WO2017221026A1 - Nouvelle composition - Google Patents

Nouvelle composition Download PDF

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Publication number
WO2017221026A1
WO2017221026A1 PCT/GB2017/051846 GB2017051846W WO2017221026A1 WO 2017221026 A1 WO2017221026 A1 WO 2017221026A1 GB 2017051846 W GB2017051846 W GB 2017051846W WO 2017221026 A1 WO2017221026 A1 WO 2017221026A1
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WIPO (PCT)
Prior art keywords
aqueous solution
glucagon
composition according
solution composition
concentration
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PCT/GB2017/051846
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English (en)
Inventor
Luca BADIALI
David GERRING
Sarah HOWELL
Jan Jezek
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Arecor Limited
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Publication of WO2017221026A1 publication Critical patent/WO2017221026A1/fr

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    • 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
    • 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
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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

Definitions

  • This invention relates to formulations of glucagon and their use in therapy, particularly in applications where chronic administration of glucagon is desirable.
  • Glucagon is a polypeptide hormone secreted by the alpha cells of the Islets of Langerhans in the pancreas. In native form it is a single chain polypeptide of 29 amino acids, the sequence of which is provided in Merck Index 10th Edition (1983).
  • glucagon plays a major role in the regulation of blood glucose levels and is involved in glycogenolyic and gluconeogenetic effects. Due to its glycogenolytic effect on the liver, glucagon has become an established treatment of acute hypoglycaemia, including in emergency treatment of acute hypoglycaemia caused by excessive insulin treatment in diabetics.
  • Glucagon is relatively insoluble in water but is soluble at a pH of less than 3 or more than 9.5.
  • glucagon compositions for injection are sold as lyophilised powders of the hydrochloride form, for reconstitution with an aqueous medium at a pH of 2-3. Whilst administration of the low-pH product is acceptable in very infrequent emergency applications, such formulations are not considered to be suitable for chronic use because the acidic compositions are likely to cause pain on injection and could result in severe injection site reactions.
  • glucagon Even in less acidic solutions a number of stability aspects affect liquid glucagon formulations, including aggregation, fibril formation and gel formation. In addition, glucagon undergoes hydrolytic processes and deamidation of glutamine and asparagine residues, particularly at and below pH 4 and at and above pH 7.
  • GB1202607 claims a stable aqueous injectable glucagon solution which comprises glucagon in an amount of from 0.1 to 5 mg/mL together with a stabilising and solubilising amount of a surfactant.
  • Anionic and cationic surfactants are described as being potentially suitable, and amongst cationic surfactants, quarternary ammonium bases in which at least one substituent is an aliphatic chain having at least 6 carbon atoms, preferably 12 to 20 carbon atoms, are preferred, especially cetrimide (cetyl trimethylammonium bromide).
  • WO99/47160 claims an aqueous glucagon solution comprising a stabilising and solubilising amount of a detergent having at least 2 positive charges, at least 2 negative charges, or a combination of at least one positive charge and one negative charge, the peptide being present in a concentration of at least about 0.1 mg/ml_ and with the proviso that the detergent is not dodecyl phosphocholine.
  • EP199992A1 (Eisai) describes use of benzethonium chloride and benzalkonium chloride in peptide compositions to prevent peptide adsorption onto plastic or glass.
  • glucagon is mentioned in this context in very general terms in the description section, there is no working example with glucagon.
  • WO2011/049713A2 discloses a stabilised glucagon formulation containing a surfactant, a mono or disaccharide, wherein the surfactant and saccharide are in an effective amount to stabilise the glucagon, and wherein the osmolarity is approximately 200 to 400 mOsm/L and the pH is between 2 and 8.
  • GB1202607A Novo Terapeutisk Labor AS discloses formulations of glucagon suitable for administration by injection, using a detergent, in particular cetrimide.
  • WO2012/059762 demonstrates the use of cationic surfactants which are benzalkonium salts and/or benzethonium salts as solubilizing agents in aqueous compositions comprising glucagon, suitably with low overall ionic strength.
  • Such compositions have been shown to have long term stability, thereby avoiding the need for reconstitution and allowing rapid administration of the glucagon which is essential in emergency applications.
  • Glucagon is a critical component of bihormonal pump systems combining the administration of insulin and glucagon, together with a continuous glucose measurement system which uses an algorithm to allow continuous control of blood glucose in diabetic patients, particularly Type 1 diabetic patients.
  • a bihormonal pump can either be attached to the body surface or be implanted intraperitoneally.
  • Such wearable or implantable bihormonal systems sometimes referred to as “artificial pancreas", have not yet been successfully developed to the standard required for human use, but there is a considerable effort in this area in the pharmaceutical industry.
  • a stable liquid formulation of glucagon is a prerequisite for successful development of such products.
  • Such a liquid formulation should ideally be stable at temperatures around 30 °C (preferably up to around 37 °C) for a minimum of one week and should also ideally be stable at storage temperatures of 2-8 °C for at least one month. Due to the chronic nature of administering the glucagon in a pump as compared with emergency applications, the formulation should be stable at a pH which is less acidic than the currently marketed emergency formulations.
  • the liquid formulation should stabilize high concentrations of glucagon. It would be expected that high concentrations of glucagon would require high concentrations of detergent or surfactant as stabilizing agent. However, this is not an attractive option for stabilizing the glucagon because of potential regulatory issues associated with the use of high concentrations of stabilizing agents in particular cationic surfactants, which would be particularly relevant for a chronically administered product such as a glucagon formulation to be used in a bihormonal pump.
  • an objective of the present invention is the provision of a glucagon formulation which is suitable for chronic use, for example in a bihormonal pump.
  • a glucagon formulation may contain a higher concentration of glucagon than in the currently marketed emergency formulations, while minimizing the use of stabilizing agents such as cationic surfactants.
  • stabilizing agents such as cationic surfactants.
  • such a formulation should be stable at ambient temperature (i.e. stable during the administration period), and also have good long term storage stability.
  • an aqueous solution composition having pH between 4 and 7 comprising: (i) glucagon at a concentration of 1 mg/mL or more; (ii) a cationic surfactant selected from benzalkonium salts and benzethonium salts at a concentration of 2.5 mg/mL or less; and (iii) a polyol at a concentration of 0.5 M or more, wherein the polyol is selected from 1 ,2-propanediol and glycerol, and wherein the ratio of glucagon to cationic surfactant (mg/mL: mg/mL) is 2: 1 or more.
  • glucagon means the polypeptide of 29 amino acids described in SEQ ID No: 1 or an analogue or variant polypeptide having glucagon activity, specifically anti- hypoglycaemic activity.
  • Specific variants include those polypeptides having a small number (e.g. 1 , 2 or 3) of amino acid substitutions especially conservative substitutions relative to the sequence of SEQ ID No: 1.
  • Analogues also include polypeptides that comprise SEQ ID No: 1 or an aforementioned variant sequence.
  • analogues include polypeptides consisting of SEQ ID No: 1 or an aforementioned variant sequence with an N and/or C terminal extension, typically a short extension for example of up to 10 amino acids (e.g.
  • Analogues also include derivatives of any of the aforementioned polypeptides such as derivatives designed to extend duration of action or blood residency such as derivatives involving attachment of one or more PEG moieties to the polypeptide (for example at one or more of amino acid positions 21 and 24 of glucagon), or attachment of fatty acid moieties (e.g. C4-C30 fatty acids) by acylation or alkylation of one or more amino acids (for example the amino acid at position 10 of glucagon).
  • Further analogues may involve incorporation of ⁇ , ⁇ -disubstituted amino acids e.g. aminoisobutyric acid for example at one, two three or four of positions 16, 20, 21 and 24 of glucagon.
  • glucagon analogues are described in WO2010/011439, WO2009/155257, WO2009/155258, WO2009/099763, WO2009/058734, WO2009/058662, WO2008/101017, WO2008/086086 and WO2007/056362 all of which are herein incorporated by reference in their entirety.
  • the glucagon employed in the formulation has the sequence of SEQ ID No: 1.
  • amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic- hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; a group of amino acids having acidic side chains is aspartate and glutamate; and a group of amino acids having sulfur-containing side chains is cysteine and methionine.
  • substitutions within these groups may be regarded as conservative.
  • Exemplary conservative amino acids substitution groups are: valine-leucine/isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine- glutamine.
  • the pH of the composition is suitably 4.0-7.0, for example 4.5-6.5 or 5-6. Preferably it is around pH 5.5.
  • a composition at such a pH is typically not painful to inject and has adequate chemical stability of glucagon.
  • the concentration of glucagon in the composition is 1 mg/mL or more, for example 1.1 mg/mL or more, 1.2 mg/mL or more, 1.3 mg/mL or more, 1.4 mg/mL or more, 1.5 mg/mL or more, 2 mg/mL or more, 2.5 mg/mL or more, 3 mg/mL or more, 4 mg/mL or more, or 4.5 mg/mL or more.
  • the concentration of glucagon is between 1 mg/mL and 10 mg/mL, such as between 1.5 mg/mL and 10 mg/mL, between 1 mg/mL and 8 mg/mL, between 1.5 mg/mL and 8 mg/mL, between 2 mg/mL and 6 mg/mL, between 2 mg/mL and 5 mg/mL or between 3 mg/mL and 5 mg/mL.
  • the concentration of cationic surfactant is 2.5 mg/mL or less, for example 2 mg/mL or less, 1.5 mg/mL or less, 1 mg/mL or less, 0.5 mg/mL or less, 0.4 mg/mL or less, 0.3 mg/mL or less, 0.2 mg/mL or less, or 0.1 mg/mL or less.
  • the concentration of cationic surfactant is between 0.05 mg/mL and 2.5 mg/mL, such as between 0.1 mg/mL and 2.5 mg/mL, between 0.05 mg/mL and 2 mg/mL, between 0.1 mg/mL and 2 mg/mL, between 0.05 mg/mL and 1.5 mg/mL, between 0.1 mg/mL and 1.5 mg/mL, between 0.05 mg/mL and 1 mg/mL, between 0.1 mg/mL and 1 mg/mL, between 0.05 mg/mL and 0.5 mg/mL, between 0.1 mg/mL and 0.5 mg/mL, between 0.05 mg/mL and 0.4 mg/mL, between 0.1 mg/mL and 0.4 mg/mL, between 0.2 mg/mL and 0.5 mg/mL or between 0.2 mg/mL and 0.4 mg/mL.
  • the cationic surfactant is selected from benzethonium salts, e.g. benzethonium halide, especially the chloride.
  • the cationic surfactant is selected from benzalkonium salts, e.g. benzalkonium halide, especially the chloride.
  • the cationic surfactant is a mixture of benzethonium salts and benzalkonium salts such as a mixture of benzethonium chloride and benzalkonium chloride.
  • the ratio of glucagon to cationic surfactant is 2:1 or more, for example 2.5:1 or more, 3:1 or more, 5:1 or more, 6: 1 or more, 8:1 or more, or 10:1 or more.
  • the ratio of glucagon to cationic surfactant is between 2:1 and 15:1 , such as between 2:1 and 10:1 , between 3:1 and 9: 1 , between 3: 1 and 8: 1 or between 5: 1 and 8: 1.
  • the aqueous composition of the invention comprises a polyol which is selected from 1 ,2- propanediol and glycerol at a concentration of 0.5 M or more, for example 1 M or more, 2 M or more, 3 M or more, 4 M or more, 5 M or more or 6 M or more.
  • concentration of 1 ,2-propanediol or glycerol is between 0.5 M and 10 M such as between 1 M and 10 M, between 3 M and 10 M, or between 4 M and 10 M.
  • the polyol is 1 ,2- propanediol.
  • the polyol is glycerol.
  • the polyol is a mixture of 1 ,2-propanediol and glycerol.
  • the aqueous composition suitably comprises 1 ,2- propanediol as polyol.
  • the ratio of polyol (selected from 1 ,2-propanediol and glycerol) to cationic surfactant (selected from benzalkonium salts and benzethonium salts) is 2:1 or more such as 3:1 or more, 4:1 or more, 5: 1 or more or 6:1 or more.
  • it may be 7: 1 or more, such as 8:1 or more, 10: 1 or more, 12:1 or more, 15:1 or more, 20: 1 , 25: 1 or more, 50:1 or more, 100:1 or more or 500: 1 or more.
  • the presently claimed invention derives from the surprising observation that compositions of glucagon (1 mg/mL) containing low concentrations of benzethonium chloride (0.1 mg/mL and 0.2 mg/mL) were stabilized by the addition of high concentrations (1 M, 2.5 M and 6.8 M) of 1 ,2-propanediol (see Example 2). That the physical stability of the glucagon formulation was improved was evidenced by reduced gel formation and/or reduced formation of particles (see Table 2).
  • the present invention resides in the discovery that the reduction in the stabilising effect by lowering the concentration of surfactant can be mitigated by the addition of high concentrations of 1 ,2-propanediol or glycerol, or a mixture thereof.
  • Aqueous compositions of the invention may typically have osmolarity of 350 mOsm/L or more such as 400 mOsm/L or more, or 500 mOsm/L or more.
  • Such relatively high osmolarity values are atypical for a composition suitable for administration by injection because compositions of high osmolarity (e.g. more than 500 mOsm/L) can result in pain on injection due to the high tonicity.
  • the tonicity of a composition i.e. the osmotic pressure exerted by the composition onto a biological membrane that separates it from a physiological fluid, such as blood plasma or cytoplasm
  • the aqueous composition of the invention may include an additional uncharged tonicity modifying agent which is not 1 ,2-propanediol or glycerol.
  • additional uncharged tonicity modifying agents include sugars and sugar alcohols, for example selected from mannitol, sorbitol, xylitol, lactitol, sucrose, raffinose and trehalose or mixtures thereof, especially mannitol or trehalose or a mixture thereof.
  • the additional uncharged tonicity modifying agents are typically added at a concentration of 50-300 mM, such as 100-300 mM or 150-300 mM.
  • the aqueous compositions of the invention may additionally comprise a preservative such as a phenolic or a benzylic preservative.
  • a preservative such as a phenolic or a benzylic preservative.
  • the concentration of preservative may be up to 100 mM, for example up to 50 mM or up to 30 mM.
  • the concentration of preservative is 1- 50 mM, 5-30 mM, 25-60 mM or 25-35 mM, for example 5 mM, 15 mM or 30 mM.
  • the optimal concentration of the preservative in the composition is selected to ensure the composition passes the Pharmacopoeia Antimicrobial Effectiveness Test (USP ⁇ 51 >, Vol. 32).
  • the preservative is suitably selected from the group consisting of phenol, m-cresol, benzyl alcohol, chlorocresol, propyl paraben and methyl paraben, in particular phenol, m-cresol and benzyl alcohol.
  • the presence of the preservative may also confer an additional benefit by further improving the physical stability of glucagon by maintaining its solubility in the composition.
  • the overall concentration of charged species in the composition is low.
  • a charged species is defined as a chemical entity which carries at least one charge under the conditions of the composition, e.g. sodium cation (Na + ), chloride anion (CI ) or an amino acid such as histidine.
  • the overall concentration of charged species, other than those originating from glucagon and the cationic surfactant, in the composition is less than 150 mM, for example less than 100 mM, such as less than 50 mM or less than 25 mM. A lower concentration of charged species has been observed to improve the stability of glucagon.
  • the composition is substantially free of ionic species (apart from glucagon) which have a charge of more than 1.
  • the composition is substantially free of ionic species (apart from glucagon) which have a charge of 2, 3, 4 or more.
  • the composition is substantially free of ionic surfactants including anionic, cationic and zwitterionic surfactants apart from a cationic surfactant selected from benzalkonium salts and benzethonium salts.
  • the composition is substantially free of surfactants selected from SDS, deoxycholate, cholate, stearate, phosphatidylcholine, 3-[(3- cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and cetrimide.
  • surfactants selected from SDS, deoxycholate, cholate, stearate, phosphatidylcholine, 3-[(3- cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and cetrimide.
  • the aqueous composition of the invention may, however, contain a non-ionic surfactant.
  • Non- ionic surfactants have been found to be beneficial for the stability of the claimed glucagon composition (see Example 3).
  • the non-ionic surfactant is present at a concentration of 0.1-20 mg/mL, such as 0.1-15 mg/mL or 0.1-10 mg/mL.
  • Suitable non-ionic surfactants include polysorbates such as polysorbate 20, 40, 60 and 80, and poloxamers such as poloxamer 188 and 171.
  • a preferred non-ionic surfactant is polysorbate 20 (also known as Tween 20).
  • substantially free means said ionic species or ionic surfactant is present at a concentration of less than 1 mM e.g. less than 0.1 mM e.g. less than 0.01 mM.
  • the aqueous compositions of the invention comprise a buffer in order to stabilise the pH of the composition.
  • the buffer can also be selected to enhance glucagon stability.
  • a buffer is selected to have a pKa close to the pH of the composition; for example acetate is suitably employed as a buffer, in particular when the pH of the composition is in the range 4.5-5.5, for example at a concentration of 1 to 20 mM, such as 2 to 10 mM, e.g. at a concentration of around 5 mM.
  • the composition of the invention is further stabilised as disclosed in WO2008/084237, which describes a composition comprising a protein and one or more additives, characterised in that the system is substantially free of a conventional buffer, i.e.
  • the pH of the composition is set to a value at which the composition has maximum measurable stability with respect to pH; the one or more additives (displaced buffers) are capable of exchanging protons with the protein and have pKa values at least 1 unit more or less than the pH of the composition at the intended temperature range of storage of the composition.
  • storage stability can generally be enhanced further, possibly substantially, by use of additives having pKa between 1 to 5 pH units, preferably between 1 to 3 pH units, most preferably from 1.5 to 2.5 pH units, of the pH of the aqueous composition at the intended temperature range of storage of the composition, for example at 25 °C or at 2-8 °C, for example 4 °C.
  • additives having pKa between 1 to 5 pH units, preferably between 1 to 3 pH units, most preferably from 1.5 to 2.5 pH units, of the pH of the aqueous composition at the intended temperature range of storage of the composition, for example at 25 °C or at 2-8 °C, for example 4 °C.
  • the concentration of any buffer is suitably such that the concentration of charged ionic species in the composition is kept low, and most suitably within the ranges given above.
  • the aqueous compositions of the invention may also comprise an antioxidant in order to minimise the formation of oxidised species derived from glucagon.
  • the antioxidant is used in a concentration of up to 5 mM, or up to 10 mM, such as 0.01 to 10 mM, 0.1 to 10 mM, 1 to 10 mM, 0.01 to 5 mM, 0.1 to 5 mM or 1 to 5 mM.
  • the antioxidant is selected from the list consisting of methionine, glutathione, butylated hydroxytoluene, lactate and butylated hydroxyquinone, and in particular is methionine. Data presented in the examples section shows that methionine has a clear beneficial effect on stability of glucagon formulations of the invention.
  • a specific embodiment that may be envisaged is a composition according to the invention with a pH of around 5.5, comprising glucagon at a concentration of 3-5 mg/mL, benzethonium chloride as cationic surfactant at a concentration of between 0.1 mg/mL and 2.5 mg/mL, 1 ,2- propanediol at a concentration of 3-10 M and acetate as buffer.
  • a composition which additionally comprises a preservative such as phenol.
  • the aqueous composition according to the invention remains as a clear solution during storage at 2-8 °C, for example about 4 °C for at least 6 months, preferably for at least 12 months, more preferably for at least 18 months and most preferably for at least 2 years. This means that no signs of visible precipitation, fibril formation or gel formation can be observed during storage.
  • the aqueous composition according to the invention remains as a clear solution during storage at temperatures of up to 25 °C for at least 1 month, preferably for at least 2 months, more preferably for at least 3 months. This means that no signs of visible precipitation, fibril formation or gel formation can be observed during storage.
  • the aqueous composition according to the invention remains as a clear solution when exposed to temperatures in the range of between 25 °C and 40 °C (for example between 28 °C and 38 °C, such as about 37 °C, or between 30 °C and 35 °C, such as about 30 °C) for a minimum of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks. This means that no signs of visible precipitation, fibril formation or gel formation can be observed during storage.
  • the aqueous composition according to the invention is a clear solution with low viscosity (e.g. dynamic viscosity of less than 20 cP at 25 °C).
  • the proportion of total chemically related glucagon species i.e.
  • aqueous composition according to the invention remains below 31% (by weight), preferably below 25%, more preferably below 20%, more preferably below 10% during storage at 2-8 °C, for example about 4 °C for at least 6 months, preferably for at least 12 months, more preferably for at least 18 months and most preferably for at least 2 years.
  • Chemically related species are suitably detected by RP-HPLC.
  • the proportion of total chemically related glucagon species in the aqueous composition according to the invention remains below 31 % (by weight), preferably below 25%, more preferably below 20%, more preferably below 10% during storage at temperatures of up to 25 °C for at least 1 month, preferably for at least 2 months, more preferably for at least 3 months.
  • the proportion of total chemically related glucagon species in the aqueous composition according to the invention remains below 31 % (by weight), preferably below 25%, more preferably below 20%, more preferably below 10% when exposed to temperatures in the range of between 25 °C and 40 °C (for example between 28 °C and 38 °C, such as about 37 °C, or between 30 °C and 35 °C such as about 30 °C) for at least 4 weeks.
  • the proportion of deamidated glucagon species in the aqueous composition according to the invention remains below 14% (by weight), preferably below 11 %, more preferably below 8%, and most preferably below 5% during storage at 2-8 °C, for example about 4 °C for at least 6 months, preferably for at least 12 months, more preferably for at least 18 months and most preferably for at least 2 years.
  • the proportion of deamidated glucagon species in the aqueous composition according to the invention remains below 14% (by weight), preferably below 11 %, more preferably below 8%, and most preferably below 5% during storage at temperatures of up to 25 °C for at least 1 month, preferably for at least 2 months, more preferably for at least 3 months.
  • the proportion of deamidated glucagon species in the aqueous composition according to the invention remains below 14% (by weight), preferably below 11 %, more preferably below 8%, and most preferably below 5% when exposed to temperatures in the range of between 25 °C and 40 °C (for example between 28 °C and 38 °C, such as about 37 °C, or between 30 °C and 35 °C, such as about 30 °C) for at least 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the proportion of oxidised glucagon species in the aqueous composition according to the invention remains below 1 % (by weight), preferably below 0.8%, more preferably below 0.6%, and most preferably below 0.4% during storage at 2-8 °C, for example about 4 °C for at least 6 months, preferably for at least 12 months, more preferably for at least 18 months and most preferably for at least 2 years.
  • the proportion of oxidised glucagon species in the aqueous composition according to the invention remains below 1 % (by weight), preferably below 0.8%, more preferably below 0.6%, and most preferably below 0.4% during storage at temperatures of up to 25 °C for at least 1 month, preferably for at least 2 months, more preferably for at least 3 months.
  • the proportion of oxidised glucagon species in the aqueous composition according to the invention remains below 1 % (by weight), preferably below 0.8%, more preferably below 0.6%, and most preferably below 0.4% when exposed to temperatures in the range of between 25 °C and 40 °C (for example between 28 °C and 38 °C, such as about 37 °C, or between 30 °C and 35 °C, such as about 30 °C) for at least 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the glucagon is at a concentration of 1 mg/mL or more.
  • the aqueous composition of the invention is a therapeutic composition.
  • a method of treatment of hypoglycaemia which comprises administering to a subject suffering therefrom a therapeutically effective amount of an aqueous composition as described herein.
  • an aqueous composition as described herein for use as a pharmaceutical, especially for use in the treatment of hypoglycaemia.
  • said treatment of hypoglycaemia is treatment in an emergency setting.
  • the aqueous composition of the invention described herein is used in the prevention of hypoglycaemia or otherwise in the effective control of blood glucose levels when administered to a patient also receiving treatment with insulin or an analogue of insulin, for example as disclosed in WO2006/004696A2 (Diobex), which is herein incorporated by reference in its entirety.
  • a method of preventing hypoglycaemia which comprises administering to a subject suffering therefrom a therapeutically effective amount of an aqueous composition as described herein.
  • an emergency glucagon kit comprising a unit dose of an aqueous composition according to the present invention.
  • a glucagon minipen (a pen to deliver small amounts of glucagon to manage mild cases of hypoglycaemia) comprising a unit dose of an aqueous composition according to the present invention.
  • the aqueous composition of the invention is suitable for use in a bihormonal pump, or a closed-loop infusion system, or an artificial pancreas.
  • the glucagon composition is used in parallel with an insulin composition to prevent hypoglycaemia, and control blood glucose levels.
  • An amount of glucagon which is suitable for administration as a single dose for emergency treatment of severe hypoglycaemia is 1 mg for adults and 0.5 mg for juveniles.
  • a corresponding volume of the aqueous composition as described herein which is suitable for administration as a single dose for treatment of hypoglycaemia is 1 mL for adult and 0.5 mL for juveniles.
  • a lower volume, higher concentration dose may also be suitable, e.g. 0.5 mL of a 2 mg/mL solution.
  • the invention should not be considered to be limited to any such amount and other doses may be formulated according to the invention if appropriate.
  • An amount of glucagon which is suitable for administration as a single dose for the treatment of moderate hypoglycaemia is between 0.02 - 0.2 mg.
  • a multi-dose pen presentation with adjustable dose volume is optimal for the delivery in such cases.
  • the pen cartridge e.g. 1 mL, 2 mL or 3 mL
  • the invention should not be considered to be limited to any such amount or concentration and other doses may be formulated according to the invention if appropriate.
  • An amount of glucagon which is suitable for use in a cartridge of a bihormonal pump or closed- loop infusion system is between 5-15 mg.
  • a cartridge volume which is suitable for use in a bihormonal pump is 1-5 mL, such as 2-4 mL, such as 3 mL.
  • a 3 mL cartridge may be filled with the aqueous composition as described herein containing for example 2 mg/mL, 3 mg/mL, 4 mg/mL or 5 mg/mL glucagon.
  • the invention should not be considered to be limited to any such amount or concentration and other doses may be formulated according to the invention if appropriate.
  • a container containing a unit dose of an aqueous composition as described herein may contain approximately 1 mL of composition and wherein the concentration of glucagon in the composition is approximately 1 mg/mL. This should be suitable as an adult dose.
  • a container may contain approximately 0.5 mL of composition and wherein the concentration of glucagon in the composition is approximately 1 mg/mL. This should be suitable as a paediatric dose.
  • “approximately” may mean +/- 5% of the specified value.
  • a single-use injector for parenteral administration such as intramuscular, sub-cutaneous administration comprising injection apparatus and a container containing a unit dose of an aqueous composition as described herein, to be injected.
  • the aqueous composition of glucagon may be filled into a syringe (e.g. 1 ml_ syringe) composed of a staked-in needle, inert rubber stopper and plunger (e.g. polypropylene plunger).
  • a syringe e.g. 1 ml_ syringe
  • the syringe containing the product may optionally be housed into an autoinjector (assembled around the syringe) ready for automatic delivery of the required dose.
  • a pump device such as a patch pump or infusion pump comprising one or more containers in fluid communication with a needle containing a plurality of unit doses of composition as described herein to be injected or infused, and therefore adapted to inject or infuse such composition into a subject at a controlled rate.
  • the pump device may administer the aqueous solution of the invention in a continuous manner.
  • step ii) adding the cationic surfactant and polyol, and any further excipients to the solution of step i).
  • the process may additionally comprise step iii), adjusting the pH to the required level.
  • the required level is suitably 4.5-6.5 such as pH 5.5.
  • step i) is carried out in 2-20 mM hydrochloric acid, preferably 3-10 mM, such as 5 mM.
  • step ii) suitably the cationic surfactant is added before adding the polyol and any excipients.
  • the concentration of hydrochloric acid in step i) may be higher, for example 2-40 mM such as 10-35 mM such as 25 mM, in preparation of a composition comprising higher concentration of glucagon such as 5 mg/mL glucagon.
  • compositions according to the invention are expected to have good physical and chemical stability as described herein.
  • Example 1 Effect of preparation method on stability of glucagon in the presence of benzethonium chloride and 1 ,2-propanediol
  • All formulations contained 5 mM sodium acetate and 0.4 mg/mL benzethonium chloride and were adjusted to pH 5.5.
  • compositions containing benzethonium chloride were prepared using the following sequence of steps:
  • All formulations tested contained 5 mM sodium acetate and 0.2 mg/mL benzethonium chloride and were adjusted to pH 5.5.
  • the invention embraces all combinations of preferred and more preferred groups and suitable and more suitable groups and embodiments of groups recited above.

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Abstract

L'invention concerne, entre autres, une composition de solution aqueuse de pH compris entre 4 et 7, et comprenant : (i) du glucagon, à une concentration de 1 mg/mL ou plus ; (ii) un tensioactif cationique sélectionné parmi les sels de benzalkonium et les sels de benzéthonium, à une concentration de 2,5 mg/mL ou moins ; et (iii) un polyol, à une concentration de 0,5 M ou plus, le polyol étant choisi entre le 1,2-propanediol et le glycérol ; le rapport du glucagon sur le tensioactif cationique (mg/mL / mg/mL) étant de 2 / 1 ou plus.
PCT/GB2017/051846 2016-06-24 2017-06-23 Nouvelle composition WO2017221026A1 (fr)

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Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1202607A (en) 1968-01-10 1970-08-19 Novo Terapeutisk Labor As Improvements in or relating to stable glucagon solutions and their preparation
EP0199992A1 (fr) 1985-03-28 1986-11-05 Eisai Co., Ltd. Composition de peptides résistant à l'adsorption et utilisation de chlorures de benzalkonium ou de benzéthonium pour sa fabrication
WO1999047160A1 (fr) 1998-03-13 1999-09-23 Novo Nordisk A/S Solutions peptidiques aqueuses stabilisees
WO2006004696A2 (fr) 2004-06-29 2006-01-12 Diobex, Inc. Compositions et methodes pour la prevention et la regulation de l'hypoglycemie induite par l'insuline
WO2007056362A2 (fr) 2005-11-07 2007-05-18 Indiana University Research And Technology Corporation Analogues de glucagon a solubilite et a stabilite physiologiques ameliorees
WO2008084237A2 (fr) 2007-01-11 2008-07-17 Arecor Limited Stabilisation de protéines
WO2008086086A2 (fr) 2007-01-05 2008-07-17 Indiana University Research And Technology Corporation Analogues de glucagon présentant une solubilité améliorée dans des tampons à ph physiologiques
WO2008101017A2 (fr) 2007-02-15 2008-08-21 Indiana Unversity Research And Technology Corporation Co-agonistes des récepteurs du glucagon/glp-1
WO2009058662A2 (fr) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Antagonistes du glucagon
WO2009058734A1 (fr) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Composés présentant une activité d'antagoniste de glucagon et d'agoniste du glp-1
WO2009099763A1 (fr) 2008-01-30 2009-08-13 Indiana University Research And Technology Corporation Promédicaments peptidiques à base d’esters
WO2009155257A1 (fr) 2008-06-17 2009-12-23 Indiana University Research And Technology Corporation Analogues de glucagon présentant des tampons de ph physiologique présentant une solubilité et une stabilité améliorées
WO2009155258A2 (fr) 2008-06-17 2009-12-23 Indiana University Research And Technology Corporation Co-agonistes du récepteur glucagon/glp-1
WO2010011439A2 (fr) 2008-06-17 2010-01-28 Indiana University Research And Technology Corporation Agonistes mixtes basés sur gip destinés au traitement de troubles métaboliques et de l’obésité
WO2011049713A2 (fr) 2009-10-22 2011-04-28 Biodel Inc. Solutions de glucagon stabilisées
WO2012059762A1 (fr) 2010-11-03 2012-05-10 Arecor Limited Nouvelle composition comprenant du glucagon

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1202607A (en) 1968-01-10 1970-08-19 Novo Terapeutisk Labor As Improvements in or relating to stable glucagon solutions and their preparation
EP0199992A1 (fr) 1985-03-28 1986-11-05 Eisai Co., Ltd. Composition de peptides résistant à l'adsorption et utilisation de chlorures de benzalkonium ou de benzéthonium pour sa fabrication
WO1999047160A1 (fr) 1998-03-13 1999-09-23 Novo Nordisk A/S Solutions peptidiques aqueuses stabilisees
WO2006004696A2 (fr) 2004-06-29 2006-01-12 Diobex, Inc. Compositions et methodes pour la prevention et la regulation de l'hypoglycemie induite par l'insuline
WO2007056362A2 (fr) 2005-11-07 2007-05-18 Indiana University Research And Technology Corporation Analogues de glucagon a solubilite et a stabilite physiologiques ameliorees
WO2008086086A2 (fr) 2007-01-05 2008-07-17 Indiana University Research And Technology Corporation Analogues de glucagon présentant une solubilité améliorée dans des tampons à ph physiologiques
WO2008084237A2 (fr) 2007-01-11 2008-07-17 Arecor Limited Stabilisation de protéines
WO2008101017A2 (fr) 2007-02-15 2008-08-21 Indiana Unversity Research And Technology Corporation Co-agonistes des récepteurs du glucagon/glp-1
WO2009058662A2 (fr) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Antagonistes du glucagon
WO2009058734A1 (fr) 2007-10-30 2009-05-07 Indiana University Research And Technology Corporation Composés présentant une activité d'antagoniste de glucagon et d'agoniste du glp-1
WO2009099763A1 (fr) 2008-01-30 2009-08-13 Indiana University Research And Technology Corporation Promédicaments peptidiques à base d’esters
WO2009155257A1 (fr) 2008-06-17 2009-12-23 Indiana University Research And Technology Corporation Analogues de glucagon présentant des tampons de ph physiologique présentant une solubilité et une stabilité améliorées
WO2009155258A2 (fr) 2008-06-17 2009-12-23 Indiana University Research And Technology Corporation Co-agonistes du récepteur glucagon/glp-1
WO2010011439A2 (fr) 2008-06-17 2010-01-28 Indiana University Research And Technology Corporation Agonistes mixtes basés sur gip destinés au traitement de troubles métaboliques et de l’obésité
WO2011049713A2 (fr) 2009-10-22 2011-04-28 Biodel Inc. Solutions de glucagon stabilisées
WO2012059762A1 (fr) 2010-11-03 2012-05-10 Arecor Limited Nouvelle composition comprenant du glucagon

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHERNG-CHYL ET AL., PDA JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 41, no. 5, 1987, pages 164 - 168
MERCK: "Merck Index 10th Edition", 1983

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