US20190282667A1 - Novel formulations - Google Patents

Novel formulations Download PDF

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US20190282667A1
US20190282667A1 US16/337,730 US201716337730A US2019282667A1 US 20190282667 A1 US20190282667 A1 US 20190282667A1 US 201716337730 A US201716337730 A US 201716337730A US 2019282667 A1 US2019282667 A1 US 2019282667A1
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zinc
formulation
insulin
concentration
insulin compound
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David GERRING
Sarah Howell
Jan Jezek
Leon Zakrzewski
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Arecor Ltd
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Arecor Ltd
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Priority claimed from GBGB1616509.4A external-priority patent/GB201616509D0/en
Priority claimed from GBGB1617866.7A external-priority patent/GB201617866D0/en
Priority claimed from GBGB1707190.3A external-priority patent/GB201707190D0/en
Application filed by Arecor Ltd filed Critical Arecor Ltd
Publication of US20190282667A1 publication Critical patent/US20190282667A1/en
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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    • 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
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    • 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
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    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
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    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A61M5/31565—Administration mechanisms, i.e. constructional features, modes of administering a dose
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    • A61M5/31593—Multi-dose, i.e. individually set dose repeatedly administered from the same medicament reservoir
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    • 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
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Definitions

  • This invention relates inter alia to rapid acting aqueous liquid formulations of insulin and insulin analogues.
  • Such compositions are suitable for the treatment of subjects suffering from diabetes mellitus, especially Type I diabetes mellitus.
  • Diabetes mellitus (“diabetes”) is a metabolic disorder associated with poor control of blood sugar levels leading to hypo or hyperglycaemia. Untreated diabetes can lead to serious microvascular and macrovascular complications including coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, neuropathy and retinopathy.
  • Type 1 diabetes resulting from the pancreas not producing insulin for which the usual treatment is insulin replacement therapy
  • Type 2 diabetes where patients either produce insufficient insulin or have insulin resistance and for which treatments include insulin sensitising agents (such as metformin or pioglitazone), traditional insulin secretagogues (such as sulfonylureas), SGLT2 inhibitors (such as dapagliflozin, canagliflozin and empagliflozin) which reduce glucose absorption in the kidneys and so promote glucose excretion, GLP-1 agonists (such as exenatide and dulaglutide) which stimulate insulin release from pancreatic beta cells and DPPIV inhibitors (such as sitagliptin or vildagliptin) which inhibit breakdown of GLP-1 leading to increased insulin secretion.
  • Patients with Type 2 diabetes may eventually require insulin replacement therapy.
  • a range of therapeutic options are possible.
  • the use of recombinant human insulin has in recent times been overtaken by use of insulin analogues which have modified properties, for example, are longer acting or faster acting than normal insulin.
  • a common regimen for a patient involves receiving a long acting basal insulin supplemented by a rapid acting insulin around mealtimes.
  • Insulin is a peptide hormone formed of two chains (A chain and B chain, respectively 21 and 30 amino acids in length) linked via disulfide bridges. Insulin normally exists at neutral pH in the form of a hexamer, each hexamer comprising three dimers bound together by zinc ions. Histidine residues on the insulin are known to be involved in the interaction with the zinc ions. Insulin is stored in the body in the hexameric form but the monomer form is the active form. Traditionally, therapeutic compositions of insulin have also been formulated in hexameric form in the presence of zinc ions. Typically, there are approximately three zinc cations per one insulin hexamer.
  • the hexameric form is absorbed from the injection site considerably more slowly than the monomeric and dimeric forms. Therefore, a faster onset of insulin action can be achieved if the hexameric form is destabilised allowing a more rapid dissociation of the zinc-bound hexamer into dimers and monomers in the subcutaneous space following injection.
  • Three insulin analogues have been genetically engineered with this principle in mind.
  • a first is insulin lispro (Humalog®) in which residues 28 and 29 of the B chain (Pro and Lys respectively) are reversed
  • a second is insulin aspart (NovoRapid®) in which residue 28 of the B chain, normally Pro, is replaced by Asp
  • a third is insulin glulisine (Apidra®) in which residue 3 of the B chain, normally Asn, is replaced by Lys and residue 29 of the B chain, normally Lys, is replaced by Glu.
  • U.S. Pat. No. 5,866,538 (Norup) describes insulin preparations of superior chemical stability comprising human insulin or an analogue or derivative thereof, glycerol and/or mannitol and 5 mM to 100 mM of a halogenide (e.g. NaCl).
  • a halogenide e.g. NaCl
  • U.S. Pat. No. 7,205,276 addresses the stability problems associated with preparing zinc-free formulations of insulin and insulin derivatives and analogues and describes an aqueous liquid formulation comprising at least one insulin derivative, at least one surfactant, optionally at least one preservative and optionally at least one of an isotonicizing agent, a buffer and an excipient, wherein the formulation is stable and free from or contains less than 0.4% (e.g. less than 0.2%) by weight of zinc based on the insulin content of the formulation.
  • the preferred surfactant appears to be polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate).
  • WO2012/006283 describes formulations containing insulin together with a zinc chelator such as ethylenediaminetetraacetate (EDTA). Modulating the type and quantity of EDTA is said to change the insulin absorption profile.
  • EDTA ethylenediaminetetraacetate
  • Modulating the type and quantity of EDTA is said to change the insulin absorption profile.
  • Calcium EDTA is the preferred form of EDTA since it is said to be associated with reduced pain at the injection site and is less likely to remove calcium from the body.
  • Preferred formulations also contain citrate which is said to further enhance absorption and to improve the chemical stability of the formulation.
  • US2010/0227795 describes a composition comprising insulin, a dissociating agent such as citric acid or sodium citrate, and a zinc chelator such as EDTA wherein the formulation has a physiological pH and is a clear aqueous solution.
  • the formulations are said to have improved stability and rapid onset of action.
  • WO2015/120457 (Wilson) describes stabilized ultra-rapid acting insulin formulations comprising insulin in combination with a zinc chelator such as EDTA, a dissolution/stabilization agent such as citric acid, a magnesium salt, a zinc compound and optionally additional excipients.
  • WO91/09617 reports that nicotinamide or nicotinic acid or a salt thereof increases the speed of absorption of insulin from aqueous preparations administered parenterally.
  • WO2010/149772 (Olsen) describes a formulation comprising insulin, a nicotinic compound and arginine. The presence of arginine is said to improve the chemical stability of the formulation.
  • WO2015/171484 (Christe) describes rapid-acting formulations of insulin wherein onset of action and/or absorption of insulin is faster due to the presence of treprostinil.
  • US2013/0231281 describes an aqueous solution composition comprising insulin or an insulin analogue and at least one oligosaccharide whose average degree of polymerisation is between 3 and 13 and whose polydispersity index is above 1.0, said oligosaccharide having partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. Such a formulation is said to be rapid acting.
  • PCT/GB2017/051254 (Arecor Limited) describes an aqueous liquid pharmaceutical formulation comprising insulin or an insulin analogue, ionic zinc, a chelating agent and polysorbate 80.
  • WO2016/100042 (Eli Lilly and Company) describes a composition of human insulin or insulin analogue that includes specific concentrations of citrate, chloride, in some cases including the addition of sodium chloride, zinc and, optionally magnesium chloride and/or surfactant, said to have faster pharmacokinetic and/or pharmacodynamic action than commercial formulations of existing insulin analogue products.
  • Suitable rapid-acting insulin formulations are available as 100 U/ml formulations (Humalog® (insulin lispro), NovoRapid® (also known as NovoLog®, insulin aspart) and Apidra® (insulin glulisine)) and 200 U/ml formulations (Humalog®).
  • Formulations having a higher concentration of insulin compound are desirable e.g. for patients that require higher insulin doses, such as obese patients or patients who have developed insulin resistance. Formulations having a higher concentration of insulin are thus desirable for these categories of patients as the required high dose can be delivered in a smaller volume.
  • analogues or formulations of insulin were available which were ultra-rapid acting, thus more closely matching the activity of physiological insulin.
  • formulations of insulin and insulin analogues which are rapid acting and stable.
  • formulations of higher concentration of insulin compound wherein the speed of onset of action of the insulin compound is maintained.
  • an aqueous liquid pharmaceutical formulation comprising (i) an insulin compound at a concentration of 500-1000 U/ml, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C., and (iv) a non-ionic surfactant; and wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C.
  • the formulation is of low ionic strength e.g. the ionic strength of the formulation is less than 40 mM, calculated using formula Ia as described herein.
  • the formulations of the invention provide insulin in a form which is rapid or ultra-rapid acting with good physical and chemical stability.
  • the formulations have a high concentration (or “high strength”) of insulin compound i.e. 500-1000 U/ml.
  • high strength or “high strength”
  • use of EDTA to chelate zinc ions in hexameric insulin does increase the rapidity of action but at the cost of greatly reduced stability.
  • the present inventors have appreciated that the use of zinc together with species which bind zinc less strongly can achieve similar effects in terms of speed of action and their moderately destabilising effects can be reduced or eliminated by using a non-ionic surfactant.
  • the present inventors have further appreciated that the presence of such a zinc binding species accelerates the onset of action of a high concentration (high strength) insulin compound formulation. Put another way, the present inventors have discovered that the addition of such a zinc binding species can mitigate the delaying effect on insulin onset of action which has been observed when the concentration of insulin compound in a formulation is increased.
  • Formulations of the invention may be used in the treatment of subjects suffering from diabetes mellitus, particularly Type 1 diabetes mellitus especially for administration at meal times.
  • formulations of the invention are significantly more stable than corresponding formulations without non-ionic surfactant.
  • the formulations achieve a rapid speed of action of insulin and are more stable than prior art rapid acting insulin formulations containing EDTA.
  • formulations of the invention contain high concentrations of insulin compound while maintaining a rapid onset of action.
  • SEQ ID NO: 1 A chain of human insulin
  • SEQ ID NO: 2 B chain of human insulin
  • SEQ ID NO: 3 B chain of insulin lispro
  • SEQ ID NO: 4 B chain of insulin aspart
  • SEQ ID NO: 5 B chain of insulin glulisine
  • FIG. 1 Pharmacodynamic profiles of formulations 7A-7D of Example 7 in a validated diabetic Yucatan miniature pig model.
  • FIG. 2 Pharmacokinetic profiles of formulations 7A, 7B and 7D of Example 7 in a validated diabetic Yucatan miniature pig model.
  • insulin compound refers to insulin and insulin analogues.
  • insulin refers to native human insulin having an A chain and a B chain as set out in SEQ ID NOs. 1 and 2 and containing and connected by disulfide bridges as in the native molecule (Cys A6-Cys A11, Cys B7 to Cys A7 and Cys-B19-Cys A20). Insulin is suitably recombinant insulin.
  • Insulin analogue refers to an analogue of insulin which is an insulin receptor agonist and has a modified amino acid sequence, such as containing 1 or 2 amino acid changes in the sequence of the A or B chain (especially the B chain). Desirably such amino acid modifications are intended to reduce affinity of the molecule for zinc and thus increase speed of action.
  • an insulin analogue has a speed of action which is the same as or preferably greater than that of insulin.
  • the speed of action of insulin or an insulin analogue may be determined in the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
  • Exemplary insulin analogues include faster acting analogues such as insulin lispro, insulin aspart and insulin glulisine.
  • insulin has the human insulin A chain but variant B chains—see SEQ ID NOs. 3-5. Further faster acting analogues are described in EP0214826, EP0375437 and EP0678522 the contents of which are herein incorporated by reference in their entirety.
  • the insulin compound is not insulin glargine.
  • the insulin compound is not insulin degludec.
  • the insulin compound is a rapid-acting insulin compound, wherein “rapid-acting” is defined as an insulin compound which has a speed of action which is greater than that of native human insulin, e.g. as measured using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
  • the insulin compound is recombinant human insulin. In another embodiment, it is insulin lispro. In another embodiment, it is insulin aspart. In another embodiment, it is insulin glulisine.
  • aqueous liquid pharmaceutical formulation refers to a formulation suitable for therapeutic use in which the aqueous component is or comprises water, preferably distilled water, deionized water, water for injection, sterile water for injection or bacteriostatic water for injection.
  • the aqueous liquid pharmaceutical formulations of the invention are solution formulations in which all components are dissolved in water.
  • the concentration of insulin compound in the formulation is in the range 500-1000 U/ml e.g. 800-1000 U/ml and another exemplary formulation contains insulin compound at a concentration of 1000 U/ml (around 36 mg/ml).
  • the concentration of insulin compound in the formulation is 500-1000 U/ml e.g. >500-1000 U/ml. In one embodiment, the concentration of insulin compound in the formulation is 600-1000 U/ml, e.g. >600-1000 U/ml. In one embodiment, the concentration of insulin compound in the formulation is 700-1000 U/ml e.g. >700-1000 U/ml. In one embodiment, the concentration of insulin compound in the formulation is 750-1000 U/ml e.g. >750-1000 U/ml. In one embodiment, the concentration of insulin compound in the formulation is 800-1000 U/ml e.g. >800-1000 U/ml. In one embodiment, the concentration of insulin compound in the formulation is 900-1000 U/ml e.g. >900-1000 U/ml.
  • U/ml as used herein describes the concentration of insulin compound in terms of a unit per volume, wherein “U” is the international unit of insulin activity (see e.g. European Pharmacopoeia 5.0, Human Insulin, pp 1800-1802).
  • the formulations of the invention contain ionic zinc i.e. Zn2+ ions.
  • the source of the ionic zinc will typically be a water-soluble zinc salt such as ZnCl2, ZnO, ZnSO4, Zn(NO3)2 or Zn(acetate)2 and most suitably ZnCl2 or ZnO.
  • the concentration of the ionic zinc in the formulation will typically be more than 0.05% e.g. more than 0.1% e.g. more than 0.2%, more than 0.3% or more than 0.4% by weight of zinc based on the weight of insulin compound in the formulation.
  • the concentration of the ionic zinc in the formulation may be more than 0.5% by weight of zinc based on the weight of insulin compound in the formulation, for example 0.5-1%, e.g. 0.5-0.75%, e.g. 0.5-0.6% by weight of zinc based on the weight of insulin compound in the formulation.
  • the weight of the counter ion to zinc is excluded.
  • the concentration of the ionic zinc will typically be more than 0.15 mM e.g. more than 0.3 mM e.g. more than 0.6 mM, more than 0.9 mM or more than 1.2 mM.
  • the concentration of the ionic zinc in the formulation may be more than 1.5 mM, for example 1.5-6.0 mM, e.g. 2.0-4.5 mM, e.g. 2.5-3.5 mM.
  • the formulations of the invention contain a zinc binding species.
  • Zinc binding species should be capable of complexing ionic zinc and will have a logK metal binding stability constant with respect to zinc ion binding of 4.5-12.3 as determined at 25° C.
  • Metal binding stability constants listed in the National Institute of Standards and Technology reference database 46 can be used.
  • the database typically lists logK constants determined at 25° C. Therefore, the suitability of a zinc binding species for the present invention can be determined based on its logK metal binding stability constant with respect to zinc binding, as measured at 25° C. and as quoted by the database.
  • the zinc binding species may also be described as an “accelerator” in the formulations according to the invention.
  • Exemplary zinc binding species include polydendate organic anions.
  • the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 is selected from citrate, pyrophosphate, aspartate, glutamate, cysteine, cystine, glutathione, ethylenediamine, histidine, DETA and TETA.
  • the zinc binding species will have a logK metal binding stability constant with respect to zinc ion binding of 4.5-10 at 25° C.
  • the most suitable concentration of the zinc binding species will depend on the agent and its logK value and will typically be in the range 1-100 mM.
  • the concentration of zinc binding species can be adjusted according to the particular concentration of insulin compound present in the composition, in order to provide the desired accelerating effect.
  • the concentration of the zinc binding species in the formulation may typically be in the range 1-50 mM.
  • the concentration of the zinc binding species in the formulation is 10-50 mM e.g. 30-50 mM e.g. 40-50 mM, more preferably around 44 mM when the zinc binding species is citrate or histidine for insulin compound 1000 U/ml formulations.
  • the concentration of the zinc binding species is 10 mM or more. In another embodiment, the concentration of the zinc binding species is 5-50 mM, e.g. 10-50 mM, 20-50 mM, 25-50 mM, 30-50 mM or 40-50 mM.
  • Anionic zinc binding species may be employed as the free acid or a salt form, such as a salt form with sodium or calcium ions, especially sodium ions.
  • a mixture of zinc binding species may be employed, although a single zinc binding species is preferred.
  • the molar ratio of ionic zinc to zinc binding species in the formulation is in the range 1:1 to 1:1000 e.g. 1:1 to 1:500 e.g. 1:1 to 1:250 or 1:3 to 1:500 e.g. 1:3 to 1:175.
  • the following ranges are particularly of interest especially for citrate or histidine as zinc binding species: 1:10-1:500 e.g. 1:10-1:200 e.g. 1:10 to 1:100 e.g. 1:10-1:50, e.g. 1:10 to 1:30, e.g. 1:10 to 1:20 (especially for insulin compound 1000 U/ml formulation).
  • a formulation containing 1000 U/ml of insulin compound may contain around 3 mM of ionic zinc (i.e. around 197 ⁇ g/ml of ionic zinc, i.e. around 0.54% by weight of zinc based on the weight of insulin compound in the formulation) and around 30-60 mM e.g. 40-60 mM zinc binding species (especially citrate).
  • ionic zinc i.e. around 197 ⁇ g/ml of ionic zinc, i.e. around 0.54% by weight of zinc based on the weight of insulin compound in the formulation
  • 30-60 mM e.g. 40-60 mM zinc binding species (especially citrate).
  • the ratio of insulin compound concentration (U/ml) to zinc binding species (mM) in the formulation is in the range 100:1 to 2:1 e.g. 50:1 to 2:1 e.g. 40:1 to 2:1.
  • the formulations of the invention are substantially free of zinc binding species which have a logK metal binding stability constant with respect to zinc binding of more than 12.3 as determined at 25° C.
  • formulations of the invention will be substantially free of tetradentate ligands or ligands of higher denticity.
  • the formulations of the invention are also substantially free of zinc binding species which have a logK metal binding stability constant with respect to zinc ion binding of 10-12.3 as determined at 25° C.
  • “Substantially free” means that the concentration of zinc binding species which have a logK metal binding stability constant with respect to zinc binding as specified (such as EDTA) is less than 0.1 mM, such as less than 0.05 mM, such as less than 0.04 mM or less than 0.01 mM.
  • Zinc ion binding species which have acid forms may be introduced into the aqueous formulations of the invention in the form of a salt of the acid, such as a sodium salt (e.g. trisodium citrate). Alternatively, they can be introduced in the form of the acid with subsequent adjustment of pH to the required level.
  • a salt of the acid such as a sodium salt (e.g. trisodium citrate).
  • they can be introduced in the form of the acid with subsequent adjustment of pH to the required level.
  • the present inventors have found that in some circumstances introducing the acid form (such as citric acid) into the formulation instead of the salt form (e.g. trisodium citrate) may have advantages in terms of providing superior chemical and physical stability.
  • the source of the citrate as zinc ion binding species is citric acid.
  • an aqueous liquid pharmaceutical formulation comprising (i) an insulin compound at a concentration of 500-1000 U/ml (ii) ionic zinc, (iii) citrate as a zinc binding species at a concentration of 1 mM or more, and (iv) a non-ionic surfactant; wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C., and wherein the ionic strength of the formulation is less than 40 mM, said ionic strength being calculated using the formula:
  • the formulations of the invention contain a non-ionic surfactant.
  • a suitable class of non-ionic surfactants is the alkyl glycosides, especially dodecyl maltoside.
  • the alkyl glycoside is decyl glucopyranoside.
  • Other alkyl glycosides include dodecyl glucoside, octyl glucoside, octyl maltoside, decyl glucoside, decyl maltoside, tridecyl glucoside, tridecyl maltoside, tetradecyl glucoside, tetradecyl maltoside, hexadecyl glucoside, hexadecyl maltoside, sucrose monooctanoate, sucrose mono decanoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate and sucrose monohexadecanoate.
  • polysorbates fatty acid esters of ethoxylated sorbitan
  • polysorbate 20 is a mono ester formed from lauric acid and polyoxyethylene (20) sorbitan in which the number 20 indicates the number of oxyethylene groups in the molecule.
  • Polysorbate 80 is a mono ester formed from oleic acid and polyoxyethylene (20) sorbitan in which the number 20 indicates the number of oxyethylene groups in the molecule.
  • Polysorbate 20 is known under a range of brand names including in particular Tween 20, and also Alkest TW 20.
  • Polysorbate 80 is known under a range of brand names including in particular Tween 80, and also Alkest TW 80.
  • Other suitable polysorbates include polysorbate 40 and polysorbate 60.
  • the non-ionic surfactant is other than polysorbate 80.
  • the non-ionic surfactant is other than polysorbate 20.
  • non-ionic surfactants is block copolymers of polyethylene glycol and polypropylene glycol, also known as poloxamers, especially poloxamer 188, poloxamer 407, poloxamer 171 and poloxamer 185.
  • Poloxamers are also known under brand names Pluronics or Koliphors.
  • Pluronics or Koliphors.
  • poloxamer 188 is marketed as Pluronic F-68.
  • alkyl ethers of polyethylene glycol especially those known under a brand name Brij, such as selected from polyethylene glycol (2) hexadecyl ether (Brij 52), polyethylene glycol (2) oleyl ether (Brij 93) and polyethylene glycol (2) dodecyl ether (Brij L4).
  • Other suitable Brij surfactants include polyethylene glycol (4) lauryl ether (Brij 30), polyethylene glycol (10) lauryl ether (Brij 35), polyethylene glycol (20) hexadecyl ether (Brij 58) and polyethylene glycol (10) stearyl ether (Brij 78).
  • alkylphenyl ethers of polyethylene glycol especially 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, also known under a brand name Triton X-100.
  • non-ionic surfactants with molecular weight of less than 1000 g/mole, especially less than 600 g/mole, such as 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol (Triton X-100) (647 g/mole), dodecyl maltoside (511 g/mole), octyl glucoside (292 g/mole), polyethylene glycol (2) dodecyl ether (Brij L4) (362 g/mole), polyethylene glycol (2) oleyl ether (Brij 93) (357 g/mole) and polyethylene glycol (2) hexadecyl ether (Brij 52) (330 g/mole).
  • Triton X-100 Triton X-100
  • dodecyl maltoside 511 g/mole
  • octyl glucoside 292 g/mole
  • polyethylene glycol (2) dodecyl ether
  • the concentration of the non-ionic surfactant in the formulation will typically be in the range 1-1000 ⁇ g/ml, e.g. 5-500 ⁇ g/ml, e.g. 10-200 ⁇ g/ml, such as 10-100 ⁇ g/ml especially around 50 ⁇ g/ml.
  • the non-ionic surfactant is present at a concentration of 10-400 ⁇ g/ml e.g. 20-400 ⁇ g/ml, 50-400 ⁇ g/ml, 10-300 ⁇ g/ml, 20-300 ⁇ g/ml, 50-300 ⁇ g/ml, 10-200 ⁇ g/ml, 20-200 ⁇ g/ml or 50-200 ⁇ g/ml.
  • the concentration of insulin compound is 800-1000 U/ml and the non-ionic surfactant is present at a concentration of 50-200 ⁇ g/ml.
  • the non-ionic surfactant is dodecyl maltoside.
  • the pH of the aqueous formulations of the invention is in the range 5.5-9.0 especially 6.5-8.0 e.g. 7.0-7.8. e.g. 7.0-7.5.
  • the pH is preferably close to physiological pH (around pH 7.4).
  • Another pH of interest is 7.6-8.0 e.g. around 7.8.
  • An additional pH of interest is 7.2-7.8, e.g. around 7.6.
  • the composition of the invention comprises a buffer (e.g. one or more buffers) in order to stabilise the pH of the formulation, which can also be selected to enhance protein stability.
  • a buffer is selected to have a pKa close to the pH of the composition; for example, histidine is suitably employed as a buffer when the pH of the composition is in the range 5.0-7.0.
  • Histidine is suitably employed as a buffer when the pH of the composition is in the range 5.0-7.0.
  • Such a buffer may be employed in a concentration of 0.5-20 mM e.g. 2-5 mM. If histidine is included in the formulation as a zinc binding species it will also have a buffering role at this pH.
  • phosphate e.g.
  • sodium phosphate is suitably employed as a buffer when the pH of the composition is in the range 6.1-8.1.
  • a buffer may be employed in a concentration of 0.5-20 mM e.g. 2-5 mM e.g. 2 mM.
  • the formulation of the invention is further stabilised as disclosed in WO2008/084237 (herein incorporated by reference in its entirety), which describes a formulation comprising a protein and one or more additives, characterised in that the system is substantially free of a conventional buffer, i.e. a compound with an ionisable group having a pKa within 1 unit of the pH of the formulation at the intended temperature range of storage of the composition, such as 25° C.
  • the pH of the formulation is set to a value at which the formulation has maximum measurable stability with respect to pH; the one or more additives (displaced buffers) are capable of exchanging protons with the insulin compound and have pKa values at least 1 unit more or less than the pH of the formulation at the intended temperature range of storage of the formulation.
  • the additives may have ionisable groups 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 formulation at the intended temperature range of storage of the composition (e.g. 25° C.).
  • Such additives may typically be employed at a concentration of 0.5-10 mM e.g. 2-5 mM.
  • the aqueous formulations of the present invention cover a wide range of osmolarity, including hypotonic, isotonic and hypertonic compositions.
  • the formulations of the invention are substantially isotonic.
  • the osmolarity of the formulation is selected to minimize pain according to the route of administration e.g. upon injection.
  • Preferred formulations have an osmolarity in the range of about 200 to about 500 mOsm/L.
  • the osmolarity is in the range of about 250 to about 350 mOsm/L. More preferably, the osmolarity is about 300 mOsm/L.
  • Tonicity of the formulation may be adjusted with a tonicity modifying agent (e.g. one or more tonicity modifying agents).
  • Tonicity modifying agents may be charged or uncharged.
  • charged tonicity modifying agents include salts such as a combination of sodium, potassium, magnesium or calcium ions, with chloride, sulfate, carbonate, sulfite, nitrate, lactate, succinate, acetate or maleate ions (especially sodium chloride or sodium sulphate, particularly sodium chloride).
  • the insulin compound formulations of the invention may contain a residual NaCl concentration of 2-4 mM as a result of the use of standard acidification and subsequent neutralization steps employed in preparing insulin formulations.
  • Amino acids such as arginine, glycine or histidine may also be used for this purpose.
  • Charged tonicity modifying agent e.g. NaCl
  • the formulation of the invention comprises ⁇ 10 mM chloride (e.g. sodium chloride), for example ⁇ 9 mM, ⁇ 8 mM, ⁇ 7 mM, ⁇ 6 mM or ⁇ 5 mM, or is substantially free of chloride (e.g. sodium chloride) i.e. no chloride is added to the formulation beyond any chloride that may be contributed as part of pH adjustment.
  • uncharged tonicity modifying agents include sugars, sugar alcohols and other polyols, such as trehalose, sucrose, mannitol, glycerol, 1,2-propanediol, raffinose, lactose, dextrose, sorbitol or lactitol (especially trehalose, mannitol, glycerol or 1,2-propanediol, particularly glycerol).
  • Uncharged tonicity modifying agent is preferably used at a concentration of 200-500 mM, e.g. around 300 mM. Another range of interest is 100-500 mM.
  • the uncharged tonicity modifying agent in the formulation is at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM. In one embodiment, the uncharged tonicity modifying agent in the formulation is glycerol at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the tonicity is suitably adjusted using an uncharged tonicity modifying agent, preferably at a concentration of 200-500 mM, e.g. around 300 mM.
  • the uncharged tonicity modifying agent is suitably selected from the group consisting of trehalose, mannitol, glycerol and 1,2-propanediol (most suitably glycerol).
  • the uncharged tonicity modifying agent is used at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the uncharged tonicity modifying agent is glycerol at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the tonicity is suitably adjusted using an uncharged tonicity modifying agent, preferably at a concentration of 200-500 mM, e.g. around 300 mM.
  • the uncharged tonicity modifying agent is suitably selected from the group consisting of trehalose, mannitol, glycerol and 1,2-propanediol (most suitably glycerol).
  • the uncharged tonicity modifying agent is used at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the uncharged tonicity modifying agent is glycerol at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the tonicity is suitably adjusted using an uncharged tonicity modifying agent, preferably at a concentration of 200-500 mM, e.g. around 300 mM.
  • the uncharged tonicity modifying agent is suitably selected from the group consisting of trehalose, mannitol, glycerol and 1,2-propanediol (most suitably glycerol).
  • the uncharged tonicity modifying agent is used at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the uncharged tonicity modifying agent is glycerol at a concentration of 100-300 mM, e.g. 150-200 mM, 170-180 mM or around 174 mM.
  • the ionic strength of a formulation may be calculated according to the formula
  • the ionic strength of the formulation is suitably less than 40 mM, e.g. less than 30 mM, less than 20 mM or less than 10 mM.
  • the insulin compound is present at a concentration 500-1000 U/ml, e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, and the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 40 mM, e.g. less than 30 mM, e.g. less than 20 mM, e.g.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 35 mM, less than 30 mM, less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 40 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the insulin compound is insulin lispro at a concentration of 500-1000 U/ml, e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, the ionic strength of the formulation is suitably kept to a minimum level since higher ionic strength formulations are less stable than lower ionic strength formulations, particularly at high concentrations of insulin.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 40 mM, e.g. less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM such as 1-10 mM.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 35 mM, less than 30 mM, less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 40 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the insulin compound is insulin aspart at a concentration of 500-1000 U/ml e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml), the ionic strength of the formulation is suitably kept to a minimum level since higher ionic strength formulations are less stable than lower ionic strength formulations.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 40 mM, e.g. less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM.
  • tonicity may suitably be adjusted using an uncharged tonicity modifying agent.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 35 mM, less than 30 mM, less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 40 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the insulin compound is insulin glulisine at a concentration of 500-1000 U/ml e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml), the ionic strength of the formulation is suitably kept to a minimum level since higher ionic strength formulations may be less stable than lower ionic strength formulations.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 40 mM, e.g. less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM.
  • tonicity may suitably be adjusted using an uncharged tonicity modifying agent.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species and the insulin compound is less than 35 mM, less than 30 mM, less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 40 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the ionic strength of a formulation may be calculated according to the formula Ib:
  • the ionic strength of the formulation is suitably less than less than 30 mM, less than 20 mM or less than 10 mM.
  • the insulin compound is present at a concentration of 500-1000 U/ml, e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, and the ionic strength taking account of ions in the formulation except for the zinc binding species, the insulin compound and the ionic zinc is less than 30 mM, e.g. less than 20 mM, e.g.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species, the insulin compound and the ionic zinc is less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the insulin compound is insulin lispro a concentration of 500-1000 U/ml, e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, the ionic strength of the formulation is suitably kept to a minimum level since higher ionic strength formulations are less stable than lower ionic strength formulations, particularly at high concentrations of insulin.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM such as 1-10 mM.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species is less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the insulin compound is insulin aspart at a concentration of 500-1000 U/ml e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, the ionic strength of the formulation is suitably kept to a minimum level since higher ionic strength formulations are less stable than lower ionic strength formulations.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species is less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the tonicity may suitably be adjusted using an uncharged tonicity modifying agent.
  • the insulin compound is insulin glulisine at a concentration of 500-1000 U/ml e.g. >500-1000 U/ml, 600-1000 U/ml, >600-1000 U/ml, 700-1000 U/ml, >700-1000 U/ml, 750-1000 U/ml, >750-1000 U/ml, 800-1000 U/ml, >800-1000 U/ml, 900-1000 U/ml, >900-1000 U/ml or 1000 U/ml, the ionic strength of the formulation is suitably kept to a minimum level since higher ionic strength formulations may be less stable than lower ionic strength formulations.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species is less than 30 mM, e.g. less than 20 mM, e.g. less than 10 mM.
  • the ionic strength taking account of ions in the formulation except for the zinc binding species is less than 25 mM, less than 20 mM, less than 15 mM, or less than 10 mM, or is in the range 5- ⁇ 30 mM, 5-30 mM, 5-20 mM, 2-20 mM, 1-10 mM, 2-10 mM or 5-10 mM.
  • the formulations of the invention can optionally include a preservative (e.g. one or more preservatives), preferably phenol, m-cresol, chlorocresol, benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride or benzethonium chloride.
  • a preservative e.g. one or more preservatives
  • the formulation includes phenol or m-cresol.
  • a mixture of preservatives is employed e.g. phenol and m-cresol.
  • the formulations of the invention may optionally comprise nicotinamide.
  • the presence of nicotinamide may further increase the speed of onset of action of insulin formulated in compositions of the invention.
  • the concentration of nicotinamide is in the range 10-150 mM, preferably in the range 20-100 mM, such as around 80 mM.
  • the formulations of the invention may optionally comprise nicotinic acid or a salt thereof.
  • the presence of nicotinic acid or a salt thereof may also further increase the speed of onset of action of insulin formulated in compositions of the invention.
  • the concentration of nicotinic acid or a salt thereof is in the range 10-150 mM, preferably in the range 20-100 mM, such as around 80 mM.
  • Example salts include metal salts such as sodium, potassium and magnesium salts.
  • nicotinamide and nicotinic acid may be included in the formulation but not both.
  • the formulations of the invention may optionally comprise treprostinil or a salt thereof.
  • the presence of the treprostinil may further increase the speed of onset of action of insulin formulated in compositions of the invention.
  • the concentration of treprostinil in the formulation is in the range of 0.1-12 ⁇ g/ml e.g. 0.1-10 ⁇ g/ml, 0.1-9 ⁇ g/ml, 0.1-8 ⁇ g/ml, 0.1-7 ⁇ g/ml, 0.1-6 ⁇ g/ml, 0.1-5 ⁇ g/ml, 0.1-4 ⁇ g/ml, 0.1-3 ⁇ g/ml, 0.1-2 ⁇ g/ml, 0.5-2 ⁇ g/ml e.g. about 1 ⁇ g/ml.
  • the formulation does not contain a vasodilator. In a further embodiment, the formulation does not contain treprostinil, nicotinamide, nicotinic acid or a salt thereof.
  • Formulations of the invention may optionally include other beneficial components including stabilising agents.
  • amino acids such as arginine or proline may be included which may have stabilising properties.
  • the formulations of the invention comprise arginine.
  • the formulations are free of acids selected from glutamic acid, ascorbic acid, succinic acid, aspartic acid, maleic acid, fumaric acid, adipic acid and acetic acid and are also free from the corresponding ionic forms of these acids.
  • the formulations are free of arginine.
  • the formulations are free of protamine and protamine salts.
  • the formulations are free of magnesium ions.
  • magnesium ions e.g. in the form of magnesium chloride may provide a stabilising effect.
  • the formulation contains magnesium ions e.g. MgCl2.
  • the formulations are free of calcium ions.
  • Formulations of the invention may further comprise an additional therapeutically active agent (an “active agent”), in particular an agent of use in the treatment of diabetes (i.e. in addition to the insulin compound in particular the rapid-acting insulin compound) e.g. an amylin analogue or a GLP-1 agonist.
  • an amylin analogue such as pramlintide, suitably at a concentration of 0.1-10 mg/ml e.g. 0.2-6 mg/ml.
  • the formulation further comprises a GLP-1 agonist such as liraglutide, dulaglutide, albiglutide, exenatide or lixisenatide, suitably at a concentration of 10 ⁇ g/ml to 50 mg/ml e.g. 200 ⁇ g/ml to 10 mg/ml or 1-10 mg/ml.
  • a GLP-1 agonist such as liraglutide, dulaglutide, albiglutide, exenatide or lixisenatide
  • high molecular weight species refers to any irreversibly formed component of the protein content which has an apparent molecular weight at least about double the molecular weight of the parent insulin compound, as detected by a suitable analytical method, such as size-exclusion chromatography. That is, high molecular weight species are multimeric aggregates of the parent insulin compound. The multimeric aggregates may comprise the parent protein molecules with considerably altered conformation or they may be an assembly of the parent protein units in the native or near-native conformation.
  • the determination of high molecular weight species can be done using methods known in the art, including size exclusion chromatography, electrophoresis, analytical ultracentrifugation, light scattering, dynamic light scattering, static light scattering and field flow fractionation.
  • the formulations of the invention are sufficiently stable that they remain substantially free of visible particles after storage at 30° C. for at least one, two or three months. Visible particles are suitably detected using the 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles).
  • a formulation is substantially free of visible particles if it has a Visual score according to Visual Assessment Method B of 1, 2 or 3, especially 1 or 2 according to the definition given in the Examples section.
  • the formulations of the invention are sufficiently stable that the concentration of related species remains low upon extended storage.
  • related species refers to any component of the protein content formed by a chemical modification of the parent insulin compound, particularly desamido or cyclic imide forms of insulin.
  • Related species are suitably detected by RP-HPLC.
  • the formulation of the invention retains at least 95%, e.g. at least 96%, e.g. at least 97%, e.g. at least 98%, e.g. at least 99% parent insulin compound (by weight of total protein) after storage at 30° C. for one, two or three months.
  • the percentage of insulin compound (by weight of total protein) may be determined by size-exclusion chromatography or RP-HPLC.
  • the formulation of the invention comprises no more than 4% (by weight of total protein), preferably no more than 2% high molecular weight species after storage at 30° C. for one, two or three months.
  • the formulation of the invention comprises no more than 4% (by weight of total protein), preferably no more than 2%, preferably no more than 1% A-21 desamido form of the insulin compound after storage at 30° C. for one, two or three months.
  • a composition of the present invention should exhibit an increase in high molecular weight species during storage which is at least 10% lower, preferably at least 25% lower, more preferably at least 50% lower, than a composition lacking the non-ionic surfactant but otherwise identical, following storage under the same conditions (e.g. 30° C.) and length of time (e.g. one, two or three months).
  • a composition of the present invention should exhibit an increase in related species during storage which is at least 10% lower, preferably at least 25% lower, more preferably at least 50% lower, than a composition lacking the non-ionic surfactant but otherwise identical, following storage under the same conditions (e.g. 30° C.) and length of time (e.g. one, two or three months).
  • a composition of the present invention exhibits a Tmax (i.e. time to peak insulin concentration) that is at least 20% shorter, preferably at least 30% shorter than a composition lacking the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 (e.g. in the range 4.5-10) at 25° C. but otherwise identical, using the model.
  • Tmax i.e. time to peak insulin concentration
  • a composition of the present invention exhibits an area under the curve on the pharmacodynamics profile within the first 45 minutes after injection that is at least 20% greater, preferably at least 30% greater than a composition lacking the zinc binding species having a logK with respect to zinc ion binding in the range 4.5-12.3 (e.g. in the range 4.5-10) at 25° C. but otherwise identical, using the model.
  • the present invention provides a composition
  • a composition comprising (i) insulin lispro at a concentration of 500-1000 U/ml, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C. e.g. citrate, and (iv) a non-ionic surfactant e.g. an alkyl glycoside; and wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C., which exhibits a Tmax (i.e.
  • time to peak insulin concentration that is at least 20% shorter, preferably at least 30% shorter than an aqueous formulation consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 ⁇ g/ml, excluding counter-ion) adjusted to pH 7.3, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
  • the present invention provides a composition
  • a composition comprising (i) insulin lispro at a concentration of 500-1000 U/ml, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C. e.g. citrate, and (iv) a non-ionic surfactant e.g.
  • an alkyl glycoside wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C., which exhibits an area under the curve on the pharmacodynamics profile within the first 45 minutes after injection that is at least 20% greater, preferably at least 30% greater than an aqueous formulation consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 ⁇ g/ml, excluding counter-ion) adjusted to pH 7.3, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
  • the present invention provides a composition
  • a composition comprising (i) insulin aspart at a concentration of 500-1000 U/ml, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C. e.g. citrate, and (iv) a non-ionic surfactant e.g. an alkyl glycoside; and wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C., which exhibits a Tmax (i.e.
  • time to peak insulin concentration that is at least 20% shorter, preferably at least 30% shorter than an aqueous formulation consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (19.7 ⁇ g/ml, excluding counter-anion) adjusted to pH 7.4, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
  • the present invention provides a composition
  • a composition comprising (i) insulin aspart at a concentration of 500-1000 U/ml, (ii) ionic zinc, (iii) a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C. e.g. citrate, and (iv) a non-ionic surfactant e.g.
  • an alkyl glycoside wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C., which exhibits an area under the curve on the pharmacodynamics profile within the first 45 minutes after injection that is at least 20% greater, preferably at least 30% greater than an aqueous formulation consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (19.7 ⁇ g/ml, excluding counter-anion) adjusted to pH 7.4, using the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model (see Examples, General Methods (c)).
  • composition of the present invention is bioequivalent to a corresponding formulation comprising the insulin compound at 100 U/ml.
  • bioequivalent means that the formulation of the invention has an equivalent or similar pharmacokinetic/pharmacodynamic (PK/PD) profile to a corresponding formulation.
  • the formulation of the invention exhibits a TMAX or T1 ⁇ 2MAX (measured in accordance with the Diabetic Pig Pharmacokinetic/Pharmacodynamic Model described in section (c) of General Methods) which is substantially the same as (e.g. within ⁇ 20%, e.g. within ⁇ 10%) of that of the corresponding formulation.
  • Bioequivalence can also be established by applying the Student's t-test to the pharmacokinetic/pharmacodynamics results achieved using two different compositions as described in the diabetic pig pharmacokinetic/pharmacodynamic model described in section (c) of General Methods.
  • corresponding formulation is meant a standard formulation i.e. a commercially available formulation of the same insulin compound at a concentration of 100 U/ml such as Humalog® (for insulin lispro) or NovoRapid® (for insulin aspart) or Apidra® (for insulin glulisine).
  • a composition of the present invention wherein the insulin compound is insulin lispro is bioequivalent to a commercial formulation of insulin lispro at a concentration of 100 U/ml e.g. an aqueous formulation consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 ⁇ g/ml, excluding counter-ion) adjusted to pH 7.3 (i.e. the formulation of Humalog®).
  • an aqueous formulation consisting of: insulin lispro (100 U/ml), sodium phosphate (13.2 mM), glycerol (174 mM), m-cresol (29 mM), ionic zinc (19.7 ⁇ g/ml, excluding counter-ion) adjusted to pH 7.3 (i.e. the formulation of Humalog®).
  • a composition of the present invention wherein the insulin compound is insulin aspart is bioequivalent to a commercial formulation of insulin aspart at a concentration of 100 U/ml e.g. an aqueous formulation consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (197 ⁇ g/ml, excluding counter-anion) adjusted to pH 7.4 (i.e. the formulation of NovoRapid®).
  • an aqueous formulation consisting of: insulin aspart (100 U/ml), sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (197 ⁇ g/ml, excluding counter-anion) adjusted to pH 7.4 (i
  • a formulation of the invention for use in the treatment of a subject suffering from diabetes mellitus.
  • a method of treatment of diabetes mellitus which comprises administering to a subject in need thereof an effective amount of a formulation of the invention.
  • a typical insulin dose of the composition of the invention is 2-30 U, e.g. 5-15 U.
  • Administration should suitably occur in the window between 15 minutes before eating (i.e. before start of a meal) and 15 minutes after eating (i.e. after end of a meal).
  • the formulation of the invention is co-administered with a long acting insulin such as insulin glargine or insulin degludec, suitably at a concentration of 50-1000 U/ml e.g. 100-500 U/ml or 100-200 U/ml.
  • a long acting insulin such as insulin glargine or insulin degludec
  • the composition of the invention is for administration by intravenous injection or infusion, or subcutaneous or intramuscular injection. In one embodiment, the composition of the invention is not for administration by intranasal delivery.
  • An aspect of the invention is a container e.g. made of plastics or glass containing one dose or a plurality of doses of the formulation of the invention.
  • the container can, for example, be a cartridge designed to be a replaceable item for use with an injection device.
  • the formulations of the invention may suitably be packaged for injection, especially sub-cutaneous or intramuscular injection.
  • Sub-cutaneous injection is preferred.
  • Injection may be by conventional syringe or more preferably via a pen device adapted for use by diabetic subjects.
  • Exemplary pen devices include the Kwikpen® device and the Flexpen® device.
  • An aspect of the invention is an injection device, particularly a device adapted for subcutaneous or intramuscular injection, for single or multiple use comprising a container containing one dose or a plurality of doses of the formulation of the invention together with an injection needle.
  • the container is a replaceable cartridge which contains a plurality of doses.
  • the needle is replaceable e.g. after each occasion of use.
  • Another aspect of the invention is a medical device comprising a reservoir comprising a plurality of doses of the formulation of the invention and a pump adapted for automatic or remote operation such that upon automatic or remote operation one or more doses of the formulation of the invention is administered to the body e.g. subcutaneously or intramuscularly.
  • a medical device comprising a reservoir comprising a plurality of doses of the formulation of the invention and a pump adapted for automatic or remote operation such that upon automatic or remote operation one or more doses of the formulation of the invention is administered to the body e.g. subcutaneously or intramuscularly.
  • Such devices may be worn on the outside of the body or implanted in the body.
  • Formulations of the invention may be prepared by mixing the ingredients.
  • the insulin compound may be dissolved in an aqueous formulation comprising the other components.
  • the insulin compound may be dissolved in a strong acid (typically HCl), after dissolution diluted with an aqueous formulation comprising the other components, and then pH adjusted to the desired pH with addition of alkali (e.g. NaOH).
  • a step of neutralising the acid solution may be performed before the dilution step and it may then not be necessary to adjust the pH after the dilution step (or a small adjustment only may be necessary).
  • a dry solid pharmaceutical composition suitable for reconstitution with an aqueous medium which comprises, following reconstitution, (i) an insulin compound at a concentration of 500-1000 U/ml, (ii) ionic zinc e.g. at a concentration of 0.05% or more e.g.
  • a formulation suitably has ionic strength of less than 40 mM, said ionic strength being calculated using the formula:
  • a method of accelerating the onset of action of an aqueous liquid pharmaceutical formulation comprising (i) an insulin compound at a concentration of 500-1000 U/ml, (ii) ionic zinc, and (iii) a non-ionic surfactant; which comprises adding to the formulation a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C.
  • a zinc binding species at a concentration of 1 mM or more selected from species having a logK with respect to zinc ion binding in the range 4.5-12.3 at 25° C. to accelerate the onset of action of an aqueous liquid pharmaceutical formulation comprising (i) an insulin compound at a concentration of 500-1000 U/ml (ii) ionic zinc, and (iii) a non-ionic surfactant, wherein the formulation is substantially free of EDTA and any other zinc binding species having a logK with respect to zinc ion binding of more than 12.3 at 25° C.
  • Ultra-high performance size exclusion chromatography of insulin preparations was performed using the Waters ACQUITY H-class Bio UPLC® system with a 1.7 ⁇ m Ethylene Bridged Hybrid 125 ⁇ pore packing material in a 300 mm by 4.6 mm column.
  • the column was equilibrated in 0.65 mg/ml L-arginine, 20% v/v acetonitrile, 15% v/v glacial acetic acid mobile phase and 10 ⁇ l of sample, acidified with 0.01M HCl, was analysed at 0.4 mL/min, with 276 nm UV detection. All analyses were performed at ambient temperature.
  • Ultra-high performance reverse phase chromatography was performed using the Waters ACQUITY H-class Bio UPLC® system with a 1.7 ⁇ m Ethylene Bridged Hybrid particle, 130 ⁇ pore resin trifunctionally immobilised with a C18 ligand in a 50 mm by 2.1 mm column. Insulin samples were bound in a 82% w/v Na 2 SO 4 , 18% v/v acetonitrile, pH 2.3 mobile phase and eluted in 50% w/v Na 2 SO 4 , 50% v/v acetonitrile gradient flow. 2 ⁇ l of sample was acidified with 0.01M HCl and analysed at 0.61 mL/min, with 214 nm UV detection. All analyses were performed at 40° C.
  • mice 10 male diabetic Yucatan miniature pigs were used. Pigs were injected subcutaneously with a sample of the test formulation and blood was taken (1 or 2 ml) at various time-points (min) with respect to the injection up to around 240 min after the injection.
  • serum was analysed for glucose (using a commercially available glucometer).
  • insulin concentration was determined in the serum using an immunoassay.
  • Visible particles are suitably detected using the 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles).
  • the apparatus required consists of a viewing station comprising:
  • any adherent labels are removed from the container and the outside washed and dried.
  • the container is gently swirled or inverted, ensuring that air bubbles are not introduced, and observed for about 5 s in front of the white panel.
  • the procedure is repeated in front of the black panel. The presence of any particles is recorded.
  • the visual scores are ranked as follows:
  • samples with visual score 1-3 Whilst the particles in samples with visual scores 4 and 5 are clearly detectable on casual visual assessment under normal light, samples with visual score 1-3 generally appear as clear solutions on the same assessment. Samples with visual scores 1-3 are considered to be “Pass”; samples with visual score 4-5 are considered to be “Fail”.
  • Insulin aspart 1000 U/ml Sodium phosphate 2 mM phenol 15.9 mM m-cresol 15.9 mM Ionic zinc (as ZnCl 2 ) 197 ⁇ g/ml (3 mM), equals 0.55% (w/w) based on the weight of insulin compound in the formulation Citric acid 44 mM Glycerol 174 mM Surfactant Selected from A1, A2 or A3 (see below) Water for injection qs Residual NaCl Acidification and subsequent neutralisation during preparation results in formation of 2-4 mM NaCl pH adjusted to 7.4
  • Example A1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Insulin aspart 1000 U/ml Sodium phosphate 2 mM phenol 15.9 mM m-cresol 15.9 mM Ionic zinc (as ZnCl 2 ) 197 ⁇ g/ml (3 mM), equals 0.55% (w/w) based on the weight of insulin compound in the formulation Citric acid 44 mM Glycerol 174 mM Surfactant Selected from B1, B2 or B3 (see below) Water for injection qs Residual NaCl Acidification and subsequent neutralisation during preparation results in formation of 2-4 mM NaCl pH adjusted to 7.8
  • Example B1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Example C1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Example D1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Example E1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Example F1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Insulin aspart 1000 U/ml Sodium phosphate 2 mM phenol 15.9 mM m-cresol 15.9 mM Ionic zinc (as ZnCl 2 ) 197 ⁇ g/ml (3 mM), equals 0.55% (w/w) based on the weight of insulin compound in the formulation TETA 5 mM Glycerol 174 mM
  • Surfactant Selected from G1, G2 or G3 (see below) Water for injection qs Residual NaCl Acidification and subsequent neutralisation during preparation results in formation of 2-4 mM NaCl pH adjusted to 7.4
  • Example G1: surfactant dodecyl maltoside (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Insulin aspart 1000 U/ml Sodium phosphate 2 mM phenol 15.9 mM m-cresol 15.9 mM Ionic zinc (as ZnCl 2 ) 197 ⁇ g/ml (3 mM), equals 0.55% (w/w) based on the weight of insulin compound in the formulation DETA 5 mM Glycerol 174 mM
  • Example I1: surfactant dodecyl malto side (0.05 mg/ml)
  • surfactant polysorbate 20 (Tween 20) (0.05 mg/ml)
  • surfactant polyethylene glycol (2) dodecyl ether (Brij L4) (0.05 mg/ml)
  • Insulin powder is added to water and HCl is added until the powder is fully dissolved (pH has to be ⁇ 3 in order to achieve full dissolution).
  • ZnCl2 is added to the required level. Once dissolved, pH is adjusted to approximately 7 and volume is adjusted with water so that the insulin concentration is 2 ⁇ the required concentration. The composition is then mixed 1:1 (v/v) with a mixture of additional excipients (all at 2 ⁇ the required concentration).
  • Stability of insulin aspart 1000 U/ml was investigated in formulations comprising trisodium citrate (44 mM), L-histidine (22 mM) or pyrophosphate (22 mM), both in the presence and in the absence of dodecyl maltoside or polysorbate 80. All compositions (except control based on NovoRapid® composition, see below) further comprised phenol (15.9 mM), m-cresol (15.9 mM), sodium phosphate (2 mM), glycerol (174 mM), sodium chloride (10 mM) and ionic zinc (197 ⁇ g/ml, excluding counter-anion, as ZnCl2) and were adjusted to pH 7.4.
  • a formulation of insulin aspart (1000 U/ml) in the composition of the 100 U/ml commercial insulin aspart product (NovoRapid®) was also included in the study.
  • This formulation was prepared using the same procedure as that used for all other 1000 U/ml formulations studied in this experiment and contained the excipients of the commercial NovoRapid® product.
  • the concentration of ionic zinc was adjusted to ensure the ratio between insulin aspart and ionic zinc was the same as that in the 100 U/ml NovoRapid® product.
  • the formulation thus comprised sodium phosphate (7 mM), glycerol (174 mM), sodium chloride (10 mM), phenol (15.9 mM), m-cresol (15.9 mM) and ionic zinc (197 ⁇ g/ml, excluding counter-anion) and was adjusted to pH 7.4.
  • the formulations comprised either glycerol (174 mM) or NaCl (150 mM) or a mixture of glycerol and NaCl as a tonicity modifier (See Table 2).
  • concentration of glycerol in the formulations comprising a mixture of glycerol and NaCl was less than 174 mM so that the overall osmolarity of the compositions remained the same as in the compositions comprising glycerol only.
  • compositions comprising glycerol (174 mM) and glycerol (154 mM)/NaCl (10 mM) mixture as tonicity modifiers Whilst only a small difference was observed between compositions comprising glycerol (174 mM) and glycerol (154 mM)/NaCl (10 mM) mixture as tonicity modifiers, a composition comprising glycerol (154 mM)/NaCl (50 mM) mixture showed a considerably impaired stability at 2-8° C.
  • Example 4 Comparison of the Source of Citrate and the pH of the Formulation on the Stability of Insulin Aspart (1000 U/Ml)
  • Citric acid and trisodium citrate were compared as the source of the citrate anion.
  • the formulation comprising citric acid was tested at pH 7.8 and the formulation comprising trisodium citrate was tested at pH 7.4.
  • Both formulations further comprised phenol (15.9 mM), m-cresol (15.9 mM), sodium phosphate (2 mM), glycerol (174 mM), dodecyl maltoside (50 ⁇ g/ml) and ionic zinc (197 ⁇ g/ml, excluding counter-anion, as ZnCl2).
  • Ionic Citric strength* T 0 2-8° C. 30° C. 30° C. 37° C. acid (mM) weeks (8 weeks) (4 weeks) (8 weeks) (4 weeks) 0 mM 14.84 1 1 1 1 3 11 mM 14.84 1 1 1 1 3 22 mM 14.84 1 1 1 2 3 33 mM 14.84 1 1 1 2 3 44 mM 14.84 1 1 1 2 3 *ionic strength calculation takes into account all ions in the formulation except for the zinc binding species (citric acid) and the insulin compound using formula Ia.
  • Example 6 Investigation of the Optimal Concentration of Dodecyl Maltoside and Polysorbate 80 on the Stability of Insulin Aspart (1000 U/Ml) in the Presence of Different Concentrations of Citric Acid
  • the stability of insulin aspart was investigated in the presence of different concentrations of citric acid and different concentrations of either dodecyl maltoside or polysorbate 80. All formulations tested further comprised phenol (15.9 mM), m-cresol (15.9 mM), sodium phosphate (2 mM), glycerol (174 mM) and ionic zinc (197 ⁇ g/ml, excluding counter-anion, as ZnCl2) and were adjusted to pH 7.8. Three concentrations of citric acid (44, 66 and 88 mM) and four concentrations of each non-ionic surfactant were tested as well as corresponding surfactant-free compositions.
  • the rate of particle formation in formulations of insulin aspart (1000 U/ml) was found to be proportional to citric acid concentration in the range between 44 and 88 mM, with the lower citric acid concentration of 44 mM being most suitable (Table 5). Whilst the presence of both dodecyl maltoside and polysorbate 80 led to a reduction in the rate of particle formation, dodecyl maltoside was found more effective in inhibiting the particle formation than polysorbate 80. The lower concentrations of dodecyl maltoside (0.05 and 0.1 mg/ml) appeared to be more effective in inhibiting the particle formation than higher concentrations (0.2 and 0.3 mg/ml). In contrast, in the case of polysorbate 80 it was the higher concentrations (0.3 and 0.5 mg/ml) that showed a greater ability to reduce the particle formation rate than the lower concentrations (0.05 and 0.1 mg/ml).
  • Example 7 Comparison of Pharmacodynamic and Pharmacodynamic Profiles of Insulin Aspart (100 and 1000 U/Ml) Formulations in the Presence and in the Absence of Citrate and Dodecyl Maltoside
  • Insulin Sodium Ionic Trisodium Dodecyl aspart phosphate NaCl Glycerol zinc* citrate maltoside Formulation (U/ml) (mM) (mM) ( ⁇ g/ml) (mM) (mg/ml) 7A 100 7 10 174 19.7 7B 1000 7 10 174 197 7C 1000 2 150 197 22 0.1 7D 1000 2 150 197 44 0.1 *Does not include the contribution of counter-anion
  • Pharmacodynamic profiles of formulations 7A-7D are shown in FIG. 1 . It was shown that increasing the concentration of insulin aspart from 100 U/ml to 1000 U/ml in the formulation of the marketed NovoRapid® product led to a slower onset of action. This is in line with previous reports of dose-dependent delays of the glucose reduction effect of rapid-acting insulins (e.g. de la Pefia et al. Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects, Diabetes Care, 34, pp 2496-2501, 2011). It was also shown ( FIG.
  • formulations 7A, 7B and 7D were in line with the pharmacodynamic profiles, showing that increasing the concentration of insulin aspart from 100 U/ml to 1000 U/ml in the formulation of the marketed NovoRapid® product led to a slower increase in serum insulin level, whereas the formulation comprising 44 mM trisodium citrate and 0.1 mg/ml dodecyl maltoside resulted in a profile that was comparable with that achieved by the formulation of the marketed NovoRapid® product (100 U/ml).
  • the pharmacokinetic profile of Formulation 7C was not tested.
  • T MAX and T 1/2MAX mean values and standard deviations (SD) relating to the pharmacokinetic profiles of formulations 7A, 7B and 7D are shown in Table 7 below.
  • T MAX and T 1/2MAX mean values and standard deviations (SD) relating to the pharmacokinetic profiles of formulations 7A, 7B and 7D.
  • Formulation 7A and 7D were shown to be bioequivalent, whereas formulations 7A and 7B and formulations 7B and 7D were shown to be non-bioequivalent.
  • SEQ ID NO: 1 GIVEQCCTSICSLYQLENYCN
  • SEQ ID NO: 2 FVNQHLCGSHLVEALYLVCGERGFFYTPKT
  • SEQ ID NO: 3 FVNQHLCGSHLVEALYLVCGERGFFYTKPT
  • SEQ ID NO: 4 FVNQHLCGSHLVEALYLVCGERGFFYTDKT
  • SEQ ID NO: 5 FVKQHLCGSHLVEALYLVCGERGFFYTPET

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CA3094237A1 (en) 2018-04-04 2019-10-10 Arecor Limited Medical infusion pump system for the delivery of an insulin compound
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