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WO2019106586A1 - Formulation de glucagon stable pour le traitement d'urgence de l'hypoglycémie - Google Patents

Formulation de glucagon stable pour le traitement d'urgence de l'hypoglycémie Download PDF

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Publication number
WO2019106586A1
WO2019106586A1 PCT/IB2018/059437 IB2018059437W WO2019106586A1 WO 2019106586 A1 WO2019106586 A1 WO 2019106586A1 IB 2018059437 W IB2018059437 W IB 2018059437W WO 2019106586 A1 WO2019106586 A1 WO 2019106586A1
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WIPO (PCT)
Prior art keywords
glucagon
pharmaceutical composition
pharmaceutically acceptable
injectable pharmaceutical
stable
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/IB2018/059437
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English (en)
Inventor
Parva Yogeshchandra Purohit
Paras Rasiklal VASANANI
Sinchan Shirishbhai SHAH
Riteshkumar Baldevbhai GURJAR
Deep Pravinbhai JAVIA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kashiv Biosciences LLC
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Kashiv Pharma LLC
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Filing date
Publication date
Application filed by Kashiv Pharma LLC filed Critical Kashiv Pharma LLC
Publication of WO2019106586A1 publication Critical patent/WO2019106586A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/26—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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/24—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic
    • A61M5/2448—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic comprising means for injection of two or more media, e.g. by mixing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A61M5/284—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle comprising means for injection of two or more media, e.g. by mixing
    • 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

Definitions

  • the present invention relates to stable liquid pharmaceutical formulations of glucagon or pharmaceutically acceptable salts thereof suitable for parenteral administration for the treatment of hypoglycemia.
  • the present invention particularly relates stable pharmaceutical formulation of glucagon or pharmaceutically acceptable salts thereof incorporated into system which can be rapidly reconstituted and can be administered very easily with minimal steps in the emergency hypoglycemic conditions.
  • Diabetes is one of the most serious health problems in present society.
  • Critical treatment for both type I and type II diabetes includes insulin.
  • Studies over the past two decades have demonstrated that tight metabolic control of glucose through the use of insulin not only reduces the incidence, but also delays the development of complications in people with type 1 and type 2 diabetes.
  • Hypoglycaemia is a common complication of patient treated with diabetes. Normally signs and symptoms of hypoglycemia include tremor, palpitations, irritability, anxiety, nervousness, tachycardia, headache, pallor and hunger. The symptoms typically disappear after restoration of normal plasma glucose level. Generally most of the episodes of minor hypoglycemia can be handled by patients themselves easily by oral administration of fast-acting carbohydrates like glucose pills or foods like juice, soft drinks or sugary snacks. There is also a significant reported mortality from hypoglycaemia.
  • Glucagon is a naturally occurring peptide hormone made up of 29 amino acids and is secreted by ⁇ -cells of the pancreas. The mechanism of action of glucagon is through antihypoglycemic Action. Glucagon induces liver glycogen breakdown, releasing glucose from the liver. Hepatic stores of glycogen are necessary for glucagon to produce an anti-hypoglycemic effect. Glucagon is used as a first-line emergency treatment of severe hypoglycemia in patients with diabetes and as a diagnostic aid during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract.
  • Glucagon is a 29 amino acid peptide. Besides being naturally produced by the human body, it can also be prepared using recombinant technology or by chemical synthesis.
  • Both recombinant and synthetic glucagon are marketed in the United States and in other countries.
  • One of these is produced by growing a modified Saccharomyces cerevisiae strain and purifying the resulting compound.
  • This human recombinant glucagon is marketed; the marketed product includes two vials: one in which 1 mg of glucagon, modified by the addition of lactose, hydrochloric acid, and sodium hydroxide, has been lyophilized, and a second vial that contains sterile water for reconstitution of the glucagon.
  • the other recombinant glucagon is grown using a modified Escherichia coli strain.
  • the marketed version of this human recombinant glucagon is similar to the other in that it has lactose and hydrochloric acid added prior to lyophilization, which occurs within a first vial, and the solvent (in a second vial) is a combination of sterile water, glycerin and hydrochloric acid.
  • Glucagon Emergency Kit (marketed by Eli Lilly and Company) and the GlucaGen Hypo-kit (marketed by Novo-Nordisk). These products are available with a vial containing 1 mg of lyophilized human recombinant glucagon and a syringe pre-filled with 1 ml of diluent i.e. water for injection & are packaged in a hard plastic outer case.
  • Glucagen Novo Nordisk product contains sterile, lyophilized white powder in a 2 ml vial.
  • the reconstituted solution contains glucagon as hydrochloride 1 mg/ml (1 unit/ml) and lactose monohydrate (107 mg).
  • Glucagen product is supplied at pH 2.5-3.5.
  • Glucagon Emergency Kit (marketed by Eli Lilly and Company) 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.
  • the diluent syringe contains 12 mg/ml of glycerine, water for injection and hydrochloric acid.
  • At least some content which is at the bottom of the vial & at surface of the vial container is difficult to withdraw with syringe and hence generally manufacturers overfill to avoid dosing error which is still not ensuring accurate dosing. Chances of air entrapment & bubble formation will also be there while withdrawing content from the vial.
  • Rylander et al. published as US20140287998 describes glucagon formulated in hydrochloric acid and mannitol containing formulations that can be readily lyophilized and reconstituted for use in dual chamber cartridges.
  • the solvent can be introduced into the chamber containing the lyophilized glucagon cake such that the time for reconstitution of the glucagon cake get reduced.
  • the formulation comprises about 1 mg/ml glucagon (or approximately 91% (w/v)), hydrochloric acid or phosphoric acid to achieve a pH between 2.5 and 3.0, and 0.5-1.0% mannitol or lactose as bulking agent.
  • Green et al. published as WO2007075839 describes method of treating a hypoglycemic patient by administering emergency glucagon to the patient using a pen injector device containing (i) glucagon mixed with an excipient and (ii) a sterile diluent.
  • the pen injector device comprises housing, two separate chambers, hypodermic needle and actuation system.
  • Glucagon is provided as a lyophilized powder combined with one or more carriers, stabilizers, or bulking agents (selected from the group consisting of lactose, mannitol, sorbitol, methyl alpha-D-mannopyranoside, trehalose, and cellobiose). Green et al. is not disclosing any example of the glucagon formulation.
  • Prestrelski et al. published as US9649364 describes lyophilized stable glucagon formulations formulated in aprotic polar solvents like DMSO (dimethylsulfoxide). These formulations showed increased stability over time at ambient or even physiological temperatures as well as longer shelf life than currently available reconstituted glucagon formulations. Prestrelski et al is not anyway teaching regarding ready to use and easy to administered dual chamber system of glucagon formulation to use in emergency situations.
  • the present invention relates to stable pharmaceutical formulations of glucagon or pharmaceutically acceptable salts thereof suitable for parenteral administration for the treatment of hypoglycemia.
  • the present invention particularly relates stable pharmaceutical formulation of glucagon or pharmaceutically acceptable salts thereof incorporated into dual chamber system composed of two separate chambers one of which contains lyophilized glucagon or pharmaceutically acceptable salts thereof as powder and another chamber contains diluent for reconstitution before parenteral administration.
  • compositions suitable to administer via parenteral route In some embodiments of the present invention provide stable lyophilized glucagon or pharmaceutically acceptable salt thereof containing compositions suitable to administer via parenteral route.
  • stable glucagon formulations of present invention comprise active glucagon or pharmaceutically acceptable salts thereof and additional pharmaceutically acceptable excipients.
  • present invention provides glucagon or pharmaceutically acceptable salts thereof along with additional pharmaceutically acceptable excipients which include but not limited to bulking agents, cryoprotectant, acidifying agents, buffers, antioxidants and/or combinations thereof.
  • present invention provides stable glucagon formulations suitable for administration via dual chamber system for parenteral administration.
  • the present invention provides greater compliance for administration of the drug into the body by overcoming operational and administration complexities of already marketed glucagon products.
  • the present invention more specifically relates to the stable, easy to reconstitute and ready to use formulation which is convenient for administration to layman and hence suffice the unmet need of emergency treatment of hypoglycemic shock.
  • the stable glucagon parenteral formulations of the present invention have been developed in response to the present state of the art, and in particular, in response to the problems and unmet needs in the art that have not been fully solved by currently available pharmaceutical formulations of glucagon into the market.
  • glucagon refers to glucagon as a preferred active pharmaceutical ingredient (API) and it may include pharmaceutically acceptable derivatives and/or salts of that recited API.
  • the term “pharmaceutically acceptable salt” refers to any salt of glucagon that is physiologically tolerated by a patient (e.g. glucagon hydrochloride).
  • stable is meant to describe composition that retains its properties without loss of potency of the active and maintains its physical characteristics over time with minimal degradation.
  • the terms “about” and “approximately” should be understood to mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
  • the term “dual Chamber system” means a device system containing housing, wherein the chambers are structurally separate.
  • acidifying agent means to include any pharmaceutically acceptable acid or combination of acids that are added to a pharmaceutical formulation to achieve a desired pH.
  • acidifying agents include hydrochloric acid; phosphoric acid and/or any combinations thereof.
  • the term “bulking agent” is understood to include any pharmaceutically acceptable additive or matrix builder that may be added to a pharmaceutical formulation as a vehicle for lyophilized preparations. Bulking agents may further include additives which are provided as stabilizers and/or tonicifiers for the pharmaceutical formulation.
  • Non-limiting examples of bulking agents include carbohydrates; amino acids; salts; mannitol; lactose; sucrose; dextran; sodium chloride or a like and/or any combinations thereof.
  • buffer means to include any compound which maintains the pH of the formulation and does not allow any alteration in pH during shelf-life of the formulations.
  • liquid for reconstitution means to include any liquid solvent required for dissolution of lyophilized powdered drug filled in vial before administration inside body.
  • cryoprotectant includes agents that provide stability to an active compound in a lyophilized formulation to militate against freezing-induced stresses. Cryoprotectant sometimes also termed as lyoprotectants.
  • Dual chamber syringe system comprises two separate chambers, one of which contains lyophilized glucagon or pharmaceutically acceptable salts thereof as powder and another chamber contains diluent for reconstitution.
  • stable glucagon formulations of present invention comprise active glucagon or pharmaceutically acceptable salts thereof and additional pharmaceutically acceptable excipients.
  • the present invention stable pharmaceutical composition contains glucagon in an amount of about 0.01% w/w to about 25% w/w by weight of composition, preferably of about 0.01% w/w to about 10% w/w by weight of composition and more preferably of about 0.1% w/w to about 5% w/w by weight of composition.
  • the pharmaceutically acceptable excipients of the present glucagon formulation may include but not limited to acidifying agents, bulking agents, buffers, antioxidants and/or any combinations thereof.
  • antioxidants examples may include but not limited to ascorbic acid; benzalkonium chloride; sodium metabisulphite, sodium ethylenediaminetetraacetate and/or any combinations thereof.
  • the antioxidant may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.01% to about 10% by weight of composition; more preferably of about 0.01% to about 5% by weight of the composition.
  • the antioxidant may present in an amount range starting from about 0.01- 15% w/v, preferably from about 1-10% w/v, more preferably from about 1-5% w/v.
  • buffers may include but not limited to hydrochloric acid; phosphoric acid; ascorbic acid; citrate salts; phosphate salts; tartarate salts; amino acids like histidine, arginine; and/or any combinations thereof.
  • the buffer may present in an amount of about 0.01% to about 20% by weight of composition; preferably of about 0.1% to about 15% by weight of composition; more preferably of about 0.1% to about 10% by weight of the composition.
  • bulking agents may include but not limited to sugar carbohydrates like lactose, sucrose, trehalose, dextran; sugar alcohols like sorbitol, mannitol; amino acids like glycine, arginine, histidine; and/or any combinations thereof.
  • the bulking agent may present in the ratio of about 1:1 to 1:50, preferably about 1:5 to 1:40, more preferably about 1:10 to 1:35 by weight of the active.
  • acidifying agents may include but not limited to hydrochloric acid, phosphoric acid, ascorbic acid and/or any combinations thereof.
  • the acidifying agent may present in an amount sufficient to achieve the desired pH range of the stable pharmaceutical formulations of glucagon or pharmaceutically acceptable salts thereof of present invention.
  • cryoprotectants may include but not limited to glycols (such as ethylene glycol, propylene glycol, and glycerol), Dimethyl sulfoxide (DMSO), sugars (such as sucrose, glucose, trehalose, mannitol, xylitol, sorbitol, erythritol, arabitol, mannose, and lactose), polymers (such as dextran, hydroxyethyl starch and polyethylene glycol), surfactants (such as polysorbates -20, polysorbates-80), and amino acids (such as glycine, histidine, arginine, leucine, and serine).
  • the amount of cryoprotectants added to a formulation is generally an amount that does not lead to an unacceptable amount of degradation/aggregation of the protein when the protein formulation is dried.
  • the pH of the present invention is maintained by buffers which may include but not limited to hydrochloric acid; ascorbic acid; phosphoric acid; citrate salts; tartrate salts; phosphate salts; amino acids like histidine, arginine and/or any combinations thereof.
  • buffers may include but not limited to hydrochloric acid; ascorbic acid; phosphoric acid; citrate salts; tartrate salts; phosphate salts; amino acids like histidine, arginine and/or any combinations thereof.
  • pH of the glucagon formulation of the present invention is maintained in the range of about 2-5; preferably in the range of about 2-4; further preferably in the range of about 2.5-3.5; further more preferably in the range of about 2.5-3.0.
  • a pharmaceutical formulation containing glucagon or pharmaceutically acceptable salts thereof is provided.
  • the present invention provides a formulation comprising glucagon or pharmaceutically acceptable salts thereof, mannitol, and an acidifying agent, such as hydrochloric acid or phosphoric acid in a pharmaceutically acceptable diluent, such as sterile water, wherein the formulation is suitable for lyophilization in a dual chamber system.
  • an acidifying agent such as hydrochloric acid or phosphoric acid
  • a pharmaceutically acceptable diluent such as sterile water
  • Other embodiments of the present invention include a pharmaceutical formulation comprising glucagon or pharmaceutically acceptable salts thereof, a bulking agent selected from mannitol, lactose, sucrose, dextran, and/or any combinations thereof, and an acidifying agent.
  • the present invention provides a dual chamber system containing the lyophilized glucagon cake in a first chamber, and the pharmaceutical solvent in a another chamber.
  • the solvent is introduced into the chamber containing the glucagon cake to dissolve or reconstituted the glucagon cake in less than 60 seconds; preferably in less than 40 seconds; further preferably in less than 20 seconds; further more preferably in less than 10 seconds.
  • This speed and the complete dissolution and reconstitution provided by this embodiment are optimal for the rapid delivery of the glucagon liquid in the treatment of severe (emergency) hypoglycemia.
  • a dual chamber system containing the glucagon cake and solvent housed in an auto-injector device that can be used to initiate the mixing process and activate the needle and system, thereby providing ease of injection of the final formulation. If a dual chamber system is employed, then it may be assembled into an auto-injector pen device in which it can be mixed immediately prior to use and injection.
  • the glucagon formulation is lyophilized in one half of the dual chamber system using a formulation of the invention that allows for a proper cake formation, stability, and rapid reconstitution time, as provided herein.
  • Lyophilization is a well-known process used to produce injectable products that are not stable in solution.
  • the process is performed in equipment called a lyophilizer (essentially a container that can be frozen and put under vacuum) and consists of four steps: (1) freezing the solution slowly by lowering the temperature; (2) slowly raising the temperature to about 0 degrees C. while the frozen solution is under vacuum (primary drying); (3) raising the temperature to about room temperature while the material is under vacuum (secondary drying); and (4) removing the vacuum with filtered nitrogen.
  • the freezing time is about 5-20 hours, and the lowest freezing temperature is about minus 55 degrees C.
  • the final lyophilized cake will have a moisture content of under 5%, and typically between 0.5-3%.
  • the lyophilized powder is evaluated with respect to its physical properties such as bulk density, tapped density, flowability.
  • the chamber holding the dried or lyophilized drug is then sealed with an elastomeric closure.
  • the specially formulated solvent of the invention is added to another chamber (to work in conjunction with the lyophilized powder) and an elastomeric stopper added to seal the end holding the liquid.
  • the resulting systems can then be shipped, for example to a location for assembly into the auto-injector device.
  • the system is placed inside the auto-injector followed by attaching the needle assembly to complete the device.
  • the completed device is then placed in a container to hold and protect the device as well as the necessary literature and instructions.
  • An auto-injector is a medical device designed to deliver a single dose of a particular drug. Some auto-injectors contain spring-loaded syringes. By design, auto-injectors are intended for ease of use and are compatible for self-administration by patients, or administration by caregivers in circumstances when the patient is unable to self-administer, such as severe hypoglycemia. The site of injection depends on the drug loaded. The injectors were initially designed to overcome the hesitation associated with self-administration of the needle-based drug delivery device. Examples of auto-injector devices include: EpiPen; Rebiject; Aranesp; and Enbrel. See EP Patent Pub. No. 1 743 666 (Scandinavian Health Limited), incorporated herein by reference.
  • a suitable auto-injector device for purposes of the present invention will generally house a dual chamber system containing lyophilized glucagon or pharmaceutically acceptable salts thereof in one chamber and a solvent in another chamber. Both the lyophilized drug and the solvent use the formulations provided herein to facilitate rapid reconstitution and administration.
  • the auto-injector either includes or is compatible with a needle assembly.
  • the stable pharmaceutical formulation of glucagon or pharmaceutically acceptable salts thereof exhibits equal or less than about 20%; preferably equal or less than about 10%; more preferably equal or less than about 5%; more preferably yet, equal or less than about 2% degradation of glucagon or pharmaceutically acceptable salts thereof during its shelf-life.
  • the formulation of glucagon is such that the glucagon or pharmaceutically acceptable salts thereof along with the pharmaceutically acceptable excipients in a solution can pass through membrane filter for the purpose of further sterilization.
  • the stable pharmaceutical formulation of glucagon or pharmaceutically acceptable salts thereof exhibits no aggregation of particles in the formulation.
  • the stable pharmaceutical formulation of glucagon or pharmaceutically acceptable salts thereof exhibits equal or less than about 10%; preferably equal or less than about 5%; more preferably equal or less than about 2%; more preferably yet, equal or less than about 1% impurities during its shelf-life.
  • one of embodiments of the present invention provides a diluent for reconstitution of lyophilized powder containing glucagon.
  • pH of final formulation may be maintained by use of diluent too.
  • diluents involve aqueous solvents and/or non-aqueous solvents.
  • Non-limiting examples of aqueous solvents as diluents include water for injection (WFI), buffer solution or mixture thereof.
  • Non-limiting examples of non-aqueous solvents include ethanol, methanol, glycerine, polyol, diethylene glycol monoethyl ether, dimethyl sulfoxide, N-methyl-2-pyrrolidone or a like and mixtures thereof.
  • the present invention has found an approach for solving problem of state of the arts by preparing a stable pharmaceutical composition of glucagon or pharmaceutically acceptable salts thereof having the stable, easy to reconstitute and ready to use formulation composition which suffice the unmet need of emergency treatment of hypoglycemic shock.
  • the diluent in another chamber selected from the aqueous solvents include water for injection (WFI), buffer solution with pH adjusting agent and/or non-aqueous solvents include ethanol, methanol, glycerine, polyol, diethylene glycol monoethyl ether, dimethyl sulfoxide, N-methyl-2-pyrrolidone or a like and mixtures thereof.
  • WFI water for injection
  • buffer solution with pH adjusting agent include ethanol, methanol, glycerine, polyol, diethylene glycol monoethyl ether, dimethyl sulfoxide, N-methyl-2-pyrrolidone or a like and mixtures thereof.
  • the final reconstituted formulation has been kept for stability testing and evaluated for other physical and chemical properties.

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Abstract

La présente invention concerne des compositions pharmaceutiques de glucagon ou de sels pharmaceutiquement acceptables appropriés pour une administration rapide par un système manuel double chambre. La présente invention concerne une formulation pharmaceutique stable de glucagon et des procédés d'utilisation desdites formulations pour le traitement de l'hypoglycémie, en particulier pour le traitement d'urgence d'une hypoglycémie sévère chez des patients souffrant de celle-ci.
PCT/IB2018/059437 2017-11-29 2018-11-29 Formulation de glucagon stable pour le traitement d'urgence de l'hypoglycémie Ceased WO2019106586A1 (fr)

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US12128089B2 (en) * 2022-05-26 2024-10-29 Slayback Pharma Llc Stable liquid compositions of glucagon

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US20120046225A1 (en) * 2010-07-19 2012-02-23 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US20140287998A1 (en) * 2011-12-09 2014-09-25 Enject, Inc. Glucagon formulations
US20170202926A1 (en) * 2014-10-27 2017-07-20 Latitude Pharmaceuticals, Inc. Parenteral Glucagon Formulations

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Publication number Priority date Publication date Assignee Title
US20120046225A1 (en) * 2010-07-19 2012-02-23 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US20140287998A1 (en) * 2011-12-09 2014-09-25 Enject, Inc. Glucagon formulations
US20170202926A1 (en) * 2014-10-27 2017-07-20 Latitude Pharmaceuticals, Inc. Parenteral Glucagon Formulations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12128089B2 (en) * 2022-05-26 2024-10-29 Slayback Pharma Llc Stable liquid compositions of glucagon

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