramal Enterprises Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Piramal Enterprises Limited filed Critical Piramal Enterprises Limited
Publication of WO2016059592A1 publication Critical patent/WO2016059592A1/en

Links

Classifications

    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a stable, non-aqueous and ready-to-use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; and processes for its preparation.
  • peptides are widely used as therapeutic agents.
  • Peptides constitute effective therapeutic agents as they exhibit relatively low toxicity as they metabolize to naturally occurring amino acids and at the same time demonstrate high potency and selectivity.
  • peptide drugs have contributed significantly to the treatment of proliferative disorders such as cancers; metabolic disorders such as diabetes; cardiovascular diseases, osteoporosis, gastrointestinal disorders, bacterial infections, viral infections, acromegaly, and several other diseases.
  • peptides have certain limitations as to their uses. For instance, due to their low oral bioavailability and rapid degradation of the peptides by proteolytic enzymes in the gastrointestinal tract, peptides are typically administered by parenteral route. Thus, parenteral administration is one of the most used routes to obtain systemic delivery of peptide drugs. Parenteral composition of peptide drugs has primarily been achieved through aqueous solutions. However, therapeutic peptides are often unstable in the aqueous compositions. Due to the stability problem of many peptides in aqueous solutions, these are commonly formulated as a solid by lyopbilization and reconstituted with a sterile diluent prior to administration.
  • Geref® (sermorelin acetate for injection) increases plasma growth hormone (GH) concentration by stimulating the pituitary gland to release GH;
  • Cubicin ® ( Daptomycin) is supplied as a sterile, lyophilized 500 mg or 350 mg cake mat must be reconstituted with sodium chloride prior to use.
  • Daptomycin is a lipopeptide antibiotic which is used in the treatment of complicated skin and skin structure infections (cSSSl) caused by susceptible isolates of the following Gram-positive bacteria; and (iv) Cetrotide ® (Cetrorelix acetate is supplied as a 0.25 mg or 3 mg sterile lyophilized powder with either lmL or 3 mL of water for reconstitution in a prefilled syringe.
  • Cetrorelix a synthetic decapeptide, is a luteinising hormone releasing hormone (LHRH) antagonist.
  • compositions including lyophilized compositions for peptide drugs are known in the art.
  • WO2014041425 discloses a lyophilized daptomycin composition comprising an additive selected from the group consisting of pharmaceutically acceptable antioxidants, pharmaceutically acceptable organic acids and pharmaceutically acceptable salts thereof, pharmaceutically acceptable glucose derivatives and pharmaceutically acceptable salts thereof, and combinations thereof.
  • WO2011063419 discloses a solid daptomycin preparation with improved reconstitution time and stability profile.
  • WO2014045296 discloses a lyophilized pharmaceutical composition comprising antibacterial agent, daptomycin and tocopheryl phosphate hydrolysate mixture with improved reconstitution time for parenteral administration and also discloses a process for its preparation.
  • WO2012077131 discloses a stable aqueous pharmaceutical preparation containing cetrorelix or its pharmaceutically acceptable salt in the form of ready-to-use solutions avoiding reconstitution step prior to use and process for preparing such preparations.
  • the examples disclosed illustrate that water is an essential ingredient of the composition.
  • compositions of peptide drugs are primarily in the form of aqueous or lyophilized compositions.
  • peptides may undergo several degradation pathways when they are formulated in aqueous solution.
  • the presence of water in the composition can lead to deterioration of the peptide because of hydrolysis. Therefore, it is desirable to develop a stable composition for peptides and for the purpose non-aqueous based composition would be appropriate for peptides.
  • inventors of the present invention have done extensive research and conducted several experiments to develop a stable, non-aqueous and ready-to-use injectable composition of therapeutic peptides, 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 the stable, non-aqueous and ready-to-use composition of peptide(s).
  • the present invention provides a stable, non-aqueous and ready-to- use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • the present invention provides a stable, non-aqueous and ready-to- use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises: (i) a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said peptide drug is other than bivalirudin;
  • a non-aqueous solvent system consisting 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 a stable, non-aqueous and ready-to-use injectable composition of a peptide 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, non-aqueous 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, non-aqueous and ready- to-use injectable composition of a peptide 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, non-aqueous and ready- to-use injectable composition of a peptide 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 peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; a non-aqueous solvent system consisting of a primary non-aqueous solvent and optionally one or more secondary nonaqueous co-solvent(s); optionally a polyol, optionally a pH adjusting agent and optionally an antioxidant; 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 peptide 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 peptide 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.
  • 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 peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; is a non-aqueous, injectable composition that is stable and is not reconstituted from a lyopbilizate.
  • RTU also encompasses within its scope, non-aqueous, injectable composition that is stable and has been diluted from a concentrated, liquid solution just prior to use.
  • non-aqueous composition means a composition with not more than 2 % water content.
  • 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), ethylene glycol, propylene glycol (PG), dipropylene glycol, tripropylene glycol, polyvinylpyrrolidone (PVP), methoxy propylene glycol (MPEG), glycerol, glycofurol or a mixture thereof.
  • non-aqueous RTU composition means the composition is devoid of any water content in the final finished product or during process for preparation of the same. However, a negligible amount i.e. not more than 2% of water or moisture may be present due to external environmental factors which does not have any impact on the physiochemical property, specifically on the stability of the composition.
  • the term "has not been reconstituted from a lyopbilizate” 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. peptide drug) to the target site without affecting the therapeutic activity of the said active agent.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt(s)” means salt(s) of the peptide drug(s), which can be prepared by treating the peptide 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, non-aqueous and ready-to-use injectable composition” are used interchangeably.
  • the active pharmaceutical ingredient is a peptide 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 peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof, of the present invention is between about 2.0 and about 11.0.
  • 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 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.
  • solvent system refers to a primary solvent and optionally one or more secondary solvent selected from a group of solvents.
  • antioxidants means a substance which is particularly used because certain compounds suitable for use in compositions of the invention are prone to degradation by autoxidation.
  • Antioxidants may comprise, but are not limited to, acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), monothioglycerol, potassium nitrate, ascorbic acid or sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, edetate (“EDTA”) (e.g., disodium edetate), diethylenetriaminepentaacetic acid (“DTPA”), triglycollamate (“NT”), DL- or D-a-tocopherol, DL- or D-a-tocopheryl acetate or a combination thereof.
  • BHA butylated hydroxyanisole
  • Antioxidants may also comprise amino acids such as methionine, histidine, cysteine and those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid.
  • amino acids such as methionine, histidine, cysteine and those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid.
  • Any stereoisomer (e.g., L-, D-, or a combination thereof) of any particular amino acid e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and combinations thereof
  • antioxidant so long as the amino acid is present either in its free base form or its salt form.
  • compositions in accordance with the invention may be added to compositions in accordance with the invention in an amount of up to, for example, 0.05% (w/v), preferably from 0.001 to 1%.
  • 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.
  • peptide drug(s) is used herein interchangeably with the terms “therapeutic peptide(s)” and "peptide(s)”.
  • 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.
  • Peptides can be classified by function and also by synthesis. Some common types of peptides classified by function include hormones, neuropeptides, and alkaloids. When classified by synthesis, peptides can be milk peptides ribosomal, non-ribosomal, and peptonic.
  • peptides are called dipeptides, tripeptides, tetrapeptides, and conjugated peptides which contain amino acid and prosthetic group such as cyclopeptide, glycopeptide, chromopeptide, lipopeptide, nucleopeptide and phosphopeptide.
  • the peptide drug is other than bivalirudin.
  • Representative examples of peptide drugs include, but are not limited to, daptomycin, nesiritide, cetrorelix acetate and a combination thereof. Combinations of peptide drugs with other drugs such as proteins, small molecules and the like are also encompassed within the scope of the present invention.
  • 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.
  • 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.
  • 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 one or more diseases, conditions or disorders (as described herein) for which a peptide drug can be suitably used.
  • the inventors of the present invention have done extensive research and conducted several experiments to develop a stable injectable composition of a peptide 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 peptide drugs.
  • the present invention relates to a stable, non-aqueous and ready-to-use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said injectable composition comprises:
  • a non-aqueous solvent system consisting of a primary non-aqueous solvent, optionally one or more secondary non-aqueous co-solvent(s);
  • the peptide drug is a peptide containing up to 50 amino acids.
  • the peptide drug is selected from but not limited to calcitonin, leptin, melatonin, nafarelin, leuprolide, interferon-alpha, interferon-beta, interferon- gamma, low molecular weight heparin, imitrex, integrelin, nesiritide, nemifitide, sandostatin, cetrorelix, ganirelix, sermorelin , zafirlukast, exanitide.
  • pramlintide vasopressin, desmopressin, glucagon, oxytocin, corticorelin ovine triflutate, corticotropin releasing hormone, daptomycin, tobramycin, triptorelin, goserelin, fuzeon, hematide, buserelin, octreotide, gonadorelin, felypressin, deslorelin, vasopressin, eptifibatide, interleuMnll, endostatin, angiostatin, N-acetyl oxyntomodulin 30-37, oxyntomodulin, ularitide, human Coiticotropin-Releasing Factor (hCRF or xerecept ® ), secretin, thymopentin, neuromedin U, neurotensin, elcatonin, antide, dynorphin A (1-13), sincalide, thymopentin, thymosin alpha 1 (
  • the peptide drug is selected either singly or in combination from daptomycin, nesiritide or cetrorelix; or a pharmaceutically acceptable salt thereof.
  • the injectable composition contains peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 1 mg/mL to about 200 mg/mL.
  • the injectable composition contains peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration in the range of about 5 mg/mL to about 80 mg/mL.
  • the injectable composition contains peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; at a concentration of about 50 mg/mL.
  • 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 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 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 can be used in the ratio of 90:10.
  • the primary non-aqueous solvent and the secondary non-aqueous co-solvent in the non-aqueous solvent system, can be used in the ratio of 85:15.
  • the non- aqueous solvent system comprises one or more solvent(s) selected from the group consisting of but not limited to ethylene glycol, ethylene glycol, propylene glycol, glycerol, polyethylene glycol, dipropylene glycol, tripropylene glycol, methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • solvent(s) selected from the group consisting of but not limited to ethylene glycol, ethylene glycol, propylene glycol, glycerol, polyethylene glycol, dipropylene glycol, tripropylene glycol, methanol, ethanol, absolute alcohol, 1-propanol and isopropanol (isopropyl alcohol) or a mixture thereof.
  • the primary non-aqueous solvent contained in the non-aqueous 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 non-aqueous solvent system is a (CrC 3 )aIkyl 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 contained in the non-aqueous solvent system is isopropyl alcohol, ethanol or absolute alcohol; or a combination thereof. In an embodiment, the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous solvent system is ethanol or absolute alcohol.
  • the optional secondary non-aqueous co-solvent contained in the non-aqueous solvent system is ethanol.
  • the optional secondary non-aqueous co-solvent contained in the non-aqueous solvent system is absolute alcohol.
  • the optional secondary non-aqueous co-solvent contained in the non-aqueous solvent system is isopropyl alcohol.
  • the optional secondary non-aqueous co-solvent(s) contained in the non-aqueous 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, trehalose or a combination thereof.
  • the polyol is in the range of about 0.01% to about 10% of the total injectable composition of a peptide drug.
  • the polyol is sorbitol or racemic salts or isomers thereof.
  • the polyol is D-sorbitol.
  • the primary non-aqueous solvent, the secondary non-aqueous co-solvent and the polyol are present in an amount such that peptide drug at the concentration of at least 50 mg/ml peptide drug is completely soluble and stable in the injectable composition.
  • the non-aqueous solvent system contains propylene glycol and ethanol.
  • the non-aqueous solvent system contains propylene glycol and absolute alcohol.
  • the non-aqueous 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.
  • non-aqueous solvent system consisting of propylene glycol and ethanol//absolute alcohol (and/or isopropyl alcohol) can be used in the ratio of 90:10.
  • non-aqueous solvent system consisting of 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 peptide drug injectable composition of the present invention is between about 2.0 and about 11.0.
  • the pH of the ready-to-use peptide drug injectable composition of the present invention is between about 4.0 and about 8.0.
  • the pH of the ready-to-use peptide drug injectable composition of the present invention is between about 4.0 and about 5.5.
  • the antioxidants may be selected from butylated hydroxytoluene, sodium metabisulphite acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole, monothioglycerol, potassium nitrate, ascorbic acid or sodium ascorbate, sodium formaldehyde sulfoxylate, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, edetate, diethylenetriaminepentaacetic acid, triglycollamate, DL- or D-a- tocopherol, DL- or D-a-tocopheryl acetate, amino acids, stereoisomers of amino acids; or a combination thereof.
  • the antioxidant may be selected from butylated hydroxytoluene or sodium metabisulphite.
  • the present invention relates to a process for the preparation of a stable, non-aqueous and ready-to-use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (b) adding the second solution of step (b) to the first solution of step (a) under constant stirring to obtain a third solution;
  • step (c) dispersing the peptide drug in the third solution of step (c) to obtain a clear solution
  • step (d) optionally filtering the solution of step (d);
  • step (e) 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, non-aqueous and ready-to-use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said process comprises the steps of:
  • step (b) adding primary non-aqueous solvent to the first solution of step (a) to obtain a second solution; c) adding peptide drug to the second solution of step (b) and allowing to disperse to produce a solution;
  • step (c) optionally filtering the solution of step (c) one or more times to obtain a clear solution
  • step (d) filling the clear solution of step (d) into a container to obtain a composition in a ready-to-use form.
  • the present invention relates to a process for the preparation of the stable, non-aqueous and ready-to-use injectable composition of a peptide 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 and antioxidant 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 peptide 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, non-aqueous and ready-to-use injectable composition of a peptide 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 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;
  • step (c) adding peptide 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 peptide drug in the process for the preparation of the injectable composition of the peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; is as described above in one or more embodiments of the invention.
  • 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 nonaqueous co-solvent in the process for the preparation of the injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non- aqueous 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 peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the nonaqueous 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 nonaqueous co-solvent(s) in the process for the preparation of the injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the nonaqueous solvent system, the primary non-aqueous solvent and the secondary nonaqueous co-solvent(s) can be used in the ratio of 90:10.
  • the primary non-aqueous solvent and the secondary nonaqueous co-solvent(s) in the process for the preparation of the injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the nonaqueous solvent system, the primary non-aqueous solvent and the secondary nonaqueous co-solvent(s) can be used in the ratio of 85: 15.
  • the primary non-aqueous solvent contained in the non-aqueous 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 is isopropyl alcohol; ethanol or absolute alcohol; or a combination thereof.
  • the secondary non-aqueous co-solvent is ethanol.
  • 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 but not limited to glycerin, sucrose, lactose, glucose, fructose, arabinose, xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol, mannitol, maltose, cellobiose, xylitol, trehalose or a combination thereof.
  • the polyol in the process for the preparation of the injectable composition of a peptide 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 peptide drug.
  • the polyol 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 polyol is sorbitol or racemic salts or isomers thereof.
  • the polyol 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 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.
  • the nonaqueous solvent system comprises propylene glycol and ethanol.
  • the nonaqueous 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.
  • the 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.
  • propylene glycol and ethanol/absolute alcohol in the process for the preparation of the injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the non-aqueous 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 in the process for the preparation of the injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; in the nonaqueous solvent system, 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 peptide drug injectable composition obtained by the process as described above is between about 2.0 and about 11.0.
  • the pH of the ready-to-use peptide drug injectable composition obtained by the process as described above is between about 4.0 and about 8.0
  • the pH of the ready-to-use peptide drug injectable composition obtained by the process as described above is between about 4.0 and about 5.5.
  • the antioxidant is selected from but not limited to butylated hydroxytoluene, sodium metabisulpbite acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole, monothioglycerol, potassium nitrate, ascorbic acid or sodium ascorbate, sodium formaldehyde sulfoxylate, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, edetate, diethylenetriaminepentaacetic acid, triglycollamate, DL- or D-a- tocopherol, DL- or D-a-tocopheryl acetate, amino acids, stereoisomers of amino acids; or a combination thereof.
  • the antioxidant is selected from butylated hydroxytoluene or sodium metabisulpbite.
  • the present invention relates to use of a stable, non-aqueous and ready-to-use composition of a peptide 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 a stable, non-aqueous and ready-to- use injectable composition of a peptide 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 peptide 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.
  • the stable, non-aqueous and ready-to-use injectable composition of a peptide 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, non-aqueous and ready-to-use injectable composition of a peptide drug or a pharmaceutically acceptable salt or a co-crystal thereof; wherein the said composition comprises of the peptide drug or a pharmaceutically acceptable salt or a co- crystal thereof; a non-aqueous solvent system consisting of a primary non-aqueous solvent and optionally one or more secondary non-aqueous co-solvent(s); optionally a polyol; optionally a pH adjusting agent and optionally an antioxidant.
  • 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, non-aqueous and ready-to-use injectable composition of a peptide 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, non-aqueous and ready-to-use injectable composition of a peptide drug of the present invention can be delivered to the subject by infusion.
  • the injectable dosage form may be delivered intravenously through infusion.
  • step (a) Sodium hydroxide was dissolved in propylene glycol of step (a) to obtain a first solution by stirring for 60 minutes and attaining temperature of 2°C to 8°C.
  • step (c) The second solution obtained in step (c) was added to first solution obtained in step (b).
  • step (e) Daptomycin was then added to the solution obtained in step (d) to obtain a solution.
  • f) The solution obtained in step (e) was subject to turbulence for 30- 120 minutes to obtain a clear 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.
  • step (a) Sodium hydroxide was dissolved in propylene glycol of step (a) to obtain a first solution by stirring for 60 minutes and attaining temperature of 2°C to 8°C.
  • step (c) The second solution obtained in step (c) was added to first solution obtained in step (b).
  • step (e) Daptomycin 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 for 30- 120 minutes to obtain a clear 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.
  • step (b) Sorbitol and butylated hydroxytoluene were dissolved in ethanol to obtain a solution.
  • step (c) The solution thus obtained in step (b) was added to propylene glycol of step (a) with continuous stirring until complete miscibility was observed.
  • step (d) Daptomycin was then added to the solution obtained in step (c) to obtain a 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.
  • step (b) Sorbitol and sodium metabisulpbite were dissolved in ethanol to obtain a solution.
  • c) The solution thus obtained in step (b) was added to propylene glycol of step (a) with continuous stirring until complete miscibility was observed.
  • step (d) Daptomycin was then added to the solution obtained in step (c) to obtain a 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicinal Preparation (AREA)
PCT/IB2015/057926 2014-10-16 2015-10-15 Stable injectable composition of peptide drugs and process for its preparation WO2016059592A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3298/MUM/2014 2014-10-16
IN3298MU2014 2014-10-16

Publications (1)

Publication Number Publication Date
WO2016059592A1 true WO2016059592A1 (en) 2016-04-21

Family

ID=55746218

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/057926 WO2016059592A1 (en) 2014-10-16 2015-10-15 Stable injectable composition of peptide drugs and process for its preparation

Country Status (1)

Country Link
WO (1) WO2016059592A1 (da)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018073269A1 (en) 2016-10-21 2018-04-26 Xellia Pharmaceuticals Aps Liquid formulations of daptomycin
CN110317265A (zh) * 2018-03-28 2019-10-11 江苏豪森药业集团有限公司 比伐芦定晶型a及其制备方法
WO2020229369A1 (en) 2019-05-10 2020-11-19 Xellia Pharmaceuticals Aps Daptomycin aqueous formulations
US11058745B1 (en) 2018-10-04 2021-07-13 Good Health, Llc Stable liquid pharmaceutical compositions of daptomycin
WO2021152463A1 (ru) * 2020-01-28 2021-08-05 Олег Аркадьевич КОТИН Фармацевтическая композиция и способ еe изготовления
WO2021183752A1 (en) * 2020-03-12 2021-09-16 Baxter International Inc. Daptomycin formulations containing a combination of sorbitol and mannitol
WO2023017326A1 (en) * 2021-08-11 2023-02-16 Rk Pharma Inc. Ready to use compositions of cetrorelix acetate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007084460A2 (en) * 2006-01-18 2007-07-26 Qps, Llc Pharmaceutical compositions with enhanced stability
WO2008008363A1 (en) * 2006-07-11 2008-01-17 Qps, Llc Pharmaceutical compositions for sustained release delivery of peptides
US20110230441A1 (en) * 2010-03-18 2011-09-22 Innopharma, Llc Stable bortezomib formulations
US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007084460A2 (en) * 2006-01-18 2007-07-26 Qps, Llc Pharmaceutical compositions with enhanced stability
WO2008008363A1 (en) * 2006-07-11 2008-01-17 Qps, Llc Pharmaceutical compositions for sustained release delivery of peptides
US20110230441A1 (en) * 2010-03-18 2011-09-22 Innopharma, Llc Stable bortezomib formulations
US20120172808A1 (en) * 2010-03-18 2012-07-05 Innopharma, Llc Stable Bortezomib Formulations

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018073269A1 (en) 2016-10-21 2018-04-26 Xellia Pharmaceuticals Aps Liquid formulations of daptomycin
US10933019B2 (en) 2016-10-21 2021-03-02 Xellia Pharmaceuticals Aps Liquid formulations of daptomycin
CN110317265A (zh) * 2018-03-28 2019-10-11 江苏豪森药业集团有限公司 比伐芦定晶型a及其制备方法
CN110317265B (zh) * 2018-03-28 2023-03-10 江苏豪森药业集团有限公司 比伐芦定晶型a及其制备方法
US11058745B1 (en) 2018-10-04 2021-07-13 Good Health, Llc Stable liquid pharmaceutical compositions of daptomycin
WO2020229369A1 (en) 2019-05-10 2020-11-19 Xellia Pharmaceuticals Aps Daptomycin aqueous formulations
WO2021152463A1 (ru) * 2020-01-28 2021-08-05 Олег Аркадьевич КОТИН Фармацевтическая композиция и способ еe изготовления
WO2021183752A1 (en) * 2020-03-12 2021-09-16 Baxter International Inc. Daptomycin formulations containing a combination of sorbitol and mannitol
US11173189B2 (en) 2020-03-12 2021-11-16 Baxter International Inc. Daptomycin formulations containing a combination of sorbitol and mannitol
US12128085B2 (en) 2020-03-12 2024-10-29 Baxter International Inc. Daptomycin formulations containing a combination of sorbitol and mannitol
WO2023017326A1 (en) * 2021-08-11 2023-02-16 Rk Pharma Inc. Ready to use compositions of cetrorelix acetate

Similar Documents

Publication Publication Date Title
WO2016059592A1 (en) Stable injectable composition of peptide drugs and process for its preparation
EP3206706A1 (en) Stable injectable composition of pharmaceutically active agents and process for its preparation
US20240342249A1 (en) Methods for producing stable therapeutic formulations in aprotic polar solvents
EP0760677B1 (en) A pharmaceutical preparation comprising glucagon
KR102327754B1 (ko) 안정한 펩티드 제형물 및 제조 방법
JP6811270B2 (ja) ランレオチドの持続放出用の医薬組成物
ES2593727T3 (es) Composición de caspofungina
US20170224789A1 (en) Stable injectable composition of bivalirudin and process for its preparation
WO2016059590A1 (en) Stable injectable composition of small molecule drugs and process for its preparation
JP2002503704A (ja) ジデムニン（Ｄｉｄｅｍｎｉｎ）化合物の医薬製剤
KR100633280B1 (ko) 약제학적 활성 펩티드의 서방형 투여 형태 및 이의 제조 방법
EP2644189B1 (en) Stable bortezomib formulations
EP3544584A1 (en) Pharmaceutical parenteral formulation containing carglumic acid
US11590205B2 (en) Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
EP3672616A1 (en) Storage stable sincalide formulations
HK1250644B (en) Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15849936

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15849936

Country of ref document: EP

Kind code of ref document: A1