HK1175409B - Pharmaceutical composition comprising a glp-1 agonist, an insulin, and methionine - Google Patents

Description

The present application is for a liquid composition containing the GLP-1 agonist of Pro36Exendin-4 ((1-39)-Lys6-NH2 and/or a pharmacologically tolerable salt thereof, insulin Gly(A21)-Arg(B31)-Arg(B32) human insulin and/or a pharmacologically tolerable salt thereof and, where appropriate, at least one pharmaceutically acceptable excipient, characterised by the presence of L-methionine and a pH of 3,5 to 4,5.

The present invention is intended to be used in the manufacture of a medicinal product for the treatment of diabetes mellitus and describes a method for the manufacture of a composition of the invention, comprising the comprehensive formulation of a GLP-1 agonist and/or a pharmacologically tolerable salt thereof with an insulin and/or a pharmaceutically acceptable salt thereof, methionine and, where appropriate, at least one pharmaceutically acceptable excipient.

Common formulations of insulin and GLP-1 compounds include an isotonic agent, a buffer to adjust the pH, and a preservative. Another commonly used component of insulin formulations is zinc, which forms a complex with insulin, thereby delaying the action of insulin.

WO 2004/035623 (Zealand Pharmaceuticals) reveals a liquid composition comprising a stabilised exendin, 50 mM histidine, 100 to 200 mM sucrose, mannitol or another acceptable sugar, 20 mM methionine, 20 mM asparagine-glutamine or asp with a pH of 5,3.

WO 2005/046716 (Novo Nordisk) reveals liquid compositions containing liraglutide and insulin aspart, a buffer pH 7,7, poloxamer 188 as surfactant, phenol, propylene glycol and possibly zinc. Without poloxamer 188 the compositions were unstable. Stabilisation was achieved by polysorbate 20.

WO 2006/029634 (Novo Nordisk) concerns liquid pharmaceutical formulations containing an insulinotropic peptide (GLP-1 agonist), an insulin peptide and a ligand for HisB10 (ligand of His at position 10 of the B chain of insulin). The formula may contain as surfactant polysorbates-20 or poloxamers-188. Specific formulations disclosed in this document include human insulin or human B28-aspartate (insulin aspartate), liraglutide (GLP-Agonist), glycerol-1 as isotonic agent, zinc phenol, pH 7.4 or 7.9. Depending on the amount of ligand, the insulin or poloxamers were released from the ligand. These formulations were made unstable after 15 days of exposure to a room temperature of 7.8 or higher. These formulations were made unstable by the combination of phenol, propyl or propyl at a pH of 7.8 or lower.

WO 2006/051103 (Novo Nordisk) reveals liquid compounds containing detemir (a basal insulin), liraglutide (a GLP-1 compound) and as surfactant poloxamer 188 or polysorbate 20. Other components include phenol, NaCl, propylene glycol, zinc acetate and sodium phosphate or glycylglycine buffers (pH 7.7). m-cresol is present in some of these compounds. The addition of poloxamer 188 or polysorbate 20 has been used to stabilise the compounds.

WO 2008/124522 (Biodel) concerns formulations containing an insulin, a zinc chelator (e.g. EDTA or EGTA) and a GLP-1 analogue.

The current treatment is the only available treatment for type I diabetes, for which replacement of the missing endocrine insulin secretion is the only possible treatment. The patients are dependent on insulin injections throughout life, usually several times a day. Unlike type I diabetes, type II diabetes does not generally have a deficiency of insulin, but in a large number of cases, especially in the advanced stage, treatment with insulin, possibly in combination with an oral anti-diabetic, is considered the most favorable form of therapy.

In healthy people, insulin release by the pancreas is strictly linked to the concentration of blood glucose. Increased blood glucose levels, as they occur after meals, are quickly compensated by a corresponding increase in insulin secretion. In the sober state, plasma insulin levels fall to a baseline value sufficient to ensure a continuous quality supply of insulin-sensitive organs and tissues with glucose and to keep hepatic glucose production low at night. Replacement of the body's own insulin secretion by exogenous, usually subcutaneous, insulin secretion usually does not approach the physiological regulation of blood glucose described above.The large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) clearly demonstrated that chronically elevated blood glucose levels are a significant contributor to the development of diabetic late-onset damage. Late-onset diabetes is micro- and macro-vascular damage that manifests itself as retinal, nephro-therapy, or neuropathy, among other things, and leads to blindness, kidney failure, and loss of limbs, and in addition to this, with an increased risk of heart/ vascular disease.The concept of intensified insulin therapy is to be achieved by several daily injections of fast and slow acting insulin preparations. Fast acting formulations are given with meals to compensate for the postprandial rise in blood glucose. Slow acting basal insulins are to ensure basic insulin supply, especially at night, without causing hypoglycaemia.

Insulin is a polypeptide of 51 amino acids, which are distributed on 2 amino acid chains: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are connected by 2 disulfide bridges. Insulin preparations have been used for many years for diabetes therapy.

Insulin analogues are analogues of naturally occurring insulins, namely human or animal insulins, which are distinguished by substitution of at least one naturally occurring amino acid residue with other amino acids and/or addition/removal of at least one amino acid residue from the corresponding otherwise identical naturally occurring insulin.

Insulin derivatives are derivatives of naturally occurring insulin or an insulin analog obtained by chemical modification. The chemical modification may consist, for example, in the addition of one or more specific chemical groups to one or more amino acids.

EP 0 278 522 describes insulin analogues which contain various amino acids, preferably proline, in position B29, but not glutamic acid. EP 0 375 437 includes insulin analogues with lysine or arginine in B28, which may optionally be modified further in B3 and/ or A21.

In EP 0 419 504 insulin analogues protected against chemical modification are disclosed by altering asparagine to B3 and at least one other amino acid in positions A5, A15, A18 or A21.

WO 92/00321 describes insulin analogues in which at least one amino acid from positions B1 to B6 is replaced by lysine or arginine. Such insulins have a prolonged action according to WO 92/00321.

The insulin preparations available on the market from naturally occurring insulins for insulin replacement differ in the origin of the insulin (e.g. bovine, porcine, human insulin) and in the composition which may influence the profile of action (start of action and duration of action). Combining different insulin preparations allows for a wide range of action profiles and to adjust physiological blood glucose levels as much as possible. Recombinant DNA technology now allows the production of such modified insulin injections. These include Glycine (GlycineA21) -ArgGB31) -Hypoglycine (ArgGB31) -Hypoglycine (ArgGB32) -Lantus, combined with insulin insulin. Glycine (ArgGB301) -ArgGB25 is a clear, more stable solution, and is therefore more stable than other insulin preparations due to its pH and its physiological properties.

The specific preparation of insulin glargine, which results in a prolonged duration of action, is characterised by a clear solution with an acid pH.

Exendins are a group of peptides that can lower blood glucose levels. Exendins have some sequence similarity to GLP-1 (7-36) (53%, Goke et al. J. Biol Chem 268, 19650-55). Exendin-3 and Exendin-4 stimulate an increase in cellular cAMP production in acinine cells of the pancreas of guinea pigs by interacting with exendin receptors (Raufman, 1996, Reg. Peptides 61:1-18). Exendin-3 causes an increase in amylase release in acinine cells of the pancreas, unlike exendin-4. Exendins act as GLP-1 agonists.

GLP-1 generally lowers glucagon levels, slows gastric emptying, stimulates (pro-) insulin biosynthesis, increases insulin sensitivity and stimulates insulin-independent glycogen biosynthesis (Holst (1999), Curr. Med. Chem 6:1005, Nauck et al. (1997) Explication C Endocrinol Diabetes 105: 187, Lopez-Delgado et al. (1998) Endocrinology 139:2811). Human GLP-1 has 37 amino analogues (Heinrich and Melanin, 99: 55-2, 115:27, 115:28, 115:28, and 99:47, and 99:47, respectively). They may be used in the treatment of diabetes and other conditions and may be used in the treatment of acne and other conditions.

The solid-phase synthesis of AVE0010 is described in WO 01/04156 A1. AVE0010 has the sequence: desPro36Exendin-4(1-39)-Lys6-NH2. This substance is published as SEQ ID NO:93 in WO 01/04156: Other

Exendin-4 (39 AS) has the following sequence: Other

Exendin-3 has the following sequence (J. Bio. Chem., 267, 1992, 7402-7405): Other

GLP-1 has the sequence: The following information shall be provided in the form of a summary of the results of the analysis:

The purpose of the present invention was to increase the stability of liquid formulations including a GLP-1 agonist and an insulin. In particular, the objective is to improve the physical and chemical integrity. This task was solved by formulating the GLP-1 agonist of the Pro36Exendin-41-39)-Lys6-NH2 and the insulin Gly(A21)-Arg(B31)-ArgB32) human insulin with L-methionine. Methionine has been found to increase the storage stability of a compound including the GLP-1 agonist AVE0010 and insulin glargine.

The stability of pharmaceutically active polypeptides can be affected by various mechanisms, including pH, temperature, light and the effects of certain components.

In the context of the present invention, a number of common constituents of insulin formulations or GLP-1 agonist formulations have been found to be detrimental to the chemical and/or physical integrity and storage stability of formulations containing an insulin and a GLP-1 agonist, such as acetate, polysorbate 20, polysorbate 80, poloxamer 188, benzalkonium chloride and lysine.

The present invention relates to a liquid composition comprising the GLP-1 agonist of Pro36Exendin-4 (1-39)-Lys6-NH2 or/and a pharmacologically tolerable salt thereof, the insulin Gly (A21)-Arg (B31)-Arg (B32) human insulin or/and a pharmacologically tolerable salt thereof and, if applicable, at least one pharmaceutically acceptable excipient, the composition being characterized by the presence of L-methionine and containing a pH of 3.5 to 4.5.

The composition of the invention contains L-methionine preferably in the amount of 0,5 mg/mL to 20 mg/mL, more preferably in the amount of 1 mg/mL to 5 mg/mL, especially preferably in the amount of 3,0 mg/mL. Methionine is used in the L-form.

In particular, the composition according to the invention is free from surfactants such as polyols and partial and fatty acid esters and ethers of multi-value alcohols such as glycerin and sorbitol. The composition according to the invention is free from partial and fatty acid esters and ethers of glycerin and sorbitol selected from a group including Span®, Tween®, Myrj®, Brij®, Cremophor®. Furthermore, the composition according to the invention is free from polyols selected from the group of polypropylene glycols, polyethylene glycols, poloxamers, polyoxuronic acids, tetronics. In particular, the composition according to the invention is free from at least one polysorbate, polysorbate and polysorbate.

In particular, the composition of the invention is essentially free, preferably free of polysorbate, such as polysorbate 20.

In particular, the composition of the invention is essentially free, preferably free of polysorbate 80.

In particular, the composition of the invention is essentially free, preferably free of poloxamers, such as poloxamers 188.

In particular, the composition of the invention is essentially free, preferably free of benzalkonium chloride.

In particular, the composition of the invention is essentially free, preferably free of histidine.

In particular, the composition of the invention is essentially free, preferably free of EDTA, in particular sodium EDTA.

In particular, the composition of the invention is essentially free, preferably free of histidine and sodium EDTA.

The composition of the invention may contain one or more substances commonly used to buffer the pH (buffer substances). Examples of such buffer substances are acetate, citrate and phosphate. In particular, the composition of the invention may contain one or more substances commonly used to buffer the pH in an amount sufficient, for example, as an ion for the GLP-1 agonist and/or insulin. The composition of the invention may contain one or more buffer substances, for example, in amounts up to 1 mg/ml, up to 0.5 buffers/ml, up to 0,1 mg/ml, up to 0,05 mg/ml, up to 0,02 mg/ml or up to 0,01 mg/ml. The composition of the invention may be free of buffer substances in the same quantity.

The composition of the invention may contain acetate, for example in amounts up to 1 mg/ml, up to 0.5 mg/ml, up to 0,1 mg/ml, up to 0,05 mg/ml, up to 0,02 mg/ml or up to 0,01 mg/ml. These amounts are sufficient, for example, as an antigen for the GLP-1 agonist. Similarly, the composition of the invention may be substantially acetate-free.

The composition of the invention may contain citrate, for example in amounts up to 1 mg/ml, up to 0.5 mg/ml, up to 0,1 mg/ml, up to 0,05 mg/ml, up to 0,02 mg/ml or up to 0,01 mg/ml. These amounts are sufficient, for example, as an antigen for the GLP-1 agonist. Similarly, the composition of the invention may be substantially free of citrate.

The composition of the invention may contain phosphate, for example in amounts up to 1 mg/ml, up to 0.5 mg/ml, up to 0,1 mg/ml, up to 0,05 mg/ml, up to 0,02 mg/ml or up to 0,01 mg/ml. These amounts are sufficient, for example, as an antigen for the GLP-1 agonist. Similarly, the composition of the invention may be substantially free of phosphate.

The pharmaceutical composition of the present invention has a pH of 3.5 to 4.5.

A pH of about 4.5 is particularly desirable, and physiologically safe diluted acids (typically HCl) or alkenes (typically NaOH) are suitable for setting the pH.

The composition of the invention may contain a suitable preservative. Suitable preservatives are e.g. phenol, m-cresol, benzyl alcohol and/or p-hydroxybenzoic acid ester. M-cresol is preferred. However, preservatives may also be omitted.

The composition of the invention may contain zinc ions, preferably in the range of 1 μg/ml to 2 mg/ml, preferably between 5 μg and 200 μg zinc/ml, in particular at a maximum of 0,06 mg/ml, preferably at 0,06 mg/ml.

The composition of the invention may also contain suitable isotonic agents, e.g. glycerin, dextrose, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium compounds such as CaCl2 etc. The concentrations of glycerin, dextrose, lactose, sorbitol, mannitol and glucose are usually in the range of 100 to 250 mM, NaCl in a concentration of up to 150 mM. Glycerin is preferred. In particular, 85 per cent glycerin is preferred at 20.0 mg/ml.

The composition of the invention may also contain additional additives, such as salts, which delay the release of at least one insulin, preferably free of these additives.

In particular, the composition of the present invention is intended for parenteral administration. The composition of the invention is preferably an injectable composition, more preferably for subcutaneous injection. In particular, the composition of the present invention is suitable for once daily injection.

In particular, the formulation of the invention shall, after storage for 1 month, 2 months, 4 months or 6 months at +5°C or 25°C, have an activity of at least 80%, at least 90%, at least 95% or at least 98% of the activity at the starting time.

Err1:Expecting ',' delimiter: line 1 column 43 (char 42)

Err1:Expecting ',' delimiter: line 1 column 43 (char 42)

The formulation of the invention shall, in particular, show chemical integrity after storage of 1 month, 2 months, 4 months or 6 months. Chemical integrity means in particular that, after storage at +5°C, 25°C or 40°C, it contains at least 80%, at least 90%, at least 95%, or at least 98% of the active substance at the starting time in a substantially unchanged chemical form.

Chemical integrity can mean the chemical integrity of the GLP-1 agonist. GLP-1 agonists may contain a methionine residue (e.g. position 14 in AVE0010). Chemical integrity of the GLP-1 agonist means in particular that oxidation of this methionine residue is prevented.

Chemical integrity can also mean the chemical integrity of insulin.

Preferably, chemical integrity means the integrity of the insulin and the GLP-1 agonist.

The formulation of the invention shall, in particular, show physical integrity after storage of 1 month, 2 months, 4 months or 6 months. Physical integrity means in particular that, after storage at +5°C, 25°C or 40°C, it contains at least 80%, at least 90%, at least 95%, or at least 98% of the active substance at the starting time in a substantially unchanged form.

Physical integrity can mean the integrity of the GLP-1 agonist. Similarly, physical integrity can mean the integrity of insulin. Physical integrity means in particular that the GLP-1 agonist and/or insulin do not form aggregations, such as fibrils.

Preferably, physical integrity means the integrity of the insulin and the GLP-1 agonist.

The GLP-1 agonist is selected from AVE0010 and pharmacologically tolerable salts thereof.

Exendin-3, exendin-3 analogues and derivatives, exendin-4 and exendin-4 analogues and derivatives can be found in WO 01/04156, WO 98/30231, US 5,424,286, in the EP application 99 610043.4 and in WO 2004/005342.

Exendin-3, exendin-4 and its analogues and derivatives described in these documents may be synthesised by the processes described herein, with modifications being made after completion of the process if necessary.

The sequences of AVE0010 (SEQ ID NO:1), Exendin-4 (SEQ ID NO:2) and Exendin-3 (SEQ ID NO:3) show a high degree of agreement. The sequences of AVE0010 and Exendin-4 are identical at positions 1-37. The sequence 1-39 from Exendin-4 is identical at 37 of the 39 positions (94%) to the Exendin-3 sequence at positions 48-86. The sequences allow the practitioner to compute the position data given herein, which refer to a particular sequence (e.g. AVE0010 or Exendin-4 sequence), to other sequences without further processing.

The manufacture of pharmaceutically tolerable salts from peptides is known to the skilled. A preferred pharmaceutically tolerable salt is acetate.

The GLP-1 agonist is AVE0010. AVE0010 has the sequence of Pro36Exendin-4 (((1-39)-Lys6-NH2 (SEQ ID NO:1).

The GLP-1 agonist AVE0010 is used in particular in amounts of 0,01 mg/ml to 0,5 mg/ml or 0,05 mg/ml to 1,5 mg/ml.

Err1:Expecting ',' delimiter: line 1 column 93 (char 92)

Gly ((A21) -Arg ((B31) -Arg ((B32) - Insulin Glargin), and/or salts thereof which are pharmacologically tolerable.

The formulations of the invention contain 60-6000 nmol/ml, preferably 240-3000 nmol/ml of insulin as defined herein. A concentration of 240-3000 nmol/ml corresponds to a concentration of approximately 1,4-35 mg/ml or 40-500 units/ml, depending on the insulin used.

A composition according to the invention as described herein includes at least the insulin

Glargine (Gly(A21)-Arg(B31)-Arg(B32) human insulin) and AVE0010 (desPro36Exendin-4(1-39)-Lys6-NH2) or/and a pharmacologically tolerable salt thereof, which have an acid pH of 3,5 to 4,5.

In a particular embodiment, the wording of the invention shall include the following components: (a) despro36Exendin-4 (b) glycogen-A21-Arg (B31)-Arg (B32) human insulin (c) zinc chloride (d) m-cresol (e) L-methionine (f) glycerol (g) hydrochloric acid, to the extent necessary to achieve a pH of about 4.5, (h) NaOH solution, to the extent necessary to achieve a pH of about 4.5, and (i) water.

In particular, the formulation of the invention shall consist of the components (a) to (i) mentioned above, where m-cresol may be omitted, in which case the formulation of the invention shall consist of the components (a) to (c) and (e) to (i).

Another subject matter is a combination of at least two formulations of the invention, providing a first, second and, where appropriate, at least one additional pharmaceutical composition each containing the insulin and the GLP-1 agonists.

Therefore, an article of the invention is a combination comprising a first pharmaceutical composition and a second pharmaceutical composition and, where appropriate, at least one additional pharmaceutical composition, each comprising the insulin glargine and at least the GLP-1 agonist AVE0010, containing at least one insulin and/or at least one GLP-1 agonist in different proportions by weight relative to the total weight of the composition.

Err1:Expecting ',' delimiter: line 1 column 82 (char 81)

Combinations containing a first and a second pharmaceutical composition of the invention are preferred.

Similarly, combinations containing a first, second and third pharmaceutical composition of the invention are preferred.

Similarly, combinations containing a first, second, third and fourth pharmaceutical composition of the invention are preferred.

Similarly, combinations containing a first, second, third, fourth and fifth pharmaceutical composition are preferred.

The weight ratios of at least one insulin and at least one GLP-1 agonist may be selected in the first pharmaceutical formulation, the second pharmaceutical formulation and, where appropriate, at least one other pharmaceutical formulation in such a way that the pharmaceutical formulas contain different insulin-to-GLP-1 agonist ratios by weight.

In this case, the first compound may contain the smallest ratio and the second compound the next largest ratio. If at least one other compound is present, it may contain the next largest ratio. If another compound is present, it may contain the next largest ratio. The compounds may therefore contain increasing ratios of insulin to GLP-1 agonist from the first to the second and, if necessary, further compounds, based on the weight ratio.

The weight ratio of one of the two active substances, i.e. at least one insulin or at least one GLP agonist, in the first pharmaceutical formulation, the second pharmaceutical formulation and, where appropriate, at least one other pharmaceutical formulation, shall be preferably selected in such a way that the prescribed dose of that active substance is delivered by administering a given volume of the first, second and/or at least one other formulation.

The weight ratio of the other of the two active substances, i.e. at least one insulin or at least one GLP-1 agonist, in the first pharmaceutical formulation, the second pharmaceutical formulation and at least one other pharmaceutical formulation, as appropriate, shall be selected preferably in such a way that the insulin-to-GLP-1 agonist ratios increase in relation to the weight ratio of the first to the second and, where appropriate, further formulas.

In addition, the weight ratio of the other of the two active substances in the pharmaceutical formulations shall be determined in such a way that one of the pharmaceutical formulations can be selected in such a way that the dose to be administered of the first of the two active substances and the dose to be administered of the second active substance are given in a given volume, thus selecting a pharmaceutical formula containing the desired ratio.

Theoretically, a pharmaceutical composition could be provided for each individual therapeutically desired ratio of the weight ratios of at least one insulin to at least one GLP-1 agonist to achieve an optimal dose of both active substances for each patient.

In the present invention, a certain number of pharmaceutical formulations is sufficient to capture the dosages required in practice for both active substances. A certain dosage range is determined for each patient within a therapeutically reasonable interval for each of the two active substances. The dose to be administered is intended to vary substantially within this dosage range for a given patient without over- or under-dosing.

Since the primary need is to adapt the amount of insulin to the individual patient and to precisely dose it, the concentration range of the GLP-1 agonist allows a pharmaceutical composition of the invention, which contains a certain ratio of at least one insulin to at least one GLP-1 agonist, to cover a therapeutic range of insulin doses at the same time as the corresponding synergistic GLP-1 agonist. The ratio can be further selected so that for each desired insulin dose a dosage of at least one GLP-1 agonist corresponds within the desired range, e.g. the synergistic range.If the dosage of the GLP-1 agonist at the desired insulin dosage of a compound (e.g. the first compound) is outside (usually above) the desired dosage range of the GLP-1 agonist, the next compound (e.g. the second compound) or a further compound with a higher ratio of at least one insulin to at least one GLP-1 agonist is selected for use, in which the amount of GLP-1 agonist at the desired insulin dose is within the desired range.that the ranges of insulin dosages corresponding to the desired dosages of at least one GLP-1 agonist are connected and/or overlap. Preferably, the ranges overlap. Overlap means in particular that at least two formulations can be selected containing at least one insulin at the desired dosage per quantity of at least one GLP-1 agonist within the desired dosage range.

For example, 3 formulations are sufficient to adjust the dose of at least one insulin for an individual patient to a value selected from the range of 15 to 80 units of insulin, while simultaneously dosing the GLP-1 agonists at a level within the range of 10 to 20 μg (see Figure 4).

Similarly, a combination according to the invention may be provided in which the ratio is selected so that each desired dose of the GLP-1 agonist corresponds to a dose of at least one insulin within the desired range. The ratios of the first, second and, where appropriate, at least one other composition of the medicinal product may also be chosen so that the ranges of GLP-1 agonist dosages corresponding to the desired dosages of at least one insulin are connected and/or overlap. Preferably, the ranges overlap. Overlap in this context means in particular that at least two compounds selected, each containing at least one dose of the GLP-1 agonist within the desired range, may contain at least one dose of DLP-1 agonist.

Preferably, the combination according to the invention contains a maximum of 10 pharmaceutical compositions as defined above, more preferably a maximum of 5, a maximum of 4, a maximum of 3 or 2 pharmaceutical compositions.

The compositions of the invention may contain at least one GLP-1 agonist in each of them in identical or different proportions by weight.

It is preferable that the first, second and any further formulations contain at least one GLP-1 agonist in substantially identical proportions by weight and that they contain at least one insulin in different proportions by weight.

However, the compositions of the invention may also contain at least one insulin in each of them in identical or different proportions by weight.

It is particularly preferable that the first, second and any further formulations contain at least one insulin in substantially identical proportions by weight and at least one GLP-1 agonist in different proportions by weight.

A first preferred composition according to the invention shall include: Other

(a) AVE0010	etwa 0,025 mg
(b) Insulin Glargin	etwa 3,64 mg
(c) Zinkchlorid	etwa 0,06 mg
(d) 85%iges Glycerin	etwa 20,0 mg
(e) m-Kresol	etwa 2,7 mg
(f) L-Methionin	etwa 3,0 mg
(g) NaOH	q.s.pH 4,5
(h) HCl 36%	q.s.pH 4,5
(i) Wasser	ad 1 mL

A second preferred composition according to the invention shall include: Other

(a) AVE0010	etwa 0,04 mg
(b) Insulin Glargin	etwa 3,64 mg
(c) Zinkchlorid	etwa 0,06 mg
(d) 85%iges Glycerin	etwa 20,0 mg
(e) m-Kresol	etwa 2,7 mg
(f) L-Methionin	etwa 3,0 mg
(g)NaOH	q.s.pH 4,5
(h)HCl 36%	q.s.pH 4,5
(i) Wasser	ad 1 mL

A third preferred composition according to the invention shall include: Other

(a) AVE0010	etwa 0,066 mg
(b) Insulin Glargin	etwa 3,64 mg
(c) Zinkchlorid	etwa 0,06 mg
(d) 85%iges Glycerin	etwa 20,0 mg
(e) m-Kresol	etwa 2,7 mg
(f) L-Methionin	etwa 3,0 mg
(g) NaOH	q.s.pH 4,5
(h) HCl 36%	q.s.pH 4,5
(i) Wasser	ad 1 mL

A fourth preferred composition according to the invention is: Other

(a) AVE0010	etwa 0,1 mg
(b) Insulin Glargin	etwa 3,64 mg
(c) Zinkchlorid	etwa 0,06 mg
(d) 85%iges Glycerin	etwa 20,0 mg
(e) m-Kresol	etwa 2,7 mg
(f) L-Methionin	etwa 3,0 mg
(g) NaOH	q.s.pH 4,5
(h) HCl 36%	q.s.pH 4,5
(i) Wasser	ad 1 mL

In particular, a combination of at least 2, 3 or 4 of the first, second, third and fourth preferred compositions mentioned above is preferred.

Err1:Expecting ',' delimiter: line 1 column 43 (char 42)

If the composition or combination of the invention includes more than one insulin, these insulins shall be selected independently.

If the composition or combination of the invention includes more than one GLP-1 agonist, these GLP-1 agonists shall be selected independently.

The combination of the invention is provided in particular as a medicinal product.

A kit shall be described as comprising a combination according to the invention comprising at least one and at most four compositions according to the invention and Lantus®, as appropriate. The kit may be intended for use by medical personnel or by lay persons, in particular the patient himself or by a caregiver such as a family member. The kit shall contain the individual pharmaceutical compositions comprising the combination according to the invention in separate packages, so that the patient can select the composition according to the current need and administer the required amount. The kit shall include, for example, the composition according to the invention in the form of a syringe, glass or satin/samples containing at least one composition of Lantus®, as appropriate, in combination with the composition.

Err1:Expecting ',' delimiter: line 1 column 260 (char 259)

In particular, the kit is a pen consisting of two separate containers from which individual therapeutic doses can be withdrawn if necessary, and the kit is a syringe consisting of two containers in which the second container is equipped with a reservoir needle.

The kit preferably consists of a combination of a first formulation containing the GLP-1 agonist, an insulin, glycerol, zinc chloride, m-cresol, L-methionine, if applicable, in water at a pH of 4,5 and a second formulation preferably containing an insulin, glycerol, zinc chloride and m-cresol in water at a pH of 4,5.

The first formulation may preferably have the following composition: Other

(a) AVE0010	etwa 0,4 mg oder etwa 0,8 mg
(b) Insulin Glargin	etwa 3,64 mg
(c) Zinkchlorid	etwa 0,06 mg
(d) 85 %iges Glycerol	etwa 20,0 mg
(e) m-Kresol	0,0 mg oder etwa 2,7 mg
(f) L-Methionin	etwa 3,0 mg
(g) NaOH	q.s.pH 4,5
(h) HCl 36%	q.s.pH 4,5
(i) Wasser	ad 1 ml.

The second formulation may preferably have the following composition: Other

(a) Insulin Glargin	etwa 3,64 mg
(b) Zinklchlorid	etwa 0,06 mg
(c) 85 %iges Glycerol	etwa 20,0 mg
(d) m-Kresol	etwa 2,7 mg
(e) NaOH	q.s.pH 4,5
(f) HCl 36 %	q.s.pH 4,5
(g) Wasser	ad 1 ml.

A procedure for the treatment of a patient with a composition of the invention is also described, including the administration of the composition to the patient.

A procedure to treat a patient with a combination of the invention or a kit as described herein shall also be described; in particular, this procedure shall involve the administration of a combination of the invention comprising a first pharmaceutical formulation and a second pharmaceutical formulation and, where appropriate, at least one additional pharmaceutical formulation, each comprising at least one insulin and at least one GLP-1 agonist, containing at least one insulin and/or at least one GLP-1 agonist in different proportions by weight relative to the total weight of the composition, the procedure comprising: (a) Select a dose of at least one insulin to be administered, (b) Select a dose of at least one GLP-1 agonist to be administered, (c) Select a composition from the first, second and, where appropriate, at least one other composition of the medicinal product containing the doses of (a) and (b) in a concentration such that the doses of (a) and (b) are present in the same volume, and (d) Determine and administer an amount corresponding to the doses of (a) and (b).

The dose determination for step (a) and/ or step (b) is based on the individual needs of the patients.

Step (c) of the treatment procedure may be performed by means of a table. This table may be part of the inventive combination, the inventive medicinal product or the inventive kit.

The composition, combination, medicinal product and/or kit of the invention are intended primarily for the treatment of diabetes mellitus, in particular for the treatment of type I or type II diabetes mellitus. Other possible indications are symptoms associated with diabetes mellitus. The composition of the invention is used preferably for adjustment of fasting, post-tolerance and/or post-absorption plasma glucose concentration, improvement of glycosetase, prevention of hypoglycaemia, prevention of loss of function of the pancreatic beta cells, weight loss and/or weight loss.

A method for the preparation of a composition, combination, and/or kit of the invention, including the formulation of the GLP-1 agonist and/or a pharmacologically tolerable salt thereof, with the insulin and/or a pharmaceutically acceptable salt thereof, L-methionine and, where appropriate, at least one pharmaceutically acceptable excipient, shall be described.

A method to produce a composition of the invention including formulation of the GLP-1 agonist and/or a pharmacologically tolerable salt thereof with L-methionine and, where appropriate, at least one pharmaceutically acceptable excipient is also described.

The use of the formulations of the invention in combination with the administration of metformin, insulin glargin or AVE0010 is further described, in particular in an add-on therapy for the administration of metformin, insulin glargin or AVE0010.

The composition includes desPro36Exendin-4 ((1-39)-Lys6-NH2 (AVE0010) and/or a pharmacologically tolerable salt thereof, insulin glargine and/or a pharmacologically tolerable salt thereof.

In particular, the preferred add-on therapy is preferred in patients with type II diabetes who cannot be adequately controlled with insulin glargine and/ or AVE0010 and are also affected in patients who are younger than 50 years of age and/ or have a body mass index of at least 30.

The add-on therapy includes in particular the treatment of type II diabetes with the composition of the invention as an add-on to metformin, AVE0010 and/or insulin glargin. The composition of the invention may be added at 24 h intervals (once-a-day dosing). Metformin, insulin glargin and AVE0010 may be administered by different routes of administration. Metformin may be administered orally, AVE0010 and insulin glargin may be administered subcutaneously.

Patients treated with the add-on therapy described may have an HbA1c of 7 to 10%, preferably between the ages of 18 and 50.

Use in add-on therapy is particularly appropriate in patients in whom type II diabetes cannot be adequately controlled with metformin, AVE0010 or insulin glargin alone.

The use of the composition of the invention as a dietary supplement to reduce blood glucose levels in type II is further described.

The use of insulin Glargin and AVE0010 is indicated in patients with diabetes.

In particular, metformin is given at least 1.0 g/ day, preferably at least 1.5 g/ day for 3 months.

The invention is further illustrated by the following illustrations and examples.

Figure 1 shows the level of oxidised methionine met ((ox) in AVE0010 after 1 month of storage at different temperatures relative to the starting time.

Figure 2 shows the level of impurities of AVE0010 without Met ((ox) after 1 month of storage at different temperatures relative to the starting time.

The boxes show the values of the AVE0010 reference formulations at 25°C and 40°C respectively.

Figure 3 shows the levels of impurities of insulin glargine after 1 month of storage at different temperatures relative to the baseline. The narrow boxes show the values of the insulin glargine reference formulations at 25°C and 40°C respectively. The wide boxes indicate the formulations with the lowest levels of AVE0010 impurities.

Err1:Expecting ',' delimiter: line 1 column 56 (char 55)

Example 1 The subject of the investigation

Physical and chemical stability of formulations including a GLP-1 agonist (AVE0010) and an insulin (insulin Glargin, Lantus) have been tested.

The Commission has not yet adopted a decision on the proposal.

For the test formulations, the substances were used in the following concentrations/amounts.

Substanz	Arzneibuch	Hersteller	Bezeichnung	eingesetzte Menge [mg/mL]
Insulin glargine	Sanofi-Aventis	3,63
		7,27
		10,67
AVE0010	Poly Peptide LabTorrance CA, USA	0,1
		0,025
Methionin	USP	MP Biomedicals	3
Zinkchlorid	Ph. Eur., USP, BP	Merck	0,03
			0,06
			0,09
Glycerin 85 %	Ph. Eur., JP	Hedinger, Stuttgart	20
			18
m-Kresol	Ph. Eur., USP	Hedinger, Stuttgart	2,7
Polysorbate 20	Ph.Eur.,JP	Kolb	Tween 20	0,02
Polysorbate 80	Ph. Eur.	SEPPIC	Tween 80	0,02
Poloxamer 188	BASF, Ludwigshafen	Lutrol F68	0,02
Benzalkoniumchlorid	Ph. Eur., JP	Sigma-Aldrich	0,02
L-Lysine		Resum, F-Ham, Degussa	1,0
			5,0
Acetat	1,75	1,75
	3,5
NaOH	Ph. Eur" JP	Merck	0,1 N, zur Einstellung des pH 4,0 oder 4,5
HCl	Ph. Eur., JP	Merck	0,1 N, zur Einstellung des pH 4,0 oder 4,5
Wfl	Ad 1 mL

Where a factor is indicated in relation to an ingredient in a formulation (e.g. 1/2, 1/4, 2x, 3x, 5x, as in 1/2 acetate, 5x lysine, 2x Lantus and 3x Lantus), the concentrations of the substance concerned have been used at a concentration reduced or increased by the factor.

The test method 3.1 Physical stability The test shall be carried out on the test vessel.

Thioflavin T (THT) binds specifically to protein fibrils, resulting in a change in THT fluorescence. THT does not bind to AVE0010 or insulin. The kinetics of fibril formation can be measured as a change in fluorescence in the presence of THT. An increase in fluorescence corresponds to fibril formation.

Fluorescence measurements were performed on a Tecan Infinite 200 fluorescence meter. To analyze the fibrillation kinetics, a Photomed FluoDia 770 high temperature fluorescence micro-plate reader was used. The thioflavin T fluorescence spectra were performed with a Tecan Infinite 200 fluorescence meter at 23 °C. 900 μl of insulin were mixed with 10 μl of thioflavin T (1 mM in H2O). The mixture was then distributed into a black V-shaped 96-hole plate of Biozym (100 μl per) The fluorescence emission of the hole was measured between 470 and 600 nm (sweath 1 nm) after stimulation at 450 nm with an acceleration of integration of 200 μs at 100 and 25 nm at room temperature.

Thioflavin T binding kinetics were measured on a Photomed FluoDia 770 high temperature fluorescence micro-plate reader. The instrument consists essentially of a 50W quartz halogen lamp for excitation, a filter wheel for excitation and emission, each of which can contain up to 4 filter sets, and a PMT detector. The 96-hole heating plate allows very high temperature accuracy (better than ±0.3 °C).

10 μl of thioflavin T solution (10.1 mM in ultrapure water) was added to 1 ml of the formulations and slightly mixed by turning the tubes several times. The mixture was then distributed in a black V-shaped 96-hole Biozym plate (100 μl per hole, 8 holes per sample). All measurements were made with the following parameters: Other

Anzahl der Zyklen:	181
Anregungsfilter:	450 nm
Intervall:	1 min
Emissionsfilter:	486 nm
Integrationszeit:	20 ms
Temperaturkontrolle:	Standard-Temperaturkontrollmodus
Anzahl der Mittlungen:	4
Zieltemperatur:	70°C
Abschwächung:	4

Fluorescence mean values were determined from 8 parallel measurements.

3.2 Chemical stability

The formulations were tested for chemical stability after manufacture (t0) or after storage for 1 month at 4°C, 25°C (60% relative humidity) and 40°C (75% relative humidity). The measurements were performed on an HPLC (type alliance) machine by Water Systems using the 100% peak area method. A gradient of 0.1% TFA and acetonitrile was used as the mobile phase and a C18 reverse phase acid (Jupiter) as the solid phase to separate the formulations. For analysis, the formulations were treated with a zinc acetate solution, resulting in the precipitation of insulin Griflarginate. The pre-precipitates were removed and only the residue was analyzed.

Impurities of insulin glargine: the amount of impurities was determined by HPLC (Water Systems) using the 100% peak area method. a sodium phosphate buffered solution (pH 2.5) with a NaCl and acetonitrile gradient was used as the mobile phase for the separation. a C18 reverse phase acid (supersher) was used as the stationary phase.

The results of the tests are presented in Table 4.

Formulierung		Zusammensetzung	pH	THT 3h, 70°C relative Fluoreszenzintensität bei 486 nm
Nr.	Charge
1	630	AVE0010 Standard industrial scale	4,5	536
2	567	AVE0010 Standard frisch	4	518
3	631	Lantus Standard industrial scale	4,0	2952
4	560	Lantus Standard frisch	4	1566
5	568	Lantus form., AVE0010	4	2037
6	569	Lantus form., AVE0010 1/2 Acetatpuffer	4	11763
7	570	Lantus form., AVE0010 Acetatpuffer	4	69184
8	582	Lantus form., AVE0010 Methionin	4	2053
9	583	Lantus form., AVE0010	4	18814
1/2 Acetatpuffer Methionin
10	584	Lantus form., AVE0010 Polysorbat 20	4	8183
11	585	Lantus form., AVE0010 Polysorbat 20 Methionin	4	6731
12	586	Lantus form., AVE0010 Polysorbat 20 1/2 Acetatpuffer	4	13897
13	587	Lantus form., AVE0010 Polysorbat 20 1/2 Acetatpuffer Methionin	4	22200
14	588	Lantus form., AVE0010 Polysorbat 20 Acetatpuffer Methionin	4	134093
15	590	Lantus form., AVE0010 Lysin	4	3362
16	591	Lantus form., AVE0010 Lysin 1/2 Acetatpuffer	4	19677
17	592	Lantus form., AVE0010 Lysin 1/2 Acetatpuffer Polysorbat 20	4	30176
18	593	Lantus form. 1/4 AVE0010	4	3107
19	594	Lantus form. 1/4 AVE0010 5x Lysin	4	74662
20	595	2x Lantus AVE0010	4	4504
21	596	3x Lantus AVE0010	4	30251
22	604	Lantus form., AVE0010	4,5	4357
23	605	Lantus form., AVE0010 1/2 Acetatpuffer	4,5	36338
24	606	Lantusform., AVE0010 Acetatpuffer	4,5	72370
25	607	Lantusform., AVE0010 Methionin	4,5	5429
26	608	Lantus form., AVE0010 1/2 Acetatpuffer Methionin	4,5	34714
27	609	Lantus form., AVE0010 Polysorbat 20	4,5	1166
28	610	Lantus form., AVE0010 Polysorbat 20 Methionin	4,5	5564
29	611	Lantusform., AVE0010 Polysorbat 20 1/2 Acetatpuffer	4,5	12115
30	612	Lantus form., AVE0010 Polysorbat 20 1/2 Acetatpuffer Methionin	4,5	16397
31	613	Lantus form., AVE0010 Polysorbat 20 Acetatpuffer Methionin	4,5	779
32	614	Lantus form., AVE0010 Lysin	4,5	9726
33	615	Lantus form., AVE0010 Lysin 1/2 Acetatpuffer	4,5	74027
34	616	Lantus form., AVE0010 Lysin 1/2 Acetatpuffer Polysorbat 20	4,5	9520
35	617	Lantus form. 1/4 x AVE0010	4,5	3713
36	618	Lantus form. 1/4 x AVE0010 5x Lysin	4,5	83384
37	619	2x Lantus AVE0010	4,5	13120
38	620	3x Lantus AVE0010	4,5	41684
39	657	Lantus form. AVE0010 Polysorbat 80 Methionin	4	9309
40	658	Lantus form., AVE0010 Poloxamer 188 Methionin	4	767
41	659	Lantus form., AVE0010 Benzalkoniumchlorid Methionin	4	1040
42	660	Lantus form., AVE0010 Polysorbat 80 Methionin	4,5	16803
43	661	Lantus form., AVE0010 Poloxamer 188 Methionin	4,5	689
44	662	Lantus form., AVE0010 Benzalkoniumchlorid Methionin	4,5	942

The test shall be carried out on the following samples:

Methionine has no effect on the tendency to fibrillation. Other

Nr.	Zusammensetzung	Fluoreszenzintensität bei 486 nm
2	AVE0010 Standard	518
4	Lantus Standard	1566
8	Lantus form., AVE0010, Methionin pH 4	2053
25	Lantus form., AVE0010, Methionin pH 4,5	5429

Other The fluorescence values are similar to those of the reference formulations (No 2 and 4).

When AVE0010, Lantus and methionine are combined with acetate buffers with or without polysorbate 20 at pH 4, there is a higher tendency to fibrillation: Other

Nr.	Zusammensetzung	Fluoreszenzintensität bei 486 nm
2	AVE0010 Standard	518
4	Lantus Standard	1566
9	Lantus form., AVE0010, ½ Acetat, Met, pH 4	18814
13	Lantus form., AVE0010, Polysorbat 20, 1/2 Acetat, Met, pH 4	22200
14	Lantus form., AVE0010, Polysorbat 20, Acetat, Met, pH 4	134093

The values for formulations 13 and 14 are well above the threshold for a tendency to fibrillation.

6.1 Summary

Polysorbate 20 and polysorbate 80 can cause cloudiness, which can be detected in the double refraction test. These two substances can therefore cause physical instability of a formulation of AVE0010 and insulin. The addition of methionine does not cause physical instability.

Chemical stability 7.1 Stability at time t0

The formulations containing methionine (with and without sodium acetate) have the lowest levels of impurities (about 1.2-1.5% in total). The value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product and the value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the product

Forms which did not contain methionine showed a higher proportion of impurities.

Polysorbate 20 has no adverse effect on the chemical stability of the formulations.

Acetate buffer does not have a negative effect on chemical stability when combined with methionine and polysorbate 20.

The total amount of impurities is higher when lysine is present in the formulations, as is the case for formulations containing polysorbate 80, poloxamer 188 and benzalkonium chloride. The determination of the impurities of insulin glargin showed that all formulations had comparable amounts of impurities (0.3 to 0.4%).

Stability after 1 month 7.2.1 Contaminants from AVE0010

The oxidised methionine content in the formulations was analysed and determined. The sequence of AVE0010 has a methionine residue at position 14. The sequence of insulin glargin has no methionine residue. Therefore, the oxidised methionine content is indicative of an oxidation of AVE0010 to the methionine residue. The data are summarised in Figure 1. In sum, the data show that without methionine at a pH of 4.5 the methionine content is higher than at pH 4.0.

In general, the highest concentrations of Met (ox) were measured at 40°C/75% relative humidity, with the lowest concentrations of Met (ox) -AVE0010 (< 1%) in formulations 8, 9, 11, 13, 14, 25, 26, 28, 30 and 31.

The impurities of AVE0010 after 1 month without Met ((ox) are shown in Figure 2. The boxes show the values of the AVE0010 reference formulations at 25°C and 40°C respectively. Formulations with the same or better impurity values as the AVE0010 reference formulations are within or below the limits. This applies to formulations 24, 25, 26, 28, 29, 30, 31, 33 and 34 at (40°C).

The following formulae show the lowest levels of methane (ox) and other impurities after storage at 40°C for one month (compare Figures 1 and 2), and are better than or equal to the AVE0010 reference formulae: Other

25	Lantus form., AVE0010, Methionin, pH 4,5
26	Lantus form., AVE0010, 1/2 Acetatpuffer, Methionin, pH 4,5
28	Lantus form., AVE0010, Polysorbat 20, Methionin, pH 4,5
30	Lantus form., AVE0010, 1/2 Acetatpuffer, Polysorbat 20, Methionin, pH 4,5

These formulations were also among the formulations with the lowest levels of AVE0010 impurities at t0. all formulations contain methionine. polysorbate 20 has no adverse effects on the impurities.

The formulations 3 and 4 are the reference formulations for insulin glargin. The values of these formulations are presented in narrow ranges. All formulations identified as best in terms of AVE0010 impurities (broad ranges, especially formulations 25, 26, 28 and 30) are better in terms of insulin glargin impurities than the reference formulations (approximately 1.5 to 2.4 % at 40°C).

It can be concluded from this experiment that methionine increases the storage stability of a composition including an insulin (e.g. Lantus) and a GLP-1 agonist (e.g. AVE0010).

The Commission has not yet adopted a decision.

The data described herein lead to the following conclusions: Methionine leads to increased chemical stability and has no adverse effect on the physical stability of formulations of a combination of a GLP-1 agonist, in particular AVE0010, and an insulin, in particular Lantus. Therefore, methionine is beneficial as a component of these compounds. Acetate can lead to physical instability. This instability is increased with increasing acetate concentration. Therefore, formulations of a combination of a GLP-1 agonist, in particular AVE0010, and an insulin, in particular Lantus, which are free of acetate, are produced, which are advantageous over corresponding compounds containing acetate.In the absence of acetate, the addition of polysorbate 20 does not provide any benefit. Therefore, formulations of a combination of a GLP-1 agonist, in particular AVE0010, and an insulin, in particular Lantus, should be prepared that are free of polysorbate 20.Lysin (at normal and higher concentrations), benzalkonium chloride, polysorbate 80 and poloxamer 188 showed chemical instability at the beginning of the studies (t0). For lysine, this also applies to the results of the TH test.

Example 2

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)For example, if a dose of 50 U insulin is prescribed, 0.5 ml of MIX B or MIX C should be administered. This dose contains 20 μg (MIX B) and 12.5 μg (MIX C) respectively of AVE0010.Most patients taking Lantus doses of 15-80 U can also receive therapeutic doses of AVE0010 between 10 and 20 μg if they use one of the three premix pens containing three different Lantus:AVE0010 ratios (Mix A, B or C).

Claims (11)

1. Liquid composition comprising a GLP-1 agonist and/or a pharmacologically tolerable salt thereof, an insulin and/or a pharmacologically tolerable salt thereof, and, optionally, at least one pharmaceutically acceptable excipient, characterised in that the composition contains L-methionine and has a pH of from 3.5 to 4.5, the GLP-1 agonist being desPro³⁶exendin-4(1-39)-Lys₆-NH₂ and the insulin being Gly(A21)-Arg(B31)-Arg(B32) human insulin.
2. Liquid composition according to claim 1, characterised in that it contains m-cresol and/or glycerol.
3. Liquid composition according to any of the preceding claims, characterised in that it contains methionine in an amount of from 0.5 mg/mL to 20 mg/mL, more particularly in an amount of from 1 mg/mL to 5 mg/mL.
4. Liquid composition according to any of the preceding claims, characterised in that it comprises the following constituents:

   (a) desPro³⁶exendin-4(1-39)-Lys₆-NH₂,

   (b) Gly(A21)-Arg(B31)-Arg(B32) human insulin,

   (c) zinc chloride,

   (d) m-cresol (optional),

   (e) L-methionine,

   (f) glycerol,

   (g) hydrochloric acid, if adjustment to a pH of approximately 4.5 is required,

   (h) NaOH solution, if adjustment to a pH of approximately 4.5 is required, and

   (i) water.
5. Combination comprising a first pharmaceutical composition according to any of claims 1 to 4 and a second pharmaceutical composition according to any of claims 1 to 4, and, optionally, at least one additional pharmaceutical composition according to any of claims 1 to 4, each comprising at least one insulin and at least one GLP-1 agonist, and containing the at least one insulin and/or the at least one GLP-1 agonist in different proportions by weight relative to the total weight of the composition.
6. Combination according to claim 5, wherein the first, second, and, optionally, additional composition(s) contain the at least one insulin in a substantially identical proportion by weight and the at least one GLP-1 agonist in different proportions by weight.
7. Combination according to claim 5, wherein the first, second, and, optionally, additional composition(s) contain the at least one GLP-1 agonist in a substantially identical proportion by weight and the at least one insulin in different proportions by weight.
8. Composition according to any of claims 1 to 4 or a combination according to claims 5 to 7 for use as a medication for treating diabetes mellitus.
9. Composition for use according to claim 8, characterised in that the use takes place with co-administration of metformin, an insulin, and/or a GLP-1 agonist, and/or a pharmacologically tolerable salt.
10. Composition for use according to claim 9, characterised in that the treated patients have an HbA1c value of from 7 % to 10 %.
11. Composition for use according to any of claims 8 to 10 for treating type II diabetes and/or obesity.