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WO2018055539A1 - Composition pharmaceutique contenant de l'insuline glargine tamponnée et un analogue de glp-1 - Google Patents

Composition pharmaceutique contenant de l'insuline glargine tamponnée et un analogue de glp-1 Download PDF

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Publication number
WO2018055539A1
WO2018055539A1 PCT/IB2017/055720 IB2017055720W WO2018055539A1 WO 2018055539 A1 WO2018055539 A1 WO 2018055539A1 IB 2017055720 W IB2017055720 W IB 2017055720W WO 2018055539 A1 WO2018055539 A1 WO 2018055539A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
liraglutide
insulin glargine
buffered
pharmaceutically acceptable
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Legal status (The legal status 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 status listed.)
Ceased
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PCT/IB2017/055720
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English (en)
Inventor
Maharaj Kishen SAHIB
Ganesh BARHATE
Mamatha KATRGADDA
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Wockhardt Ltd
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Wockhardt Ltd
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Publication of WO2018055539A1 publication Critical patent/WO2018055539A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K38/28—Insulins
    • 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
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the invention relates to an aqueous pharmaceutical composition
  • an aqueous pharmaceutical composition comprising: (a) from about 1 IU/ml to about 500 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of a GLP-1 analogue, and (c) one or more pharmaceutically acceptable excipients.
  • the invention relates to an aqueous pharmaceutical composition comprising: (a) liraglutide and buffered insulin glargine in a weight ratio of about 1: 1 to about 1:20, and (b) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. Since people suffering from diabetes are subject to chronic treatment over several decades, there is a major need for safe, convenient and life quality improving insulin formulations.
  • insulin formulations In the treatment of diabetes mellitus, many varieties of insulin formulations have been suggested and used, such as regular insulin, isophane insulin (designated NPH), insulin zinc suspensions (such as SEMILENTE ® , LENTE ® , and ULTRALENT ® ), and biphasic isophane insulin.
  • NPH isophane insulin
  • insulin zinc suspensions such as SEMILENTE ® , LENTE ® , and ULTRALENT ®
  • biphasic isophane insulin Some of the commercial available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action.
  • Fast-acting insulin formulations are usually solutions of insulin, while retarded acting insulin formulations can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both.
  • GLP-1 glucagon-like peptide- 1
  • Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized in the L-cells in the distal ileum, in the pancreas and in the brain. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. GLP-1 stimulates insulin secretion in a glucose-dependant manner, stimulates insulin biosynthesis, and promotes beta cell rescue, decreases glucagon secretion, gastric emptying and food intake. As the type 2 diabetes population is rapidly increasing in the world there is a much larger need for simpler administration of more effective drugs.
  • US Patent Application No. 20120021978 Al discloses a composition of GLP-1 agonist and Insulin peptide.
  • US Patent Application No. 20120295846 Al discloses a composition of GLP-1 agonist and Insulin with Methionine.
  • US Patent Application No. 20120122774 Al discloses composition comprising insulin glargine and analogue of exedin-4.
  • PCT publication WO 2006/051103 A2 discloses pharmaceutical composition comprising insulinotropic peptide and basal insulin.
  • PCT Publication No. WO 1995031214 Al discloses a treatment of insulin requiring diabetes comprising administration of insulin and GLP-1.
  • PCT Publication No. WO 2003020201 A3 discloses pre-mixed formulation of GLP-1 compounds and basal insulin.
  • PCT Publication No. WO 2017145104 Al discloses a pharmaceutical composition of insulin glargine with two amino acids and another insulin analogue.
  • an aqueous pharmaceutical composition comprising: (a) from about 1 IU/ml to about 500 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of a GLP-1 analogue, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • the GLP-1 analogue comprises exenatide, liraglutide, lixisenatide, semaglutide, dulaglutide and albiglutide.
  • the GLP-1 analogue is liraglutide, present in the amount from about 0.3 mg/ml to about 2 mg/ml.
  • the buffered insulin glargine is present in about 40IU/mL to about 500IU/mL.
  • the one or more pharmaceutically acceptable excipients comprise a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • the composition is stable for at least 24 hours when stored at 25 C and relative humidity of 60%.
  • the composition is stable for at least 6 months when stored at 25 C and relative humidity of 60%.
  • the buffered insulin glargine comprises insulin glargine and two amino acids viz., arginine and isoleucine.
  • the two amino acids, arginine and isoleucine are present in a weight ratio of about 1: 1 to about 1:5, preferably about 1:2.
  • the pharmaceutical composition of the present invention is suitable for parenteral administration such as intramuscular, subcutaneous, intradermal and intravenous administration.
  • parenteral administration such as intramuscular, subcutaneous, intradermal and intravenous administration.
  • the pharmaceutical composition is suitable for subcutaneous injection administration.
  • an aqueous pharmaceutical composition comprising: (a) from about 100 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of liraglutide, (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • the buffered insulin glargine and liraglutide are present separated from each other or as a mixture.
  • the buffered insulin glargine and liraglutide are formulated as a fixed dose composition.
  • an aqueous pharmaceutical composition comprising: (a) about 100 IU/ml of buffered insulin glargine, (b) about 0.6 mg/mL of liraglutide, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • an aqueous pharmaceutical composition comprising: (a) liraglutide and buffered insulin glargine in a weight ratio of about 1:1 to about 1:20, and (b) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • the one or more pharmaceutically acceptable excipients comprise a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • an aqueous pharmaceutical composition comprising: (a) about 100 IU/ml of buffered insulin glargine, (b) about 0.3 mg/mL to about 2 mg/mL of liraglutide, and (c) one or more pharmaceutically acceptable excipients selected from a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • amount of liraglutide is about 0.6 mg/mL or about 1.2 mg/mL or about 1.8 mg/mL.
  • an aqueous pharmaceutical composition comprising: (a) 3.64 mg of buffered insulin glargine, (b) about 0.3 mg of liraglutide, (c) 10 mg of 85% glycerol, (d) 30 ⁇ g of zinc Chloride, (e) 2.7 mg of m-cresol, (f) 5mM of L- arginine and 10 mM of isoleucine and (g) 1 mg of dipotassium phosphate, and wherein the pharmaceutical composition has a pH of 8.2 + 0.2.
  • an aqueous pharmaceutical composition comprising: (a) 3.64 mg of buffered insulin glargine, (b) about 0.6 mg of liraglutide, (c) 10 mg of 85% glycerol, (d) 30 ⁇ g of zinc Chloride, (e) 2.7 mg of m-cresol, (f) 5mM of L- arginine and 10 mM of isoleucine and (g) 1 mg of dipotassium phosphate, and wherein the pharmaceutical composition has a pH of 8.2 + 0.2.
  • an aqueous pharmaceutical composition comprising first component and second component, wherein said first component comprises (a) buffered insulin glargine, and (b) a pharmaceutically acceptable excipient, and said second component comprises (a) liraglutide, and (b) a pharmaceutically acceptable excipient.
  • the first component and second component can be administered as mixture or separately.
  • the composition is formulated as a fixed dose composition.
  • pharmaceutically acceptable excipients from first and second component are selected from a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof
  • kits comprising an aqueous composition comprising first component and second component, wherein said first component comprises (a) buffered insulin glargine, and (b) a pharmaceutically acceptable excipient, and said second component comprises (a) liraglutide, and (b) a pharmaceutically acceptable excipient.
  • the composition is formulated as a fixed dose composition.
  • pharmaceutically acceptable excipients from first and second component are selected from a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • a method of treating diabetes mellitus in a subject comprises parenterally administering to said subject an aqueous pharmaceutical composition comprising: (a) from about 1 IU/ml to about 500 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of a GLP-1 analogue, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • said method comprises parenterally administering to said subject an aqueous pharmaceutical composition comprising: (a) liraglutide and buffered insulin glargine in a weight ratio of about 1: 1 to about 1:20, and (b) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • aqueous composition of any aspect of this invention for the preparation of medicament for treating diabetes, for adjusting the fasting, postprandial and/or post absorptive blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of function of the pancreatic ⁇ -cells and for weight loss and/or for preventing weight gain in a patient in need thereof.
  • kits comprising aqueous composition comprising first component and second component, wherein said first component comprises (a) buffered insulin glargine, and (b) a pharmaceutically acceptable excipient, and said second component comprises (a) liraglutide, and (b) a pharmaceutically acceptable excipient, wherein the process comprises the steps of:
  • step (iii) adding the solution of at least two amino acids in the solution of step (i) and adjusting the pH to about 3 to about 4 using a pH modifying agent
  • step (v) mixing the solutions of step (iii) and (iv) and adjusting the pH to about 8.2+ 0.2 to obtain the pharmaceutical composition.
  • step (iii) adding the solution of at least two amino acids in the solution of step (i) and adjusting the pH to about 6 to about 9 using a pH modifying agent,
  • step (v) mixing the solutions of step (iii) and (iv) and adjusting the pH to about 8.2+ 0.2 to obtain the pharmaceutical composition.
  • the general aspect of the invention relates to an aqueous pharmaceutical composition
  • an aqueous pharmaceutical composition comprising: (a) buffered insulin glargine, (b) a GLP-1 analogue, and (c) a pharmaceutically acceptable excipient.
  • aqueous pharmaceutical composition herein relates to a liquid formulation suitable for parenteral administration such as intramuscular, subcutaneous, intradermal and intravenous administration.
  • the term "buffered insulin glargine” refers to insulin glargine and two amino acids in weight ratio of about 1: 1 to about 1:5, wherein two amino acids selected from the group consisting of arginine, lysine, betaine, norleucine, aspartic acid, glutamic acid, asparagines, proline, glutamine, histidine, serine, threonine, glycine, alanine, methionine, leucine, isoleucine, valine, phenylalanine, tryptophan, phosphatidylethanolamine, phosphatidylserine and tyrosine.
  • the buffered insulin glargine contains insulin glargine and two amino acids viz., arginine and isoleucine in a weight ratio of about 1:2.
  • the amount of 100 IU/mL of insulin glargine corresponds to 3.64 mg of insulin glargine.
  • GLP-1 analogue refers to glucagon- like peptide- 1 receptor agonists also known as GLP-1 receptor agonists or incretin mimetics.
  • GLP-1 analogue comprises exenatide, liraglutide, lixisenatide, semaglutide, dulaglutide and albiglutide.
  • pharmaceutically acceptable excipients herein relates to non-active pharmaceutical ingredients which are within the scope of sound medical judgment suitable for use in pharmaceutical products.
  • stable herein relates to a physical and/or chemical stability of pharmaceutical composition of insulin and/or Liraglutide, when stored at certain conditions of temperature and relative humidity.
  • an aqueous pharmaceutical composition comprising: (a) from about 1 IU/ml to about 500 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of a GLP-1 analogue, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • the GLP-1 analogue comprises exenatide, liraglutide, lixisenatide, semaglutide, dulaglutide and albiglutide.
  • the GLP-1 analogue is liraglutide, present in the amount from about 0.3 mg/ml to about 2 mg/ml.
  • the buffered insulin glargine is present in about 40IU/mL to about 500IU/mL.
  • the one or more pharmaceutically acceptable excipients comprise a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • the composition is stable for at least 24 hours when stored at 25 C and relative humidity of 60%.
  • the composition is stable for at least 6 months when stored at 25 C and relative humidity of 60%.
  • the buffered insulin glargine comprises insulin glargine and two amino acids viz., arginine and isoleucine.
  • the two amino acids, arginine and isoleucine are present in a weight ratio of about 1: 1 to about 1:5, preferably about 1:2.
  • buffered insulin glargine is present in about 40IU/mL to about 500IU/mL.
  • buffered insulin glargine is present in about 80IU/mL to about 400IU/mL, or about lOOIU/mL to about 300IU/mL, or about 200IU/mL to about 300IU/mL.
  • buffered insulin glargine is present in about 50IU/mL, or about 60IU/mL, or about 70IU/mL, or about 80IU/mL, or about 90IU/mL, or about lOOIU/mL, or about l lOIU/mL, or about 120IU/mL, or about 130IU/mL, or about 140IU/mL, or about 150IU/mL, or about 160IU/mL, or about 170IU/mL, or about 180IU/mL, or about 190IU/mL, or about 200IU/mL, or about 250IU/mL, or about 300IU/mL, or about 350IU/mL, or about 400IU/mL, or about 450IU/mL. Each of this concentration constitutes an alternate embodiment of the invention.
  • the GLP-1 analogue is liraglutide, present in the amount from about 0.3 mg/ml to about 2 mg/ml or about 06 mg/mL to about 1.8 mg/mL or about 1.2 mg/mL. Each of these amounts constitutes an alternate embodiment of the invention.
  • the pharmaceutical composition has a pH in between about 3 to about 9.
  • the composition has pH in between about 4 to about 8, or about 5 to about 7, or about 6 to about 7, or about 7 to about 8, or about 8 to about 9.
  • Each of the pH range constitutes an alternate embodiment of the invention.
  • the one or more pharmaceutically acceptable excipients comprise pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • the pH maintaining agent as used herein include, but are not limited to, phosphate, acetate, citrate or TRIS (i.e. 2-amino-2-hydroxymethyl-l,3-propanediol) and corresponding salts.
  • the solubilizing agent are selected from the group consisting of partial and fatty acid esters and ethers of polyhydric alcohols such as of glycerol, sorbitol, glycine and the like (Span®, Tween®, in particular Tween® 20 and Tween®80, Myrj®, Brij®, Cremophore® or poloxamers, Pluronics® and Tetronics®), polysorbates (TweenTM), sodium dodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide, cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols polyoxy ethylene sorbitan, Octoxynol (Triton X100TM), N, N - dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether, Brij 721TM,
  • the isotonic agent as used herein includes salts, e.g., sodium chloride, dextrose, lactose or combination thereof.
  • the preservative as used herein include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, 2-penoxyethanol, phenyl mercuric nitrate, thimerosal, metacresol or combinations thereof.
  • the concentration of preservative is about O. lmg/mL to about 5mg/mL, or about lmg/ml, or about 2 mg/ml or about 2.5 mg/mL or about 3 mg/mL.
  • the pH modifying agents as used herein refers to a combination of acid and alkali.
  • the pH modifying agents can be selected from the group comprising of hydrochloric acid, o- phosphoric acid, citric acid, acetic acid, succinic acid, lactic acid, gluconic acid, tartaric acid, 1,2,3,4-butane tetracarboxylic acid, fumaric acid and malic acid.
  • Alkali is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium hydroxide, ammonium hydroxide, magnesium oxide, calcium hydroxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicates, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine and combination thereof.
  • the composition is stable for at least 24 hours when stored in glass vials at 25 C and relative humidity of 60%. In another embodiment, the composition is stable for at least 6 months when stored in glass vials at 25 C and relative humidity of 60%. In another embodiment, the stability studies were performed as per standard in-house method.
  • the two amino acids, arginine and isoleucine are present in a weight ratio of about 1: 1 to about 1:5, or about 1:2 to about 1:3, or about 1:3 to about 1:4, or about 1:4 to about 1:5, preferably about 1:2.
  • the concentration of arginine or isoleucine ranges from about ImM to lOOmM, or about 2mM to 50mM, or about 3mM to 25mM. In an embodiment, the concentration of arginine is about 2mM to 20mM, or about 2mM to lOmM.
  • the concentration of arginine is about 3mM, or about 4mM, or about 5mM, or about 6mM, or about 7mM, or about 8mM, or about 9mM.
  • the concentration of isoleucine is about 2mM to 20mM, or about 2mM to 15mM.
  • the concentration of isoleucine is about 3mM, or about 4mM, or about 5mM, or about 6mM, or about 7mM, or about 8mM, or about 9mM, or about lOmM, or about l lmM, or about 12mM, or about 13mM, or about 14mM.
  • the concentration of arginine is about 7mM and the concentration of isoleucine is about 14mM.
  • the pharmaceutical composition of the present invention is suitable for parenteral administration such as intramuscular, subcutaneous, intradermal and intravenous administration.
  • parenteral administration such as intramuscular, subcutaneous, intradermal and intravenous administration.
  • the pharmaceutical composition is suitable for subcutaneous injection administration.
  • an aqueous pharmaceutical composition comprising: (a) from about 100 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of liraglutide, (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • the buffered insulin glargine and liraglutide are present separated from each other or as a mixture.
  • the buffered insulin glargine and liraglutide are formulated as a fixed dose composition.
  • an aqueous pharmaceutical composition comprising: (a) about 100 IU/ml of buffered insulin glargine, (b) about 0.6 mg/mL of liraglutide, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • an aqueous pharmaceutical composition comprising: (a) about 100 IU/ml of buffered insulin glargine, (b) about 0.3 mg/mL of liraglutide, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • amount of liraglutide is about 0.6 mg/mL or about 1.2 mg/mL or about 1.8 mg/mL.
  • an aqueous pharmaceutical composition comprising: (a) 3.64 mg of buffered insulin glargine, (b) about 0.3 mg of liraglutide, (c) 10 mg of 85% glycerol, (d) 30 ⁇ g of zinc Chloride, (e) 2.7 mg of m-cresol, (f) 5mM of L- arginine and 10 mM of isoleucine and (g) 1 mg of dipotassium phosphate, and wherein the pharmaceutical composition has a pH of 8.2 + 0.2.
  • an aqueous pharmaceutical composition comprising: (a) 3.64 mg of buffered insulin glargine, (b) about 0.6 mg of liraglutide, (c) 10 mg of 85% glycerol, (d) 30 ⁇ g of zinc Chloride, (e) 2.7 mg of m-cresol, (f) 5mM of L- arginine and 10 mM of isoleucine and (g) 1 mg of dipotassium phosphate, and wherein the pharmaceutical composition has a pH of 8.2 + 0.2.
  • an aqueous pharmaceutical composition comprising: (a) liraglutide and buffered insulin glargine in a weight ratio of about 1: 1 to about 1:20, and (b) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • liraglutide and buffered insulin glargine present in a weight ratio of about 1:2 to about 1: 18, or about 1:3 to about 1: 15, or about 1:6 to about 1: 12, wherein the one or more pharmaceutically acceptable excipients comprise a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • an aqueous pharmaceutical composition comprising: (a) about 100 IU/ml of buffered insulin glargine, (b) about 0.3 mg/mL to about 2 mg/mL of liraglutide, and (c) one or more pharmaceutically acceptable excipients selected from a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • the pharmaceutical composition comprises about 0.6 mg/mL of liraglutide, and wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • an aqueous pharmaceutical composition comprising first component and second component, wherein said first component comprises (a) buffered insulin glargine, and (b) a pharmaceutically acceptable excipient, and said second component comprises (a) liraglutide, and (b) a pharmaceutically acceptable excipient.
  • the first component and second component can be administered as mixture or separately.
  • composition is formulated as a fixed dose composition.
  • pharmaceutically acceptable excipients from first and second component are selected from a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof
  • kits comprising an aqueous composition comprising first component and second component, wherein said first component comprises (a) buffered insulin glargine, and (b) a pharmaceutically acceptable excipient, and said second component comprises (a) liraglutide, and (b) a pharmaceutically acceptable excipient.
  • the composition is formulated as a fixed dose composition.
  • pharmaceutically acceptable excipients from first and second component are selected from a pH maintaining agent, solubilising agent, isotonic agent, preservative, pH modifying agent or combination thereof.
  • a method of treating diabetes mellitus in a subject comprises parenterally administering to said subject an aqueous pharmaceutical composition comprising: (a) from about 1 IU/ml to about 500 IU/ml of buffered insulin glargine, (b) therapeutically effective amount of a GLP-1 analogue, and (c) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 3 to about 9.
  • said method comprises parenterally administering to said subject an aqueous pharmaceutical composition comprising: (a) liraglutide and buffered insulin glargine in a weight ratio of about 1: 1 to about 1:20, and (b) one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has a pH between about 6 to about 9.
  • aqueous composition of any aspect of this invention for the preparation of medicament for treating diabetes, for adjusting the fasting, postprandial and/or post absorptive blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of function of the pancreatic ⁇ -cells and for weight loss and/or for preventing weight gain in a patient in need thereof.
  • kits comprising aqueous composition comprising first component and second component, wherein said first component comprises (a) buffered insulin glargine, and (b) a pharmaceutically acceptable excipient, and said second component comprises (a) liraglutide, and (b) a pharmaceutically acceptable excipient, wherein the process comprises the steps of:
  • step (iii) adding the solution of at least two amino acids in the solution of step (i) and adjusting the pH to about 3 to about 4 using a pH modifying agent
  • step (v) mixing the solutions of step (iii) and (iv) and adjusting the pH to about 8.2+ 0.2 to obtain the pharmaceutical composition.
  • step (iii) adding the solution of at least two amino acids in the solution of step (i) and adjusting the pH to about 6 to about 9 using a pH modifying agent,
  • EXAMPLE 1 Aqueous composition of buffered glargine and liraglutide Part A. Preparation of buffered insulin glargine
  • Zinc-containing crystals of insulin glargine were dissolved in water for injection with the help of 1M HC1.
  • dipotassium phosphate, L-arginine and isoleucine in water for injection were added to get final concentration.
  • the pH was adjusted to 4.0+0.2 with 1M HC1 or 1M NaOH.
  • the solution was filtered with 0.2 micron filter in a sterile container.
  • Zinc-containing crystals of insulin glargine were dissolved in water for injection with the help of IM HCl.
  • the endogenous zinc level was supplemented by adding appropriate volume of zinc chloride solution (1% w/v). To this L-arginine and isoleucine was added with mixing. The pH was adjusted to 4.0+0.2 with IM HCl or IM NaOH.
  • a solution was prepared by dissolving m-cresol, glycerol and dipotassium phosphate in water for injection to get final concentration. 3. Liraglutide was dissolved in the solution of step 2 and pH was adjusted to 8.0+0.2 with IM HCl or IM NaOH.
  • Manufacturing process Manufacturing process is same as mentioned in Example 2.

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Abstract

L'invention concerne une composition pharmaceutique aqueuse comprenant : (a) d'environ 1 IU/ml à environ 500 UI/ml d'insuline glargine tamponnée, et (b) un ou plusieurs excipients pharmaceutiquement acceptables, la composition pharmaceutique ayant un pH compris entre environ 6 et environ 9.
PCT/IB2017/055720 2016-09-22 2017-09-21 Composition pharmaceutique contenant de l'insuline glargine tamponnée et un analogue de glp-1 Ceased WO2018055539A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN115335073A (zh) * 2020-01-16 2022-11-11 上海仁会生物制药股份有限公司 包含glp-1和/或glp-1类似物，以及胰岛素和/或胰岛素类似物的组合疗法
EP3474820B1 (fr) 2017-08-24 2024-02-07 Novo Nordisk A/S Compositions glp-1 et ses utilisations

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WO1995031214A1 (fr) 1994-05-12 1995-11-23 London Health Association Traitement du diabete
WO2003020201A2 (fr) 2001-08-28 2003-03-13 Eli Lilly And Company Pre-melanges de polypeptide glp-1 et d'insuline basale
WO2006051103A2 (fr) 2004-11-12 2006-05-18 Novo Nordisk A/S Préparations stables de peptides
US20110152185A1 (en) * 2007-11-16 2011-06-23 Novo Nordisk A/S Pharmaceutical Compositions Comprising GLP-1 Peptides or Extendin-4 and a Basal Insulin Peptide
US20120021978A1 (en) 2008-10-17 2012-01-26 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a glp-1-agonist
US20120122774A1 (en) 2010-05-19 2012-05-17 Sanofi Long-acting formulations of insulins
US20120295846A1 (en) 2009-11-13 2012-11-22 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
US20130079279A1 (en) * 2010-05-28 2013-03-28 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising ave0010 and insulin glargine
US20130178415A1 (en) * 2012-01-09 2013-07-11 Adocia Injectable solution at pH 7 comprising at least one basal insulin the PI of which is between 5.8 and 8.5 and a substituted co-polyamino acid
US20140371141A1 (en) * 2013-06-17 2014-12-18 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US20160199452A1 (en) * 2014-12-12 2016-07-14 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
WO2017145104A1 (fr) 2016-02-25 2017-08-31 Wockhardt Limited Composition pharmaceutique d'insuline glargine et d'acides aminés

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Publication number Priority date Publication date Assignee Title
WO1995031214A1 (fr) 1994-05-12 1995-11-23 London Health Association Traitement du diabete
WO2003020201A2 (fr) 2001-08-28 2003-03-13 Eli Lilly And Company Pre-melanges de polypeptide glp-1 et d'insuline basale
WO2006051103A2 (fr) 2004-11-12 2006-05-18 Novo Nordisk A/S Préparations stables de peptides
US20110152185A1 (en) * 2007-11-16 2011-06-23 Novo Nordisk A/S Pharmaceutical Compositions Comprising GLP-1 Peptides or Extendin-4 and a Basal Insulin Peptide
US20120021978A1 (en) 2008-10-17 2012-01-26 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a glp-1-agonist
US20120295846A1 (en) 2009-11-13 2012-11-22 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a glp-1 agonist, an insulin and methionine
US20120122774A1 (en) 2010-05-19 2012-05-17 Sanofi Long-acting formulations of insulins
US20130079279A1 (en) * 2010-05-28 2013-03-28 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising ave0010 and insulin glargine
US20130178415A1 (en) * 2012-01-09 2013-07-11 Adocia Injectable solution at pH 7 comprising at least one basal insulin the PI of which is between 5.8 and 8.5 and a substituted co-polyamino acid
US20140371141A1 (en) * 2013-06-17 2014-12-18 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US20160199452A1 (en) * 2014-12-12 2016-07-14 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
WO2017145104A1 (fr) 2016-02-25 2017-08-31 Wockhardt Limited Composition pharmaceutique d'insuline glargine et d'acides aminés

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3474820B1 (fr) 2017-08-24 2024-02-07 Novo Nordisk A/S Compositions glp-1 et ses utilisations
US12214017B2 (en) 2017-08-24 2025-02-04 Novo Nordisk A/S GLP-1 compositions and uses thereof
CN115335073A (zh) * 2020-01-16 2022-11-11 上海仁会生物制药股份有限公司 包含glp-1和/或glp-1类似物，以及胰岛素和/或胰岛素类似物的组合疗法

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