FR2985429A1 - Composition in injectable aqueous solution form with specific pH value, useful to treat diabetes, comprises basal insulin with specific isoelectric point and polyamino acid bearing carboxylate charges and substituted with hydrophobic group - Google Patents

Abstract

Composition in the form of an injectable aqueous solution having a pH of 6-8, comprises a basal insulin having an isoelectric point of 5.8-8.5, and a polyamino acid bearing carboxylate charges and substituted with hydrophobic groups. Composition in the form of an injectable aqueous solution having a pH of 6-8, comprises a basal insulin having an isoelectric point of 5.8-8.5, and a polyamino acid bearing carboxylate charges and substituted with hydrophobic groups, of formula (R1-[NH-CH(A-C(=O)-R)-C(=O)] n-[NH-CH(A-C(=O)-R3)-C(=O)] m-R2) (I). A, B1 : -CH 2- (aspartic unit) or -CH 2-CH 2- group (glutamic unit); R1 : H, linear 2-10C-acyl, branched 3-10C-acyl, benzyl, terminal amino acid unit or pyroglutamate unit; R2 : -N(R1a)(R2a); either R1a, R2a : 1-10C-alkyl or benzyl; or NR1aR2a : one or more optionally saturated and/or aromatic rings, which are carbon-based and/or which optionally comprise heteroatoms consisting of O, N or S; R3 : H or a cationic entity comprising metal cations; R : monovalent radical of formula (-NH-CH(B1-C(=O)-O-R11)-C(=O)-O-R11) or (-NH-CH(R5)-C(=O)-O-R11), or R11; R11 : linear or branched 8-30C-radical (optionally saturated and optionally contains heteroatoms) or a radical capable of forming carbonaceous rings, which are optionally saturated and/or aromatic and optionally contain hetero atoms, where the rings are optionally ortho-condensed or peri-condensed; R5 : H, 1-4C-alkyl or a benzyl group; and n/(n+m) : = 1-50 mol.%, where n/(n+m) represents molar degree of grafting with hydrophobic radical of the monomeric units, n+m represents the degree of polymerization of the polyamino acid, i.e. the average number of monomeric units per chain of polyamino acid, and the n+m is 5-1000. Independent claims are included for a single-dose formulation at a pH of 7-7.8, comprising the basal insulin and a prandial insulin, or the basal insulin and a gut hormone, or the basal insulin, the prandial insulin and the gut hormone. ACTIVITY : Antidiabetic. MECHANISM OF ACTION : None given.

Description

PH 7 INJECTABLE SOLUTION COMPRISING AT LEAST ONE BASIC INSULIN, THE PI OF WHICH IS BETWEEN 5.8 AND 8.5, AND A SUBSTITUTED POLYAMINOACID OBTAINED BY A CONTROLLED POLYMERIZATION PROCESS [0001] The invention relates to insulin injection therapeutics ( s) to treat diabetes. Insulin therapy, or diabetes therapy by insulin injection, has in recent years remarkable progress thanks to the development of new insulins offering better correction of blood glucose in patients in comparison with insulin. human. [0003] When a type II diabetes is diagnosed in a patient, a gradual treatment is put in place. The patient first takes oral anti-diabetic drugs (ADOs) such as Metformin. When ADOs alone are no longer sufficient to regulate the level of glucose in the blood, a change in treatment must be made and, depending on the specifics of the patients, different combinations of treatments can be implemented. The patient may, for example, have a treatment based on a basal insulin glargine or detemir in addition to OAD, and then depending on the evolution of the pathology treatment based on basal insulin and mealtime insulin. [0004] Today, to ensure the transition of treatments by ADOs, when they are no longer able to control the level of glucose in the blood, to a basal insulin / prandial insulin treatment the injection of analogues GLP-1 is recommended. [0005] Basal insulins ensure the maintenance of glycemic homeostasis of the patient, outside the periods of food intake. They act essentially to block the endogenous production of glucose (hepatic glucose). The daily dose of basal insulin is usually 40-50% of the total daily insulin requirement. Depending on the basal insulin used, this dose is given in 1 or 2 injections, regularly distributed during the day. The most commonly used basal insulins are Levemir ° (insulin detemir from Novo Nordisk) and Lantus® (insulin glargine from Sanofi). [0006] Insulin glargine is considered today as the best basal insulin marketed. Its hypoglycemic effect is almost constant over a period of 24 hours which allows most patients to be limited to one injection per day. [0007] Insulin glargine is formulated as an injectable solution at acidic pH. During subcutaneous injection, the passage of insulin glargine from an acid pH (pH 4-4.5) to a physiological pH (neutral pH) causes its precipitation under the skin. The slow redissofution of insulin glargine micro-particles ensures a slow and prolonged action. However, the necessarily acidic pH of the insulin glargine formulation can be a real drawback, since this acidic pH of the insulin glargine formulation sometimes causes patients to experience injection pain and especially prevents its formulation in combination with other active ingredients which are formulated at physiological pH. [0008] Prandial insulins allow rapid management (metabolization and / or storage) of glucose provided during meals and snacks. The patient should inject mealtime insulin before each food intake, ie approximately 2 to 3 injections per day. The most widely used prandial insulins are recombinant human insulin, insulin aspart (NovoLog® from NOVO NORDISK), insulin lispro (Humalog® from ELI LILLY) and insulin glulisine (Apidra® from Sanofi). GLP-1 for Glucagon-Like Peptide-1, are insulinotropic or incretin peptides, and belong to the family of gastrointestinal hormones (or Gut Hormones) that stimulate insulin secretion when blood glucose is too high. high, for example after a meal. [00010] Gastrointestinal hormones (Gut hormones) are also known as satiety hormones. They include GLP-1 (Glucagon like peptide-1) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide ( PP), ghrelin and enterostatin which have peptide or protein structures. They also stimulate the secretion of insulin, in response to glucose and fatty acids and are therefore potential candidates for the treatment of diabetes. Among these, GLP-1 are the ones that have brought to date the best results in the development of drugs. They have enabled patients with type II diabetes to lose weight while having better control of their blood glucose levels under physiological conditions. Analogs or derivatives have been developed in particular to improve their stability. Nobody has succeeded, to our knowledge to solubilize at neutral pH the 35 basal insulins whose isoelectric point is between 5.8 and 8.5 of the insulin glargine type while maintaining a difference in solubility between the medium. -vitro (the container) and in-vivo medium (under the skin), regardless of pH. From the analysis of the compositions described in the literature and patents, it appears that the insolubility at pH 7 insulin basal insulin glargine, is a prerequisite to have a slow action. Indeed, the same principle, explained above, basal insulins glargine type, whose isoelectric point is between 5.8 and 8.5, is that they are soluble at acidic pH and precipitate at pH physiological. This diverts those skilled in the art from any solution in which insulin glargine insulin would be solubilized at pH 6-8 while retaining its essential property which is to precipitate in a subcutaneous environment. From a therapeutic point of view, however, it has been shown, as illustrated below, that treatments combining either insulin glargine and mealtime insulin, or insulin glargine and a GLP-1 analogue, are of real interest [00017] Regarding the combination of insulin glargine and prandial insulin, clinical studies made public at the 70th annual scientific sessions of the American Diabetes Association (ADA) of 2010, abstract 2163-PO and abstract number 0001-LB, particularly those conducted by Sanofi, have shown that treatments that combine Lantus®, insulin glargine, and mealtime insulin are much more effective than treatments based on products such as Premix ", Novolog Mix® or Humalog Mix®. [00018] With regard to the combination of insulin glargine and a GLP-1 analogue, the FDA (Food and Drug Administration) recently approved, in October 2011, the injection of Exenatide (Byetta, Amylin Pharmaceuticals, Inc. and Eii Lilly and Company) as a complementary insulin glargine therapy for patients with type II diabetes who are not able to achieve glycemic control with Basal insulin analogue alone. However, because the same principle, discussed above, basal insulins whose isoelectric point is between 5.8 and 8.5, is that they are soluble at acidic pH and precipitate at physiological pH, all the solutions proposed for combining them with other products such as prandial insulins or analogues or derivatives of GLP-1 are based on solubilization tests of prandial insulins or analogues or derivatives of GLP-1 at acidic pH, see by example W02007 / 121256, W02009 / 021955, W02011 / 144673, W02011 / 147980 or W02009 / 063072. For example, in the case of combinations of insulin glargine and fast insulin, the company Biodel, described in particular in patent application US Pat. No. 7,718,609, compositions comprising a basal insulin and a prandial insulin at a pH between 3.0 and 4.2 in the presence of a chelating agent and polyacids.

This patent teaches how to make acid-prandial insulin compatible with insulin glargine. does not teach how to prepare a combination of insulin glargine insulin and prandial insulin at neutral pH. Also by way of example, with regard to the solubilization of insulin glargine at neutral pH and combinations with a GLP-1 analogue, mention may be made of patent application WO2011 / 144676 published on November 24, 2011, on behalf of Sanofi which discloses glargine pH 9.5 formulations with cyclodextrin SVE4 13-CYD in which the solubility of glargine is improved from 0.75 mM to 1.25 mM. This application also mentions compositions further comprising GLP-1, although not exemplified. The solubilising effect at pH 7.4 in a phosphate buffer is mentioned. These solubilization results at pH 7.4 are described in the publication entitled "Effect of sulfobutyl ether-p-cyclodextrin on bioavailability of insulin glargine and blood glucose after subcutaneous injection to rats" (International Journal of Pharmaceutics, 419 (2011)). 71-76) in Figure 3A. Sulfobutyl ether-p-cyclodextrin improves the solubility of insulin glargine at pH 7.4 from 5 μM to 8 μM which is not of therapeutic interest, insofar as the commercial concentration of insulin glargine is 600 μM (100 IU / mL). The problem has thus not been satisfactorily solved by the invention described in this patent application, to our knowledge, it has therefore never been described formulation, stable at physiological pH, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 alone or in combination with mealtime insulin and / or a gastrointestinal hormone, in which the solubility of insulin is sufficient for therapeutic treatment. The present invention allows: to provide a composition in the form of a homogeneous solution at physiological pH and in accordance with the requirements of the American and European Pharmacopoeia comprising a basal insulin, whose isoelectric point is between 5.8 and 8, 5, to provide a composition in the form of a homogeneous solution at physiological pH and in accordance with the requirements of the American and European Pharmacopoeia comprising a basal insulin, whose isoelectric point is between 5.8 and 8.5, in combination with a prandial insulin and / or a gastrointestinal hormone, to decrease the number of injections as part of the treatment of diabetes. The compositions according to the invention have a hypoglycemic slit action despite solubilization at pH 7 before injection of basal insulin whose isoelectric point is between 5.8 and 8.5. This remarkable property comes from the fact that insulin glargine insulin solubilized at pH 7 in the composition of the invention precipitates subcutaneously by a change in composition of the medium. The element triggering the precipitation of basal insulin whose isoelectric point is between 5.8 and 8.5 is no longer the change in pH but a change in the composition of the environment during the transition from the pharmaceutical composition to physiological medium. The solution according to the invention for solubilizing basal insulin, whose isoelectric point is between 5.8 and 8.5 at pH 7, preserves its biological activity, both in vitro and in vivo. In combinations of insulin-like insulin glargine with mealtime insulin, objects of the invention, the rapid action of mealtime insulin is preserved despite the insulin-like insulin glargine precipitation. In addition, the presence of mealtime insulin does not modify the solubility of basal insulin at a pH of between 6 and 8, and also does not modify the precipitation properties of basal insulin. [00027] invention comprising in combination a basal insulin, whose isoelectric point is between 5.8 and 8.5, and a gastrointestinal hormone such as a GLP-1, an analogue or a derivative of GLP-1, the activity of the gastrointestinal hormone is preserved despite the precipitation of basal insulin. In addition, the presence of the gastrointestinal hormone does not alter the solubility of basal insulin at pH between 5.8 and 8.5 and does not alter the precipitation properties of basal insulin. The invention relates to a composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least a) a basal insulin whose isoelectric point pI is between 5, 8 and 8,5, b) a polyamino acid carrying carboxylate charges and substituted by hydrophobic radicals, of formula I: ## STR2 ## in which: - - - A represents, independently, a group -CH2- (aspartic unit) or -0-12-012- (glutamic unit), R 'is selected from the group consisting of H, linear C 2 -C 10 acyl group, branched C 3 acyl group. C10, a benzyl, a terminal "amino acid" unit and a pyroglutamate, R2 is selected from the group consisting of a secondary amino group -NR'R ", R 'and R" same or different being selected from the group consisting of linear or branched or cyclic C1 to C10 alkyls, benzyl and said R 'and R "alkyls being able to form o together saturated, unsaturated and / or aromatic carbon rings and / or possibly containing heteroatoms selected from the group consisting of O, N and S, the same or different R3 groups are selected from the group consisting of an H or an entity cationic group chosen from the group comprising metal cations, the R groups each independently represent a monovalent radical chosen from radicals of general formula II or II ': ## STR5 ## In which R4 represents a linear or branched, saturated or unsaturated C8-C30 radical which may comprise heteroatoms or a radical which may form carbon-containing rings or which may comprise saturated, unsaturated and / or aromatic heteroatoms, said cycles possibly being ortho-fused or per-fused, B is independently -CH2- (aspartic unit) or -CH2-CH2- (glutamic unit), R5 is independently is H, linear or branched C1 to C4 alkyl or a benzyl group, R is a linear or branched, saturated or unsaturated C8 to C30 radical which may contain heteroatoms or a radical which may form carbon rings or may comprise saturated, unsaturated and / or aromatic heteroatoms, said rings being orthocondensed or peri-condensed, n / (n + m) is defined as the molar grafting rate of the hydrophobic radical of the monomeric units and is between 1 and 50 mol% , n + m represents the degree of polymerization of the polyamino acid, that is to say the average number of monomeric units per polyamino acid chain and 5 n + m 1000. In one embodiment the composition according to the invention is characterized in that the group A is a group -CH2- (aspartic unit). When the polyamino acid consists of aspartic units, they can undergo structural rearrangements. In one embodiment, the composition according to the invention is characterized in that the polyamino acids may furthermore comprise monomeric units of formula IV and / or IV ': OR3 0 ONNHH Formula IV Formula IV [00032] In an embodiment of the composition according to the invention is characterized in that the group A is a group -CH 2 -CH 2 - (glutamic unit). In one embodiment, the composition according to the invention is characterized in that the R group is a tocopheryloxy- or cholesteryloxy- radical. [00034] In one embodiment, the composition according to the invention is characterized in that -NR'R "is -N-morpholyl [00035] In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 500. [00036] In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 250. [00037] In one embodiment, The composition according to the invention is characterized in that n / (n + m) is between 1 and 30 mol%. [00038] In one embodiment the composition according to the invention is characterized in that n / ( n + m) is between 1 and 20 mol% Basal insulin whose isoelectric point is between 5.8 and 8.5 insoluble insulin at pH 7 and whose duration of action is between 8 and 24 hours or higher in standard diabetes models. [0040] These basal insulins whose isoelectric point are between 5.8 and 8.5 are recombinant insulins whose primary structure has been modified mainly by introduction of basic amino acids such as Arginine or Lysine. They are described for example in the following patents, patent applications or publications WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, so the contents are incorporated by reference. In one embodiment, the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine. In one embodiment, the compositions according to the invention comprise between 40 and 500 Ur / ml. basal insulin whose isoelectric point is between 5.8 and 8.5. In one embodiment, the compositions according to the invention comprise 100 IU / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5. In one embodiment, the compositions according to the invention comprise 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5. In one embodiment, the compositions according to the invention comprise 200 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5. In one embodiment, the compositions according to the invention comprise 500 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5. In one embodiment, the concentration of substituted polyamino acid is at most 60 mg / ml. In one embodiment, the concentration of substituted polyamino acid is at most 40 mg / ml. In one embodiment, the concentration of substituted polyamino acid is at most 20 mg / ml. In one embodiment, the concentration of substituted polyamino acid is at most 10 mg / ml. In one embodiment, the compositions according to the invention further comprise a mealtime insulin. The prandial insulins are soluble at pH 7. [00052] "Prandial insulin" is understood to mean so-called fast or "regular" insulin. The so-called fast prandial insulins are insulins which must meet the needs caused by the ingestion of proteins and carbohydrates during a meal, they must act in less than 30 minutes, [00054] In one embodiment insulin "regular" meal is human insulin. [00055] Human insulin is for example marketed under the trade names Humulin® (Eli Lilly) and Novolin® (Novo Nordisk). The so-called fast acting mellitus insulins are insulins which are obtained by recombination and which are modified to reduce their time of action. In one embodiment, fast-acting prandial insulins are chosen from the group comprising insulin lispro (1-lumalog®), insulin glulisine (Apidrae) and insulin aspart (NovoLog). In one embodiment, the compositions according to the invention comprise in total between 40 and 500 IU / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8. 5. In one embodiment, the compositions according to the invention comprise a total of 500 IU / ml of insulin with a combination of prandial insulin and basal insulin whose isoelectric point is between 5.8 and 8.5. In one embodiment, the compositions according to the invention comprise a total of 200 IU / ml of insulin with a combination of prandial insulin and basal insulin whose isoelectric point is between 5.8 and 8.5. . In one embodiment, the compositions according to the invention comprise a total of 100 IU / ml of insulin with a combination of prandial insulin and basal insulin whose isoelectric point is between 5.8 and 8.5. . In one embodiment, the compositions according to the invention comprise a total of 40 IU / ml of insulin with a combination of prandial insulin and basal insulin whose isoelectric point is between 5.8 and 8.5. . The proportions between the basal insulin whose isoelectric point is between 5.8 and 8.5 and the prandial insulin are for example in IU / mL of 25/75, 30/70, 40/60, 50 / 50, 60/40, 70/30. However any other proportion can be realized. In one embodiment, the compositions according to the invention further comprise a gastrointestinal hormone. The term "gastrointestinal hormones", the hormones selected from the group consisting of GLP-1 (Glucagon like peptide-1) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon) , peptide YY, amylin, cholecystokinin, pancreatic polypeptide (PP), ghrelin and enterostatin, their analogs or derivatives and / or their pharmaceutically acceptable salts. In one embodiment, the gastrointestinal hormones are analogues or derivatives of GLP-1 selected from the group consisting of exenatide or Byetta®, developed by Eli Lilly & Co and Amylin Pharmaceuticals, liraglutide or Victoza ® developed by Novo Nordisk, or the lixisenatide or Lyxumia ® developed by Sanofi, their analogues or derivatives and their pharmaceutically acceptable salts. In one embodiment, the gastrointestinal hormone is exenatide or Byetta® its analogues or derivatives and their pharmaceutically acceptable salts. In one embodiment, the gastrointestinal hormone is liraglutide or Victoza® its analogues or derivatives and their pharmaceutically acceptable salts. In one embodiment, the gastrointestinal hormone is lixisenatide or Lyxumia® its analogues or derivatives and their pharmaceutically acceptable salts. The term "analogue", when used with reference to a peptide or a protein, a peptide or a protein, in which one or more constituent amino acid residues have been substituted by other residues of amino acid and / or wherein one or more constituent amino acid residues have been deleted and / or wherein one or more constituent amino acid residues have been added. The percentage of homology allowed for the present definition of an analogue is 50%. The term "derivative", when used with reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or protein or the reference analogue, i.e., a peptide or protein that has been modified by creation of covalent bonds, to introduce substituents. In one embodiment, the substituent is selected from the group consisting of fatty chains. In one embodiment, the concentration of gastrointestinal hormone is in a range of 0.01 to 10 mg / mL. In one embodiment, the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.05 to 0.5 mg / ml. In one embodiment, the concentration of liraglutide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 1 to 10 mg / ml. In one embodiment, the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1 mg / mL. In one embodiment, the compositions according to the invention are produced by mixing commercial solutions of basal insulin whose isoelectric point is between 5.8 and 8.5 and commercial solutions of GLP-1, d analog or GLP-1 derivative in volume ratios in the range of 10/90 to 90/10. In one embodiment, the composition according to the invention comprises a daily dose of basal insulin and a daily dose of gastrointestinal hormone. In one embodiment, the compositions according to the invention comprise between 500 IU / ml and 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / mL exenatide. In one embodiment, the compositions according to the invention comprise between 500 UT / ml and 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg. / ml of iiraglutide. In one embodiment, the compositions according to the invention comprise between 500 IU / ml and 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / mL lixisenatide. In one embodiment, the compositions according to the invention comprise 500 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / ml. exenatide. In one embodiment, the compositions according to the invention comprise 500 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide. In one embodiment, the compositions according to the invention comprise 500 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / ml. of lixisenatide. In one embodiment, the compositions according to the invention comprise 200 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / ml. exenatide. In one embodiment, the compositions according to the invention comprise 200 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide. In one embodiment, the compositions according to the invention comprise 200 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / ml. of lixisenatide. In one embodiment, the compositions according to the invention comprise 100 IU / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.05 to 0.5 mg / mL of exenatide. In one embodiment, the compositions according to the invention comprise 100 IU / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5 and 1-10 mg / mL liraglutide. In one embodiment, the compositions according to the invention comprise 100 IU / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.05 to 0.5 mg / mL of lixisenatide. In one embodiment, the compositions according to the invention comprise 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / ml. exenatide. In one embodiment, the compositions according to the invention comprise 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide. In one embodiment, the compositions according to the invention comprise 40 IU / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.05 to 0.5 mg / ml. of lixisenatide. In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration of between 0 and 1000 μM. In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration of between 50 and 600 micrometers. In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration of between 100 and 500 μM. In one embodiment, the compositions according to the invention further comprise buffers. In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM, preferably between 15 and 50 mM. In one embodiment, the compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer or Tris (trishydroxymethylaminomethane). In one embodiment, the buffer is sodium phosphate. In one embodiment, the compositions according to the invention further comprise preservatives. In one embodiment, the preservatives are selected from the group consisting of m-cresol and phenol alone or in admixture. [000103] In one embodiment, the concentration of the preservatives is between 10 and 40 mM. In one embodiment, the compositions according to the invention further comprise a surfactant. In one embodiment, the surfactant is selected from the group consisting of propylene glycol or polysorbate. [000106] The compositions according to the invention may further comprise additives such as tonicity agents. In one embodiment, the tonicity agents are selected from the group consisting of glycerine, sodium chloride, mannitol and glycine. The compositions according to the invention may further comprise all the excipients according to the pharmacopoeia and compatible with the insulins used at the concentrations of use. The invention also relates to single-dose formulations with a pH of between 7 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin. The invention also relates to single-dose formulations having a pH of between 7 and 7.8, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above, [000110] The invention also relates to single-dose formulations having a pH of between 7 and 7.8, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, as defined above. In one embodiment, the single-dose formulations further comprise a substituted polyamino acid as defined above. In one embodiment, the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine. In one embodiment, the mealtime insulin is human insulin. In one embodiment, the prandial insulin is chosen from the group comprising insulin lispro (Humalog®), insulin glulisine (Apidra®) and insulin aspart (NovoLog 8) [000116]. embodiment, the GLP-1, analogue or derivative of GLP-1 is selected from the group consisting of exenatide (Byetta ()), liraglutide (Victoza®), lixisenatide (Lyxumia®) or a derivative thereof. In one embodiment, the gastrointestinal hormone is exenatide. [000118] In one embodiment, the gastrointestinal hormone is liraglutide. [000119] In one embodiment, the gastrointestinal hormone is lixisenatide. The solubilization at pH between 7 and 7,8 of the basal insulins whose isoelectric point is between 5.8 and 8.5, by the substituted polyamino acids of formula I, can be observed and controlled in a simple manner, at the naked eye, thanks to a change of appearance of the solution. Furthermore and just as importantly, the Applicant has been able to verify that a basal insulin whose isoelectric point is between 5.8 and 8.5, solubilized in the presence of a substituted polyamino acid of formula I n ' had in no way lost its insulin-like action either alone or in combination with prandial insulin or a gastrointestinal hormone. The Applicant has also been able to verify that a prandial insulin solubilized in the presence of a polyamino acid of formula I and a basal insulin whose isoelectric point is between 5.8 and 8.5, had nothing to do with it. lost his action. The Applicant has also been able to verify that a GLP-1, an analogue or a derivative of GLP-1, solubilized in the presence of a polyamino acid of formula I and a basal insulin whose isoelectric point is between 5 , 8 and 8.5, had not lost its insulinotropic action. The term "insulinotropic action", the ability to stimulate insulin secretion in response to high levels of glucose, thereby causing glucose consumption by cells and inducing a decrease in plasma glucose levels. Insulinotropic activity is easily measured in humans by quantifying insulin levels or C-peptide levels. An analog or derivative of GLP-1 has insulinotropic activity if Langherans islets secrete insulin levels in the presence of the analogue or derived from GLP-1 greater than the background. The preparation of a composition according to the invention has the advantage of being possible by simple mixing of an aqueous solution of basal insulin whose isoelectric point is between 5.8 and 8.5. , a mealtime insulin solution, and a substituted polyamino acid of formula I, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH 7. [000127] The preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of basal insulin whose point isoelectric is between 5.8 and 8.5, a solution of GLP-1, an analogue or derivative of GLP-1, and a polysaccharide of formula I, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH 7. The preparation of a composition according to the invention has the advantage of being possible by simple mixing of an aqueous solution of basal insulin whose point isoelectric is between 5.8 and 8.5, a prandial insulin solution, a solution of GLP-1 or an analog or derivative of GLP-1 and a substituted polyamino acid of formula I, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH 7.

Examples Part A Synthesis of polyamino acids No. Example Polyamino acid 1 PLG40Asp (OC12) 2 (0.09) 2 PLG200VE (0.10) 3 PLA20Asp (OC12) 2 (0.04) 4 PLA20LeuChol (0.03) Table 1: list of synthesized polyamino acids Example 1 Polyglutamate sodium modified with dilauryl aspartate Polyamino acid 1 [000129] A poly-γ-benzyl-L-glutamic acid polymer with a degree of polymerization of about 40 is synthesized from the acid y-benzyl N-carboxyanhydride glutamic according to the method described in J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H ,, et al.) Using N-trimethylsilyl-morpholine as initiator. For the hydrolysis of the benzyl esters, 10 g of polymer are heated at reflux for 16 hours in a THF / MeOH mixture in the presence of 1N sodium hydroxide. After returning to ambient temperature, a white solid is isolated by filtration and analyzed by 1 H NMR. The solid obtained is dissolved in water, acidified on an anionic Purolite resin and then lyophilized in order to generate the corresponding pofy-L-glutamic acid. [000131] Dilauryl aspartate, para-toluenesulfonic acid salt is prepared according to the method described in US Pat. No. 4,826,818 (Kenji M., et al.). 2 g of poly-L-glutamic acid (15.5 mmol of monomer) are solubilized in DMF and then cooled to 0 ° C. 0.5 g (0.8 mmol) dilauryl aspartate, para-toluenesulfonic acid salt is suspended in DMF. 0.08 g (0.8 mmol) of triethylamine is then added to this suspension. Once the polymer solution is at 0 ° C, 1.73 g (17.1 mmol) NMM and 1.85 g (17.1 mmol) EtOCOCI are then added. After 10 min of reaction, the dilauryl aspartate solution is added and the medium maintained at 10 ° C. for 45 minutes. The medium is then heated to 50 ° C. At 30 ° C., 40 ml of an aqueous solution of imidazole at 100 g / l and 25 ml of water are added. After 1 hour 30 minutes of stirring, the solution obtained is ultrafiltered on a 5 kD PES membrane against a solution of NaCl 0.9%, 0.01N sodium hydroxide and water. The solution is lyophilized and 1 H-1 NMR analysis in deuterated trifluoroacetic acid is performed to determine the rate of acidic functions converted to dilauryl aspartate amide. According to the 1 H NMR: the molar grafting rate by the dilauryl aspartate of the acids per monomer is 9%. Example 2: Alpha-Tocopherol Modified Polyglutamate Polyamino Acid 2 [000134] 2 g of poly-L-glutamic acid (15.5 mmol monomer) with a degree of polymerization of about 200 are synthesized by a method similar to that described in Example 1. [000135] The poly-L-glutamic acid is modified by alpha-tocopherol (SIGMA) according to the process described in Patent FR 2,840,614 (Ping, CU et al.) . The alpha-tocopherol-modified sodium poly-L-glutamate solution obtained is freeze-dried and an NMR-I-1 analysis in deuterated acid trifluoroacetic acid is carried out to determine the rate of acid functions converted into ester of alpha-tocopherol. According to the 1 H NMR: the molar grafting rate by alpha-tocopherol acids per monomer is 10%.

Example 3: Sodium polyaspartate modified with dilauryl aspartate Polyamino acid 3 [000138] Dilauryl aspartate, para-toluenesulphonic acid salt is prepared according to the process described in US Pat. No. 4,826,818 (Kenji M., et al.). 2 g of poly-L-aspartic acid (15.5 mmol of monomer) with a degree of polymerization of about 20 are synthesized by a method similar to that described in Example 1. [000140] Acid poly-L-aspartic acid is modified with dilauryl aspartate according to the method described in Example 1. [000141] The solution of dilauryl-modified aspartate-modified sodium polyaspartate is freeze-dried and 11-I NMR analysis in D20 is performed to determine the rate of acidic functions converted to dilauryl aspartate amide. According to the 1 H NMR: the molar grafting rate by the dilauryl aspartate of the acids per monomer is 40%.

EXAMPLE 4 Polyaspartate of Sodium Modified with Cholesterol Leucinate Polyamino Acid 4 [000143] The cholesterol leucinate salt of para-toluenesulphonic acid is prepared according to the process described in US Pat. No. 4,826,818 (Kenji M., et al.). 2 g of poly-L-aspartic acid (15.5 mmol of monomer) with a degree of polymerization of about 20 are synthesized by a method similar to that described in Example 1. [000145] Acid poly-L-aspartic acid is modified with cholesterol reucinate by a method similar to that described in Example 1. [000146] The cholesterol leucinate-modified sodium poly-L-aspartate solution obtained is lyophilized and analyzed. 1H NMR in D20 is performed to determine the rate of acid functions converted to cholesterol leucinate amide. According to 1 H NMR: the molar grafting rate by chlolesterol leucinate of the acids per monomer is 3%. Part B Demonstration of the Properties of the Compositions According to the Invention Example BI: Fast Analogous Insulin Solution (NovoLog) at 100 IU / mL [000148] This solution is a commercial solution of insulin aspart marketed by the company Novo Nordisk under the name of NovoLog® in the USA and Novorapid® in Europe. This product is a fast analog insulin. Example B2: Fast Analogous Insulin Solution (Humalog) at 100 IU / mL [000149] This solution is a commercial solution of Lispro insulin sold by Ell Lilly under the name Humalog. This product is a fast analog insulin. Example 63 Rapid Insulin Analogue Solution (Apidra) at 100 IU / mL [000150] This solution is a commercial solution of insulin glulisine marketed by Sanofi under the name Apidra®. This product is a fast analog insulin. Example 64 Slow Analog Insulin Solution (Lantus) at 100 IU / mL [000151] This solution is a commercial solution of insulin glargine marketed by Sanofi under the name Lantus This product is a slow analog insulin. Example B5: Human Insulin Solution (ActRapid®) at 100 IU / mL [000152] This solution is a commercial solution of Novo Nordisk sold under the name ActRapid®. This product is a human insulin. Example B6: Exenatide Analogous GLP-1 Solution (Byetta®) at 0.25 mg / mL [000153] This solution is an exenatide solution marketed by Eh Lilly and Company under the name Byetta®.

Example B7: Solution of GLP-1 derived liragiutide (Victoza) 6mg / mL [000154] This solution is a solution of liraglutide marketed by the company Novo Nordisk under the name of Victoza®.

Example B8: Solubilization of Lantus 100 IU / mL and at pH 7 with a substituted polyamino acid at the concentration of 10 mg / mL [000155] 20 mg of a substituted polyamino acid selected from those described in Table 1 are weighed precisely. This lyophilizate is taken up in 2 ml of the insulin glargine solution of Example B4 in order to obtain a solution whose concentration of substituted polyamino acid is equal to 10 mg / ml as described in Table 3. After mechanical stirring on rollers at room temperature, the solution becomes clear. The pH of this solution is 6.3. The pH is adjusted to 7 with 0.1N sodium hydroxide solution. This clear solution is filtered through a membrane (0.22 μm) and then placed at + 4 ° C. The solubilization test according to the above protocol was carried out with the polyamino acids 1, 2, 3 and 4. These solutions are referenced in Table 2. Example solution B8 Polyamino acid substituted Substituted polyamino acid concentration 10 mg / mL 10 mq / ml B8 (a) 1 B8 (b) 2 B8 (c) 3 10 mq / ml B8 (d) 4 10 mg / ml Table 2: Solutions according to Example B8 with polyamino acids 1, 2, 3 and 4 concentration 10 mg / mL Generalization: Clear solutions of Lantus® at 100 IU / mL and pH 7 were also obtained with concentrations of substituted polyamino acids of 20, 40 or 60 mg / mL following the same protocol as that described in Example B8.

Thus, a freeze-dried substituted polyamino acid mass among those described in Table 1 is accurately weighed. This lyophilizate is taken up by the insulin glargine solution of Example B4 so as to obtain a solution whose concentration of substituted polyamino acid is 20, 40 or 60 mg / ml as described in Table 3. After mechanical stirring on rollers at temperature the pH of this solution is below 7. The pH is then adjusted to 7 with 0.1 N sodium hydroxide solution. This clear final solution is filtered through a membrane (0.22 μm) and is then filtered. placed at + 4 ° C.

Final Polyamino Acid Mass Concentration Volume of Substituted Substituted Substituted Polyamino Acid Solution (mg) Insulin Glargine (mg / mL) Example B4 Added (mL) Table 3: Preparation of a solution of Lantus at 100 UT / mL and at pH 7 using a substituted polyamino acid at a concentration of 10, 20, 40 or 60 mg / mL Example B9: Preparation of a substituted polyamino acid composition 1 / Lantus / Apidrae with a Lantus® / Apidra® 75/25 ratio at pH 7. [000157] 0.75 ml of the substitute polyamino acid / Lantuse solution prepared according to the protocol described in Example B8 (a) is added 0.25 ml of Apidra® of Example B3 to form 1 ml of a composition at pH 7. The composition is clear attesting to the good solubility of Lantuse and Apidra® under these formulation conditions. This clear solution is filtered over 0.22 μm and is then placed at + 4 ° C. Example B10: Preparation of a Substituted Polyamino Acid Composition 1 / Lantus® / Humalog® with a Lantus® / Humaloge 75/25 Ratio at pH 7 [000158] A 0.75 mL of the substituted polyamino acid solution 1 / Lantuse prepared according to US Pat. protocol described in Example B8 (a) is added 0.25 ml of the Humalog® solution of Example B2 to form 1 ml of a composition at pH 7. The composition is clear, attesting to the good solubility of Lantuse and Humalog® under these conditions of formulation. This clear solution is filtered over 0.22 μm and is then placed at + 4 ° C. Example B11: Preparation of a substituted polyamino acid composition 1 / Lantus® / NovoLog® with a Lantuse / Novolog 75/25 ratio at pH 7 [000159] A 0.75 mL of the substituted polyamino acid solution 1 / Lantuse prepared at the Example B8 (a) is added 0.25 mL of NovoLoge from Example B1) to form 1 mL of a composition at pH 7. The composition is clear attesting to the good solubility of Lantus® and NovoLog® under these conditions formulation. This clear solution is filtered over 0.22 μm and is then placed at + 4 ° C.

Example B12: Preparation of a substituted polyamino acid composition 1 / Lantus / ActRapid® with a Lantus® / ActRapid® ratio 75/25 to pH 7 [000160] A 0.75 mL of the substituted polyamino acid solution 1 / Lantus ° prepared in Example B8 (a) is added 0.25 ml of ActRapid® of Example B5 to form 1 ml of a composition at pH 7. The composition is clear indicating the good solubility of Lantus® and ActRapid Under these conditions of formulation. This clear solution is filtered over 0.22 μm and is then placed at + 4 ° C.

Example B13: Preparation of a substituted polyamino acid composition 1 / Lantus® / Apidra® with a ratio of Lantus® / Apidra® 60/40 to pH 7 [000161] A 0.6 mL of the substituted polyamino acid solution 1 / Lantus® prepared in Example B8 (a) is added 0.4 mL of Apicfrac) of Example B3 to form 1 mL of a composition at pH 7. The composition is clear attesting the good solubility of Lantus ° and Apidra Under these conditions of formulation. This clear solution is filtered over 0.22 μm and is then placed at + 4 ° C. Example B14: Preparation of a substituted polyamino acid composition 1 / Lantuse / Apidra® with a Lantus® / Apidra® 40/60 ratio at pH 7 [000162] 0.4 ml of the substituted polyamino acid solution 1 / Lantus® prepared at Example B8 (a) is added 0.6 ml of Apidra® of Example B3 to form 1 ml of a composition at pH 7. The composition is clear indicating the good solubility of Lantus® and Apidra Under these conditions of formulation. This clear solution is filtered on 0.22 prrl and is placed at + 4 ° C.

Example B15: Precipitation of Lantus® [000163] 1 ml of Lantus® of Example B4 is added in 2 ml of a solution of P135 (phosphate buffer, phosphate buffered saline) containing 20 mg / ml of BSA (bovine serum albumin) bovine serum albumin). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears which is in good agreement with the operating mechanism of Lantus ° (precipitation to injection due to the increase of the pH). [000164] Centrifugation at 4000 rpm is carried out to separate the precipitate from the supernatant. Then Lantus® is assayed in the supernatant. As a result, at least 90% of Lantus® is in a precipitated form.

Example 1316 Precipitation of a substituted polyamino acid composition 1 / Lantus® [000165] 1 ml of substituted polyamino acid solution 1 / Lantus® prepared in Example B8 (a) is added in 2 ml of a solution of PBS containing 20 mg / mL of BSA (bovine serum albumin). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears. Centrifugation at 4000 rpm is performed to separate the precipitate from the supernatant. Then Lantus® is assayed in the supernatant. As a result, at least 50% of Lantus® is found in a precipitated form. Solubilization and precipitation tests identical to those described in Example B8 (a) and B16 were carried out with other polyamino acids substituted at the same concentration of 10 mg / ml of substituted polyamino acid per 100 IU / ml of Lantus®. 10 mg of substituted polyamino acid in the form of lyophilizate are accurately weighed. This lyophilizate is taken up in 1 ml of Lantus® of Example B4. A temporary precipitate appears but the solution becomes clear after about 30 minutes to a few hours (depending on the nature of the polyamino acid). The pH of this solution is 6.3. The pH is adjusted to 7 with a 0.1N sodium hydroxide solution. This clear solution is filtered over 0.22 μm and is then placed at + 4 ° C. The results are summarized in Table 4.

Substituted Polyamino Acid Solubilization of Lantus® Precipitation Lantus® (Precipitation Rate z 50%) 1 Yes Yes 2 Yes Yes 3 Yes Yes 4 Yes Yes Table 4: Solubilization and Precipitation Tests of a Substituted Polyamino Acid / Lantus® Example B17: Precipitation of a substituted polyamino acid composition 1 / Lantus® / Apidra® with a Lantus® / Apidra® 75/25 ratio at pH 7 [000167] 1 rnt .. of the substituted polyamino acid composition 1 / Lantusc) / Apidra 75 / 25 (containing 7.5 mg / ml of substituted polyamino acid 1.75 IU / ml of Lantus® and 25 IU / ml of Apidra®) prepared according to the protocol of Example B12 is added in 2 ml of a solution of PBS containing 20 mg / ml BSA (bovine serum albumin). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears.

Centrifugation at 4000 rpm is performed to separate the precipitate from the supernatant. Then Lantus® is assayed in the supernatant. As a result, at least 50% of Lantus ° is found in a precipitated form.

Example B18: Precipitation of Different Compositions by Varying the Nature of the Substituted Polyamino Acid [000168] Other tests under the same conditions as those of Example B17 were carried out in the presence of other polyamino acids. The results are summarized in the following Table 5 and it is observed that the solubilization and the precipitation of Lantus® are preserved. Polyamino acid No. Solubilization Lantus Lantuse / Apiclra 75/25 Precipitation (precipitation rate? 50%) 1 Yes Yes 2 Yes Yes 3 Yes Yes 4 Yes Yes Table 5: Solubilization and precipitation tests of a substituted polyamino acid / Lantus composition ® / Apidra 75/25 pH 7 Example B19: Precipitation of various compositions by varying the nature of mealtime insulin [000170] Compositions are prepared by mixing 0.75 mL of the substituted polyamino acid / Lantus® solution prepared according to the protocol of Example 68 (a) with 0.25 mL of a mealtime insulin to form 1 mL of substituted polyamino acid / Lantus® / prandial insulin composition (containing 7.5 mg / mL of substituted polyamino acid, 1.75 IU / mL of Lantus® and 25 UT / mL of mealtime insulin). This composition is added in 2 ml of PBS containing 20 mg / ml of BSA (bovine serum albumin). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears. Centrifugation at 4000 rpm is performed to separate the precipitate from the supernatant. Then Lantuse is dosed in the supernatant. In the presence of the 4 prandial insulins tested, Lantus® precipitates at least 50%. The results are summarized in Table 6.

Nature of Prandial Insulin Solubilization Precipitation of Lantus® Lantus / Insulin (Precipitation Rate k 50%) Prandial 75/25 Apidra® Yes Yes NovoLog® Yes Yes Humalog® Yes Yes ActRapid® Yes Yes Table 6 Solubilization and Precipitation Tests of a substituted polyamino acid composition 1 / Lantuse / Prandial Insulin 75/25 Example 820 Preparation of a Lantus® / Byetta® 70/30 Composition at pH 7.5 [0001721A 0.21 mL of the insulin glargine solution Example B4 is added 0.09 mL of the exenatide solution of Example 86 to obtain 0.3 mL of a composition having a pH of 4.5 in the mixture. The composition containing 70 IU / ml of Lantus® and 0.075 mg / ml of Byetta® is clear attesting to the good solubility of Lantus® and Byetta® under these formulation conditions (pH 4.5). The pH is then adjusted to 7.5 with a 0.1N sodium hydroxide solution. The composition then becomes cloudy, attesting to the poor solubility of the Lantus® / Byetta composition at pH 7.5. Lantus® / Byetta® 70/30 compositions were also prepared at pH 4.5-5.5-6.5-8.5 and 9.5 by following a protocol similar to that described in the example 620. For each of these compositions, to 0.21 ml of the insulin glargine solution of Example B4 is added 0.09 ml of the exenatide solution of Example B6 to obtain 0.3 ml of a composition whose pH is 4.5 to the mixture. The composition is clear attesting to the good solubility of Lantus® and Byetta® under these formulation conditions (pH 4.5). The pH is adjusted to 5.5 or 6.5 or 8.5 or 9.5 with a 0.1 N sodium hydroxide solution. After adjusting the pH, the composition at pH 5.5 is slightly cloudy, the pH compositions 6.5 and 8.5 are very turbid and the composition at pH 9.5 is clear. These compositions are placed at + 4 ° C. for 48 hours.

After 48h at + 4 ° C., only the composition at pH 4.5 remains clear. The visual appearance after 48 hours of the Lantus® / Byetta® 70/30 compositions at different pH is summarized in Table 7, Lantus® / Byetta® Compositions 70/30 at different pH pH Visual Aspects at t = 48h 4.5 Clear 5, Presence of a precipitate 6.5 Presence of a precipitate 7.5 Presence of a precipitate 8.5 Presence of a precipitate 9.5 Presence of a precipitate Table? Visual aspect after 48 hours at 4 ° C. of the Lantus / Byetta 70/30 compositions at different pH levels. Example B21: Preparation of a Lantus® / Victoza® 70/30 Composition at pH 7.5 [000174] At 0.21 mL of the insulin glargine solution of Example B4 is added 0.09 ml of the liraglutide solution of Example B7 to obtain 0.3 ml of a composition whose pH is 7 in the mixture. The composition containing 70 UT / ml of glargine and 1.8 mg / ml of liraglutide is cloudy, attesting to the poor solubility of the Lantus® / Victozae composition under these formulation conditions. The pH is adjusted to 7.5 with 0.1N sodium hydroxide solution. After adjusting the pH, the composition remains cloudy. This composition is placed at + 4 ° C for 48 hours. Lantus® / Victoza 70/30 compositions were also prepared at pH 4.5-5.5-6.5-8.5 and 9.5 using a protocol similar to that described in Example 821. For each of these compositions, to 0.21 ml of the insulin glargine solution of Example B4 is added 0.09 ml of the liraglutide solution of Example 87 to obtain 0.3 ml of a composition. whose pH is 7. The composition is cloudy attesting to the poor solubility of the composition Lantus® / Victoza® under these conditions of formulation (pH 7). The pH is adjusted to 4.5 or 5.5 or 6.5 with a 0.1 N hydrochloric acid solution or at pH 9.5 with 0.1 N sodium hydroxide solution. at pH 4.5 - 5.5 6.5 and 8.5 are cloudy, attesting to the poor solubility of the composition Lantuse / Victozae under these conditions of formulation. These compositions are placed at + 4 ° C. for 48 hours. After 48 hours at 4 ° C., only the composition at pH 9.5 is clear. The visual appearance after 48 hours of the Lantusc® / Victoza® 70/30 compositions at different pH is summarized in the table8.30 Lantus' / Victoza® 70/30 Compositions at different pH pH Visual Aspect at t = 48h 4.5 Presence of a precipitate 5.5 Presence of a precipitate 6.5 Presence of a precipitate 7.5 Presence of a precipitate 8.5 Presence of a precipitate 9.5 Limpid Table 8: Visual appearance after 48h at 4 ° C. Lantus® / Victoza®70 / 30 compositions at different pH levels Example B22: Preparation of a substituted polyamino acid / Lantus® / Byetta® composition with a Lantus® / Byetta® 70/30 ratio at pH 7 [000176] A 0, 21 ml of the solution of substituted polyamino acid 1 / Lantus prepared according to the protocol of Example B8 (a) is added 0.09 ml of the exenatide solution of Example B6 to obtain 0.3 ml of a composition at pH 5.3. The pH is adjusted to 7 with a 0.1N sodium hydroxide solution. The composition containing 7 mg / ml of substituted polyamino acid, 1.70 IU / ml of Lantus® and 0.075 mg / ml of Byetta® is clear, attesting to good solubility. of Lantus® and Byetta® in the presence of the substituted polyamino acid 1 at pH 7. This clear solution is placed at + 4 ° C. Generalization: Substituted polyamino acid / Lantus® / Byetta® compositions at pH 7 were also prepared at VLantus / VBvetta volume ratios of 90/10, 50/50 and 30/70 following the same protocol as that described in the example. B22. Thus, at a volume VLantus of the solution of substituted polyamino acid / Lantus® prepared according to the protocol of Example B8 is added a volume VByett, of the exenatide solution of Example B6 to obtain a composition whose pH is adjusted. at 7 with 0.1 N sodium hydroxide solution. The compositions obtained (see Table 9) are clear, demonstrating the good solubility of Lantus® and Byette in the presence of a substituted polyamino acid 1 at pH 7. These clear solutions are placed at + 4 ° C. Example B23: Preparation of a substituted polyamino acid composition 1 / Lantus® / Byetta® with a 100/50 Lantus® / Byetta® ratio at pH 7 0.150 ml of the exenatide solution of Example B6 are lyophilized, then 0, 3 ml of a solution of substituted polyamino acid / Lantus® prepared according to the protocol of Example B8 (a) are added to the lyophilizate in order to obtain a composition whose pH is adjusted to 7 with a 0.1 N sodium hydroxide solution. The composition containing 10 mg / ml of substituted polyamino acid 1,100 Ur / ml of Lantus and 0,125 mg / ml of Byetta® is clear attesting to the good solubility of Lantus and Byetta in the presence of Lantus® [substituted polyamino acid Byetta® 1 ] (mg / mL) (mg / mL) IU / mL mg / mL 100/50 100 3.5 10 0.125 90/10 90 3.15 9 0.025 70/30 70 2.45 7 0.075 50/50 50 1, Table 5: Final concentrations of the compositions obtained in Examples B22 and B23 with Lantus®, substituted polyamino acid 1 and Byetta® Example B24: Preparation of a substituted polyamino acid composition 1 / Lantus® / Victoza® with a 70/30 Lantus / Victoza ratio at pH 7 [000177] 0.21 ml of the substituted polyamino acid / Lantus® solution prepared according to the protocol of Example B8 (a) 0.09 ml of the liraglutide solution of Example B7 is added to give 0.3 ml of a composition at pH 7.6. The pH is adjusted to 7 with a 0.1N hydrochloric acid solution. The composition containing 7 mg / ml of substituted polyamino acid, 1.70 IU / ml of Lantus® and 1.8 mg / ml of Victoza® is clear to attest the good solubility of Lantus® and Victoza® in the presence of the substituted polyamino acid 1 at pH 7. This clear solution is placed at + 4 ° C. The final composition obtained is summarized in Table 10. [000178] Generalization: Substituted polyamino acid / Lantus® / Victoza® compositions at pH 7 were also prepared at VLantus / VVictoza volume ratios of 90/10, 50/50 and 30%. / 70 following the same protocol as that described in Example B24. Thus, at a volume VLantus of the solution of substituted polyamino acid 1 / Lantus® at a polyamino acid concentration of 40 mg / mL prepared according to the protocol of Example B8 is added a Vvctoza volume of the liraglutide solution of Example B7. to obtain a composition whose pH is adjusted to 7 with 0.1 N hydrochloric acid solution, [000179] The compositions obtained (see Table 10) are clear, demonstrating the good solubility of Lantus® and Victoza® in the presence of a polyamino acid substituted at pH 7. These clear solutions are placed at + 4 ° C. pol Lantus® [Victoza® polyamino acid (mg / mL) substituted 1] (mg / mL) IU / mL mg / mL 90/10 90 3.15 36 0.6 1.8 70/30 70 2.45 28 50 / 50 50 1.75 20 3 30/70 30 1.05 12 4.2 Table 0: Final concentrations of the compositions obtained in Examples B24 and B25 with Lantus®, substituted polyamino acid 1 and Victoza® Example B26: Preparation of a substituted polyamino acid composition 1 / - Lantus® / Apidra® / Byetta® with a Lantus® / Apidra® / Byetta® 60/20/20 ratio at pH 7 [000180] 20 mg of lyophilized substituted polyamino acid 1 are accurately weighed. This lyophilizate is taken up in 2 ml of the insulin glargine solution of Example B4. After mechanical stirring on rollers at room temperature, the solution becomes clear.

The pH of this solution is 6.3. The pH is adjusted to 7 with a 0.1N sodium hydroxide solution. To 0.6 ml of the previously prepared polyamino acid / Lantus® solution, 0.2 ml of the exenatide solution of Example B6 and 0 are added. 2 ml of the insulin glulisine solution of Example B3 to obtain 1 ml of a composition at pH 7. The composition containing 6 mg / ml of substituted polyamino acid 1.60 IU / ml of Lantus®, 20 IU / ml mL of Apidra® and 0.05 mg / mL of Byetta® is clear evidence of the good solubility of Lantus®, Apidra® and Byetteen the presence of the substituted polyamino acid 1 at pH 7. This clear solution is filtered on membrane ( 0.22 μm) and then placed at + 4 ° C.

Example B27: Precipitation of a substituted polyamino acid composition / Lantus® / Byetta® with a Lantus® / Byetta® 70/30 ratio at pH 7 [000181] 0.250 mL of the substituted polyamino acid / Lantus® / Byetta® composition prepared according to US Pat. Example B22 protocol is added in 0.5 mL of a solution of PBS containing 20 mg / mL of BSA. The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears. [000182] Centrifugation at 4000 rpm is carried out to separate the precipitate from the supernatant. Then Lantus® and Byetta® are assayed in the supernatant. The result is summarized in Table 11.

Example B28 Precipitation of a substituted polyamino acid / Lantus / Victoza® composition with a Lantuse / Victozae 70/30 ratio at pH 7 [000183] 0.250 mL of the substituted polyamino acid composition 1 / Lantuse / Victozae prepared according to the protocol of Example B24 is added in 0.5 ml of a solution of PBS containing 20 mg / ml of BSA (bovine serum albumin). The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears. Centrifugation at 4000 rpm is performed to separate the precipitate from the supernatant. Then Lantus® is assayed in the supernatant. The result is shown in Table 12. Example B29: Precipitation of Different Compositions by Varying the Nature of the Substituted Polyamino Acid [000184] Other assays under the same conditions as those described in US Pat. Examples B27 and B28 were carried out in the presence of other substituted polyamino acids and are respectively shown in Tables 11 and 12. Results with at most 10 mg / mL of substituted polyamino acid and Lantus® / Byetta® composition 70 / At pH 7 are grouped in the following Table 11. It is observed that the solubilization and the precipitation of Lantus® are preserved.

Polyamino acid Solubilization Precipitation of Lantus® substituted at most Lantus® / Byetta® (Precipitation rate> 50 ok) from 10 mg / mL 70/30 to pH 7 1 Yes Yes 2 Yes Yes 3 Yes Yes 4 Yes Yes Tableaull: Test results solubilization and precipitation obtained with at most 10 mg / mL of substituted polyamino acid and a Lantus® / Byetta® 70/30 composition at pH 7 [000186] Results with at most 40 mg / mL of substituted polyamino acid and a Lantus® composition / Victoza® 70/30 at pH 7 are grouped in the following Table 12. It is observed that the solubilization and the precipitation of Lantus® are preserved.

Polyamino acid Solubilization Lantus® precipitation at most Lantus® / Victoza® (50% precipitation rate) 40 mg / mL 70/30 at pH 7 1 Yes Yes 2 Yes Yes 3 Yes Yes 4 Yes Yes Table 12: Results solubilization and precipitation tests obtained with not more than 40 mg / mL of polyamino acid and a Lantus® / Victoza® 70/30 composition at pH 7. Example B30 Precipitation of a substituted polyamino acid composition / Lantus® / Apidra / Byetta® 60 / 20/20 at pH 7 [000187] 0.250 ml of the polybutyl amino acid-substituted / Lantus® / Apidrae / Byetta® composition prepared in Example B26 are added in 0.5 ml of a solution of PBS containing 20 mg / ml of BSA. The PBS / BSA mixture simulates the composition of the subcutaneous medium. A precipitate appears. [000188] Centrifugation at 4000 rpm is carried out to separate the precipitate from the supernatant. Then, Lantus® is assayed in the supernatant. As a result, at least 50% of Lantus® is in a precipitated form.

Claims (32)

REVENDICATIONS1. A composition in the form of an aqueous injectable solution, the pH of which is between 6.0 and 8.0, comprising at least: a) a basal insulin whose isoelectric point pI is between 5.8 and 8.5; b) a polyamino acid carrying carboxylate charges and substituted by hydrophobic radicals, of formula I: ## STR1 ## in which A represents, independently, a group -CH 2 - (aspartic unit) or a group - CH 2 -CH 2 - (glutamic unit), - R 1 is selected from the group consisting of H, linear C 2 -C 10 acyl group, branched C 3 -C 10 acyl group, benzyl, terminal amino acid unit and a pyroglutamate, R2 is selected from the group consisting of: a secondary amino group -NR'R ", R 'and R", which may be identical or different, being selected from the group consisting of linear or branched or cyclic C1 to C4 alkyls; CIO, benzyl and said alkyl R 'and R "may together form saturated, unsaturated and / or aromatic carbon rings and / or may contain heteroatoms selected from the group consisting of O, N and S, OR310- R3 groups identical or different are chosen from the group consisting of an H or a cationic entity selected from the group comprising metal cations, the R groups each independently represent a monovalent radical chosen from radicals of general formula II or H ': O / R 40 R 0 0 0 Wherein R4 represents a linear or branched, saturated or unsaturated C8-C30 radical which may contain heteroatoms or a radical which may form carbon-based rings or which may contain saturated, unsaturated heteroatoms and / or wherein said rings may be ortho-fused or peri-fused; B is independently -CH2- (aspartic unit) or -CH2-CH2- (glutamic unit); R5 is independently H, alkyl; linear or branched C1 to C4 or a benzyl group, - R is a linear or branched, saturated or unsaturated C8 to C30 radical, which may contain heteroatoms or a radical to form carbon-based rings or which may comprise saturated, unsaturated and / or aromatic heteroatoms, said rings being able to be orthocondensed or peri-condensed; - n / (n + m) is defined as the degree of hydrophobic radical molar grafting of the monomeric units and is between 1 and 50 mole percent; n + m represents the degree of polymerization of the polyamino acid, i.e., the average number of monomeric units per polyamino acid chain and 5 n + m 1000. 2. Composition according to claim 1, characterized in that the group A is a group -CH2- (aspartic unit). 3. Composition according to claim 2, characterized in that the polyamino acids may further comprise monomeric units of formula IV and / or IV ': O \\ ,,, / 0R3 H Formula IV Formula IV' 4. Composition according to claim 1, characterized in that the group A is a group -CH2-C1-12- (glutamic unit). 5. Composition according to any one of the preceding claims, characterized in that the R group is a tocopheryfoxy- or cholesteryloxy- radical. 6. Composition according to any one of the preceding claims, characterized in that -NR'R "is -N-morphofyl. 7. Composition according to any one of the preceding claims, characterized in that n + m is between 10 and 500. 8. Composition according to any one of the preceding claims, characterized in that n + m is between 15 and 250. H 30 9. Composition according to any one of the preceding claims, characterized in that n / (n + m) is between 1 and 30 mol%. 10. Composition according to any one of the preceding claims, characterized in that n / (n + m) is between 1 and 20 mol%. 11. Composition according to any one of the preceding claims, characterized in that the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine. 12. Composition according to any one of the preceding claims, characterized in that it comprises between 40 and 500 IU / mL of basal insulin whose isoelectric point is between 5.8 and 8.5. 13. Composition according to any one of the preceding claims, characterized in that the concentration of substituted polyamino acid is at most 60 mg / ml. 14. Composition according to any one of claims 1 to 12, characterized in that the concentration of substituted polyamino acid is at most 40 mg / ml. 15. Composition according to any one of claims 1 to 12, characterized in that the concentration of substituted polyamino acid is at most 20 mg / mL. 16. Composition according to any one of claims 1 to 12, characterized in that the concentration of substituted polyamino acid is at most 10 mg / mL. 17. Composition according to any one of the preceding claims, characterized in that it also includes a mealtime insulin. 18. Composition according to the preceding claim, characterized in that the prandial insulin is human insulin. 19. Composition according to any one of claims 17 to 18, characterized in that in total it comprises between 40 and 500 IU / mL. insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8.5. 20. Composition according to any one of claims 17 to 19, characterized in that the proportions between the basal insulin whose isoelectric point is between 5.8 and 8.5 and the prandial insulin are in IU / mL of 25/75, 30/70, 40/60, 50/50, 60/40 or 70/30. 21. Composition according to any one of the preceding claims, characterized in that it further comprises a gastrointestinal hormone 22. A composition according to claim 21, characterized in that the gastrointestinal hormone is selected from the group consisting of exenatide or Byetta®, developed by Eli Lilly & Co and Amylin Pharmaceuticals, liraglutide or Victoza® developed by Novo Nordisk, or lixisenatide or Lyxumia® developed by Sanofi, their analogues or derivatives and their pharmaceutically acceptable salts. 23. Composition according to any one of claims 21 to 22, characterized in that the gastrointestinal hormone is exenatide or Byetta® its analogues or derivatives and their pharmaceutically acceptable salts. 24. Composition according to any one of Claims 21 to 22, characterized in that the gastrointestinal hormone is liraglutide or Victoza® its analogues or derivatives and their pharmaceutically acceptable salts. 25. Composition according to any one of claims 21 to 22, characterized in that the gastrointestinal hormone is lixisenatide or Lyxumia® its analogues or derivatives and their pharmaceutically acceptable salts. 26. Composition according to any one of claims 21 to 25, characterized in that the concentration of gastrointestinal hormone is in a range of 0.01 to 10 mg / ml. 27. Composition according to any one of claims 21 to 23, characterized in that it comprises between 500 IU / mL and 40 IU / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.05 to 0.5 mg / mL of exenatide. 28. Composition according to any one of claims 21 to 22 and 24 characterized in that it comprises between 500 IU / mL and 40 UT / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / mL of liraglutide. 29. Composition according to any one of claims 21 to 22 and 25, characterized in that it comprises between 500 UT / mL and 40 IU / mL of basal insulin whose isoelectric point is between 5.8 and 8, 5 and 0.05 to 0.5 mg / mL of lixisenatide. 30. Single-dose formulation at a pH of between 7 and 7.8, including a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin. 31. A single-dose formulation at a pH of between 7 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone. 32. Single-dose formulation at a pH of between 7 and 7.8 including a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone.