WO2011138802A1 - Solution injectable - Google Patents

Solution injectable Download PDF

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Publication number
WO2011138802A1
WO2011138802A1 PCT/IN2011/000321 IN2011000321W WO2011138802A1 WO 2011138802 A1 WO2011138802 A1 WO 2011138802A1 IN 2011000321 W IN2011000321 W IN 2011000321W WO 2011138802 A1 WO2011138802 A1 WO 2011138802A1
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WO
WIPO (PCT)
Prior art keywords
solution
glucagon
stable
ready
use solution
Prior art date
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
Application number
PCT/IN2011/000321
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English (en)
Inventor
Alok Namdeo
Sulekha Bhadra
Hiren Khatri
Subhas Bhowmick
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Sun Pharma Advanced Research Co Ltd
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Sun Pharma Advanced Research Co Ltd
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Publication of WO2011138802A1 publication Critical patent/WO2011138802A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to stable ready-to-use solution comprising glucagon.
  • the solution is suitable for parenteral administration, particularly suitable for self administration.
  • Glucagon is a polypeptide hormone identical to human glucagon that increases blood glucose and relaxes smooth mus of the gastrointestinal tract.
  • Glucagon is a single-chain polypeptide that contains 29 amino acid residues. It is insoluble in water but is soluble at a pH of less than 3 or more than 9.5. Due to limitations in both chemical and physical stability of glucagon, it is supplied in the form of a lyophilized powder which must be used immediately following reconstitution with its supplied aqueous diluents. It is available for use intravenously, intramuscularly, or subcutaneously in a kit that contains a vial of sterile glucagon and a syringe of sterile diluent.
  • the vial contains 1 mg (1 unit) of glucagon and 49 mg of lactose or 107mg of lactose monohydrate (Novo nordisk).
  • the diluent syringe contains 12 mg/mL of glycerin, Water For Injection, and hydrochloric acid or only water For Injection.
  • Glucagon is administered as an emergency medication in case of hypoglycemic shocks. Therefore, administration of a ready-to-use aqueous solution that does not require any step of reconstitution may be a better preferred approach, particularly, in emergency cases and when the patient needs to self administer the drug.
  • the biggest constraint of glucagon aqueous solution is that it is physically and chemically unstable.
  • step(b) incubating micelles from step(b) with one or more biologically active amphipathic compound (s) under conditions in which said compound(s) becomes associated with said micelles in a more biologically active conformation.
  • aqueous solution of glucagon having distearoyl-phosphotidylethanolamine covalently bonded to polyethylene glycol was chemical and physical stability to the solution, particularly in terms of protein conformation, particularly, at a pH between 5 and 7.5.
  • the present invention provides a stable, ready-to-use solution which comprises therapeutically effective amounts of glucagon and pharmaceutically acceptable vehicle.
  • a stable, ready-to-use solution which comprises therapeutically effective amounts of glucagon and pegylated distearoyl-phosphotidylethanolamine adjusted to a pH of about 5-7.5 and pharmaceutically acceptable vehicle.
  • micellar solution as described in A wherein the pegylated distearoyl-phosphotidylethanolamine has molecular weight of about 300 to 5000 and is present in amount ranging from 1 mg ml to 40 mg/ml.
  • G A stable, ready-to-use solution as described in A wherein the solution further comprises a stabilizer is selected from the group consisting of fatty acids or zwitterionic choline derivatives or mixtures thereof.
  • H A stable, ready-to-use solution as described in G wherein choline derivative is dimyristoyl phosphotidylcholine and is present in concentration of about 1 mg/ml to 2 mg/ml.
  • the term 'stable' as used herein means that the solution remains physically and chemically stable. Particularly, the solution remains clear on long term storage at either 2-8°C or preferably, at room temperature for at least three months, preferably about 6 months to 12 months.
  • the physical stability of the solution of the present invention is determined by recording the percentage transmission at 650 nm & absorbance at 420 nm. Further the solution retains potency which is determined by bioassay methods official in pharmacopoeia as well as the chemical assay such as HPLC.
  • the solution is said to be stable when the total impurities do not exceed more than 10 %, preferably more than 10 % when the solution is stored for a period of about three months at room temperature and/ or at 2-8°C for a period of about three month or more. Additionally, the solution is said to be stable when the related substances of glucagon, such as glucagon sulphoxide, D-trp (25)- glucagon or D- phen (22)- glucagon do not exceed 3 % at the end of storage period, such as room temperature for three months or more or when stored at 2-8°C for six months or more.
  • glucagon such as glucagon sulphoxide, D-trp (25)- glucagon or D- phen (22)- glucagon do not exceed 3 % at the end of storage period, such as room temperature for three months or more or when stored at 2-8°C for six months or more.
  • the term 'ready-to-use' as used herein means that the solution is in the form that can be administered without additional step of reconstitution.
  • product that is available in the market is in the form of a lyophilized form.
  • Glucagon is a therapeutic substance that is administered as an emergency medication in case of hypoglycemic shocks.
  • the patient can self administer the glucagon solution without any delay in administration.
  • the ready-to-use stable, micellar solution of the present invention is suitable for a single dose parenteral self administration wherein the composition is dispensed in a prefilled syringe.
  • the amount of glucagon per single administration may range from 1 mg to about 5 mg per ml of the solution, preferably, 1 mg per ml.
  • the solution is filled in prefilled syringe with an autoinjector.
  • an autoinjector is spring powered and designed to administer the entire contents of the prefilled syringe in one single dose. It may not have any fluid path and may not have any contact with the drug or biologic contained within the syringe.
  • the components of autoinjector may be made up of plastic and steel.
  • the design and performance features of the autoinjector device may include a safety mechanism to prevent inadvertent activation, automatic sheathing of the used needle, cutout window on the front assembly, locking tabs to prevent disassembly of the auto-injector device once the two sub assemblies have been connected, and self disabling to prevent reuse.
  • micellar' as used herein means that the solution is in the form of micelles which appears to be a clear solution by visual observation.
  • the micelles here are stabilized by phospholipids.
  • the micellar solution is said to be physically stable when there are no signs of conformation changes such as gel formation/aggregation, change in CD spectra showing alpha helix structure and/or the solution is clear in terms of particulate matter immediately after preparation and on storage at various storage conditions such as room temperature, 2-8° C for a period of about 6 months.
  • micellar solution of the present invention is suitable for parenteral administration.
  • suitable for parenteral administration it is meant that the solution comprises the excipients in amounts that are safe and are approved by regulatory authority like USFDA, for parenteral use.
  • micellar solution comprising glucagon in therapeutically effective amounts and distearoyl-phosphatidylethanolamine covalently bonded to PEG (PEG-DSPE) and, optionally, one or more stabilizers and pharmaceutically acceptable vehicle, wherein the pH of the solution is at about 5-7.5.
  • the ready-to-use solution of the present invention comprises glucagon in the concentration ranging from about 0.5 mg/ml to about 5 mg/ml. Further, it comprises pegylated distearoyl- phosphotidylethanolamine in the concentration ranging from 4 mg/ml to 40 mg/ml.
  • the molecular weight of pegylated distearoyl-phosphotidylethanolamine ranges from about 300 to 5000 Daltons, particularly, about 2000 & 5000 Daltons.
  • ready-to-use glucagons solution of the present invention comprises pegylated distearoyl-phosphotidylethanolamine having molecular weight of about 300 to 5000. It is used in an amount of 1 mg/ml to 8 mg/ml. It was found that addition of a polar aprotic solvent such as dimethyl sulphoxide, allows decrease in the amount of pegylated distearoyl- phosphotidylethanolamine required to solubilize the glucagon. In some embodiment,polar aprotic solvent constitutes 5% to 15% v/v of the total volume.
  • the micellar solution further comprises a stabilizer which has a tendency to reside in the hydrophobic portions of the micelle.
  • the stabilizer is selected from the group consisting of fatty acid or a zwitterions choline derivative.
  • fatty acids includes aliphatic (saturated or unsaturated) monocarboxylic acids derived from or contained in esterified form, in an animal or vegetable fat, oil or wax.
  • fatty acids or its salts that may be used in the compositions of the present invention include but are not limited to fatty acids or its salts having 'n' number of carbon atoms wherein 'n' ranges from about 4 to about 28.
  • the fatty acid may be a saturated fatty acid or an unsaturated fatty acid, and their salt and combinations thereof.
  • the saturated fatty acid and its salts may be selected from butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, sodium caprylate, sodium laurate, sodium myristate, sodium palmitate and the like and/or mixtures thereof.
  • the unsaturated fatty acid and its salts may be selected from myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, sodium oleate, sodium arachidonate and the like and/or mixtures thereof.
  • the stabilizer is a zwitterion choline derivative selected from the group consisting of dimyristoyl phosphotidylcholine, egg phosphotidylcholine, dipalmityol phosphotidylcholine, distearoyl phosphotidylcholine, hydrogenated soya phosphotidylcholine, dilauryl phosphotidylcholine, dioleaoyl phosphotidylcholine and their-lyso products.
  • the solution of the present invention comprises dimyristoyl phosphotidylcholine in the concentration ranging from about 1 mg ml to 2 mg/ml.
  • the micellar solution comprises caprylic acid as a stabilizer in the concentration ranging from about 0.1 mg/ml to 3 mg/ml, particularly, 1 mg/ml. Addition of these stabilizers improves the stability of glucagon in that the solution can be stored at room temperature for a period of about six months.
  • the ready-to-use solution of the present invention further comprises pharmaceutically acceptable vehicle which may comprise one or more acids, buffers, preservatives, tonicity adjusting agents and mixtures thereof.
  • pharmaceutically acceptable vehicle which may comprise one or more acids, buffers, preservatives, tonicity adjusting agents and mixtures thereof.
  • the buffers that may used in the pharmaceutically acceptable vehicle are selected from the group consisting of histidine, succinate, phosphate, citrate and the like and mixtures thereof.
  • the tonicity imparting agents that may be added to the micellar solution may be selected from the group consisting of mono-saccharides like dextrose, sucrose, mannitol, lactose and glycerine and mixtures thereof.
  • glucagon was solubilized and stabilized with the help of a pegylated distearoyl- phosphotidylethanolamine alone or in combination with a detergent like dimyristoyl phosphotidylcholine or a fatty acid such as caprylic acid, pH was adjusted to about 5.0 to 7.5, preferably, pH of about 6 to 7.
  • glucagon solution Effect of pH on the glucagon solution was studied.
  • a bulk solution of glucagon (lmg/ml) was prepared using 8mg/ml MPEG-DSPE2K having molecular weight of 2000. This solution was divided in 3 portions & pH was adjusted to 3.0, 6.0, & 9.0. After storage at 40°C/75% RH for 3 days, these solutions were analyzed for assay of glucagon. Table 1 shows the data of the solutions indicating physical and chemical stability.
  • mPEG-DSPE 2000 and sucrose were dissolved in purified water at room temperature. pH of this solution was adjusted to 6.5 using lactic acid and/or sodium bicarbonate solution (Example 1) or to a pH of 6.0 with histidine
  • glucagon required amount of glucagon was dissolved in the above solution using magnetic stirrer at room temperature. This solution was filtered through 0.8/0.2 ⁇ PVDF filter in aseptic area and packed in 5ml USP-Type I glass vials. The final product was kept for stability study as per ICH guidelines at 2-8°C, 25°C/60%RH & 40°C/75%RH. Results of the stability are given below.
  • Example 2 Composition of Example 2 was found to be not stable at room temperature as turbidity started appearing on 33 day when stored at room temperature. Therefore, it may be concluded that when glucagon was formulated into a solution by use of mPEG-DSPE wherein the pH is adjusted to a specific range of 5 to 7.5, the solution was found to be stable under 2-8°C for a period of three months only. However, the solution was not stable when stored at room temperature. The room temperature stability was further improvised by addition of a stabilizer such as fatty acid or dimyristoyl phosphotidylcholine. EXAMPLE 3 -5
  • Example 4 mPEG-DSPE 2000 was dissolved in WFI. Glucagon was added to this solution & dissolved by continuous stirring at room temperature. Sucrose, histidine & caprylic acid were added one by one & dissolved. pH was adjusted between 6.0-6.5 & volume was made up with WFI. This solution was filtered through 0.2 ⁇ PVDF filter in aseptic area. The filtered bulk was filled in 1ml pre-filled syringes (with attached needle) & stoppered. The final solution was kept for stability study as per ICH guidelines at 2-8°C& 25°C/60%RH.
  • Example 5 mPEG-DSPE 5000 was dissolved in purified water at room temperature.
  • glucagon required amount of glucagon was dissolved in the above solution using magnetic stirrer at room temperature. Sucrose, histidine & caprylic acid were added & dissolved one by one in the above solution with continuous stirring. pH of this solution was adjusted to 6.5 using sodium bicarbonate solution and/or lactic acid solution if needed. A clear colourless solution was formed. This solution was filtered through 0.8/0.2 ⁇ PVDF filter in aseptic area and packed in 5ml USP-Type I glass vials.
  • Glucagon solution of Examples 3 & 4 were found to be stable. Without wishing to be bound by any theory, this effect said to be due to stabilization of micelles by fatty acid like caprylic acid or zwitterions choline derivative like DMPC in combination with mPEG-DSPE. Histidine is added in this solution to act as buffer. Thus, it may be concluded that mPEG-DSPE can improve physical & chemical stability of glucagon solution. But, precipitation starts appearing in glucagon solution containing mPEG-DSPE alone within 6 months, even when stored at 2- 8°C. However, addition of a stabilizer like caprylic acid or DMPC can further improve physical & chemical stability of glucagon solution micellar solution.
  • the solution similar to example 3 and example 4 were subjected to physical characterization (%Transmittance at 650nm & absorbance at 420nm), bioassay and chemical assay of glucagon as well as content of related substance at initial time point and at various storage conditions such as 2-8°C and 25°C/60%RH for three months.
  • the physical stability of the hormone in the solution form in terms of conformation is confirmed by performing bioassay of the glucagon after the solution is stored at six months at room temperature.
  • the procedure for the bioassay was as per USP monograph for glucagon injection. The results are tabulated in table 7 and table 8, respectively.
  • aprotic solvents like dimethyl sulfoxide mPEG-DSPE 3 mg/ml was dissolved in water for injection. Glucagon was added to dimethyl sulfoxide (equivalent to 10% of total volume) & dissolved by continuous stirring at room temperature. The solution of glucagon was slowly added to the solution of mPEG-DSPE with continuous stirring. pH was adjusted between 6.0-7.0 & volume was made up with WFI. This solution was filtered through 0.2 ⁇ PVDF filter in aseptic area.
  • Micellar solution with less mPEG-DSPE with small amount of polar aprotic solvent was found to be chemically stable for three months at room temperature.

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Abstract

L'invention concerne une solution stable prête à l'emploi contenant des quantités thérapeutiquement efficaces de glucagon et des distéaroyl-phosphatidyléthanolamines pégylées.
PCT/IN2011/000321 2010-05-07 2011-05-06 Solution injectable Ceased WO2011138802A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1449MU2010 2010-05-07
IN1449/MUM/2010 2010-05-07

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WO2011138802A1 true WO2011138802A1 (fr) 2011-11-10

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3067247A1 (fr) 2018-06-07 2018-12-14 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
CN109562063A (zh) * 2016-06-07 2019-04-02 阿道恰公司 包含人胰高血糖素和末端接枝的共聚氨基酸的可注射水溶液形式的组合物
WO2019110836A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
WO2019110837A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
WO2019110838A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
US10335489B2 (en) 2012-01-09 2019-07-02 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
US10449256B2 (en) 2013-02-12 2019-10-22 Adocia Injectable solution at pH 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer
FR3083087A1 (fr) 2018-06-29 2020-01-03 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
US11191812B2 (en) 2017-12-07 2021-12-07 Adocia Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
WO2025088640A1 (fr) * 2023-10-26 2025-05-01 Dr. Reddy's Laboratories Limited Compositions liquides stables de peptides

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WO2009114959A1 (fr) * 2008-03-20 2009-09-24 中国人民解放军军事医学科学院毒物药物研究所 Formulation pharmaceutique injectable à libération prolongée et procédé de préparation associé

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US6384016B1 (en) * 1998-03-13 2002-05-07 Novo Nordisk A/S Stabilized aqueous peptide solutions
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US20070087957A1 (en) * 2005-09-06 2007-04-19 Miriam Kidron Methods and compositions for oral administration of proteins
WO2009114959A1 (fr) * 2008-03-20 2009-09-24 中国人民解放军军事医学科学院毒物药物研究所 Formulation pharmaceutique injectable à libération prolongée et procédé de préparation associé

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10335489B2 (en) 2012-01-09 2019-07-02 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
US10449256B2 (en) 2013-02-12 2019-10-22 Adocia Injectable solution at pH 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer
CN109562063A (zh) * 2016-06-07 2019-04-02 阿道恰公司 包含人胰高血糖素和末端接枝的共聚氨基酸的可注射水溶液形式的组合物
US10485851B2 (en) 2016-06-07 2019-11-26 Adocia Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
US10383918B2 (en) 2016-06-07 2019-08-20 Adocia Compositions in the form of an injectable aqueous solution comprising human glucagon and a statistical co-polyamino acid
WO2019110837A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
WO2019110838A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
WO2019110836A1 (fr) 2017-12-07 2019-06-13 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
US10987426B2 (en) 2017-12-07 2021-04-27 Adocia Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
US11191812B2 (en) 2017-12-07 2021-12-07 Adocia Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
FR3067247A1 (fr) 2018-06-07 2018-12-14 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
FR3083087A1 (fr) 2018-06-29 2020-01-03 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide
WO2025088640A1 (fr) * 2023-10-26 2025-05-01 Dr. Reddy's Laboratories Limited Compositions liquides stables de peptides

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