EP3142686A2 - Schnell wirkende insulinzusammensetzung mit einer substituierten anionischen verbindung und einer polyanionischen verbindung - Google Patents

Schnell wirkende insulinzusammensetzung mit einer substituierten anionischen verbindung und einer polyanionischen verbindung

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Publication number
EP3142686A2
EP3142686A2 EP15726556.2A EP15726556A EP3142686A2 EP 3142686 A2 EP3142686 A2 EP 3142686A2 EP 15726556 A EP15726556 A EP 15726556A EP 3142686 A2 EP3142686 A2 EP 3142686A2
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EP
European Patent Office
Prior art keywords
radical
anionic compound
compound
substituted anionic
formula
Prior art date
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EP15726556.2A
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English (en)
French (fr)
Inventor
Olivier Soula
Richard Charvet
Bertrand Alluis
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Adocia SAS
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Adocia SAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic

Definitions

  • the present invention relates to a fast-acting insulin composition
  • a fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound.
  • One of the problems to be solved to improve the health and comfort of diabetic patients is to provide them with insulin formulations which make it possible to provide a hypoglycemic response that is faster than that of human insulin and, if possible, approaching the physiological response of the healthy person.
  • the secretion of endogenous insulin in the healthy individual is immediately triggered by the increase in blood glucose.
  • the goal is to minimize the time between insulin injection and the start of the meal.
  • the principle of fast analogous insulins is to form hexamers at a concentration of 100 IU / mL to ensure the stability of insulin in the commercial product while promoting the very rapid dissociation of these hexamers into monomers after injection sub- cutaneous to obtain rapid action.
  • Human insulin as formulated in its commercial form, does not allow to obtain a close hypoglycemic response in terms of kinetics of the physiological response generated by the start of a meal (increase in blood sugar), because at the concentration of use (100 IU / mL), in the presence of zinc and other excipients such as phenol or m-cresol, it assembles in hexamer form while it is active in the form of monomer and dimer.
  • Human insulin is prepared in the form of hexamers to be stable for 2 years at 4 ° C because in the form of monomers, it has a very high propensity to aggregate and fibrillate which makes it lose its activity. Moreover, in this aggregated form, it presents an immunological risk for the patient.
  • polysaccharides described in applications WO 2010 / 122385A1 and US 2012 / 094902A1 as excipients are compounds consisting of chains whose lengths are statistically variable and which have a great wealth of possible interaction sites with protein active ingredients. This richness could induce a lack of specificity in terms of interaction and a smaller and better defined molecule could allow to be more specific on this subject.
  • a molecule with a well-defined skeleton is generally more easily traceable (MS / MS for example) in biological media during pharmacokinetic or ADME experiments (administration, distribution, metabolism, elimination) by compared to a polymer that generally gives a very diffuse and noisy signal in mass spectrometry.
  • the Applicant has, however, succeeded in developing formulations that can accelerate insulin using a substituted anionic compound in combination with a polyanionic compound.
  • the hexameric nature of the insulin is not affected, so the stability of the formulations is not affected, as is confirmed by the examples of a combination state of human insulin or lispro analog insulin in circular dichroism in the presence of substituted anionic compounds according to the invention, and optionally of polyanionic compound.
  • the present invention solves the various problems described above, in whole or in part, since it can in particular to achieve an insulin formulation, human or the like, capable after administration, to accelerate the passage of human insulin or its analogues in the blood and reduce blood sugar more rapidly compared to the corresponding commercial insulin products.
  • the invention consists of a composition, in the form of an aqueous solution, comprising insulin in hexameric form, at least one substituted anionic compound of non-saccharide structure and at least one polyanionic compound different from said substituted anionic compound.
  • the pH of the composition is between 6 and 8.
  • aqueous solution is meant a solution within the meaning of the European Pharmacopoeia.
  • the solution according to the invention can thus meet the European Pharmacopoeia 8.0 which defines an injectable preparation of soluble insulin has the characteristics of colorless liquid, non-opalescent, free of foreign substances; of the traces of very fine sediments that can be deposited during storage (01/2008: 0834).
  • the solution according to the invention may be a non-opalescent liquid, or even clear.
  • a liquid is considered limpid when it has an opalescence which is not more pronounced than that of the control suspension I, which has an opalescence value of 3 NTU.
  • the opalescence of the solution can be determined by the visual method and / or by the instrumental method, called turbidimetry. These methods are defined in European Pharmacopoeia 8.0 under 2.2.1.
  • the solution according to the invention has a turbidity less than or equal to 3 NTU according to the different methods described in European Pharmacopoeia 8.0 in section 2.2.1.
  • non-saccharide structure is meant that these compounds do not contain in their saccharide unit structure, whether in cyclic form or in open, reduced or oxidized form.
  • saccharide unit is meant pentoses, hexoses, uronic acids, and N-acetylhexosamines in cyclic form or in open form, oxidized or reduced.
  • compositions according to the invention are sterilized by 0.22 ⁇ m membrane filtration, for example by filtration on a SLGV033RS membrane, Millex-GV from Millipore, 0.22 ⁇ m PVDF membrane.
  • the pH of the composition is between 6 and 8.
  • the composition according to the invention is characterized in that the substituted anionic compound of non-saccharide structure comprises a hydrocarbon radical R at least monovalent comprising from 3 to 12 carbon atoms, optionally comprising at least one a function chosen from ether, alcohol and carboxylic acid functions,
  • said hydrocarbon radical R carrying at least one AA radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative comprising a phenyl group or an indole group, substituted or unsubstituted, said AA radical being attached to the hydrocarbon radical R:
  • a function F chosen from amide, carbamate or urea functions, resulting from a reaction between the amine of the amino acid aromatic and a function of the precursor of the hydrocarbon radical R chosen from carboxylic acid, amine and alcohol functions,
  • spacer E which is an at least divalent radical, comprising from 2 to 6 carbon atoms, E being linked on the one hand to the hydrocarbon radical R by a function F 'chosen from amide, carbamate or urea functions, and linked on the other hand to the AA radical by a function F "chosen from amide, carbamate and urea functions, resulting from a reaction between the amine of the aromatic amino acid and a function of the spacer E selected from the functions carboxylic acid, amine and alcohol,
  • said substituted anionic compound comprising at least two carboxylic acid functions in the form of alkali metal salt salts selected from the group consisting of Na + and K
  • E is an at least divalent radical, linear or branched alkyl.
  • E represents a linear or branched, saturated or unsaturated hydrocarbon radical comprising from 2 to 6 carbon atoms, optionally comprising at least one functional group chosen from alcohol and carboxylic acid functional groups.
  • the composition according to the invention is characterized in that the substituted anionic compound of non-saccharide structure comprises a hydrocarbon radical R at least monovalent comprising from 3 to 12 carbon atoms, optionally comprising at least one a function chosen from ether, alcohol and carboxylic acid functions,
  • said hydrocarbon radical R carrying at least one AA radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative comprising a phenyl group or an indole group, substituted or unsubstituted, said AA radical being attached to the hydrocarbon radical R:
  • a function F chosen from amide, carbamate or urea functions, resulting from a reaction between the amine of the aromatic amino acid and a function of the precursor of the hydrocarbon radical R chosen from carboxylic acid, amine and alcohol,
  • spacer E which is a divalent radical comprising from 2 to 6 carbon atoms, E being linked on the one hand to the hydrocarbon radical R by a function F 'chosen from amide, carbamate or urea functions, and linked to other part of the AA radical by a function F "chosen from amide, carbamate and urea functions, resulting from a reaction between the amine of the aromatic amino acid and a function of the spacer E selected from the carboxylic acid, amine and alcohol functions,
  • said substituted anionic compound comprising at least two carboxylic acid functions in the form of alkali metal salt salts selected from the group consisting of Na + and K *.
  • composition according to the invention is characterized in that the substituted anionic compound corresponds to the following Formula I:
  • R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions,
  • AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function,
  • E represents an at least divalent radical, comprising from 2 to 6 carbon atoms
  • F, F ', F independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of the AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E,
  • p being an integer from 1 to 3
  • n is an integer from 0 to 6
  • m + n is an integer from 1 to 6;
  • said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na + and K + .
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least 2 carboxylic acid functions in the form of an alkali metal salt are carried by the radicals R, AA or E.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkali are carried by radicals R and E.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkali are carried by the radicals R and AA.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkaline are carried by the radicals AA and E.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkali are carried by the radical R, comprising 3 to 12 carbon atoms,.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkaline are carried by the radical AA.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of a metal salt. alkaline are carried by the radical E.
  • composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which, E is an at least divalent radical, linear or branched alkyl.
  • the composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which, E represents a linear or branched, saturated or unsaturated hydrocarbon radical comprising from 2 to 6 carbon atoms, optionally comprising at least one functional group chosen from alcohol and carboxylic acid functions,
  • composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F is chosen from amide or carbamate functions.
  • composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F is an amide function.
  • the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which F is a carbamate function.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F 'is a urea function.
  • F ' is an amide function
  • the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which F 'is a carbamate function.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F and F 'are chosen from amide or carbamate functions.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F and F 'are amide functions.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F and F 'are carbamate functions.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F "is a urea function.
  • F is an amide function
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F "is a carbamate function. In one embodiment, the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which F 'is an amide function and F "is a carbamate function.
  • composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the anionic compound known as:
  • R represents a hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions,
  • AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having a free acid function,
  • E represents a radical comprising from 2 to 6 carbon atoms
  • F, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a radical AA,
  • p being an integer from 1 to 3
  • n is an integer from 0 to 6
  • m + n is an integer from 1 to 6;
  • said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na + and K + .
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radicals R, AA or E.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the radicals R and E.
  • the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and AA.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radicals AA and E.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radical R, comprising 3 to 12 carbon atoms,
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radical AA.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radical E.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which E is an at least divalent radical, linear or branched alkyl.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which E represents a linear or branched, saturated or unsaturated hydrocarbon radical containing from 2 to 6 carbon atoms. , optionally comprising at least one functional group chosen from alcohol and carboxylic acid functions,
  • the composition is characterized in that the substituted anionic compound is chosen from compounds of formula I in which the radical R may comprise from 4 to 10 carbon atoms, in particular from 4 to 6 atoms. of carbon.
  • the radical R comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated.
  • the radical R comprising 3 to 12 carbon atoms, is a saturated linear hydrocarbon radical.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when it is bisubstituted, is chosen from the compounds of formula I in which radical -R- is chosen from radicals comprising 3 to 12 carbon atoms,
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is equal to 0 or 1, when the groups R qt , R q2 , R r i and R r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least two groups R q or R r are -COOH.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in wherein the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV:
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a 3 ⁇ q + r * t ⁇ 12, a is 0 or 1, when q R i, R q2, R r and R i r2 are independently of each other, selected from -H, -OH or -COOH; 2 ⁇ q + r * t ⁇ 12, a is 0 or 1, when the groups R q1 , R q2 , R r1 and R r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R q or R r is -COOH.
  • a is 0 or 1, where the groups R ql, q2 R, R and R rl r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R q or R r groups are -COOH.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in wherein the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV ": Formula IV "in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is 0 or 1, when the groups R q1 , R q2 , R r1 and R r2 are, independently of one another, selected from -H, -OH, - COOH; 1 ⁇ q + r * t ⁇ 11, a is 0 or 1, when the groups R q , R q2 , R r i and R r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R q or R r is -COOH.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound, when monosubstituted, is chosen from the compounds of formula I in wherein the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV ":
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is 0 or 1 where the groups R ql, q2 R, R r and R i r2 are independently of each other, selected from -H, -OH, or -COOH and at least two groups R q or R r are -COOH.
  • q is an integer between 3 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH, -COOH;
  • - q is an integer between 2 and 12, when the R i groups and R q q2 are independently from each other selected from -H, -OH and -COOH and at least one Rq is -COOH.
  • q is an integer between 1 and 12, when the groups R q1 and R q2 are, independently of each other, chosen from -H, -OH and -COOH and at least two R q are -COOH.
  • q is an integer between 3 and 12, when the groups q 1 and R q 2 are, independently of one another, chosen from -H, -OH, -COOH;
  • - q is an integer between 2 and 12, when the groups R qi and R q2 are, independently of each other, selected from -H, -OH and -COOH and at least one Rq is a -COOH.
  • - q is an integer between 1 and 12, where R q] and q2 R groups are independently from each other selected from -H, -OH and -COOH, and at least two R q are -COOH .
  • - q is an integer between 2 and 11, when the R qi and q2 R groups are independently from each other selected from -H, -OH, -COOH;
  • R q is an integer between 1 and 11, when the groups R q1 and R q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one R q is a -COOH.
  • - q is an integer between 3 and 12, when the groups R i and R q2 q are independently of each other, selected from -H, -OH, -COOH;
  • R q is an integer between 2 and 12, when the groups R qi and R q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one R q is a -COOH.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the substituted anionic compound is chosen from the compounds of formula I in which the radical -R- is a radical derived from a compound comprising 3 to 12 + (m + n) carbon atoms.
  • -X and -Y are the same or different reactive functions that react with the precursor of E or AA to form F 'or F, respectively, and are selected from -COOH, -OH, -IMH2,
  • R q i and R q ⁇ are, independently of one another, selected from -H, -OH, -COOH,
  • -X and -Y are the same or different reactive functions that react with the precursor of E or AA to form F 'or F, respectively, and are selected from -COOH, -OH, -IMH2,
  • -X and -Y are the reactive functions which react with the precursor of E or AA to form F 'or F, respectively.
  • the precursor of R is chosen from the precursors of formula VI or VII in which -X and -Y, identical or different, are chosen from -COOH, -OH.
  • the radical R comprising 3 to 12 carbon atoms, may comprise at least one function, in particular chosen from alcohol and carboxylic acid functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises o carboxylic acid functions, o being an integer between 1 and 3, in particular o being equal to 1 or 2, and in particular o is 1.
  • the radical R comprising 3 to 12 carbon atoms, is devoid of carboxylic acid functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises at least one alcohol function, in particular it comprises from 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions.
  • the radical R comprising 3 to 12 carbon atoms, is devoid of alcohol function.
  • the radical R comprising 3 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.
  • the radical R comprising 3 to 12 carbon atoms, may come from a polycarboxylic acid, especially a dicarboxylic acid.
  • all the carboxylic acid functions of the polycarboxylic acid are involved in the functions F and F '.
  • all the carboxylic acid functions of the precursor of R are involved in the functions F and F '.
  • all the carboxylic acid functions of the polycarboxylic acid are not involved in the functions F and F '.
  • 1 or 2 carboxylic acid functions are not involved in the functions F and F ', especially 1 carboxylic acid function is not involved in the functions F and F'.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, pentanedioic acid, hexanedioic acid (or adipic acid), heptanedioic acid, octanedioic acid, nonanedioic acid, butenedioic acid, pentenedioic acid, and hexadienedioic acid.
  • a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, pentanedioic acid, hexanedioic acid (or adipic acid), heptanedioic acid, octanedioic acid, nonanedioic acid, butenedioic acid, pentenedioic acid, and he
  • the radical R comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, and acid. pentanedioic acid and hexanedioic acid (or adipic acid).
  • the radical R comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid) or tartaric acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from an amino acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from an amino acid selected from glutamic acid and aspartic acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from a diol.
  • the diol may be chosen from diethylene glycol, triethylene glycol and tetraethylene glycol, propane diol, butanediol, pentanediol, hexanediol, heptane diol and octane diol.
  • the radical R comprising 3 to 12 carbon atoms, of the substituted anionic compound is derived from a dicarboxylic acid, an amino acid or a diol.
  • the AA radical is derived from an aromatic amino acid comprising a substituted or unsubstituted phenyl or indole, or an aromatic amino acid derivative.
  • FIRE I LLE OF REM PLACEM ENT (RULE 26) having substituted or unsubstituted phenyl or indole.
  • the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.
  • the radical AA is linked to the radical E or the radical R by a function F or F "involving the amine of the aromatic amino acid or an aromatic amino acid derivative.
  • aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole
  • a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amine function and a functional group. acid.
  • aromatic amino acid derivative is meant the decarboxylated derivatives, amino-alcohol derivatives, or amino-amides corresponding to aromatic amino acids having a phenyl or a substituted or unsubstituted indole.
  • the derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.
  • AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids.
  • the aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.
  • the aromatic amino acid comprising a phenyl or an indole, substituted or unsubstituted is a natural amino acid, especially chosen from phenylalanine, tyrosine and tryptophan, especially phenylalanine.
  • aromatic amino acids comprising a phenyl or a substituted or unsubstituted indole and their derivatives may, where appropriate, be in laevorotatory, dextrorotatory or racemic form. In particular they are in laevorotic form.
  • the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.
  • the composition is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the radical E is derived from a linear or branched alkyl compound comprising at least two functions chosen from the group consisting of -OH, -COOH, -NH 2 .
  • the radical E is derived from a compound comprising from 2 to 6 carbon atoms, and optionally comprising 1 or 2 carboxylic acid functions and / or 1, 2 or 3 alcohol functions.
  • the radical E is a radical at least divalent, in particular divalent, trivalent or tetravalent.
  • the radical E is derived from a linear or branched alkyl compound, optionally carrying one or two carboxylic acid functions.
  • the radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3. propanediol or TRIS, serinol, and threoninol.
  • radical E when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.
  • the radical E may be derived from an amino acid comprising two carboxylic acid functions, in particular aspartic acid or glutamic acid.
  • the radical E can be linked to one or two AA radicals.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E does not comprise an -NH 2 function.
  • composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the radical E is different from the radical R.
  • composition according to the invention is characterized in that the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E is different from the precursor of the radical R.
  • the composition according to the invention is characterized in that the substituted anionic compound comprises from 2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.
  • the substituted anionic compound does not comprise an AA radical bonded via a spacer E.
  • the substituted anionic compound does not comprise an AA radical bonded via the F function to the radical R.
  • the radical R comprising 3 to 12 atoms of carbon, is derived from tartaric or succinic acid and comprises an acid function where R is a radical derived from a diol.
  • the radical R comprising 3 to 12 carbon atoms, is derived from tartaric or succinic acid and comprises an acid function or the radical R, comprising 3 to 12 carbon atoms, is a radical derived from a diol.
  • the composition is characterized in that the molar ratios of substituted anionic compound / insulin are between 0.6 and 300.
  • the composition is characterized in that the molar ratios of substituted anionic compound / insulin are between 0.6 and 120.
  • the composition is characterized in that the molar ratios substituted anionic compound / insulin are between 0.7 and 80.
  • the composition is characterized in that the molar ratios of substituted anionic compound / insulin are from 1.4 to 60.
  • the composition is characterized in that the molar ratios of substituted anionic compound / insulin are between 1.9 and 40.
  • the composition is characterized in that the molar ratios substituted anionic compound / insulin are between 2.3 and 40.
  • the composition is characterized in that the molar ratio of substituted anionic compound / insulin is equal to 8, 12 or 16.
  • the number of moles of insulin is understood as the number of moles of insulin monomer.
  • the composition is characterized in that the weight ratios substituted anionic compound / insulin are between 0.5 and 30.
  • the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 0.5 and 20.
  • the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 0.5 and 10.
  • the composition is characterized in that the weight ratios substituted anionic compound / insulin are between 0.6 and 7.
  • the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 1.2 and 5.
  • the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 1.6 and 4.
  • the composition is characterized in that the mass ratios substituted anionic compound / insulin are between 2 and 4.
  • the composition is characterized in that the weight ratio substituted anionic compound / insulin is 2, 3, 4 or 6.
  • the composition is characterized in that the insulin is human insulin.
  • human insulin insulin obtained by synthesis or recombination whose peptide sequence is the sequence of human insulin, including allelic variations and homologues.
  • the composition is characterized in that the insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
  • the composition is characterized in that the insulin is a similar insulin.
  • insulin analog is meant a recombinant insulin whose primary sequence contains at least one modification with respect to the primary sequence of human insulin.
  • the insulin analogue is selected from the group consisting of insulin lispro (Humalog ®), insulin aspart (Novolog ®, Novorapid ®) and insulin glulisine (Apidra).
  • the composition is characterized in that the insulin analog is insulin lispro (Humalog ® ).
  • the composition is characterized in that the insulin analogue is insulin aspart (Novolog®, Novorapid®).
  • the composition is characterized in that the insulin analog is insulin glulisine (Apidra ® ).
  • the composition is characterized in that the insulin is in hexameric form.
  • the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 240 and 3000 ⁇ (40 to 500 IU / ml).
  • the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 3000 ⁇ (100 to 500 IU / ml).
  • the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 2400 ⁇ (100 to 400 IU / mL).
  • the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 1800 ⁇ (100 to 300 IU / ml).
  • the composition is characterized in that the pharmaceutical composition is characterized in that the insulin concentration is between 600 and 1200 ⁇ (100 to 200 IU / ml).
  • the composition is characterized in that it relates to a pharmaceutical composition characterized in that the insulin concentration is 600 ⁇ (100 IU / ml), 1200 ⁇ (200 IU / ml), 1800 ⁇ (300 IU / mL), 2400 ⁇ M (400 IU / mL) or 3000 ⁇ M (500 IU / mL).
  • This dissociation constant is the reaction constant associated with the dissociation of the complex (PNP compound) r - (Ca 2+ ) s , that is to say at the following reaction: (PNP compound) r- ( Ca 2+ ) s r (PNP compound) + sCa 2+ .
  • the dissociation constants (Kd) of the various polyanionic compounds with respect to the calcium ions are determined by external calibration using a specific electrode for Calcium ions (Mettler Toledo) and a reference electrode. All measurements are carried out in 150 mM NaCl at pH 7. Only the concentrations of free calcium ions are determined; the calcium ions bound to the polyanionic compound do not induce electrode potential.
  • the composition is characterized in that the polyanionic compound is selected from the group consisting of polycarboxylic acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
  • the composition is characterized in that the polyanionic compound is an anionic molecule.
  • the composition is characterized in that the anionic molecule is selected from the group consisting of citric acid, aspartic acid, glutamic acid, malic acid and tartaric acid.
  • the composition is characterized in that the anionic molecule is citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ .
  • the composition is characterized in that the polyanionic compound is chosen from anionic compounds consisting of a saccharide skeleton formed of a discrete number u of between 1 and 8 (1 ⁇ u ⁇ 8). saccharide units, said saccharide units being selected from the group consisting of hexoses, cyclic form or open reduced form, identical or different, linked by identical or different glycosidic linkages substituted by carboxyl groups, and their salts.
  • the composition is characterized in that the polyanionic compound consisting of a saccharide skeleton formed by a discrete number of saccharide units is obtained from a disaccharide compound selected from the group consisting of trehalose, maltose, lactose, sucrose, cellobiose, isomaltose, maltitol and isomaltitol.
  • a disaccharide compound selected from the group consisting of trehalose, maltose, lactose, sucrose, cellobiose, isomaltose, maltitol and isomaltitol.
  • the composition is characterized in that the polyanionic compound consisting of a saccharide backbone formed by a discrete number of saccharide units is obtained from a compound consisting of a skeleton formed of a discrete number of saccharide units selected from the group consisting of maltotriose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, maltooctaose and iso maltotriose
  • the composition is characterized in that the polyanionic compound consisting of a saccharide skeleton formed by a discrete number of saccharide units is chosen from the group consisting of carboxymethylmaltotriose, carboxymethylmaltotetraose and carboxymethylmaltopentaose. carboxymethyl maltohexaose, carboxymethylmaltoheptaose, carboxymethylmaltooactose and carboxymethylisomaltotriose.
  • the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 100 mg / mL. 3
  • the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 50 mg / ml.
  • the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 36 mg / mL.
  • the composition is characterized in that the concentration of substituted anionic compound is between 1.8 and 36.5 mg / mL.
  • the composition is characterized in that the concentration of substituted anionic compound is between 2.1 and 25 mg / mL.
  • the composition is characterized in that the concentration of substituted anionic compound is between 4.2 and 18 mg / ml.
  • the composition is characterized in that the concentration of substituted anionic compound is between 5.6 and 15 mg / ml.
  • the composition is characterized in that the concentration of substituted anionic compound is between 7 and 15 mg / ml.
  • the composition is characterized in that the concentration of substituted anionic compound is 7.3 mg / mL.
  • the composition is characterized in that the concentration of substituted anionic compound is 10.5 mg / ml.
  • the composition is characterized in that the concentration of substituted anionic compound is 14.6 mg / mL.
  • the composition is characterized in that the concentration of substituted anionic compound is 21.9 mg / mL.
  • the composition is characterized in that the polyanionic compound concentration is between 2 and 150 mM.
  • the composition is characterized in that the polyanionic compound concentration is between 2 and 100 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 2 and 75 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 2 and 50 mM.
  • the composition is characterized in that the polyanionic compound concentration is between 2 and 30 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 2 and 20 mM.
  • the composition is characterized in that the polyanionic compound concentration is between 2 and 10 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 150 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 100 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 75 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 50 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 30 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 20 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 5 and 10 mM.
  • the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 30 mg / mL.
  • the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 25 mg / mL.
  • the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 10 mg / ml.
  • the composition is characterized in that the concentration of polyanionic compound is between 0.5 and 8 mg / ml.
  • the composition is characterized in that the concentration of polyanionic compound is between 1 and 30 mg / ml. In one embodiment, the composition is characterized in that the concentration of polyanionic compound is between 1.5 and 25 mg / ml.
  • the composition is characterized in that the concentration of polyanionic compound is between 2 and 25 mg / ml.
  • the composition is characterized in that the concentration of polyanionic compound is between 2 and 10 mg / ml.
  • the composition is characterized in that the concentration of polyanionic compound is between 2 and 8 mg / ml.
  • the composition is characterized in that the pH of the composition is between 6 and 8.
  • the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound as defined above, and citric acid or its Na + , K + , Ca 2+ or Mg 2+ salts, in particular as defined above.
  • the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula I as defined above, and citric acid or its salts of Na + , K + , Ca 2+ or Mg 2+ , especially as defined above.
  • the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula III as defined above, and citric acid or its salts of Na + , K + , Ca 2+ or Mg 2+ , especially as defined above.
  • the composition according to the invention comprises insulin, in particular as defined above, at least one substituted anionic compound corresponding to Formula IV as defined above, and citric acid or its salts of Na + , K + , Ca 2+ or Mg 2+ , especially as defined above.
  • the "regular" human insulin compositions on the market at a concentration of 600 ⁇ (100 IU / ml) have an action time of between 50 and 90 minutes and an end of action of about 360 to 420 minutes in humans.
  • the time to reach the maximum insulin concentration in the blood is between 90 and 180 minutes in humans.
  • the fast analogous insulin compositions on the market at a concentration of 600 ⁇ have an action time of between 30 and 60 minutes and an end of action of approximately 240-300 minutes. in humans.
  • the time to reach the maximum insulin concentration in the blood is between 50 and 90 minutes in humans.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of between 240 and 3000 ⁇ (40 and 500 IU / ml), the action time of which in humans is lower than that of the reference composition at the same insulin concentration in the absence
  • FIRE I LLE OF REM PLACEM ENT (RULE 26) substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition of at least one least one polyanionic compound.
  • the composition is characterized in that the insulin is in hexameric form.
  • the composition is characterized in that the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of between 600 and 1200 ⁇ (100 and 200 IU / ml), the action time of which in humans is lower than that of the reference composition at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of 600 ⁇ (100 IU / ml), whose action time in humans is less than 60 minutes characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of 1200 ⁇ (200 IU / ml), the action time of which in humans is less than 10% less than that of the composition of human insulin at the same concentration (200 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of 1800 ⁇ (300 IU / ml), the action time of which in humans is less than 10% less than that of the composition of human insulin at the same concentration (300 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of 2400 ⁇ (400 IU / ml), whose action time in humans is less than 10% less than that of the composition of human insulin at the same concentration (400 IU / ml) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition having an insulin concentration of 3000 ⁇ (500 IU / ml), the action time of which in humans is less than minus 10% to that of the composition of human insulin at the same concentration (500 IU / mL) and in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention consists in the preparation of a so-called rapid human insulin composition characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) ) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a human insulin composition at a concentration of 600 ⁇ (100 IU / ml) whose action time in humans is less than 60 minutes, preferably less than 45 minutes, and even more preferably less than 30 minutes, characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of addition to said composition of at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a similar insulin composition having an insulin concentration of between 240 and 3000 ⁇ (40 and 500 IU / ml), the action time of which in humans is lower than that of the reference composition at the same insulin concentration in the absence of substituted anionic compound and polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a similar insulin composition having an insulin concentration of between 600 and 1200 ⁇ (100 and 200 IU / ml), the action time of which in humans is lower than that of the reference composition at the same concentration of insulin analog in the absence of substituted anionic compound substituted anionic compound and polyanionic compound, characterized in that it comprises (1) a step of addition to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 600 ⁇ / L (100 IU / mL), the action time of which in humans is less than 30 minutes, characterized in that it comprises (1) a step of adding to said composition at least one substituted anionic compound, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 1200 ⁇ (200 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 1800 ⁇ (300 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing an insulin-like composition having an insulin concentration of 2400 ⁇ (400 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a method for preparing a similar insulin composition having an insulin concentration of 3000 ⁇ (500 IU / ml), the action time of which in humans is less than less than 10% to that of the composition of the insulin analogue in the absence of substituted anionic compound and of a polyanionic compound characterized in that it comprises (1) a step of adding to said composition at least one anionic compound substituted, and (2) a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention consists in the preparation of a so-called fast-acting analog insulin composition characterized in that it comprises a step of adding to said composition at least one substituted anionic compound, said compound comprising groups partially substituted carboxyl functional groups, unsubstituted carboxyl-functional groups being salifiable
  • the preparation further comprises a step of adding to said composition at least one polyanionic compound.
  • the insulin is in hexameric form.
  • the pH of the composition is between 6 and 8.
  • the invention relates to the use of at least one substituted anionic compound, in combination with a polyanionic compound, to prepare a pharmaceutical composition of human insulin, which, after administration, makes it possible to accelerate the passage of human insulin into the blood and to reduce blood glucose more quickly compared to a composition free of substituted anionic compound.
  • the invention relates to the use of at least one substituted anionic compound, in combination with a polyanionic compound, to prepare a similar insulin composition, allowing, after administration, to accelerate passage of the insulin analogue into the blood and to reduce blood glucose more rapidly compared to a composition free of substituted anionic compound.
  • the pH of the composition is between 6 and 8.
  • the invention also relates to a pharmaceutical composition according to the invention, characterized in that it is obtained by drying and / or lyophilization.
  • compositions according to the invention also comprise the addition of zinc salts at a concentration of between 0 and 500 ⁇ , in particular between 0 and 300 ⁇ , and in particular between 0 and 200 ⁇ . .
  • compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM, preferably between
  • the buffer is Tris.
  • compositions according to the invention further comprise preservatives.
  • the preservatives are selected from the group consisting of m-cresol and phenol alone or in admixture.
  • the concentration of preservatives is between 10 and 50 mM, especially between 10 and 40 mM.
  • compositions according to the invention may further comprise additives such as tonicity agents such as glycerine, sodium chloride (NaCl), mannitol and glycine.
  • tonicity agents such as glycerine, sodium chloride (NaCl), mannitol and glycine.
  • compositions according to the invention may further comprise additives according to the pharmacopoeia such as surfactants, for example polysorbate.
  • surfactants for example polysorbate.
  • compositions according to the invention may furthermore comprise all excipients compatible with the pharmacopoeia and compatible with the insulins used at the concentrations of use.
  • the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
  • the mode of administration is the subcutaneous route.
  • transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
  • the invention also relates to the use of a composition according to the invention for the composition of a human insulin solution or the like of a concentration of 100 IU / ml or 200 IU / ml intended for implantable insulin pumps. or transportable.
  • the invention also relates to the substituted anionic compounds as defined above.
  • the substituted anionic compound corresponds to the following Formula I:
  • R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical containing from 3 to 12 carbon atoms, comprising at least one functional group chosen from ether and alcohol functions, and possibly comprising a carboxylic acid function
  • AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function
  • - E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,
  • F, F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E, p being an integer between 1 and 3,
  • n is an integer from 0 to 6
  • m + n is an integer from 1 to 6;
  • said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na + and K + ,
  • the at least 2 carboxylic acid functions in the form of an alkali metal salt are borne by radicals R, AA or E.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the radicals R and E.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and AA.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the AA and E radicals.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radical R, comprising 3 to 12 carbon atoms.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the AA radical.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the radical E.
  • R comprises at least one carboxylic acid function. * represents the mathematical sign multiplication.
  • F is chosen from amide or carbamate functions.
  • F is an amide function
  • F is a carbamate function
  • F ' is a urea function
  • F ' is an amide function
  • F ' is a carbamate function.
  • F and F ' are chosen from amide or carbamate functions.
  • F and F 'are amide functions.
  • F and F 'are carbamate functions.
  • F is a urea function
  • F is an amide function
  • F is a carbamate function
  • F ' is an amide function and F "is a carbamate function.
  • the radical R comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated.
  • the radical R is a saturated linear hydrocarbon radical.
  • m + n 6.
  • m + n 5.
  • m + n 3.
  • m + n 2.
  • m + n 1.
  • the substituted anionic compound when bisubstituted, is chosen from the compounds of formula I in which the radical -R- is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV, comprising at least one function chosen from ether and alcohol functions:
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 3 ⁇ q + r * t ⁇ 12, a is 0 or 1, when the groups R q1 , R q2 , R r1 and R r2 are, independently of one another, selected from -H, -OH or - COOH; 2 ⁇ q + r * t ⁇ 12, a is 0 or 1, when the groups RR q2 , R r i and R r2 are, independently of one another, selected from -H, -OH, or -COOH and at least one R q or R r is -COOH.
  • a is equal to 0 or 1, when the groups RR q2 , R r i and R r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least two groups R q or R r are -COOH.
  • a is equal to 1.
  • the substituted anionic compound when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV, comprising at least one function selected from the ether functions
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is 0 or 1 when R qi, R q2, rl R and R r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R q or R r groups are -COOH.
  • a is equal to 1.
  • the substituted anionic compound when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms, of formula IV ", comprising at least one functional group chosen from ether and alcohol functions:
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is equal to 0 or 1, when the groups R q i, R q2 , R r i and R r2 are, independently of one another, chosen from -H, -OH, -COOH;
  • a is 0 or 1 where the groups R qlj R q2, R r and R i r2 are independently of each other, selected from -H, -OH, or - COOH and at least one R q or R r is -COOH.
  • a is equal to 1.
  • the substituted anionic compound when monosubstituted, is chosen from compounds of formula I in which the radical -R- comprising 3 to 12 carbon atoms is chosen from radicals comprising 3. to 12 carbon atoms of formula IV ", comprising at least one function selected from the functions
  • a is 0 or 1 when q R i, R q2, R r and R i r2 are independently of each other, selected from -H, -OH, or -COOH and at least two R q or R r groups are -COOH.
  • a is equal to 1.
  • q is an integer between 3 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH, and COOH,
  • - q is an integer between 2 and 12, when the R gl and q2 R groups are independently from each other selected from -H, -OH and -COOH and at least one R q is -COOH,
  • R q is an integer between 1 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R q are -COOH and at least one R q1 or R q2 is -OH.
  • - q is an integer between 3 and 12, when the R qi and q2 R groups are independently from each other selected from -H, -OH, and -COOH
  • - q is an integer between 2 and 12, when the groups R q and R q2 are independently from each other selected from -H, -OH and -COOH and at least one Rq is -COOH,
  • R q is an integer between 1 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R q are -COOH and at least one R q1 or R q2 is -OH.
  • - q is an integer between 2 and 11, when the groups R i and R q2 q are independently of each other, selected from -H, -OH, and -COOH
  • - q is an integer between 1 and 11, when the groups R i and R q2 q are, independently from each other selected from -H, -OH and -COOH and at least one R q is -COOH and at least one R q1 or R q2 is -OH.
  • - q is an integer between 3 and 12, when the R qi and q2 R groups are independently from each other selected from -H, -OH, and -COOH,
  • R q is an integer between 2 and 12, when the groups R q1 and R q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one R q is a -COOH,
  • R q is an integer between 1 and 12, when the groups R qi and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R q are -COOH and at least one R q1 or R q2 is -OH.
  • the substituted anionic compound is chosen from the compounds of formula I in which the radical -R- is a radical derived from a compound comprising 3 to 12 + (m + n) carbon atoms.
  • the radical R comprising 3 to 12 carbon atoms, comprises o carboxylic acid functions, o being an integer between 1 and 3, in particular o being equal to 1 or 2, and in particular o is 1.
  • the radical R comprising 3 to 12 carbon atoms, is free of carboxylic acid functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.
  • the radical R comprising 3 to 12 carbon atoms, can come from a polycarboxylic acid, especially a dicarboxylic acid. According to one embodiment, all the carboxylic acid functions of the polyoxycarboxylic acid are involved in the functions F and F '.
  • all the carboxylic acid functions of the polyoxycarboxylic acid are not involved in the functions F and F '.
  • 1 or 2 carboxylic acid functions are not involved in the functions F and F ', especially 1 carboxylic acid function is not involved in the functions F and F'.
  • the radical R comprising 3 to 12 carbon atoms, is derived from malic acid or tartaric acid.
  • the radical R comprising 3 to 12 carbon atoms, is derived from tartaric acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from a diol.
  • the diol may be chosen from diethylene glycol, triethylene glycol and tetraethylene glycol, propane diol, butanediol, pentanediol, hexanediol, heptane diol and octane diol.
  • the radical R comprising 3 to 12 carbon atoms, of the substituted anionic compound is derived from a carboxylic diacid, an amino acid or a diol.
  • the AA radical is derived from an aromatic amino acid having a phenyl or a substituted or unsubstituted indole, or an aromatic amino acid derivative having a phenyl or a substituted or unsubstituted indole.
  • the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.
  • the radical AA is linked to the radical E or the radical R by a function F or F "involving the amine of the aromatic amino acid or an aromatic amino acid derivative.
  • aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole
  • a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amino function and a functional group. acid.
  • aromatic amino acid derivative is intended to mean the decarboxylated derivatives, the amino-alcohol derivatives, or amino-amides corresponding to the aromatic amino acids comprising a substituted or unsubstituted phenyl or indole.
  • the derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.
  • AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids.
  • Aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.
  • the aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole is a natural amino acid, especially chosen from phenylalanine, tyrosine and tryptophan, especially phenylalanine.
  • aromatic amino acids comprising a phenyl or a substituted or unsubstituted indole, and their derivatives may, where appropriate, be in laevorotatory, dextrorotatory or racemic form. In particular they are in laevorotic form.
  • the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.
  • the radical E is derived from a linear or branched alkyl compound comprising at least two functions selected from the group consisting of -OH, -COOH, -NH 2 .
  • radical E is derived from a compound comprising from 2 to 6 carbon atoms, and optionally comprising 1 or 2 carboxylic acid functions and / or 1, 2 or 3 alcohol functions.
  • the radical E is an at least divalent radical, in particular divalent, trivalent or tetravalent radical.
  • the radical E is derived from a linear or branched alkyl compound, optionally carrying one or two carboxylic acid functions.
  • the radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3. propanediol or TRIS, serinol, and threoninol. According to one embodiment, when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.
  • the radical E may be derived from an amino acid comprising two carboxylic acid functions, in particular aspartic acid or glutamic acid.
  • the radical E can be linked to one or two AA radicals.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E does not comprise an -NH 2 function.
  • the substituted anionic compound is chosen from the compounds of formula I in which the radical E is different from the radical R.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E is different from the precursor of the radical R.
  • the substituted anionic compound comprises from 2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.
  • m + n ⁇ P 1.
  • n + n * P 2.
  • m + n 5 P 6.
  • m + n "* p 7.
  • m + n * p gives the number of carboxylate functions provided by AA.
  • the radical R comprising 3 to 12 carbon atoms, comprises free carboxylate functions, then the total number of free carboxylate functions is greater than m + n * p.
  • the substituted anionic compound does not comprise an AA radical bonded via a spacer E.
  • the substituted anionic compound does not comprise an AA radical linked via a spacer E
  • the substituted anionic compound can have the formula I in which n 0 and corresponds to formula II:
  • the substituted anionic compound does not comprise an AA radical bonded via the F function to the radical R.
  • the substituted anionic compound does not comprise an AA radical bonded via the F moiety to the R radical, the substituted anionic compound can meet the Form and corresponds to the formula III: Formula III
  • the substituted anionic compound corresponds to the following Formula I:
  • R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 6 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions;
  • F, F ', F independently of one another represent a function chosen from amide, carbamate or urea functions, F and F" being functions resulting from a reaction involving the amine of the aromatic amino acid, precursor of a AA radical, F 'being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E,
  • AA is a radical derived from an aromatic amino acid comprising a phenyl group or an indole group, substituted or unsubstituted, or an aromatic amino acid derivative having a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function
  • E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,
  • p being an integer from 1 to 3
  • n is an integer from 0 to 6
  • m + n is an integer from 1 to 6;
  • said compound comprising at least 2 carboxylic acid functions in the form of an alkali metal salt selected from Na * and K + .
  • R comprises at least one carboxylic acid function. * represents the mathematical sign multiplication.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the R, AA or E radicals.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and E.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the radicals R and AA.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are borne by the AA and E radicals.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radical R, comprising 3 to 12 carbon atoms.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the AA radical.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radical E.
  • F is chosen from amide or carbamate functions.
  • F is an amide function
  • F is a carbamate function
  • F ' is a urea function
  • F ' is an amide function.
  • F ' is a carbamate function.
  • F and F ' are chosen from amide or carbamate functions.
  • F and F 'are amide functions.
  • F and F 'are carbamate functions.
  • F " is a urea function.
  • F " is an amide function.
  • F is a carbamate function
  • F ' is an amide function and F "is a carbamate function.
  • the radical R comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated.
  • the radical R comprising 3 to 12 carbon atoms, is a saturated linear hydrocarbon radical.
  • m + n 6.
  • m + n 5.
  • m + n 4.
  • m + n 3.
  • m + n 2.
  • m + n 1.
  • the substituted anionic compound when bisubstituted, is chosen from the compounds of formula I in which the radical -R- is chosen from carbon radicals of formula IV:
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is 0 or 1 where the groups R ql, q2 R, R r and R r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R q or R r groups are -COOH.
  • a is equal to 1.
  • the substituted anionic compound when monosubstituted, is chosen from compounds of formula I in which the radical -R-, comprising 6 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms,
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is 0 or 1 where the groups R ql / q2 R, R r and R r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R q or R r groups are -COOH.
  • a is equal to 1.
  • the substituted anionic compound when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 6 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV ":
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 5 ⁇ q + r * t ⁇ 11, a is 0 or 1 when the groups R q1; R q2 , R r and R r2 are, independently of each other, selected from -H, -OH, -COOH; 4 ⁇ q + r * t ⁇ 11, a is 0 or 1, where the groups R qi, q2 R, R r and R i r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R q or R r is -COOH.
  • a is equal to 1.
  • the substituted anionic compound when monosubstituted, is chosen from compounds of formula I in which the radical -R- comprising 6 to 12 carbon atoms is chosen from radicals comprising 3. to 12 carbon atoms of formula IV ":
  • a is 0 or 1
  • R i, R q2, R r and R r2 are independently of each other, selected from -H, -OH, or -COOH and at least two groups R q or R r are -COOH.
  • a is equal to 1.
  • - q is an integer between 6 and 12, when the groups R q i and R q2 are, independently of each other, selected from -H, -OH and -COOH;
  • - q is an integer between 5 and 12, when the R i groups and R q q2 are independently from each other selected from -H, -OH and -COOH and at least one Rq is -COOH.
  • - q is an integer between 4 and 12, when the R qi and q2 R groups are independently from each other selected from -H, -OH and -COOH, and at least two R q are -COOH.
  • the -R- radical when monosubstituted, is chosen from radicals comprising 6 to 12 carbon atoms, of formula IV in
  • - q is an integer between 6 and 12, when the R qi and q2 R groups are independently from each other selected from -H, -OH;
  • R q is an integer between 5 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least one Rq is a -COOH.
  • R q is an integer between 4 and 12, when the groups R q i and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R q are -COOH .
  • - q is an integer between 5 and 11, when the groups R i and R q2 q are, independently from each other selected from -H, -OH;
  • R q is an integer between 4 and 11, when the groups R q i and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least one R q is a -COOH .
  • q is an integer between 6 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH;
  • - q is an integer between 5 and 12, when the groups R and R qI q2 are independently from each other selected from -H, -OH and -COOH and at least one R q is -COOH.
  • - q is an integer between 4 and 12, when the R ql and q2 R groups are independently from each other selected from -H, -OH and -COOH, and at least two R q are -COOH.
  • the substituted anionic compound is chosen from the compounds of formula I in which the radical -R- is a radical. derived from a compound comprising 6 to 12 + (m + n) carbon atoms.
  • q and r are integers between 0 and 12, groups R ql, q2 R, R and R rl r2 are independently of each other, selected from -H, -OH, -COOH,
  • -X and -Y are the same or different reactive functions which react with the precursor of E or AA to form respectively F 'or F, and are chosen from -COOH, -OH, -NH 2 ,
  • the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH, -COOH,
  • -X and -Y are the same or different reactive functions that react with the precursor of E or AA to form F 'or F, respectively, and are selected from -COOH, -OH, -NH 2 ,
  • the precursor of R is chosen from the precursor of formula VI or VII in which -X and -Y, identical or different, are chosen from -COOH, -OH.
  • the radical R comprising 6 to 12 carbon atoms, may comprise at least one function, in particular chosen from the alcohol and carboxylic acid functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises o carboxylic acid functions, o being an integer between 1 and 3, in particular o being equal to 1 or 2, and in particular o is 1.
  • the radical R comprising 6 to 12 carbon atoms, is free of carboxylic acid functions.
  • the radical R comprising 6 to 12 carbon atoms, comprises at least one alcohol function, in particular it comprises 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions. According to another embodiment, the radical R, comprising 6 to 12 carbon atoms, is devoid of alcohol function.
  • the radical R comprising 6 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.
  • the radical R comprising 6 to 12 carbon atoms, may come from a polycarboxylic acid, especially a dicarboxylic acid.
  • all the carboxylic acid functions of the polycarboxylic acid are involved in the functions F and F '.
  • all the acid functional groups of the polycarboxylic acid are not involved in the functions F and F '.
  • 1 or 2 carboxylic acid functions are not involved in the functions F and F ', especially 1 carboxylic acid function is not involved in the functions F and F'.
  • the radical R comprising 6 to 12 carbon atoms, may be derived from a dicarboxylic acid selected from heptanedioic acid, octanedioic acid, nonanedioic acid.
  • the radical R comprising 6 to 12 carbon atoms, may be derived from a diol.
  • the diol may be chosen from triethylene glycol and tetraethylene glycol, hexanediol, heptane diol and octane diol.
  • the radical R comprising 6 to 12 carbon atoms, of the substituted anionic compound is derived from a dicarboxylic acid, an amino acid or a diol.
  • the AA radical is derived from an aromatic amino acid having a phenyl or a substituted or unsubstituted indole, or an aromatic amino acid derivative having a phenyl or an indole, substituted or unsubstituted.
  • the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.
  • AA radical is bonded to the radical E or to the radical R by a function F or F 1 involving the amine of the aromatic amino acid or an aromatic amino acid derivative.
  • aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole is meant a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amino function and a functional group. acid.
  • aromatic amino acid derivative is intended to mean the decarboxylated derivatives, the amino-alcohol derivatives, or amino-amides corresponding to the aromatic amino acids comprising a substituted or unsubstituted phenyl or indole.
  • the derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.
  • AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids.
  • Aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.
  • the aromatic amino acid comprising a phenyl or an indole, substituted or unsubstituted is a natural amino acid, especially chosen from phenylalanine, tyrosine and tryptophan, especially phenylalanine.
  • aromatic amino acids comprising a phenyl or an indole, substituted or not, and their derivatives may, where appropriate, be levorotatory, dextrorotatory or in racemic form. In particular they are in laevorotic form.
  • the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.
  • the radical E is derived from a linear or branched alkyl compound comprising at least two functions chosen from the group consisting of -OH, -COOH, -NH 2 .
  • radical E is derived from a compound comprising from 2 to 6 carbon atoms, and optionally comprising 1 or 2 carboxylic acid functions and / or 1, 2 or 3 alcohol functions.
  • the radical E is an at least divalent radical, in particular divalent, trivalent or tetravalent radical.
  • the radical E is derived from a linear or branched alkyl compound, optionally carrying one or two carboxylic acid functions.
  • the radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3 propanediol or TRIS, serinol, and threoninol.
  • radical E when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.
  • the radical E may be derived from an amino acid comprising two carboxylic acid functions, in particular aspartic acid or glutamic acid.
  • the radical E can be linked to one or two AA radicals.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E does not comprise an -NH 2 function.
  • the substituted anionic compound is chosen from the compounds of formula I in which the radical E is different from the radical R.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of radical E is different from the precursor of radical R.
  • the substituted anionic compound comprises from 2 to 8, in particular from 2 to 6, or even from 2 to 4 carboxylic acid functions.
  • n + n * * P 2.
  • m + n * f P 3.
  • the radical R comprising 6 to 12 carbon atoms, comprises free carboxylate functions
  • the total number of free carboxylate functions is greater than m + n * p.
  • the substituted anionic compound does not comprise an AA radical bonded via a spacer E.
  • the substituted anionic compound does not comprise an AA radical linked via a spacer E
  • the substituted anionic compound can correspond to formula I in which n formula II:
  • the substituted anionic compound does not comprise an AA radical bonded via the F function to the radical R.
  • the substituted anionic compound does not comprise an AA radical bonded via the F function to the R radical, the substituted anionic compound can meet the Form and corresponds to the formula III: Formula III
  • the substituted anionic compound corresponds to the following Formula I:
  • R represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon radical comprising from 3 to 12 carbon atoms, optionally comprising at least one functional group chosen from ether, alcohol and carboxylic acid functions
  • F ', F "independently of one another represent a function chosen from amide, carbamate or urea functions, F" being a function resulting from a reaction involving the amine of the aromatic amino acid, precursor of the radical AA, F being a function involving a reactive function of the precursor of R and a reactive function of the precursor of E,
  • AA is a radical derived from an aromatic amino acid comprising a phenyl group or a substituted or unsubstituted indole group, or an aromatic amino acid derivative containing a substituted or unsubstituted phenyl or indole, said AA radical having at least one free acid function, - E represents an at least divalent radical, linear or branched alkyl, comprising from 2 to 6 carbon atoms,
  • p being an integer from 1 to 3
  • n is an integer from 1 to 6;
  • said compound comprising at least 2 carboxylic acid functional groups in the form of an alkali metal salt selected from Ma + and K + .
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the R, AA or E radicals.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radicals R and E.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the radicals R and AA.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are borne by the AA and E radicals.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the radical R, comprising 3 to 12 carbon atoms.
  • the at least two carboxylic acid functions in the form of an alkali metal salt are carried by the AA radical.
  • the at least two carboxylic acid functional groups in the form of an alkali metal salt are carried by the radical E.
  • R comprises at least one carboxylic acid function. * represents the mathematical sign multiplication.
  • F ' is a urea function
  • F ' is an amide function.
  • F ' is a carbamate function.
  • F " is a urea function.
  • F is an amide function
  • F is a carbamate function.
  • F ' is an amide function and F "is a carbamate function.
  • the radical R may comprise from 4 to 10 carbon atoms, in particular from 4 to 6 carbon atoms.
  • the radical R comprising 3 to 12 carbon atoms, may be a linear, branched or cyclic hydrocarbon radical, and may be saturated or unsaturated.
  • the radical R is a saturated linear hydrocarbon radical.
  • n 6.
  • n 5.
  • n 4.
  • n 3.
  • n 2.
  • n 1.
  • the substituted anionic compound when bisubstituted, is chosen from the compounds of formula I in which the radical -R- is chosen from carbon radicals of formula IV:
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is equal to 0 or 1, when the groups R q1 ( R q2 , R r i and R r2 are, independently of one another, chosen from -H, -OH or - COOH; 2 ⁇ q + r * t ⁇ 12, a is 0 or 1, where the groups R qli R q2, R r and R r2 are independently of each other, selected from -H, -OH, or -COOH and at least one R q or R r is -COOH.
  • a is 0 or 1, when the groups R q1 , R q2 , R r1 and R r2 are, independently of one another, selected from -H, -OH, or -COOH and at least two groups R q or R r are -COOH.
  • the substituted anionic compound when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms,
  • q and r are integers between 0 and 12, r is an integer between 0 and 3 and:
  • a is 0 or 1, when q R i, R q2, rl R and R r2 are independently of each other, selected from -H, -OH or - COOH;
  • a is 0 or 1, when the groups R q1 , R q2 , r i and R r2 are, independently of one another, selected from -H, -OH, or - COOH and at least one R q or R r is -COOH.
  • a is 0 or 1 where the groups R ql, q2 R, R and R rl r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R q or R r groups are -COOH.
  • the substituted anionic compound when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV ":
  • Formula IV "in which, q and r are integers between 0 and 12, r is an integer between 0 and 3 and: 2 q q + r * t 11 11, a is equal to 0 or 1, when the groups R q1, R q2 , R r and R r2 are, independently of one another, chosen from -H, -OH, - COOH; 1 ⁇ q + r * t ⁇ 11, a is equal to 0 or 1, when the groups R qi ⁇ R q2 , R r i and R r2 are, independently of one another, chosen from -H, -OH, or -COOH and at least one R q or R r is -COOH.
  • the substituted anionic compound when monosubstituted, is chosen from the compounds of formula I in which the radical -R-, comprising 3 to 12 carbon atoms, is chosen from radicals comprising 3 to 12 carbon atoms of formula IV ":
  • a is 0 or 1 when q R groups (R q2, rl R and R r2 are independently of each other, selected from -H, -OH, or - COOH and at least two R q or R r groups are -COOH.
  • - q is an integer between 3 and 12, when the R qi and q2 R groups are independently from each other selected from -H, -OH, and -COOH;
  • R q is an integer between 2 and 12, when the groups R q1 and R q2 are, independently of each other, chosen from -H, -OH and -COOH and at least one Rq is a -COOH.
  • - q is an integer between 1 and 12, when the groups R i and R q2 q are, independently from each other selected from -H, -OH and -COOH, and at least two R q are -COOH .
  • q is an integer between 3 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH and -COOH;
  • - q is an integer between 2 and 12, when the groups R qi and R q2 are, independently of each other, selected from -H, -OH and -COOH and at least one Rq is a -COOH.
  • - q is an integer between 1 and 12, when the groups R i and R q2 q are, independently from each other selected from -H, -OH and -COOH, and at least two R q are -COOH .
  • - q is an integer between 2 and 11, where R q, and R q2 groups are independently from each other selected from -H, -OH and -COOH;
  • - q is an integer between 1 and 11, when the groups R qi and R q2 are, independently of each other, selected from -H, -OH and -COOH and at least one R q is a -COOH.
  • q is an integer between 3 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH and -COOH;
  • R q is an integer between 2 and 12, when the groups R q1 and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least one R q is a -COOH.
  • R q is an integer between 1 and 12, when the groups R q) and R q2 are, independently of one another, chosen from -H, -OH and -COOH and at least two R q are -COOH .
  • the substituted anionic compound is chosen from compounds of formula I in which the radical -R- is a radical derived from a compound comprising 3 to 12 + n carbon atoms.
  • q and r are integers between 0 and 12, groups R qi, q2 R, R r and R i r2 are independently of each other, selected from -H, -OH, -COOH,
  • -X and -Y are the same or different reactive functions which react with the precursor of E or AA to form respectively F 'or F, and are chosen from -COOH, -OH, -NH 2 ,
  • the radical -R- comprising 3 to 12 carbon atoms
  • R q1 and R q2 groups are, independently of one another, chosen from -H, -OH, -COOH, -X and -Y are the same or different reactive functions which react with the precursor of E or AA to form respectively F 'or F, and are chosen from -COOH, -OH, -NH 2 ,
  • the precursor of R is chosen from the precursor of formula VI or VII in which -X and -Y, which are identical or different, are chosen from -COOH, -OH.
  • the radical R comprising 3 to 12 carbon atoms, may comprise at least one function, in particular chosen from the alcohol and carboxylic acid functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises o carboxylic acid functions, o being an integer between 1 and 3, in particular o being equal to 1 or 2, and in particular o is 1.
  • the radical R comprising 3 to 12 carbon atoms, is free of carboxylic acid functions.
  • the radical R comprising 3 to 12 carbon atoms, comprises at least one alcohol function, in particular it comprises 1 to 4 alcohol functions, in particular 1 or 2 alcohol functions.
  • the radical R comprising 3 to 12 carbon atoms, is devoid of alcohol function.
  • the radical R comprising 3 to 12 carbon atoms, comprises 1 or 2 alcohol functions and 1 carboxylic acid function.
  • the radical R comprising 3 to 12 carbon atoms, can come from a polycarboxylic acid, especially a dicarboxylic acid.
  • all the carboxylic acid functions of the polybasic carboxylic acid are involved in the functions F '.
  • all the carboxylic acid functions of the precursor of R are involved in the functions F '.
  • all the acid functions of the polycarboxylic acid are not involved in the functions F '.
  • 1 or 2 carboxylic acid functions are not involved in the functions F ', especially 1 carboxylic acid function is not involved in the functions F'.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, hexanedioic acid ( or adipic acid), heptanedioic acid, octanedioic acid, nonanedioic acid, pentanedioic acid, butenedioic acid, pentenedioic acid, and hexadienedioic acid (or adipic acid).
  • a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, hexanedioic acid ( or adipic acid), heptanedioic acid, octanedioic acid, nonanedioic acid, pentanedioic acid, butenedioic acid, pentenedi
  • the radical R comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), tartaric acid, malic acid, and acid. pentanedioic acid and hexanedioic acid (or adipic acid).
  • the radical R comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid), malic acid or tartaric acid.
  • the radical R comprising 3 to 12 carbon atoms, is derived from a dicarboxylic acid chosen from butanedioic acid (or succinic acid) or tartaric acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from an amino acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from an amino acid selected from glutamic acid and aspartic acid.
  • the radical R comprising 3 to 12 carbon atoms, may be derived from a diol.
  • the diol may be chosen from diethylene glycol, triethylene glycol and tetraethylene glycol, propane diol, butanediol, pentanediol, hexanediol, heptane diol and octane diol.
  • the radical R, comprising 3 to 12 carbon atoms, of the substituted anionic compound is derived from a dicarboxylic acid, an amino acid or a diol.
  • the AA radical is derived from an aromatic amino acid having a phenyl or a substituted or unsubstituted indole, or an aromatic amino acid derivative having a phenyl or an indole, substituted or unsubstituted.
  • the AA radical is derived from an aromatic amino acid having a substituted or unsubstituted phenyl or indole.
  • the AA radical is linked to the radical E by a function F "involving the amine of the aromatic amino acid or an aromatic amino acid derivative.
  • aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole
  • a compound comprising from 7 to 20 carbon atoms, a substituted or unsubstituted phenyl or indole, an amine function and a functional group. acid.
  • aromatic amino acid derivative is intended to mean the decarboxylated derivatives, the amino-alcohol derivatives, or amino-amides corresponding to the aromatic amino acids comprising a substituted or unsubstituted phenyl or indole.
  • the derivatives of said aromatic amino acids comprising a substituted or unsubstituted phenyl or indole may in particular be chosen from amino-alcohols and amino-amides.
  • AA is derived from an aromatic amino acid comprising a phenyl or an indole, substituted or not, chosen from alpha or beta amino acids.
  • Aromatic amino acids having a substituted or unsubstituted phenyl or indole may be selected from the group consisting of phenylalanine, alpha-methyl phenylalanine, 3,4-dihydroxyphenylalanine, alpha phenylglycine, 4-hydroxyphenylglycine 3,5-dihydroxyphenylglycine, tyrosine, alpha-methyl tyrosine, O-methyl tyrosine and tryptophan.
  • the aromatic amino acid comprising a phenyl or a substituted or unsubstituted indole is a natural amino acid, especially chosen from phenylalanine, tyrosine and tryptophan, especially phenylalanine.
  • aromatic amino acids comprising a phenyl or an indole, substituted or not, and their derivatives may, where appropriate, be levorotatory, dextrorotatory or in racemic form. In particular they are in laevorotic form.
  • the substituted anionic compound comprises from 1 to 6 AA radicals, and in particular from 1 to 3 AA radicals.
  • the radical E is derived from a linear or branched alkyl compound comprising at least two functions selected from the group consisting of -OH, -COOH, -NH 2 .
  • radical E is derived from a compound comprising from 2 to 6 carbon atoms, and optionally comprising 1 or 2 carboxylic acid functions and / or 1, 2 or 3 alcohol functions.
  • the radical E is an at least divalent radical, in particular divalent, trivalent or tetravalent radical.
  • the radical E is derived from a linear or branched alkyl compound, optionally carrying one or two carboxylic acid functions.
  • the radical E may be derived from an amino alcohol, an amino-diol or an amino-triol, in particular chosen from the group consisting of trishydroxymethylaminomethane, also called 2-amino-2-hydroxymethyl-1,3 propanediol or TRIS, serinol, and threoninol.
  • radical E when the radical E is derived from an amino-diol or an amino-triol, it is respectively substituted with 2 or 3 AA radicals.
  • the radical E may be derived from an amino acid comprising two carboxylic acid functions, in particular aspartic acid or glutamic acid.
  • the radical E can be linked to one or two AA radicals.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of the radical E does not comprise an -NH 2 function.
  • the substituted anionic compound is chosen from the compounds of formula I in which the radical E is different from the radical R.
  • the substituted anionic compound is chosen from the compounds of formula I in which the precursor of radical E is different from the precursor of radical R.
  • the substituted anionic compound comprises of
  • n * p 1.
  • n * p 2.
  • n * p 3.
  • n * p 4.
  • n * p 5.
  • n * p 6.
  • n * p 7.
  • n * p 8.
  • n * p gives the number of carboxylate functions provided by AA.
  • the radical comprising 3 to 12 carbon atoms, comprises free carboxylate functions, then the total number of free carboxylate functions is greater than n * p.
  • Table 1 below shows, without limitation, examples of compounds according to the invention.
  • the substituted anionic compound Al or N- (3-carboxy-1-oxopropyl) -L-phenylalanine is obtained according to a modification of the process described in the application WO 96/33699 (Milstein, S.) starting from l ethyl ester of L-phenylalanine and
  • Molecule 1 isocyanate of L-phenylalanine ethyl ester
  • Molecule 2 product obtained by reaction between tris (hydroxymethyl) aminomethane and mono-methylsuccinate
  • the substituted anionic compound A2 in acid form is dissolved in water and the solution is neutralized by gradual addition of 10N sodium hydroxide to give an aqueous solution of substituted anionic compound A2 which is then lyophilized.
  • the substituted anionic compound A5 in acid form is dissolved in water and the solution is neutralized by progressive addition of ION sodium hydroxide to give an aqueous solution of substituted anionic compound A5 or N- (-carboxypropionyl) -L-phenylalanine which is then lyophilized.
  • the molecule 9 is obtained according to the method described in patent WO2008 / 30119 starting from 20 g of tris (hydroxymethyl) aminomethane.
  • Molecule 11 Hydrochloride salt of the product obtained by deprotection of the Boc group of the molecule 10
  • Molecule 12 product obtained by reaction between molecule 11 and ⁇ , ⁇ '-diacetyl-tartaric anhydride
  • the molecule 11 (5.7 g, 7.4 mmol) is solubilized in dichloromethane (50 mL) and a saturated solution of NaHCO 3 (30 mL) is added.
  • the aqueous phase is extracted with dichloromethane and the organic phase is dried over Na 2 SO 4 , filtered and concentrated to a volume of approximately 20 ml.
  • This solution is poured onto a solution of ⁇ , ⁇ '-diacetyl tartaric anhydride (1.6 g, 7.4 mmol) in THF (35 mL) at 0 ° C. After stirring for 4 h, the medium is concentrated in vacuo to give a white foam.
  • the product is purified by flash chromatography (dichloromethane / methanol) to give a white foam.
  • the substituted anionic compound A6 (3.8 g) in acid form is suspended in water and 1.0025M sodium hydroxide is gradually added to pH 7.18. After lyophilization, the desired product is obtained as a white solid.
  • Molecule 13 product obtained by reaction between the molecule 5 and ⁇ , ⁇ '-diacetyl-tartaric anhydride
  • the substituted anionic compound A7 (3.24 g) in acid form is suspended in 50 ml of water and 0.521M sodium hydroxide is added dropwise to pH 7.08. After lyophilization, the desired product is obtained as a white solid.
  • the mixture After heating for 1 hour, the mixture is diluted with water, neutralized with acetic acid and then purified by ultrafiltration on a PES membrane of 1 kDa against water.
  • the compound concentration of the final solution is determined by dry extract, and then an acid / base assay in a 50/50 water / acetone (V / V) mixture is carried out to determine the degree of substitution of sodium methylcarboxylate.
  • the degree of substitution of sodium methylcarboxylates per saccharide unit is 1.65.
  • the polyanionic compounds are selected by measuring their dissociation constant with respect to the calcium ions and their property of not destabilizing the hexameric form of the insulin.
  • Novolog® Nordisk sold as Novolog®. This product is a fast analog insulin.
  • This solution is a commercial solution of Eli Lilly lispro insulin sold under the name of Humalog®. This product is a fast analog insulin. B3. Human insulin solution Humulin® R at 100 IU / mL
  • This solution is a commercial solution of human insulin Eli Lilly sold under the name Humulin® R.
  • This product is a human insulin composition.
  • This solution is a commercial solution of insulin glulisin from Sanofi sold under the name of Apidra®. This product is a fast analog insulin.
  • the sodium citrate solution is obtained by solubilizing 9.0811 g of sodium citrate (30.9 mmol) in 25 ml of water in a volumetric flask. The pH is adjusted to 7.4 by adding 1 ml of HCl 1. The solution is filtered through 0.22 ⁇ m.
  • the clear solution is filtered through a 0.22 ⁇ m membrane and stored at 4 ° C.
  • the clear solution is filtered through a 0.22 ⁇ m membrane and stored at 4 ° C.
  • the final pH is adjusted to 7.4 ⁇ 0.4.
  • the clear solution is filtered through a 0.22 ⁇ m membrane and stored at 4 ° C.
  • Humuîin® R commercial solution 100 mL
  • the clear solution is filtered through a 0.22 ⁇ m membrane and stored at 4 ° C.
  • the final pH is adjusted to 7.4 ⁇ 0.4.
  • the clear solution is filtered through a 0.22 ⁇ m membrane and stored at 4 ° C.
  • the final pH is adjusted to 7.4 ⁇ 0.4.
  • the polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.
  • the final pH is adjusted to 7.4 ⁇ 0.4.
  • the polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or another salt compatible with an injectable formulation.
  • the polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or other salt compatible with an injectable formulation .
  • the final pH is adjusted to 7.4 ⁇ 0.4.
  • the clear solution is filtered through a 0.22 ⁇ m membrane and stored at 4 ° C.
  • the polyanionic compound 1 can be used in the acid form or the basic form in the form of sodium salt, potassium salt or other salt compatible with an injectable formulation .
  • the final pH is adjusted to 7.4 ⁇ 0.4.

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EP15726556.2A 2014-05-14 2015-05-15 Schnell wirkende insulinzusammensetzung mit einer substituierten anionischen verbindung und einer polyanionischen verbindung Withdrawn EP3142686A2 (de)

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US20160082106A1 (en) 2016-03-24
WO2015173427A3 (fr) 2016-03-31

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