Combination of an insulin and a glp-1 agonist

[0001] The invention relates to a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, which each contain 100 U / ml human insulin

Gly (A21) -Arg (B31) -Arg (B32) and 20 to 150 μg / ml desPro³⁶Exendin-4 (1-39) -Lys6-NH2 and human insulin Gly (A21) -Arg (B31) -Arg (B32) and desPro³⁶exendin-4 (1-3 -9) -Lys6-NH2 in various weight proportions based on the total weight of the composition.

[0002] Around 250 million people worldwide suffer from diabetes. For patients with type 1 diabetes, replacement of missing endocrine insulin secretion is currently the only possible therapy. Patients are doomed their whole lives, usually many times a day, to insulin injections. Unlike type 1 diabetes, type 2 diabetes usually has essentially no insulin deficiency, but in many cases, especially in the advanced stage, insulin treatment, optionally in combination with an oral antidiabetic drug, is seen as the most beneficial form of therapy.

[0003] In healthy people, insulin release from the pancreas is closely related to blood glucose. Increased blood glucose levels, such as those that occur after meals, are quickly compensated by a corresponding increase in insulin secretion. In the fasted state, plasma insulin levels fall to baseline, which is sufficient to ensure a continuous supply of insulin-sensitive organs and tissues and to maintain low levels of glucose production in the liver at night. The replacement of endogenous insulin secretion by exogenous, usually subcutaneous insulin application, generally does not even achieve the quality of physiological blood glucose regulation described above. Often there is a derailment of blood glucose up or down, which can be life-threatening in the most severe forms. In addition, elevated blood glucose levels for years pose a serious health risk even without any initial symptoms. Large-scale DCCT in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) clearly indicated that chronically elevated blood glucose is significantly responsible for the development of late diabetic damage. Late diabetic damage is microvascular and macrovascular damage that can manifest in some cases, including retinopathy, nephropathy or neuropathy, and leads to blindness, renal failure and limb loss, and is associated with an increased risk of cardiovascular disease. From this it can be concluded that the improvement of diabetes treatment must first of all be aimed at maintaining blood glucose as close as possible to the physiological range. According to the idea of ​​intensive insulin therapy, this should be achieved by repeated daily injections of fast and slow-acting insulin preparations. Fast-acting formulations are served at mealtimes to compensate for postprandial growth

-2 glucose in the blood. Slow-acting basic insulins should provide a basic insulin supply, especially at night, without leading to hypoglycaemia.

[0004] Insulin is a polypeptide made up of 51 amino acids that are divided into 2 amino acid chains: A chain with 21 amino acids and B chain with 30 amino acids. The chains are connected to each other via 2 disulfide bridges. Insulin preparations have been used for many years to treat diabetes. Not only naturally occurring insulins are used, but recently also insulin derivatives and analogues.

[0005] Insulin analogs are analogues of naturally occurring insulins, namely human or animal insulin, which differ by substituting at least one of the naturally occurring amino acid residues with another amino acid and / or adding / removing at least one amino acid residue from a suitable, otherwise identical to naturally occurring insulin. It can also be amino acids that do not occur naturally.

[0006] Insulin derivatives are derivatives of naturally occurring insulin or insulin analogue that have been obtained by chemical modification. Chemical modification may involve, for example, the addition of one or more specific chemical groups to one or more amino acids. As a rule, insulin derivatives and insulin analogues have slightly changed effects compared to human insulin.

[0007] Accelerated onset insulin analogues are disclosed in EP 0 214 826, EP 0 375 437 and EP 0 678 522. EP 0 214 826 discloses inter alia substitution B27 and B28. EP 0 678 522 discloses insulin analogues that have different amino acids at position B29, preferably proline, but not glutamic acid. EP 0 375 437 contains insulin analogues with lysine or arginine in B28, which can optionally be further modified in B3 and / or A21. The insulin analogues disclosed in EP-A-0 885 961 also have an accelerated effect.

[0008] WO 2005/046716 discloses a pharmaceutical composition comprising insulinotropic peptide (liraglutide) and meal-dependent insulin (fast acting) insulin peptide (insulin aspart).

[0009] EP 0 419 504 discloses insulin analogues that are protected against chemical modifications by altering asparagine in B3 and at least one further amino acid at positions A5, A15, A18 or A21.

[0010] WO 92/00321 discloses insulin analogues in which at least one amino acid at positions B1-B6 is replaced by lysine or arginine. According to WO 92/00321, such insulins have a prolonged effect. The insulin analogues disclosed in EP-A 0 368 187 and in German Patent Application Nos. 10 2008 003 568.8 and 10 2008 003 566.1 and in international application WO 2009/087081 also have delayed action.

[0011] WO 2006/051103 discloses a storage stable pharmaceutical composition comprising insulinotropic peptide, basal insulin, pharmaceutically

-Acceptable preservative, zwitterionic surface active substance and poloxamer or polysorbate 20 at a pH of about 7.0 to about 8.5.

[0012] WO 2003/020201 discloses a pharmaceutical composition comprising exendin-4 and insulin glargine.

[0013] Insulin formulations of naturally occurring insulins for insulin substitution present on the market differ in the origin of insulin (e.g. bovine, porcine, human insulin) as well as the composition, whereby the action profile (occurrence and duration of action) can be influenced. By combining different insulin preparations, very different action profiles can be obtained and the physiological blood sugar values ​​can be set. Recombinant DNA technology now allows the production of such modified insulins. Therefore, insulin glargine (human insulin Gly (A21) Arg (B31) Arg (B32) is one of those with prolonged duration of action. Insulin glargine is injected as an acidic, clear solution and precipitates due to its properties in solution in the physiological pH range of the subcutaneous tissue as a stable hexameric association compound. Insulin glargine is injected once a day and is characterized in comparison to other long-acting insulins by its flat serum profile and the associated reduction in the risk of nocturnal hypoglycemia (Schubert-Zsilavecz et al., 2: 125130 (2001)).

[0014] A particular insulin glargine preparation that leads to a prolonged duration of action is characterized by a transparent solution with an acidic pH.

[0015] Glucagon-like peptide (GLP-1) is an endocrine hormone that increases the insulin response after oral ingestion of glucose or fat. GLP-1 generally regulates glucagon, 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) Exp Clin Endocrinol Diabetes 105: 187, Lopez-Delgado et al. (1998) Endocrinology 139: 2811).

[0016] Human GLP-1 has 37 amino acid residues (Heinrich et al., Endocrinol. 115: 2176 (1984), Uttenthal et al., J Clin Endocrinol Metabol (1985) 61: 472). Active fragments of GLP-1 include GLP-1 (7-36) amide and GLP-1 (7-37).

[0017] Exendins are another 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 the growth of cellular cAMP production in guinea pig's acinar cells by interacting with exendin receptors (Raufman, 1996, Reg. Peptides 61: 1-18). Unlike exendin-4, exendin-3 increases the release of amylase in the acinar cells of the pancreas.

[0018] Exendin-3, exendin-4 and exendin agonists have been proposed for the treatment of diabetes mellitus and the prevention of hyperglycemia, which reduce gastric contractility and emptying (US 5,424,286 and WO98 / 05351).

[0019] Exendin analogs can be characterized by amino acid substitutions and / or the c-terminal truncation of the native exendin-4 sequence. Exendin analogs of this kind are disclosed in WO 99/07404, WO 99/25727, WO 99/25728.

[0020] Combinations of insulin and GLP for the treatment of diabetes are known from WO 2004/005342.

[0021] Tews et al. (Horm Metab Res 40: 172-180, 2008) reveal increased protection against cytokine or fatty acid-induced apoptosis in pancreatic β cells by combination therapy with GLP-1 receptor agonists and insulin analogues in a cellular in vitro assay system .

[0022] In clinical practice, the amount of insulin administered is adapted to the individual needs of individual diabetic patients. Individual patients usually require different amounts of insulin and / or GLP-1 agonist. Typically, a predetermined dose is administered by administering a specific amount of the composition at a given concentration. It follows that a composition that contains insulin and GLP-1 allows simultaneous administration of only a specific ratio of insulin and GLP-1. This means that only one of both amounts of insulin and GLP-1 can be optimally adapted to the patient's needs. Since the correct setting of the amount of insulin administered is essential in practice, it can be assumed that when, when administering a specific ratio of insulin to GLP-1, the GLP-1 agonist is either in an insufficient dose or is overdosed and at best accidentally correct.

[0023] Various injection systems for combinations of active compounds are known. The active compounds can be formulated into a composition and delivered in a device, e.g. in the ready syringe. Although such a system allows dosing of the combination, it is only in a fixed ratio of the active compounds as contained in the composition. As shown here, this is disadvantageous for the combination of insulin with a GLP-1 agonist because different amounts of insulin and a GLP-1 agonist need to be administered depending on the therapeutic need.

In the same way, two active compounds can be administered in two separate formulations, each containing one of the two active compounds and which are injected independently of each other with the aid of a device (e.g. ready syringes). In injection therapy, such as insulin injection patient cooperation is an essential requirement for the success of therapy. In general, in injection therapy, pain, needle phobia, and the ability to receive an injection device are problems that can lead to reduced collaboration. If the patient uses two separate injection devices, these problems get worse.

[0025] A single device for administering insulin and a GLP-1 agonist is preferred compared to using two separate devices for administering insulin and a GLP-1 agonist to a patient / user. In addition, using only one device instead of two devices can reduce the number of steps that the patient / user must perform, which reduces the frequency of application errors. This reduces the risk of unwanted side effects.

[0026] US 4,689,042, US 5,478,323, US 5,253,785 and WO 01/02039 disclose devices for co-administering two injection products to a patient. These devices contain two containers, which each contain one composition. In these devices, both compositions are injected through one needle. By this, it is possible to overcome the disadvantages that arise when using two separate devices. By mixing the concentrations of both active compounds are diluted. This may negatively affect pharmacokinetics.

[0027] Insulin pharmacokinetics, especially insulin glargine, is affected by dilution of insulin in the administered composition. Therefore, to guarantee reliable performance of a specific insulin dose, insulin levels should be kept as constant as possible. The dosage should depend essentially on the volume of insulin composition administered. This also applies to the administration of a combination of insulin and a GLP-1 agonist. When administering a combination of insulin and a GLP-1 agonist, this requirement can only be met if both substances in the composition are dosed in a fixed relationship to each other. If both substances are provided in separate compositions and mixed for injection in a suitable device (e.g. of WO 01/02039), this constant insulin concentration can only be achieved if the insulin composition is not substantially diluted by the GLP-1 agonist composition. Thus, independent dosing of insulin and a GLP-1 agonist is only a limitation possible.

[0028] A possible solution would be to provide the GLP-1 agonist at such a high concentration that the addition of the GLP-1 agonist does not result in a significant dilution of the insulin composition (e.g. not more than 10%). Polypeptides such as insulins (e.g. Insulin glargine, Lantus®) or GLP-1 agonists cannot be arbitrarily concentrated. First, protein solubility is limited and high protein concentrations can change the flow behavior of the solution. The most important problem when using solutions with a high concentration of active compound is the accuracy of dosage. At high concentrations, small volumes would have to be administered or added to another solution. Although devices for precise dosing of small or very small volumes are known. However, they are expensive and due to their operation are intended only for use by trained personnel, e.g. in the lab. Since patients usually self-inject insulin or / and GLP-1 agonists, the use of such insulin and / or GLP-1 agonist devices is excluded. The devices disclosed, for example, in US 4,689,042, US 5,478,323, US 5,253,785 and WO 01/02039, with which the patient can self-inject solutions of active compounds, are not suitable for dosing smaller and smallest volumes.

[0029] When injecting a combination of insulin and a GLP-1 agonist, the following problems arise:

• the ratio of active compounds must be variable, • the pharmacokinetics of at least one of the active compounds (insulin) is affected by concentration / dilution,

The pharmacokinetics of at least one of the other active compounds (GLP-1 agonist) is not influenced or significantly affected by concentration / dilution. [0030] The object of the invention was therefore to provide a medicament that at least partly overcomes the disadvantages of the prior art. Furthermore, it should be achieved that only one administration per day should be possible.

[0031] It has been surprisingly found that the combination of insulin (human insulin (Gly (A21) Arg (B31) -Arg (B32)) with a GLP-1 agonist (desPro³⁶Exendin-4 (1-39) -Lys6-NH2) has synergistic effects in the regulation of blood glucose in the postprandial and post-absorption phase, compared to using insulin alone or the GLP-1 agonist alone:

• Higher effectiveness due to a combination of complementary effects on fasting and postprandial glucose values ​​that complement each other (examples 2 and 3). The combination shows a reduction in postprandial glucose (= improved glucose tolerance), like the GLP-1 agonist itself, and in addition postabsorptive glucose lowering, like insulin (Example 9).

• Reducing the risk of hypoglycemia (Examples 2-4).

• Better matching of blood glucose with normoglycemic values ​​(Example 8).

• Improved glucose tolerance and decrease of post-absorption glucose levels (Example 9).

• Synergic effects of the combination on the glucose concentration are observed over a range of GLP-1 agonist concentrations by an order of magnitude (factor 10). (Example 6 compared to Examples 4 and 2). Already at lower GLP doses or higher insulin to GLP-1 ratios, the effects of insulin prevail.

• Maintenance of β-cell function (Example 10).

• Weight loss / reduction of weight gain.

• All examples show that GLP-1 and insulin agonists do not have negative interactions.

• It is possible to reduce the number of administrations of the combination to once a day by interacting with fasting, post-absorption and post-absorption blood glucose levels.

[0032] A medicament is described herein comprising at least one insulin and at least one GLP-1 agonist, the medicament being formulated and / or packaged so that it contains insulin and GLP-1 agonist in a predetermined amount each time and can be administered in a dose adjusted to the patient's needs in each case.

[0033] The object of the invention is a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, which each contain 100 U / ml insulin

-7 human Gly (A21) -Arg (B31) -Arg (B32) and 20 to 150 μg / ml desPro³⁶Exendin-4 (1-39) -Lys6NH2 and contain human insulin Gly (A21) -Arg (B31) -Arg (B32) and desPro³⁶Exendin-4 (1-39) Lys6-NH2 in various weight proportions based on the total weight of the composition.

[0034] The medicament according to the invention is especially used for the treatment of patients with diabetes, especially patients with type 1 or type 2 diabetes.

[0035] By the medicament according to the invention, the blood glucose concentration in diabetic patients, especially type 1 or type 2 diabetes, can be better adapted to normoglycemic values. Preferably, it is used to adjust fasting blood glucose, after meals, and / or post-absorption diabetes patients, especially patients with type 1 or type 2 diabetes. More preferably, the medicament according to the invention is used for setting postprandial and / or post-absorption blood glucose in diabetic patients, especially in patients with type 1 or type 2 diabetes. Setting means in this context that substantially normoglycemic blood glucose or at least close to it is achieved. Normoglycemic values ​​mean, in particular, blood glucose levels within the normal range (range 60-140 mg / dl, corresponding to 3.3 to

7.8 mmol / L). This range of fluctuations includes blood glucose levels under fasting, fed and post-absorption conditions.

[0036] Postprandial and post-absorption are terms known to those skilled in the art of diabetes. By postprandial is meant in particular the post-meal phase and / or after the glucose load in the experiment. This phase is characterized especially in healthy people by an increase and a decrease in blood glucose again. In particular, the post-prandial phase is defined as the post-absorption or post-absorption phase. The postprandial phase usually ends up to 4 hours after a meal and / or glucose load. The post-absorption phase usually lasts from 8 to 16 hours.

[0037] The medicament according to the invention is also preferably used to improve glucose tolerance in the treatment of a diabetic patient, especially type 1 or type 2 diabetes. By improving glucose tolerance is meant that the therapeutic agent of the invention postprandial blood glucose is lowered. Similarly, by improving glucose tolerance, it is meant that the therapeutic agent of the invention post-absorption blood glucose is lowered. In particular, lowering means that blood glucose levels generally reach normoglycemic values ​​or at least approach them. The medicament according to the invention may reduce the risk of hypoglycaemia, which may e.g. occur in the post-absorption phase. The medicament according to the invention is preferably used for the prevention of hypoglycemia in the treatment of a diabetic patient, especially type 1 or type 2 diabetes, wherein hypoglycemia may occur especially in the post-absorption phase.

[0038] The medicament according to the invention can maintain the function of pancreatic β cells. The medicament according to the invention is preferably used to prevent the loss of pancreatic β cell function in a diabetic patient, especially type 1 or type 2 diabetes. The loss of β cell function may be caused in particular by apoptosis.

[0039] In addition, the medicament according to the invention may cause weight loss and / or be used to prevent weight gain in patients with diabetes, especially type I or type II. In patients with diabetes, especially type 2, weight gain and overweight are common problems. Thus, administration of the therapeutic agent of the invention may support therapy for the treatment of obesity.

[0040] It is understood that the therapeutic agent of the invention may be used to treat patients with diabetes, especially type 1 or type 2 diabetes, in more than one of the preferred indications disclosed herein. Thus, the invention encompasses not only individual preferred indications, but also any combination of indications. Thus, the medicament according to the invention can be used to treat one or more of the indications disclosed herein in diabetic patients, especially patients with type 1 and type 2 diabetes, e.g. for setting fasting blood glucose, after food and / or post-absorption, for improving glucose tolerance, for preventing hypoglycemia, for preventing the loss of pancreatic β cell function, for weight loss and / or for preventing weight gain. Setting fasting, postprandial and / or post-absorption blood glucose, improving glucose tolerance or / and preventing hypoglycemia is preferred.

[0041] The medicament according to the invention can be used in the same way for the manufacture of a medicament for the treatment of one or more of the indications disclosed herein, e.g. for setting fasting blood glucose, after a meal and / or post-absorption, for improving glucose tolerance, for prevention hypoglycaemia, for the prevention of loss of pancreatic β-cell function, for weight loss and / or for prevention of weight gain.

[0042] Insulin human Gly (A21) -Arg (B31) -Arg (B32) and at least one insulin and desPro disclosed herein³⁶exendin-4 (1-39) -Lys6-NH2 and at least one GLP-1 agonist disclosed herein can be used in the same manner for the preparation of a medicament for the treatment of one or more of the indications disclosed herein, e.g. for setting fasting blood glucose , after meals and / or after absorption, for improving glucose tolerance, for the prevention of hypoglycemia, for the prevention of loss of pancreatic β cell function, for weight loss and / or for the prevention of weight gain.

[0043] DesPro³⁶exendin-4 (1-39) -Lys6-NH2 and at least one GLP1 agonist and human Gly (A21) -Arg (B31) -Arg (B32) insulin disclosed herein and at least one insulin disclosed herein can be delivered together in one pharmaceutical composition. A first, second composition and optionally at least one further pharmaceutical composition are provided which each contain insulin and a GLP-1 agonist. Thus, a medicament is disclosed herein comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, which each contain at least one insulin and at least one GLP-1 agonist and contain at least one insulin and / or at least one agonist GLP-1 in various weight proportions based on the total weight of the composition.

[0044] In the application "optionally at least one further pharmaceutical composition" means that the medicament according to the invention may contain in addition to the first and second

A pharmaceutical composition at least one further pharmaceutical composition. The medicament according to the invention may thus contain e.g. 3, 4, 5, 6, 7, 8, 9, 10 or more pharmaceutical compositions according to the invention.

[0045] Medicaments that contain the first and second pharmaceutical compositions of the invention are preferred.

[0046] Medicaments that contain the first, second and third pharmaceutical compositions of the invention are equally preferred.

[0047] Medicaments that contain the first, second, third and fourth pharmaceutical compositions of the invention are equally preferred.

[0048] Medicines that contain the first, second, third, fourth and fifth pharmaceutical composition are equally preferred.

[0049] The weight proportions of at least one insulin and at least one GLP-1 agonist in the first pharmaceutical composition, the second pharmaceutical composition and optionally at least one further pharmaceutical composition are selected such that the pharmaceutical compositions comprise different ratios of insulin to the GLP-1 agonist in by weight.

[0050] The first composition may comprise the smallest ratio and the second composition the next larger ratio. If at least one subsequent composition is present, it may contain the next larger ratio. If another composition is present, it may contain the next larger ratio again. Thus, the compositions may contain increasing ratios of insulin to GLP-1 agonist by weight, from the first to the second and optionally further compositions.

[0051] The weight proportion of one of the two active compounds, i.e. at least one insulin and at least one GLP-1 agonist, in the first pharmaceutical composition, the second pharmaceutical composition and optionally at least one further pharmaceutical composition are selected each time such that by administering a specific the volume of the first, second or / and at least one subsequent composition can be administered a predetermined dose of active compound. Particularly preferably, the active compound is at least one insulin.

[0052] The weight proportion of the other or both active compounds, i.e. at least one insulin or at least one GLP-1 agonist in the first pharmaceutical composition, the second pharmaceutical composition and optionally at least one further pharmaceutical composition are selected in each case such that the insulin ratios for GLP-1 agonists increase with respect to the weight ratio of the first to second and optionally subsequent compositions. Particularly preferably this active compound is at least a GLP-1 agonist.

[0053] In addition, the weight proportion of the second of the two active compounds in the pharmaceutical compositions is determined so that one of the pharmaceutical compositions can be selected such that the administered dose of the first of the two active compounds for the administered dose

The second active compound is administered in a given volume. Thus, a pharmaceutical composition is selected that contains the desired ratio.

[0054] Theoretically, for each individual therapeutically desired ratio of weight proportions of at least one insulin to at least one GLP-1 agonist, a pharmaceutical composition may be provided to obtain the optimal dosage as needed for both active compounds for each patient.

[0055] In the invention, a certain number of pharmaceutical compositions are sufficient to cover the doses necessary in practice for both active compounds. For each patient, the specified dosage range is determined in the therapeutically reasonable range for each of the two active compounds. The dose administered is expected to vary significantly within this dose range for a particular patient, although no overdose or underdosing occurs.

[0056] Surprisingly, it has been found that synergistic effects of the combination of insulin (human insulin Gly (A21) -Arg (B31) -Arg (B32)) and GLP-1 agonist (desPro³⁶exendin-4 (1-39) -Lys6NH2) for blood glucose occur in the range of GLP-1 agonist concentrations of the order of units (factor 10). Because, above all, the amount of insulin must be tailored to the individual patient and precisely dosed, it allows a synergistic concentration area of ​​the GLP-1 agonist, so that the pharmaceutical composition of the invention, which contains a specific ratio of at least one insulin to at least one GLP-1 agonist, covers the therapeutic range of insulin doses simultaneously with associated synergistic amounts of the GLP-1 agonist. The ratio can be chosen such that each desired dose of insulin corresponds to a dose of at least one GLP-1 agonist that falls within the desired range, e.g. synergistic range. As stated above, the ratios of the first, second and optionally at least one subsequent medicament composition are further selected so that the ratios increase from the first to the second and optionally at least one subsequent composition. If the GLP-1 agonist dosage at the desired insulin dosage composition (e.g. first composition) is outside (usually above) the desired dosage range of the GLP-1 agonist, then another composition is selected (e.g. second composition) or a further composition with a greater ratio of at least one insulin to at least one GLP-1 agonist for use, wherein the amount of the GLP-1 agonist is within the desired range at the desired insulin dose. The ratios of the first, second and optionally at least one subsequent therapeutic agent composition may further be chosen such that insulin dosage ranges that correspond to the desired doses of at least one GLP-1 agonist start with one another and / or overlap. Preferably the ranges overlap. In particular, application means that at least two compositions can be selected which contain at least one insulin in the desired doses, each in an amount of at least one GLP-1 agonist that is within the desired dosage range.

[0057] For example, 3 compositions are sufficient to set a dose of at least one insulin for individual patients to values ​​selected from the range of 15 to

-1180 units of insulin and simultaneous dosing of GLP-1 agonist in an amount within the range of 10 to 20 μg (see example 11).

[0058] Similarly, the medicament of the invention can be provided in which the ratio is selected such that for each desired dose of GLP-1 agonist corresponds to a dosage of at least one insulin that falls within the desired range, e.g. synergistic range. The ratios of the first, second and optionally at least one subsequent drug composition can also be selected such that the GLP-1 agonist dosage ranges, which correspond to the desired dosages of at least one insulin, start with one another and / or overlap. Preferably the ranges overlap. Application in this context means especially that at least two compositions can be selected which, in the desired doses of at least one GLP-1 agonist, each contain an amount of at least one insulin that falls within the desired dosage range.

[0059] Preferably the medicament according to the invention comprises a maximum of 10 pharmaceutical compositions as defined above, more preferably a maximum of 5, maximum 4, maximum 3 or 2 pharmaceutical compositions. The compositions of the invention may contain at least one insulin in equal or different weight proportions in each case. For example, at least two compositions of the invention may contain at least one insulin in a substantially identical weight proportion.

[0060] It is preferred that the first, second and optionally further composition contain at least one insulin in a substantially identical weight proportion and contain at least one GLP-1 agonist in various weight proportions.

[0061] The compositions of the invention may contain at least one GLP-1 agonist in equal or different weight proportions in each case. For example, at least two compositions of the invention may contain at least one GLP-1 agonist in a substantially identical weight proportion.

[0062] It is equally preferred that the first, second and optionally further composition contains at least one GLP-1 agonist in a substantially identical weight proportion and contains at least one insulin in various weight proportions.

[0063] In addition to the first, second and optionally at least one further composition, the therapeutic agent of the invention may contain at least one further pharmaceutical composition that contains either at least one insulin or at least one GLP-1 agonist. Similarly, the medicament of the invention may contain at least one additional pharmaceutical composition that contains at least one insulin and at least one GLP-1 agonist in a weight ratio as in the first, second or optionally further pharmaceutical composition disclosed herein.

[0064] Further disclosed herein is a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one insulin and the second pharmaceutical composition comprises at least one GLP-1 agonist and wherein the medicament is formulated and / or

It is prepared for independent administration of the first and second pharmaceutical compositions.

[0065] Example 12 shows how a combination of two or more active compounds can be formulated such that when a combination of two or more compositions both active compounds can be administered in any amounts and in any ratios to each other. It is contemplated that at least one of the active compounds cannot be diluted by the combination (e.g. by mixing immediately before administration).

[0066] Herein is provided a medicament that comprises a first active compound and a second active compound and optionally at least one further active compound, said active compounds being provided in a first, second and optionally at least one subsequent composition. The first active compound is included in all compositions. The second active compound is included in the second formulation and optionally at least one further active compound is included in the optionally at least one subsequent composition. Thus, the second and each subsequent composition contain the first active compound in combination with another active compound.

[0067] Herein, a medicament is disclosed, which comprises the first pharmaceutical composition and the second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one first active compound, and wherein the second pharmaceutical composition comprises at least one first active compound and at least one second active compound, and wherein at least one further pharmaceutical composition comprises at least one first and at least one further active compound. The active compounds can be any active compounds.

[0068] Another object of the invention is a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises 100 U / ml human insulin Gly (A21) -Arg (B31) -Arg ( B32) and wherein the second pharmaceutical composition contains 100 U / ml human insulin Gly (A21) -Arg (B31) Arg (B32) and 20 to 150 mg / ml desPro³⁶Exendin-4 (1-39) -Lys6-NH2 and wherein at least one further pharmaceutical composition contains human insulin Gly (A21) -Arg (B31) Arg (B32) and at least one further active compound.

[0069] Preferably the first composition contains as active compound only at least one first active compound.

[0070] The first, second and optionally at least one subsequent composition may contain the first active compound in substantially equal weight or in different weight proportions based on the total weight of the composition.

[0071] It is preferred that the first pharmaceutical composition, second pharmaceutical composition and optionally at least one further pharmaceutical composition contain the first active compound in substantially equal weight percentages based on the total weight of the composition. By this you can achieve that you can

- apply any arbitrary ratio of the first and second, and optionally any ratio of the first and at least one subsequent composition, wherein the first active compound is dosed by the total amount of compositions administered. By the ratio of the two compositions, the amount of active compound which is contained only in the second and optionally in at least one subsequent composition can be infinitely added. Thus, without any difficulty, any desired amount and any desired ratio of first to second active compound and optionally first active compound to subsequent active compound can be easily dosed without changing the concentration of the first active compound.

[0072] The first active compound may be at least one insulin. The second active compound may be at least one GLP-1 agonist. A therapeutic agent is beneficial which comprises the first pharmaceutical composition and the second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one insulin, and wherein the second pharmaceutical composition comprises at least one insulin and at least one GLP-1 agonist, and wherein at least one subsequent pharmaceutical composition contains at least one insulin and at least one further active compound.

[0073] Preferably the first composition contains only at least one insulin as the active compound.

[0074] The next active compound can be any active compound. In particular, another active compound is an active compound that is used to treat patients with diabetes (type 1 or / and type 2), with active compounds for the treatment of diabetes co-morbidities also included.

[0075] The first, second and optionally at least one subsequent composition may contain insulin in a substantially equal weight proportion or in different weight proportions based on the total weight of the composition.

[0076] It is preferred that the first pharmaceutical composition, second pharmaceutical composition and optionally at least one further pharmaceutical composition contain insulin in substantially equal weight parts based on the total weight of the composition. By this it can be achieved that any arbitrary ratio of the first and second and optionally any arbitrary ratio of the first and at least one subsequent composition can be used, wherein the dosage of insulin is by the total amount of compositions administered. By the ratio of the two compositions, the amount of active compound which is contained only in the second and optionally in at least one subsequent composition can be infinitely added. Thus, any desired amount and any desired ratio of insulin to GLP-1 agonist and optionally insulin to the subsequent active compound can be easily dosed without any change in concentration without at least one insulin.

[0077] In the invention, the term "substantially equal weight" of the active compound in two compositions should be understood to mean that one of both compositions contains

-14 active compound by weight, which is not more than 10%, not more than 5%, not more than 1%, or not more than 0.1% than its weight proportion in another composition.

[0078] In the same way, the first active compound may be at least one GLP-1 agonist. The second active compound may be at least one insulin. A therapeutic agent is beneficial which comprises the first pharmaceutical composition and the second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one GLP-1 antagonist, and wherein the second pharmaceutical composition comprises at least one GLP-1 antagonist and at least one insulin, and wherein at least one further pharmaceutical composition comprises at least one GLP-1 agonist and at least one further active compound.

[0079] Preferably the first composition contains only at least one GLP-1 agonist as active compound.

[0080] The first, second and optionally at least one subsequent composition may contain GLP-1 agonists in substantially equal weight or in different weight proportions based on the total weight of the composition. It is preferred that the first pharmaceutical composition, second pharmaceutical composition and optionally at least one further pharmaceutical composition contain at least one GLP-1 agonist in substantially equal weight percentages based on the total weight of the composition. [0081] Thus, the invention provides a therapeutic agent that has many advantages over prior art compositions which consist of separate compositions in each case with an active compound, especially an insulin or GLP-1 agonist:

• The ratio of the first active compound to the second active compound and optionally the first active compound to the next active compound can be freely selected by the user.

• Since the first active compound is present in all compositions, especially in equal weight proportions, this active compound is not diluted when the first composition is mixed with the second and optionally subsequent compositions. This is important for active compounds, such as insulins, in which pharmacokinetics are affected by concentration / dilution.

• The injection volume is reduced (see Example 12). As a result, the dilution of the second active compound (e.g., GLP-1 agonist) and optionally the next active compound are reduced.

[0082] Another object of the invention is a kit comprising a medicament according to the invention. The kit of the invention may be intended for use by medical personnel or medical professionals, in particular by the patient himself or those assisting him, such as relatives. In the kit of the invention, individual pharmaceutical compositions that contain the therapeutic agent of the invention,

-15 set in separate packages so that the patient can choose a composition adapted to each current demand and give the appropriate amount. The kit according to the invention contains, for example, the medicament according to the invention in the form of a set of syringes, glass ampoules or / and sticks which contain the composition according to the invention.

[0083] The therapeutic agent of the invention may be administered by various routes. The therapeutic agent can be administered parenterally. The medicament can be injected using injection systems with or without an injection needle. In addition, the therapeutic agent can be administered by inhalation. In this case, liquid compositions can be inhaled, the above compositions can be inhaled as a powder. In addition, the medicament according to the invention can be administered by a spray, in particular a nasal spray. In addition, the therapeutic agent of the invention may be administered via a transdermal patch. The skilled person knows these administration methods and can formulate the therapeutic agent of the invention so that it can be effectively administered by one of these administration methods. It is preferred that the medicament compositions of the invention are liquid. In addition, it is preferred that the medicament according to the invention is administered parenterally, in particular by injection.

[0084] Another object of the invention is a device for administering a medicament according to the invention. This device contains pharmaceutical compositions which are contained in the medicament according to the invention in separate containers and allows pharmaceutical compositions to be dosed independently of one another. The device of the invention may be a parenteral administration device. The device according to the invention may comprise an injection device with or without an injection needle. Furthermore, the device may be an inhalation device, wherein the liquid compositions are inhaled, the above compositions may be inhaled as a powder. Furthermore, the device may be a spray delivery device, in particular a nasal spray. In addition, the device may be a transdermal delivery system. It is preferred that the device of the invention is a parenteral administration device, especially an injection device.

[0085] "Packaging" is a term that is known to the skilled person and means in pharmacology post-treatment, e.g. portioning and packaging of medicinal products for use by the end user. In the application, "assembled" or "assembled" means especially that the pharmaceutical compositions of the invention are packaged in therapeutically effective amounts in a suitable manner to allow the selection disclosed herein of at least one of the therapeutic agent compositions of the invention for the desired dosage of at least one insulin and at least one GLP-1 agonist. Parenteral administration, preferably injection, most preferably subcutaneous injection is especially provided. A suitable packaging is e.g. a syringe or glass container with a suitable closure from which therapeutically effective doses can be withdrawn if necessary. Injection sticks ("sticks", "pens") for administering insulin that contain a container (e.g. cartridge) which contains the pharmaceutical compositions of the invention.

[0086] "Formulation" or "formulation" is a term that is known to one of skill in the art and means in the field of pharmacology the manufacture of medicaments and compositions of medicaments and preparations with excipients. In the application, "formulate" or "formulation" means in particular that the composition of the invention is provided in a suitable form that allows administration of a therapeutically effective amount of the active compound. A formulation for parenteral administration, preferably for injection, more preferably for subcutaneous injection is especially provided.

[0087] Here, the term "GLP-1 agonist" includes GLP-1, its analogs and derivatives, exendin3 and its analogs and derivatives, exendin-4 and its analogs and derivatives. The compositions of the invention contain one or more independently selected from the group consisting of glucagon-like peptide 1 (GLP-1), GLP-1 analogues and derivatives, exendin-3, analogs and derivatives of exendin-3, exendin-4, analogs and exendin-4 derivatives and their pharmacologically acceptable salts. In addition, substances that have biological activity of GLP-1 are included.

[0088] GLP-1 analogues and derivatives are disclosed, e.g. in WO 98/08871, exendin-3, exendin-3 analogs 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 application EP 99 610043.4, in WO 2004/005342 and WO 04/035623. These documents are incorporated herein by reference. Exendin-3, Exendin-4 disclosed therein and their analogues and derivatives disclosed therein can be used in the compositions of the invention as GLP-1 agonists. Likewise, any combinations of exendin-3, exendin-4 and analogues and derivatives disclosed therein may be used as GLP-1 agonists. The at least one GLP-1 agonist is preferably selected independently from the group consisting of exendin-4, analogs and derivatives of exendin-4 and their pharmacologically acceptable salts.

[0089] Another preferred GLP-1 agonist is an exendin-4 analog selected from the group consisting of:

H-desPro³⁶-eksendyny-4-Lys6-NH2,

H-des (Pro^36,37) -Eksendyny-4-Lys4-NH2,

H-des (Pro^36,37) -endendin-4-Lys5-NH2 and their pharmacologically acceptable salts.

[0090] Another preferred GLP-1 agonist is an exendin-4 analog selected from the group consisting of:

desPro³⁶ [Asp²⁸] Exendin-4 (1-39), desPro³⁶ [IsoAsp²⁸] Exendin-4 (1-39), desPro³⁶ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39), desPro³⁶ [Met (O)¹⁴, isoAsp²⁸] Exendin-4 (1-39), desPro³⁶ [Trp (O2)²⁵, Asp²⁸] Exendin-2 (1-39), desPro³⁶ [Trp (O2)²⁵, isoAsp²⁸] exendin-2 (1-39),

-17desPro³⁶ [Met (O)¹⁴Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39), desPro³⁶ [Met (O)¹⁴Trp (O2)²⁵, isoAsp²⁸] exendin-4 (1-39) and their pharmacologically acceptable salts.

[0091] Another preferred GLP-1 agonist is an exendin-4 analog selected from the group described in the previous paragraph in which the peptide -Lys6-NH2 is attached to the C-terminus of the exendin-4 analogs.

[0092] Another preferred GLP-1 agonist is an exendin-4 analog selected from the group consisting of:

H- (Lys) 6-des Pro³⁶[Asp²⁸] Exendin-4 (1-39) -Lys6-NH2 des Asp²⁸Pro³⁶, Pro³⁷, Pro38exendin-4 (1-39) -NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] exendin-4 (1-39) -NH2,

H-Asn- (Glu) 5 des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] Exendin-4 (1-39) -NH2, des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H- (Lys) 6- des Pro³⁶ [Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) -Lys6-NH2,

H- des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Trp (O2)²⁵] exendin-4 (1-39) -NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Trp (O2)²⁵, Asp²⁸] exendin-4 (1-39) -NH2,

H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) -NH2, des Pro³⁶, Pro³⁷, Pro³⁸ [Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) - (Lys) 6NH2,

H- (Lys) 6- des Pro³⁶ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) -Lys6-NH2, des Met (O)¹⁴ Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸exendin-4 (1-39) -NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) -NH2, H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) -NH2, des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) -Lys6-NH2, H-Asn- (Glu) 5 des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2, H- (Lys) 6- des Pro³⁶ [Met (O)¹⁴, Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) -Lys6-NH2, des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Trp (O2)²⁵] exendin-4 (1-39) -NH2,

-18H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Trp (O2)²⁵, Asp²⁸] exendin-4 (1-39) -NH2,

H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Asp²⁸] Exendin-4 (1-39) -NH2, des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) - (Lys) 6-NH2,

H- (Lys) 6- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) (Lys) 6-NH2,

H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Met (O)¹⁴, Trp (O2)²⁵, Asp²⁸] Exendin-4 (1-39) (Lys) 6-NH2 and their pharmacologically acceptable salts.

[0093] Another preferred GLP-1 agonist is selected from the group consisting of Aig^{3 |},forest²⁶(N- (Y'-gliitainYlo (A '⁽'-lxaclekanoyl))) CTl.P-1 (7-37) [liraglutide] and their pharmacologically acceptable salts.

[0094] Another preferred GLP-1 agonist is AVE0010. AVE0010 has the des Pro sequence³⁶eksendyna- | (1-39) NH2 -lys6. This material is disclosed as SEQ ID NO: 93 in WO 01/04156. The pharmacologically acceptable salts of AVE0010 are equally preferred.

[0095] Ternin "at least one GlP-1 agonist" includes combinations of the GLP-1 agonists disclosed herein that are used in the compositions disclosed herein, e.g., any combination of two or more GLP-1 agonists selected from the GlP-1 agonists disclosed herein . At least one GlP-1 agonist is further selected independently from Exendin-, des Pro³⁶Exendin-4 (1-39) -Lys6-NH2 and Arg³⁴, Lys²⁶(N-Y-glutamyl (N^andhexadecanoyl))) GlP-1 (7-37) [liraglutide] and their pharmacologically acceptable salts.

[0096] The compositions disclosed herein contain GLP-1 agonists in an amount of from 10 μg / ml to 20 mg / ml, preferably from 25 μg / ml to 15 mg / ml. For acid to neutral dissolved GLP-1 agonists, preferably 20 μg / ml to 300 μg / ml and for neutral to basic preferably 500 μg / ml to 10 mg / ml. For exendin-4 analogues, they are preferably 20 μg / ml to 150 μg / ml.

[0097] As described herein, the term "insulin" includes not only unmodified insulins, but also insulin analogues, insulin derivatives and insulin metabolites. The compositions described herein contain one or more independently selected from the group consisting of insulins (e.g., unmodified insulins), insulin analogues, insulin derivatives and insulin metabolites, and any combinations thereof.

[0098] The at least one insulin may be independently selected from the group consisting of bovine insulins, their analogs, derivatives and metabolites, porcine insulins, their analogs, derivatives and metabolites and human insulins, their analogs, derivatives and metabolites. More preferably, at least one insulin is independently selected from human insulins, analogs, derivatives and metabolites thereof.

[0099] In addition, the insulin disclosed herein may be independently selected from unmodified insulins, especially bovine, porcine and human insulins.

[0100] At least one insulin may be independently selected from the group consisting of bovine, porcine and human insulins. More preferably, at least one insulin is independently selected from human insulins. The insulin disclosed herein may be selected from unmodified insulins, especially bovine, porcine and human insulins.

[0101] The insulin derivatives disclosed herein are derivatives of naturally occurring insulin and / or insulin analogue that have been obtained by chemical modification. Chemical modification may involve, for example, the addition of one or more specific chemical groups to one or more amino acids.

[0102] Insulin analogues that are disclosed in EP 0 214 826, EP 0 375 437, EP 0 678 522, EP 0 885 961, EP 0 419 504, WO 92/00321, German Patent Applications No. 10 2008 003 568.8 and No. 10 2008 003 566.1 and EP-A 0 368 187 may be a component of the compositions disclosed herein.

[0103] A preferred insulin analog disclosed herein may be selected from the group consisting of human insulin Gly (A21) -Arg (B31) -Arg (B32) (insulin glargine, Lantus); insulin human amide Arg (A0) -His (A8) -Glu (A15) -Asp (A18) -Gly (A21) -Arg (B3 1) -Arg (B32), human insulin Lys (B3) -Glu (B29) ; human insulin bald^B28Pro^B29 (insulin Lyspro), human insulin B28 Asp (insulin Aspart), human insulin in which proline at position B28 is substituted by Asp, Lys, Leu, Val or Ala and where at position B29 Lys can be substituted by Pro; AlaB26 human insulin; human insulin Des (B28-B3 0); human insulin Des (B27) or B29Lys1-tetradecanoyl), human insulin des (B30) (insulin Detemir).

[0104] The preferred insulin derivative disclosed herein may be selected from the group consisting of human insulin B29-N-myristoyl des (B30), human insulin B29-N-palmitoilodes (B30), human insulin B29-N-myristoyl, human insulin B29-Npalmitoil, human insulin B28-N-myristoyl Lys^B28Pro^B29, human insulin B28-N-palmitoyl-Lys^B28Pro^B29, human insulin B30-N-myristoyl-Thr^B29lys^B30, human insulin B3 0-N-palmitoylThr^B29lys^B30, human insulin B29-N- (N-palmitoyl-Y-glutamyl) -des (B30), human insulin B29-N- (N-lithocholyl-Y-glutamyl) -des (B30), human insulin Β29-Ν- ( ω-carboxyheptadecanoyl) -des (B30) and human insulin B29-N-^ - carboxyheptadecanoyl).

[0105] The more preferred insulin derivative disclosed herein can be selected from the group consisting of human insulin Gly (A21) -Arg (B3 1) -Arg (B32), human insulin Lys^B28Pro^B29 (insulin Lyspro), human insulin B28 Asp (insulin Aspart), human insulin B29Lys ^ tetradecanoyl), human insulin desB30 (insulin Detemir).

[0106] The term "at least one insulin" includes combinations of the insulins, analogs, derivatives and metabolites disclosed herein that are used in the compositions disclosed herein, e.g., any combination of two or more selected from the insulins disclosed herein, their analogs, derivatives and metabolites.

[0107] The compositions disclosed herein contain 60-6000 nmol / ml, preferably 240-3000 nmol / ml insulin, as defined herein. The concentration of 240-3000 nmol / ml corresponds to the concentration of approximately 1.4-35 mg / ml or 40-500 units / ml depending on the insulin used.

[0108] The idea of ​​2- to 10-, preferably 3- to 5- pens covers all compositions are in the range of 20 μg / ml GLP-1 agonist and 100 U / ml insulin up to 300 μg / ml GLP-1 and 500 agonist U / ml insulin. The following concentration ranges are preferred: 25 μg / ml and 100 U / ml, 33 μg / ml and 100 U / ml, 40 μg / ml and 100 U / ml, 66 μg / ml and 100 U / ml as well as 75 μg / ml and 100 U / ml.

[0109] A desirable dose range for insulin is especially a synergistic dose. Here the values ​​are from 5 to 100 U, preferably from 15 to 80 U. For GLP-1 agonists, the values ​​for the dosage range are from 5 μg to 2 mg, preferably from 10 μg to 1.8 mg, particularly preferably from 10 μg to 30 pg.

[0110] The preferred administration form of the pharmaceutical compositions according to the invention are liquid compositions which are particularly suitable for parenteral administration, particularly preferably for injection, most preferably for subcutaneous injection. The pharmaceutical composition according to the invention is particularly suitable for once daily injection.

[0111] The pharmaceutical composition of the invention may have an acidic or physiological pH. The acidic pH range is preferably in the range of pH 1-6.8, more preferably pH 3.5-6.8, even more preferably pH 3.5-4.5, most preferably in the pH range of about 4.0-4.5. The physiological pH is preferably in the range of pH 4.0-8.5, more preferably pH 5.0 to 8.5, even more preferably pH 6.0 to 8.5.

[0112] 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.

[0113] In addition, the composition of the invention may contain a suitable buffer. As buffering substances, especially for adjusting the pH value between 4.0 and 8.5, e.g. use sodium acetate, sodium citrate, sodium phosphate, etc. In addition, physiologically harmless dilute acids (usually HCl) or alkalis (usually NaOH) are also suitable for pH adjustment. Preferred concentrations of buffers and corresponding salts are in the range of 5-250 mM, more preferably in the range of 10-100 mM. The composition according to the invention may contain zinc ions. The concentration of zinc ions is preferably in the range from 0 μg / ml to 500 μg / ml, more preferably from 5 μg to 200 μg zinc / ml.

[0114] In addition, the composition of the invention may contain a suitable isotonizing agent. Suitable are e.g. glycerol, dextrose, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium compounds such as CaCl2 etc. glycerol, dextrose, lactose, sorbitol, mannitol and glucose are usually in the range of 100-250 mM, NaCl in a concentration of up to 150 mM.

[0115] In addition, the composition of the invention may contain tenside. Tenzide can significantly increase the stability of acidic insulin compositions. Yes you can make it even

-21 compositions that guarantee excellent stability against hydrophobic aggregation embryos for many months under temperature loading.

[0116] Tenzide is preferably selected from the group consisting of partial esters and esters of fatty acids and ethers of polyvalent alcohols such as glycerol and sorbitol, polyols; wherein the partial and fatty acid esters and ethers of glycerol and sorbitol are selected from the group consisting of Span®, Tween®, Myrj®, Brij®, Cremophor®; wherein the polyols are selected from the group consisting of polypropylene glycols, polyethylene glycols, poloxamers, polysorbates, pluronics, tetronics. Preferred concentrations of tensides are in the range of 5-200 μg / ml, preferably 5-120 μg / ml and particularly preferably 20-75 μg / ml.

[0117] In addition, the composition of the invention may contain further additives, such as salts, which delay the release of at least one insulin.

[0118] One of the items disclosed herein is a medicament as disclosed herein comprising at least one insulin selected independently from Lys human insulin^B28Pro^B29(insulin Lyspro), human insulin B²⁸ Asp (insulin Aspart), human insulin B29Lys ^ tetradecanil), human insulin desB30 (insulin Detemir), and insulin human insulin glargine (Gly (A21) -Arg (B31) -Arg (B32)), and containing AVE0010 or / and pharmacologically acceptable salt. Another particularly preferred object is a medicament as disclosed herein comprising insulin glargine (human insulin Gly (A21) -Arg (B31) -Arg (B32) and AVE0010 (des Pro³⁶exendin-4 (1-39) -Lys6-NH2) or / and a pharmacologically acceptable salt. The compositions of this particularly preferred therapeutic agent preferably have an acidic pH of 1-6.8, more preferably pH 3.5-6.8, even more preferably pH 3.5-5.0, most preferably in the pH range of about 4.0-4. 5. In addition, compositions of this particularly preferred therapeutic agent may contain tenside as disclosed herein.

[0119] Another object of the invention is the combination of insulin glargine (human insulin (Gly (A21) -Arg (B31) -Arg (B32)) and AVE0010 (des Pro³⁶exendin-4 (1-39) -Lys6-NH2) or / and pharmacologically acceptable salts.

[0120] In particular, the invention relates to a pharmaceutical composition comprising (a) human insulin Gly (A21) -Arg (B31) -Arg (B32) or / and a pharmacologically acceptable salt thereof at a concentration of 100 U / ml, and (b) desPro³⁶Exendin-4 (1-39) -Lys6-NH2 or / and its pharmacologically acceptable salt at a concentration of 20 to 150 μg / ml.

[0121] Another object of the invention is a pharmaceutical composition comprising (a) human insulin Gly (A21) -Arg (B31) -Arg (B32) or / and a pharmacologically acceptable salt thereof at a concentration of 100 U / ml, and (b) desPro³⁶Exendin-4 (1-39) -Lys6-NH2 or / and its pharmacologically acceptable salt at a concentration of 20 to 150 μg / ml.

[0122] Another object described herein is a method of treating a patient with the medicament or kit of the invention described herein.

[0123] The method of treating a patient described herein comprises administering a medicament disclosed herein comprising at least one insulin and at least one GLP-1 agonist,

Wherein the therapeutic agent is formulated and / or packaged so that it contains insulin and a GLP-1 agonist in a predetermined amount and is administered at a dose adapted to the patient's needs.

[0124] The method particularly comprises administering a medicament comprising the first pharmaceutical composition and the second pharmaceutical composition and optionally at least one further pharmaceutical composition, which in each case contain at least one insulin or / and at least one GLP-1 agonist and at least one insulin and / or at least one GLP-1 agonist is included in different weight percentages based on the total weight of the composition, the method comprising:

(a) selecting a dose of at least one insulin to be administered, (b) selecting a dose of at least one GLP-1 agonist to be administered, (c) selecting a composition from the first, second and optionally at least one subsequent agent composition therapeutic, which contains doses of (a) and (b) in a concentration such that the doses of (a) and (b) are in equal volume, and (d) determining and administering an amount that corresponds to the doses of (a) and ( b).

[0125] The determination of the dose according to step (a) or / and step (b) is based on the individual needs of the patient.

[0126] Step (c) of the treatment method disclosed herein can be performed based on the table. This table may be a component of the medicament according to the invention. Example 11 contains an example of a table according to the invention. The method of treating a patient may especially include administering a therapeutic agent, wherein the medicament comprises a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one active compound, and wherein the second pharmaceutical composition comprises at least one active compound and at least one second active compound, and wherein at least one further pharmaceutical composition comprises at least a first active compound and at least one further active compound, and wherein the method comprises the steps of:

(i) selecting a dose of at least one first active compound, which is to be given and determining the total first quantity, a second and optionally at least one further pharmaceutical composition, that the selected dose of at least one active compound is included in the total amount, (ii) selecting a dose of at least one second active compound, to be administered and determining the amount of the second pharmaceutical composition so that the selected dose of at least one second active compound is contained in the amount of the second composition, (iii) optionally selecting a dose of at least one further active compound, which is to be given and determining the amount of at least one subsequent composition, that

The selected dose of at least one further active compound is included in the amount of at least one subsequent composition, (iv) administering to the patient an amount of the first composition, wherein the amount given corresponds to the total amount according to step (i) after deducting the amount of the second composition according to step (ii) and optionally after deducting the amount of at least one further composition according to step (iii), and (v) administering to the patient an amount of a second composition, which was determined in step (ii) and optionally the amounts of at least one subsequent composition, which was determined in step (iii).

[0127] The first active compound may be insulin, and the second active compound may be a GLP-1 agonist. Thus, the method of treating a patient may include, in particular, administering a therapeutic agent, wherein the medicament comprises a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one insulin, and wherein the second pharmaceutical composition comprises at least one insulin and at least one GLP-1 agonist, and wherein at least one further pharmaceutical composition contains at least one insulin and at least one further active compound, and wherein the method comprises the steps of:

(i) selecting a dose of at least one insulin, which is to be given and determining the total first quantity, a second and optionally at least one further pharmaceutical composition, that the selected dose of at least one insulin is included in the total amount, (ii) selecting a dose of at least one GLP-1 agonist, to be administered and determining the amount of the second pharmaceutical composition so that the selected dose of at least one GLP-1 agonist is contained in the amount of the second composition, (iii) optionally selecting a dose of at least one further active compound, which is to be given and determining the amount of at least one subsequent composition, that the selected dose of at least one further active compound is contained in the amount of at least one subsequent composition, (iv) administering to the patient an amount of the first composition, wherein the amount given corresponds to the total amount according to step (i) after deducting the amount of the second composition according to step (ii) and optionally after deducting the amount of at least one further composition according to step (iii), and (v) administering to the patient an amount of a second composition, which was determined in step (ii) and optionally the amounts of at least one subsequent composition, which was determined in step (iii).

[0128] The first active compound may be a GLP-1 agonist, and the second active compound may be insulin. Thus, a method of treating a patient may include, in particular, administering a medicament, the medicament comprising the first composition

The pharmaceutical and second pharmaceutical composition and optionally at least one further pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one GLP-1 agonist, and wherein the second pharmaceutical composition comprises at least one GLP-1 agonist and at least one insulin, and wherein at least one further pharmaceutical composition comprises at least one GLP-1 agonist and at least one further active compound, and wherein the method comprises the steps of:

(i) selecting a dose of at least one GLP-1 agonist, which is to be given and determining the total first quantity, a second and optionally at least one further pharmaceutical composition, that the selected dose of at least one GLP-1 agonist is included in the total amount, (ii) selecting a dose of at least one insulin, to be administered and determining the amount of the second pharmaceutical composition so that the selected dose of at least one insulin is contained in the amount of the second composition, (iii) optionally selecting a dose of at least one further active compound, which is to be given and determining the amount of at least one subsequent composition, that the selected dose of at least one further active compound is contained in the amount of at least one subsequent composition, (iv) administering to the patient an amount of the first composition, wherein the amount given corresponds to the total amount according to step (i) after deducting the amount of the second composition according to step (ii) and optionally after deducting the amount of at least one further composition according to step (iii), and (v) administering to the patient an amount of a second composition, which was determined in step (ii) and optionally the amounts of at least one subsequent composition, which was determined in step (iii).

[0129] Steps (i), (ii) or / and (iii) can be carried out according to at least one table which can be an ingredient of a therapeutic agent. An independent table can be provided for each of the stages (i), (ii) and (iii).

[0130] The method of treatment disclosed herein can be especially used to treat patients with diabetes, especially type 1 or type II diabetes. Preferably, the method is used to adjust fasting blood glucose, after a meal and / or after absorption, to improve glucose tolerance, to prevent hypoglycemia, to prevent loss of pancreatic β cell function, to lose weight and / or to prevent weight gain.

[0131] Disclosed herein is a method for producing a medicament disclosed herein, which includes formulation and / or confectioning such that it contains insulin and a GLP-1 agonist in a predetermined amount each time and can be administered at a dose adapted to the patient's needs. Preferably, in the method of manufacture, the medicament is formulated and packaged so that one of the medicaments disclosed herein can be obtained, for example, a medicament comprising the first pharmaceutical composition and the second pharmaceutical composition and optionally at least one further composition

Pharmaceutical compositions which in each case contain at least one insulin and at least one GLP-1 agonist and at least one insulin and / or at least one GlP-1 agonist are included in different weight percentages based on the total weight of the composition.

[0132] Another object of the invention is a method for producing a medicament according to the invention, comprising formulation and / or confectioning such that human Gly (A21) -Arg (B31) Arg (B32) and desPro human insulin are included in each predetermined amount.³⁶exendin-4 (1-39) -lys6-NH2 and can be administered in a dose adjusted to the patient's needs in each case.

[0133] The invention is illustrated by the following figures and example below, although they do not constitute a limitation of the invention in any way. legend of figures [0134]

Figure 1: Study design for oral glucose tolerance test.

Fig. 2: OGTT in a dog: Effect of insulin glargine on Placebo.

Fig. 3: OGTT in a dog: Action of AVE0010 against Placebo.

Fig. 4: OGTT in a dog: Action of the AVE0010 / insulin glargine combination on blood glucose.

Figure 5: OGTT in a dog: Action of the AVE0010 insulin glargine combination on plasma insulin levels and c-peptide levels.

Figure 6: OGTT in a dog: Effect of dose reduction of AVE0010 with different ratios to insulin glargine in a combined formulation.

Figure 7: Effect of AVE0010-insulin glargine combination on blood glucose in diabetic db / db mice.

Figure 8: Action of the AVE0010-insulin glargine combination in the oral glucose tolerance test in diabetic db / db mice.

Figure 9: Effect of the AVE0010 - insulin glargine combination on cytokine-induced apotosis of β-cells in vitro.

Fig. 10: The idea "3 pens cover everything".

Examples

Example 1

Model: Oral glucose tolerance test (OGTT) in healthy dogs: Comparison of insulin glargine-AVE0010 combination with both active compounds administered separately. Animals [0135] male Beagle normoglycemic

-26 • body weight: ~ 15 kg • Number per group: n = 6

Study design (see Fig. 1) [0136] • Single subcutaneous injection of placebo or test formulation at time point 0 • 2 oral glucose administrations of 2 g glucose / kg body weight at 30 min and 5h time points • Blood samples are taken to determine blood glucose, insulin in plasma and peptide c Division into groups (n = 6) [0137] • placebo (= Lantus-placebo formulation without API) • Insulin glargine (0.3 IU / kg sc, equivalent to 1.8 nmol / kg). Insulin glargine is human insulin Gly (A21) -Arg (B31) -Arg (B32).

• AVE0010 (10 mg / kg sc in the Lantus placebo formulation, equivalent to 2 nmol / kg). AVE0010 is Pro³⁶exendin-4 (1-39) -Lys6-NH2.

• AVE0010 combination - insulin glargine (10 μg / kg AVE0010 / 0.3 IU / kg insulin glargine sc)

Example 2

OGTT in a dog: Effect of insulin glargine on Placebo [0138] The experiment was carried out according to the protocol disclosed in Example 1.

• OGTT repeated (2g / kg po) • Beagle males, n = 6 • MW ± Sem • placebo = placebo Lantus • Insulin glargine (0.3 U / kg sc) [0139] Result: Data are shown in Figure 2. Insulin glargine alone does not prevent OGTT-induced blood glucose increase. Insulin glargine increases the expected delayed blood glucose lowering in the post-absorption phase. Example 3

OGTT in a dog: Action of AVE0010 against placebo.

[0140] The experiment was carried out according to the protocol disclosed in Example 1.

• repeated OGTT (2g / kg po) • Beagle males, n = 6

-27 • MW ± Sem • placebo = placebo lanthus • AVE0010 (10 μg / kg sc) [0141] Result: Data are shown in Fig. 3. AVE0010 prevents almost completely induced OGTT- postprandial blood glucose increase. There is no effect on glucose concentration in the post-absorption phase. This example shows that the action of AVE0010 on postprandial blood glucose elevation induced by OGTT is complementary to the blood sugar lowering effect of insulin glargine in the post-absorption phase.

Example 4

OGTT in a dog: Action of the AVE0010 - insulin glargine combination on blood glucose [0142] The experiment was performed according to the protocol disclosed in Example 1.

• repeated OGTT (2g / kg po) • male Beagle, n = 6 • MW ± Sem • placebo = placebo lanthus • AVE0010 (10 μg / kg sc) • Insulin glargine (0.3 U / kg sc) • AVE + Lan (= premix with 10 μg / kg AVE0010 and 0.3 U / kg insulin glargine in one formulation) [0143] Result: Data are shown in Fig. 4. The combination acts on postprandial glucose increase like AVE0010 (compare Example 3). The hypoglycemic effect of insulin glargine in the post-absorption phase is just as present but attenuated (cf. Example 2). This is a synergistic effect of insulin glargine and AVE0010, because AVE0010 alone has no effect on re-falling glucose after administration of glucose and insulin glargine alone does not affect postprandial glucose.

Example 5

OGTT in a dog: Action of the AVE0010 insulin glargine combination on plasma insulin levels and c-peptide levels.

[0144] The experiment was carried out according to the protocol disclosed in Example 1.

• repeated OGTT (2g / kg po) • Beagle males, n = 6 • MW ± Sem • placebo = placebo lanthus • AVE0010 (10 μg / kg sc)

• Insulin glargine (0.3 U / kg sc) • AVE + Lan (= premix with 10 μg / kg AVE0010 and 0.3 U / kg insulin glargine in one formulation) [0145] Peptide C is released when proinsulin is converted into insulin and serves as a marker of insulin secretion in pancreatic β cells. As part of the glucose loading test, the ability of the pancreas to react with C peptide can be determined.

[0146] Result: The data are shown in Figs. 5a and 5b. In the group receiving the combination, after postprandial insulin reduction, there is an increased post-absorption insulin glargine level. Combination C peptide levels correspond to the insulin curve with AVE0010 during the postprandial phase and insulin glargine during the post-absorption phase.

Example 6

OGTT in a dog: Effect of dose reduction AVE0010 with different ratios to insulin glargine in a combined formulation.

[0147] The experiment was carried out according to the protocol disclosed in Example 1.

• repeated OGTT (2g / kg po) • Beagle males, n = 11/6/6/6 • MW ± Sem • control group = placebo Lantus • AVE + Lan (= premix from 0.15 to Hhig / kg AVE0010 and 0.3 U / kg insulin glargine in one formulation). In Examples 2 to 5, concentrations of 10 μg / kg AVE0010 were used.

[0148] Result: The data are shown in Fig. 6. Reduction of the AVE0010 dose from 10 μg / kg (cf. especially example 4) to 1 μg / kg (i.e. by a factor of 10) and the increase in the insulin glargine to AVE0010 ratio thus obtained does not affect the synergistic activity of the combination of AVE0010 with insulin glargine (see especially Example 4). Already at much lower doses of AVE0010 the effect of the combination is close to the action of insulin glargine alone (compare especially with fig. 2). The dose of AVE0010 can therefore vary at least in the order of magnitude (i.e. at least by a factor of 10), however, no synergistic effect is lost.

Example 7

Model: Diabetic insulin resistant db / db mouse: Comparison of insulin glargine-AVE0010 combination with both active compounds administered separately. Animals [0149] • Female db / db mice • Age: 10-11 weeks

-29 • Number per group: n = 10

Study design [0150] • Single subcutaneous injection of placebo or test formulation • Blood sampling for determination of blood glucose

Grouping [0151] • placebo (= Lantus-placebo formulation without API) • AVE0010 (10 μg / kg sc) • Insulin glargine (5 IU / kg sc) • Combination of AVE0010 insulin glargine (premix with 10 μg / kg AVE0010 plus 5 IU / kg insulin glargine sc)

Example 8

Action of the AVE0010-insulin glargine combination on blood glucose in diabetic db / db mice [0152] The experiment was performed according to the protocol disclosed in Example 7.

• Female db / db mice, 10 weeks old • n = 10, MW ± Sem • vehicle = placebo Lantus • AVE0010 (10 μg / kg sc) • Lantus (5 U / kg sc) • AVE0010 - insulin Glargine (= premix of 10 μg / kg AVE0010 and insulin glargine 5 U / kg in one formulation) [0153] Result: Data are shown in Fig. 7. The combination AVE0010 - insulin glargine caused diabetic db / db mice with a faster and stronger decrease in blood glucose compared to both individual active compounds. This combination leads db / db diabetic mice closer to normoglycemia than either of the two active compounds separately.

Example 9

Operation of the AVE0010-insulin glargine combination in the oral glucose tolerance test in diabetic db / db mice [0154] The experiment was performed according to the protocol disclosed in Example 7.

In addition, OGTT (2 g / kg @ 30 min) was performed.

-30 • Female db / db mice, 11 weeks old • n = 10, MW ± Sem • control group = placebo lanthus • AVE0010 (10 μg / kg sc) • Insulin glargine (5 U / kg sc) • AVE0010 - insulin Glargine ( = premix with 10 μg / kg AVE0010 and insulin glargine 5 U / kg in one formulation) [0155] Result: Data are shown in Fig. 8. The combination of AVE0010 - insulin glargine leads to significantly improved glucose tolerance and low post-absorption glucose levels. Example 10

Combination of AVE0010 - insulin glargine on cytokine-induced apotosis and lipotoxicity in vitro [0156] • Rats INS-1 insulinoma cell line • Incubation with test compound for 5h • Subsequent incubation with a mixture of cytokines for 22h (1 ng / ml IFN-γ + 4 ng / ml IL-1 β) or • Subsequent incubation with 0.5 mM FFA for 18h (palmitate: BSA 3: 1) [0157] Caspase-3 activity and cell nuclei fragmentation which correlate with apoptosis.

[0158] Result: The data are shown in Fig. 9. AVE0010 or insulin glargine (= Glargin, Glar) separately prevent apoptosis by ~ 40-50%. The combination of AVE0010 and insulin glargine prevents apoptosis much better. Due to this synergistic effect, the combination results in increased protection against cytokine-induced apoptosis and llipotoxicity. Example 11 [0159] The idea "3 pens cover everything" (Fig. 10) • 3 sticks with a premix (pens with a premix) with 3 different predefined ratios:

- Mixture A: 100 U insulin glargine + 66.66 μg AVE0010 per ml

- Mixture B: 100 U insulin glargine + 40 μg AVE0010 per ml

- Mixture C: 100 U insulin glargine + 25 μg AVE0010 per ml • Use of 3 sticks with premixture: The exemplary table in Fig. 10 gives a therapeutic range of 15 to 80 U per dose of insulin glargine and 10 to 20 μg AVE0010. The dose of insulin administered is determined or determined earlier for the individual patient

-31glargine. The pre-determined dose is searched for in the left column. While in the columns Mixture A - Mixture C the corresponding dose of AVE0010 is given in the range from 10 to 20 μ &, the appropriate Mix is ​​selected, dosed and administered. Overlapping ranges: e.g. with a requirement of 26 to 30 U insulin glargine, it was possible to select either Mix A or Mix B (higher dose AVE0010). Suitable for Mixture B and C. For example, if a 50 U insulin dose has been determined, 0.5 mL of Mix B or Mix C should be dosed. This dose contains 20 ug (Mixture B) or 12.5 μg (Mixture C) AVE0010.

• Final conclusion: Assuming that a probable AVE0010 effect of 10 to 15 μg and a therapeutic effect of 15 to 22 μg will be achieved, almost all patients who receive insulin glargine doses of 15-80 U can receive the same therapeutic doses of AVE0010 from 10 up to 20 μg if they use one of three premix sticks that contain three different ratios of insulin glargine: AVE0010 (Mixture A, B or C). Due to the wide range of possible ratios of insulin glargine to AVE0010 (cf. example 6) with synergistic effects, the pen ratios can be agreed so that for each dose of insulin glargine in at least one pen is included a synergistic dose AVE0010.

Example 12 [0160] This example shows how a combination of two or more active compounds can be formulated such that with a combination of two or more compositions both active compounds can be administered in any amounts and in any ratios to each other. It is contemplated that at least one of the active compounds cannot be diluted by the combination (e.g. by mixing immediately before administration).

[0161] In this context, the terms "active compound A" and "active compound B" mean any active compound. The active compound A is especially insulin, and the active compound B is a GLP-1 agonist. The active compound A may also be a GLP-1 agonist, and the active compound B may also be insulin.

1. Comparative Example [0162] For combination therapy with active compound A (e.g. insulin) and active compound B (e.g. GLP-1 agonist) there is provided a container 1 with the composition of the active compound A at a concentration of a mg / ml and container 2 with the composition with active compound B at a concentration of b mg / ml.

[0163] To administer the combination of both active compounds, a volume of V1 ml from container 1 and a volume of V2 ml from container 2 are mixed.

[0164] For dosing of both active compounds at the given concentrations a and b, the administered volumes of V1 and V2 are selected depending on the amount of active compounds A and B administered. The volumes of V1 and V2 of both active compounds are determined on the basis of the amount of active compounds as follows:

-32 Amount of active compound A: V1 · a mg

Amount of active compound B: V2 · b mg [0165] The concentrations of the active compounds A and B in the mixture of both compositions are determined as follows.

Active compound A: x mg / ml = V1 · a / (V1 + V2)

Active compound B: y mg / ml = V2 · b / (V1 + V2) [0166] V1 + V2 is the total volume administered. This means that both active compounds dilute each other. Thus, with this system it is not possible to maintain e.g. the concentration of active compound A (e.g. insulin) with varying amounts of active compound B at a predetermined value.

2. Example of the invention [0167] In this example, for combination therapy with an active compound A (e.g., insulin) and an active compound B (e.g., a GLP-1 agonist), a container 1 is provided with the composition with the active compound A at a concentration of a mg / ml and container 2 with the composition with active compound A at a concentration of a mg / ml and with active compound B at a concentration of b mg / ml. The concentration of active compounds A is therefore equal in both compositions.

[0168] To administer the combination of both active compounds, a volume of V3 ml from container 1 and a volume of V2 ml from container 2 are mixed.

[0169] For dosing of both active compounds at the given concentrations a and b, the administered volumes of V3 and V2 are selected depending on the amount of active compounds A and B administered. The volumes of V3 and V2 of both active compounds are determined on the basis of the amount of active compounds as follows:

Amount of active compound A: (V3 · a + V2 · a) mg Amount of active compound B: V2 · b mg [0170] The concentrations of the active compounds A and B are determined as follows.

Active compound A: a mg / ml = (V3 · a + V2 · a) / (V3 + V2)

Active compound B: with mg / ml = V2. b / (V3 + V2) [0171] V3 + V2 is the total volume given. The above calculation shows that the concentration of active compound A is always a mg / ml, so it is constant regardless of what volume ratio V3 / V2 is given.

[0172] If a comparative example (see item 1) is compared with this example according to the invention, it turns out that with the same amount of active compounds A and B given in the example according to the invention, a smaller total volume is required.

[0173] For a given dose (amount of active compound) of active compound A applies

In the comparative example:

V1 · a mg

In the example according to the invention, the following applies: (V3 · a + V2 · a) mg [0174] Since in both cases the amount of active compound should be equal, it applies (V₃ 3 * + * fi) ⁼ V- a (V₃ + V.₂) a = V, a

<img file="PL2349324T3_D0001.tif" />

or

<img file="PL2349324T3_D0002.tif" />

[0175] The volume of V2 in which the active compound B is administered is the same in both cases.

The total volume in the comparative example is V1 + V2

The total volume in the example according to the invention is V3 + V2

According to the above equation, for the example according to the invention the following applies:

<img file="PL2349324T3_D0003.tif" />

[0176] This volume V1 is smaller than the volume V1 + V2 of the comparative example.

[0177] By mixing the composition with active compound A and B with the composition with active compound A, the active compound B is diluted. This dilution is less than the dilution of active compound B in the comparative example (i.e. concentration b&gt; concentration z&gt; concentration y):

b&gt; zb&gt; V₂ b / (V₃ + V.₂) b&gt; b V₂/ (V₃+ V₂), where V2 / (V3 + V2) is &lt;1, and

<img file="PL2349324T3_D0004.tif" />

[0178] Thus, the dosing system of the invention for administering different doses of active compound A (e.g. insulin) and B (e.g. GLP-1 agonist) has three advantages over the comparator system:

• The concentration of active compound A (e.g. insulin) can be constantly maintained at a predetermined value. • At the same administered doses of active compounds A and B, the total volume administered is smaller.

• The dilution of the active substance B (eg GLP-1 agonists) is less than in the comparative experiment. This allows the concentration of active compound B to be more easily maintained within a predetermined range.

[0179] This example can be extended without any difficulty to a therapeutic agent with three or more active compounds, the first active compound being included in all compositions (preferably in equal weight proportions) and in each subsequent composition at least another active compound is included. The first composition can be mixed with each subsequent composition in any ratio, although the concentration of active compound in the first composition is not diluted.