HK1196084A

HK1196084A - Combination of an insulin and a glp-1 agonist

Info

Publication number: HK1196084A
Application number: HK14109512.4A
Authority: HK
Inventors: 乌尔里克.沃纳; 巴贝尔.罗特豪泽; 克里斯托弗.J.史密斯
Original assignee: 赛诺菲-安万特德国有限公司
Priority date: 2008-10-17
Filing date: 2011-12-14
Publication date: 2014-12-05

Description

Combination of insulin and GLP-1 agonist

The application is a divisional application of an invention application with the application date of 09.10.2009, Chinese application number of 200980150799.X and the name of the invention of a combination of insulin and a GLP-1 agonist.

The present invention relates to a medicament comprising at least one insulin and at least one GLP-1 receptor agonist (hereinafter GLP-1 agonist), which medicament is formulated and/or mixed in such a way that it comprises insulin and a GLP-1 agonist each in a predetermined amount and can be administered in a dose suitable for the individual requirements of the patient.

More specifically, the present invention relates to a medicament comprising a first and a second pharmaceutical composition, and optionally at least one further pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and containing different fractions of said at least one insulin and/or said at least one GLP-1 agonist relative to the total weight of the composition.

More specifically, the present invention relates to a medicament comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist, and optionally at least one further pharmaceutical composition comprising at least one insulin and at least one further active compound.

Around 2.5 million people worldwide suffer from diabetes. For among them type 1 diabetic patients, the replacement of deficient endocrine insulin secretion is currently the only possible therapy. Those affected depend on insulin injections to sustain life, usually several times a day. Type 2 diabetes is in contrast to type 1 diabetes in that there is not always a deficiency in insulin, but in a large number of cases, particularly in the late stages, treatment with insulin (in combination with oral antidiabetic agents where appropriate) is considered to be the most advantageous form of treatment.

In healthy individuals, insulin release from the pancreas is strictly coupled to blood glucose concentrations. Elevated blood glucose levels (such as those that occur after a meal) are rapidly compensated by a corresponding increase in insulin secretion. In the fasting state, plasma insulin levels drop to baseline values, which are sufficient to ensure a continuous supply of glucose to insulin-sensitive organs and tissues, and to maintain low hepatic glucose production during the night. Replacement of endogenous insulin secretion with exogenous, usually subcutaneously administered insulin generally does not approach the quality of the physiological regulation of blood glucose described above. There are often instances where blood glucose is shed upward or downward from the trajectory, and in its most severe form, these can be life threatening. In addition, however, elevated blood glucose levels over the years without initial symptoms constitute a considerable health risk. The large-scale DCCT study (The Diabetes Control and complications Research Group (1993) N.Engl.J.Med.329, 977-986) in The United states clearly shows that chronically elevated blood glucose levels contribute to The development of late-stage diabetic complications. Complications of end stage diabetes are microvascular and macrovascular lesions that in some cases manifest as retinopathy, nephropathy or neuropathy, and lead to blindness, renal failure, and loss of bone mass (loss of maturity), and are additionally associated with an increased risk of cardiovascular disorders. From this point of view, it can be concluded that the improvement of diabetes therapy must be aimed primarily at keeping blood glucose in the physiological range as closely as possible. This is achieved by means of injections several times a day of fast-acting and slow-acting insulin preparations, in accordance with the principles of intensive insulin therapy. The fast-acting formulation is administered at mealtime to compensate for postprandial blood glucose elevation. Slow acting basal insulin is intended to ensure basal insulin supply especially at night, without causing hypoglycemia.

Insulin is a polypeptide consisting of 51 amino acids, which are distributed over 2 amino acid chains: an A chain (with 21 amino acids) and a B chain (with 30 amino acids). The chains are linked together by 2 disulfide bridges. Insulin preparations have been used for the treatment of diabetes for many years. Such formulations not only use naturally occurring insulin, but more recently insulin derivatives and insulin analogs.

Insulin analogs are naturally occurring insulins, i.e., analogs of human or animal insulin, which differ by the substitution of at least one naturally occurring amino acid residue with another amino acid and/or the addition/deletion of at least one amino acid residue from the corresponding, otherwise identical naturally occurring insulin. The amino acid in question may also be a non-naturally occurring amino acid.

An insulin derivative is a derivative of a naturally occurring insulin or insulin analog obtained by chemical modification. For example, a chemical modification may consist in adding one or more defined chemical groups to one or more amino acids. In general, the activity of insulin derivatives and insulin analogs is slightly altered compared to human insulin.

Insulin analogues with accelerated onset of action are described in EP0214826, EP0375437, and EP 0678522. EP0214826 relates to the substitutions B27 and B28 etc. EP0678522 describes insulin analogues with different amino acids, preferably proline, instead of glutamic acid in position B29. EP0375437 encompasses insulin analogs with lysine or arginine in B28, which optionally may also be modified in B3 and/or a 21. Insulin analogues described in EP-A-0885961 also exhibit accelerated activity.

EP0419504 discloses insulin analogues protected against chemical modification by modification of asparagine in B3 and at least one individual amino acid in position a5, a15, a18 or a 21.

WO92/00321 describes insulin analogues in which at least one of the amino acids in positions B1-B6 has been replaced with lysine or arginine. Such insulins according to WO92/00321 have a prolonged activity. Insulin analogues described in EP-A0368187 and insulin analogues described in German patent applications 102008003568.8 and 102008003566.1 also exhibit delayed activity.

Insulin preparations sold for insulin replacement of naturally occurring insulin differ in the origin of the insulin (e.g. bovine, porcine, human insulin) but also in its composition, whereby the profile of action (onset of action and duration of action) can be influenced. By combining different insulin products, it is possible to obtain a very wide variety of profiles of action and to set blood glucose levels as close to physiological as possible. Recombinant DNA technology now allows the production of such modified insulins. These include insulin glargine (Gly (a21) -Arg (B31) -Arg (B32) human insulin) which has an extended duration of action. Insulin glargine is injected as an acidic clear solution and co-precipitates as stable hexamers due to its solution properties in the physiological pH range of the subcutaneous tissue. Insulin glargine is injected once daily and is significant in its flat serum profile and associated reduced risk of nocturnal hypoglycemia relative to other long-acting insulins (Schubert-Zsilavecz et al, 2:125-130 (2001)).

Certain insulin glargine formulations that result in extended duration of action are characterized by clear solutions with acidic pH.

Glucagon-like peptide 1(GLP-1) is an endocrine hormone that increases insulin response upon oral ingestion of glucose or fat. GLP-1 generally modulates glucagon concentration, slows gastric emptying, stimulates insulin (pro) biosynthesis, increases sensitivity to insulin, and stimulates insulin-independent glycogen biosynthesis (Holst (1999), curr. Med. Chem6:1005, Nauck et al (1997) Exp Clin endocrine Diabetes105:187, Lopez-Delgado et al (1998) Endocrinology139: 2811).

Human GLP-1 has 37 amino acid residues (Heinrich et al, Endocrinol.115:2176(1984), Uttenhal 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).

Exendin (exendin) is another group of peptides capable of lowering blood glucose concentration. Exendin has some similarity in sequence to GLP-1(7-36) (53%, Goke et al J.biol Chem268, 19650-55). Exendin-3 and Exendin-4 stimulate an increase in cellular cAMP production in acinar cells of guinea pig pancreas by interacting with Exendin receptors (Raufman,1996, Reg. Peptides61: 1-18). In contrast to exendin-4, exendin-3 produces an increase in amylase release in acinar cells of the pancreas.

Exendin-3, exendin-4, and exendin agonists have been proposed for the treatment of diabetes and the prevention of hyperglycemia; they reduce gastric motility and gastric emptying (US5,424,286 and WO 98/05351).

Exendin analogs can be characterized by amino acid substitutions and/or C-terminal truncations of the native exendin-4 sequence. Such exendin analogs are described in WO99/07404, WO99/25727, WO 99/25728.

From WO2004/005342 a combination of insulin and GLP-1 is known for the treatment of diabetes.

In clinical practice, the amount of insulin to be administered is adjusted for the individual requirements of the individual diabetic patient. Individual patients typically require varying amounts of insulin and/or GLP-1 agonist. Typically, the predetermined dose is administered by administering a defined amount of the composition having a defined concentration. The result of this is that a composition comprising both insulin and GLP-1 allows the administration of only one specific ratio of insulin and GLP-1. This means that only one of the two amounts of insulin and GLP-1 can be optimally adapted to the requirements of the patient. Since it is in fact crucial to correctly regulate the amount of insulin administered, it is assumed that a GLP-1 agonist is underdosed or overdosed, and at most occasionally correct, when a specific ratio of insulin to GLP-1 is administered.

There are various known systems for injecting combinations of active compounds. The active compound may be formulated in a composition and provided in a device, such as, for example, in a pre-filled syringe. Such systems do allow the combined dosing, but only with a fixed proportion of the active compound present in the composition. As listed therein, this is disadvantageous for combinations of insulin and GLP-1 agonist, since different amounts of insulin and GLP-1 agonist must be administered according to the therapeutic requirements.

It is also possible that the two active compounds are administered in two separate formulations, each comprising one of the two active compounds, which are each injected independently of one another with one device (e.g. a prefilled syringe). In the case of injection therapy, such as insulin injection, for example, patient compliance is a key prerequisite for the success of the therapy. In general, in the case of injection therapy, pain, needle-phobia (needle-phobia), and the ease of carrying the injection device are issues that can lead to reduced compliance. These problems are doubled if the patient is to use two separate injection devices.

A single device for administering insulin and a GLP-1 agonist is advantageous to the patient/user over the use of two separate devices for administering insulin and a GLP-1 agonist. Furthermore, the use of only one device instead of two devices may reduce the number of steps that the patient/user has to perform, which reduces the error frequency of use. This reduces the risk of unwanted side effects.

US4,689,042, US5,478,323, US5,253,785, and WO01/02039 describe devices for administering two injectable products to a patient simultaneously. These devices comprise two containers, each containing one composition. In these devices, two compositions are injected through one needle. This does make it possible to overcome the drawbacks resulting from the use of two separate devices. Due to the mixing process, there is a dilution of the concentration of the two active compounds. This can adversely affect pharmacokinetics.

The pharmacokinetics of insulin, particularly insulin glargine, is affected by the dilution of insulin in the administered composition. Therefore, in order to ensure reliable activity of a specific dose of insulin, the concentration of insulin should be kept as constant as possible. Dosing should occur substantially via 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 proviso is only met when the two substances are administered in a composition in a fixed ratio to each other. In case the two substances are provided in separate compositions and mixed for injection in a suitable device (e.g. from WO 01/02039), then a constant concentration of insulin may only be achieved if the insulin composition is not substantially diluted by a GLP-1 agonist composition. This imposes a limit on the possibility of independent dosing of insulin and GLP-1 agonist.

One desirable solution would be to provide a GLP-1 agonist at a high concentration such that the addition of the GLP-1 agonist administered does not result in significant dilution (e.g., no more than 10%) of the insulin composition. Polypeptides such as insulin (e.g., insulin glargine,) Or the GLP-1 agonist cannot be infinitely concentrated. First, the solubility of proteins is limited and high concentrations of proteins can alter the flow characteristics of the solution. The most important issue with respect to the use of solutions with high concentrations of active compound is dosing accuracy. At high concentrations, it may be necessary to administer small volumes or to administer doses into different solutions. Devices for the precise dosing of small or very small volumes are known. However, such devices are expensive and, based on their operation, are only intended for use by trained personnel, as for example in a laboratory. In general, the use of such devices for administering insulin and/or a GLP-1 agonist is precluded because the patient self-injects insulin and/or a GLP-1 agonist. The devices described in e.g. US4,689,042, US5,478,323, US5,253,785, and WO01/02039, which allow the patient to self-inject a solution of the active compound, are not suitable for the administration of small and very small volumes of doses.

The problems that arise with injecting a combination of insulin and a GLP-1 agonist are as follows:

● the proportion of active compound must be variable;

● the pharmacokinetics of at least one active compound (insulin) is affected by concentration/dilution;

● the pharmacokinetics of at least one other active compound (GLP-1 agonist) is unaffected, or substantially unaffected, by concentration/dilution.

It is therefore an object of the present invention to provide a medicament which at least partially overcomes the above-mentioned disadvantages of the prior art. The other intention is that it should be administered as once a day as possible.

It has surprisingly been found that the combination of insulin and a GLP-1 agonist exhibits a synergistic effect in regulating blood glucose after meals and in the post-absorption phase compared to the use of insulin or a GLP-1 agonist alone:

● are based on the higher activity of complementary combinations of activities on fasting and postprandial glucose levels that are complementary to each other (example 2 and example 3). The combination exhibited a post-prandial decrease in glucose concentration (i.e. improved glucose tolerance) as did the GLP-1 agonist alone, and additionally exhibited a post-absorption decrease in glucose as did insulin (example 9).

● the risk of hypoglycemia is reduced (examples 2-4).

● adaptation of blood glucose concentration to euglycemia improved (example 8).

● improved glucose tolerance and decreased glucose concentration after absorption (example 9).

● synergistic activity of the combination on glucose concentration was observed in a range of GLP-1 agonist concentrations of one order of magnitude (factor 10) (example 6 compared to examples 4 and 2). Insulin activity dominates only in the case of relatively small GLP-1 doses and/or a relatively large proportion of insulin to GLP-1.

● maintain beta-cell function (example 10).

● weight loss/weight gain reduction.

● all the examples show that GLP-1 agonists and insulin do not exhibit an adverse interaction.

● due to its activity on fasting, postprandial, and post-absorption blood glucose concentrations, it became possible to reduce the number of administrations of the combination to once a day.

The present invention provides a medicament comprising at least one insulin and at least one GLP-1 agonist, said medicament being formulated and/or mixed in such a way that it comprises insulin and a GLP-1 agonist each in a predetermined amount and can be administered in a dose suitable for the requirements of a patient individual.

In particular, the medicament of the invention is used to treat diabetic patients, more particularly type 1 or type 2 diabetic patients.

In the case of patients with diabetes, more particularly type 1 or type 2 diabetes, the medicament of the invention allows a more effective adaptation of the blood glucose concentration to the normoglycemic level.

Preferably, the medicament is used to regulate fasting, postprandial and/or post-absorption blood glucose concentrations in diabetic patients, more particularly type 1 or type 2 diabetic patients. More preferably, the medicament of the invention is used to modulate postprandial and/or postabsorptive blood glucose concentrations in diabetic patients, more particularly in type 1 or type 2 diabetic patients. Regulation in this context means that the euglycemic blood glucose concentration is substantially achieved or at least an approximation thereof is obtained. More specifically, the euglycaemic level means the blood glucose concentration in the normal range (fluctuation width 60-140mg/dl, corresponding to 3.3 to 7.8 mmol/l). This fluctuation range covers blood glucose concentrations in fasting, postprandial, and postabsorption conditions.

Postprandial and post-absorption are terms of skill in the art of diabetes. More specifically, postprandial is used herein to refer to the post-prandial and/or post-glucose-loading phase of an experiment. More specifically, this phase is characterized in healthy individuals by an increase and a decrease again in the blood glucose concentration. More specifically, post-absorption or post-absorption phase is used herein to refer to the phase after the post-prandial phase. The postprandial phase typically ends up to 4 hours after a meal and/or glucose load. The post-absorption phase usually lasts until 8 to 16 hours.

Preferably, the medicament of the invention is also used to improve glucose tolerance in the treatment of diabetic, more particularly type 1 or type 2 diabetic patients. Improving glucose tolerance means that the drug of the present invention reduces postprandial blood glucose concentrations. Improving glucose tolerance is also used to mean that the agents of the invention reduce the post-absorption blood glucose concentration. More specifically, decreasing means that the blood glucose concentration substantially reaches or at least approaches the glycemic norm value.

The medicament of the present invention can reduce the risk of hypoglycemia, which may occur, for example, in the post-absorption stage. Preferably, the medicament of the invention is used to prevent hypoglycemia, more particularly likely to occur in the post-absorption stage, in the treatment of patients with diabetes, more particularly type 1 or type 2 diabetes.

The medicament of the invention can maintain the function of pancreatic beta-cells. Preferably, the medicament of the invention is used to prevent loss of pancreatic beta-cell function in diabetic, more particularly type 1 or type 2 diabetic patients. More specifically, loss of function of β -cells may be caused by apoptosis.

Furthermore, the medicament of the invention may cause weight loss and/or prevent weight gain in diabetic, more particularly type I or II, patients. Weight gain and excess weight are frequent problems in diabetic patients, particularly those with type 2 diabetes. Thus, administration of the medicament of the invention may support therapy for treating the overweight.

It will be appreciated that the medicament of the invention may be used to treat more than one of the preferred indications described therein in diabetic, more particularly type 1 or type 2 diabetic patients. Thus, the present invention encompasses not only individual preferred indications, but also any combination of indications. Thus, the medicament of the present invention may be used to treat one or more of the indications described herein in diabetic patients, more particularly type 1 or type 2 diabetic patients, for example to regulate fasting, postprandial and/or post-absorption blood glucose concentrations, to improve glucose tolerance, to prevent hypoglycemia, to prevent loss of function of pancreatic β -cells, to reduce weight and/or to prevent weight gain. Preferably, fasting, postprandial and/or post-absorption blood glucose concentrations are adjusted to improve glucose tolerance and/or prevent hypoglycemia.

The medicament of the invention may also be used to produce a medical product for the treatment of one or more of the indications described herein, such as for example for the regulation of fasting, postprandial and/or post-absorption blood glucose concentrations, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of function of pancreatic β -cells, for weight loss and/or for preventing weight gain.

At least one insulin and at least one GLP-1 agonist may also be used to produce a medical product for treating one or more of the indications described herein, such as, for example, for regulating fasting, postprandial, and/or post-absorption blood glucose concentrations, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of function of pancreatic β -cells, for weight loss, and/or for preventing weight gain.

The at least one GLP-1 agonist and the at least one insulin may be provided together in one pharmaceutical composition. In this case, a first and a second composition and optionally at least one further pharmaceutical composition are provided, each comprising insulin and a GLP-1 agonist. Thus, the present invention provides a medicament comprising a first and a second pharmaceutical composition and optionally at least one further pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and containing different weight fractions of said at least one insulin and/or said at least one GLP-1 agonist relative to the total weight of the composition.

In the present specification, "optionally, at least one additional pharmaceutical composition" means that the medicament of the present invention may further comprise at least one additional pharmaceutical composition in addition to the first and second pharmaceutical compositions. Thus, the medicament of the invention may comprise, for example, 3, 4, 5, 6, 7, 8, 9, 10 or more pharmaceutical compositions of the invention.

Preferred medicaments are those comprising the first and second pharmaceutical compositions of the invention.

Likewise, medicaments comprising the first, second, and third pharmaceutical compositions of the invention are preferred.

Likewise, drugs comprising the first, second, third, and fourth pharmaceutical compositions of the present invention are preferred.

Likewise, drugs comprising the first, second, third, fourth, and fifth pharmaceutical compositions are preferred.

The weight fraction of the at least one insulin and the at least one GLP-1 agonist in the first pharmaceutical composition, the second pharmaceutical composition, and, where used, the at least one further pharmaceutical composition, may be selected in such a way that the pharmaceutical compositions contain different ratios of insulin to GLP-1 agonist based on the weight fraction.

In this case, the first composition may contain the smallest proportion, while the second composition may contain the next larger proportion. Where at least one additional composition is present, it may contain the next greater proportion. Where there is another composition present, it may then contain the next greater proportion. Thus, the composition may contain a ratio of insulin to GLP-1 agonist that increases from the first to the second and, where used, the other composition on a weight fraction basis.

Preferably, the weight fraction of one of the two active compounds, i.e. of the at least one insulin or of the at least one GLP-1 agonist, in the first pharmaceutical composition, in the second pharmaceutical composition and, in the case of use, in the at least one further pharmaceutical composition, is selected in each case such that a predetermined dose of this active compound can be administered by administering a defined volume of the first, second and/or at least one further composition. Particularly preferably, the active compound is at least one insulin.

Preferably, the weight fraction of the other of the two active compounds, i.e. the at least one insulin or the at least one GLP-1 agonist, in the first pharmaceutical composition, the second pharmaceutical composition, and in case of use the at least one further pharmaceutical composition is selected such that the ratio of insulin to GLP-1 agonist based on the weight fraction increases from the first to the second and in case of use the further composition. Particularly preferably, the active compound is at least one GLP-1 agonist.

Furthermore, the weight fraction of the other of the two active compounds in the pharmaceutical composition is determined such that one of the pharmaceutical compositions can be selected in such a way that the dose of the first of the two active compounds to be administered and the dose of the second active compound to be administered are administered in a defined volume. Accordingly, the pharmaceutical composition is selected to contain the desired ratio.

In theory, it would be possible to provide a pharmaceutical composition for each individual in a weight fraction of at least one insulin and at least one GLP-1 agonist in a therapeutically desirable ratio to obtain an optimal dosage of the two active compounds for each patient, as required.

In the present invention, a specific number of pharmaceutical compositions is sufficient to cover the actually required dose of the two active compounds. For each patient, the defined dosage range is defined within the therapeutically rational interval for each of the two active compounds. Thus, the dose to be administered should fluctuate substantially within this dosage range for a particular patient without any overdosing or underdosing.

Surprisingly, it has been found that a synergistic effect of a combination of at least one insulin and at least one GLP-1 agonist on plasma glucose concentration occurs in a GLP-1 agonist concentration range of one order of magnitude (factor 10). Since primarily the amount of insulin must be adapted and precisely administered to the individual patient, a synergistic concentration range of the GLP-1 agonist allows the pharmaceutical composition of the invention containing a defined ratio of at least one insulin to at least one GLP-1 agonist to cover the therapeutic range of insulin doses simultaneously with the relevant, synergistic amount of GLP-1 agonist. The ratio may be selected such that each desired insulin dose has its corresponding dose of the at least one GLP-1 agonist within a desired range, e.g., a synergistic range. As previously listed herein, the ratio of the first, second, and in-use at least one additional composition of the drug may also be selected such that the ratio increases from the first to the second and in-use at least one additional composition. If the composition (e.g., the first composition) is outside (and typically outside) the desired dosage range of the GLP-1 agonist at the desired GLP-1 agonist dosage of the insulin dosage, then the next composition (e.g., the second composition) or another composition having a greater ratio of the at least one insulin to the at least one GLP-1 agonist is selected for use, wherein the GLP-1 agonist dosage of the desired insulin dosage is within the desired range. The proportions of the first, second, and, where used, the at least one additional composition of the medicament may further be selected such that the insulin dosage ranges corresponding to the desired dosage of the at least one GLP-1 agonist are contiguous with each other and/or overlap with each other. Preferably, the ranges overlap. More specifically, overlapping means that it is possible to select at least two compositions each containing an amount of the at least one GLP-1 agonist within a desired dosage range at a desired dosage of the at least one insulin.

For example, the three compositions are sufficient to adjust the dose of at least one insulin to a level selected from the insulin range of 15 to 80 units for an individual patient, while simultaneously administering a GLP-1 agonist in an amount ranging from 10 to 20 μ g (see example 11).

It is also possible to provide a medicament of the invention, wherein the ratio is selected such that for each desired dose of the GLP-1 agonist there is a corresponding dose of at least one insulin within a desired range (e.g. a synergistic range). The proportions of the first, second, and, where used, the at least one additional composition of the medicament may also be selected such that GLP-1 agonist dosage ranges corresponding to the desired dosage of the at least one insulin abut each other and/or overlap each other. Preferably, the ranges overlap. More specifically, overlapping in this context means that it is possible to select at least two compositions each containing an amount of at least one insulin within a desired dosage range at a desired dosage of the at least one GLP-1 agonist.

Preferably, the medicament of the invention contains no more than 10 pharmaceutical compositions as defined above, more preferably no more than 5, no more than 4, no more than 3 or 2 pharmaceutical compositions.

The compositions of the present invention may contain the same or different weight fractions of at least one insulin. For example, at least two compositions of the present invention may contain substantially the same weight fraction of at least one insulin.

It is preferred that the first, second, and where used, further compositions contain substantially the same weight fraction of the at least one insulin and a different weight fraction of the at least one GLP-1 agonist.

The compositions of the invention may contain the same or different weight fractions of at least one GLP-1 agonist. For example, at least two compositions of the invention may contain substantially the same weight fraction of at least one GLP-1 agonist.

It is also preferred that the first, second, and where used, further compositions contain substantially the same weight fraction of the at least one GLP-1 agonist and a different weight fraction of the at least one insulin.

The medicament of the invention may comprise, in addition to the first, second, and where used, at least one additional pharmaceutical composition containing at least one insulin or at least one GLP-1 agonist. The medicament of the invention may also comprise at least one further pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist in a similar (like) weight fraction ratio as the first, second or further pharmaceutical composition in case of use described herein.

The invention further provides a medicament comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one GLP-1 agonist, formulated and/or mixed for separate administration of the first and second pharmaceutical compositions.

Example 12 shows how a combination of two or more active compounds can be formulated such that when the two or more compositions are combined, the two active compounds can be administered in any desired amount and in any desired ratio to each other. This takes into account the fact that at least one of the active compounds must not be diluted by the combination (e.g. via mixing immediately before administration).

The present invention provides a medicament comprising a first active compound and a second active compound and optionally at least one additional active compound, the active compounds being provided in a first, second, and optionally at least one additional composition. The first active compound is present in all compositions. The second active compound is present in the second formulation, while the at least one additional active compound (where used) is present in optionally at least one additional composition. Thus, the second and each additional composition comprises the first active compound in combination with another active compound.

Thus, the present invention further provides a medicament comprising a first pharmaceutical composition comprising at least one first active compound and a second pharmaceutical composition comprising at least one first active compound and at least one second active compound and optionally at least one further pharmaceutical composition comprising at least one first and at least one further active compound. The active compound herein may be any desired active compound.

Preferably, the first composition comprises only at least one first active compound as active compound.

The first, second, and where used, at least one additional composition may comprise substantially the same weight fraction or a different weight fraction of the first active compound relative to the total weight of the composition.

The first pharmaceutical composition, the second pharmaceutical composition, and, where used, the at least one further pharmaceutical composition preferably comprise a substantially equal weight fraction of the first active compound relative to the total weight of the composition. This means that it is possible to ensure that dosing of the first active compound can take place via the total amount of the composition administered, using any desired ratio of the first and second compositions and, where appropriate, any desired ratio of the first and at least one further composition. Via the ratio of the two compositions, it is possible to steplessly increase the amount of active compound present only in the second composition and, where appropriate, in at least one further composition. Thus, in this way, it is readily possible to dose any desired amount and any desired ratio of the first and second active compounds and, where appropriate, the first active compound with the further active compound without changing the concentration of the first active compound.

The first active compound may be at least one insulin. The second active compound may be at least one GLP-1 agonist. Preferably a medicament comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist and optionally at least one further pharmaceutical composition comprising at least one insulin and at least one further active compound.

Preferably, the first composition comprises only at least one insulin as active compound.

The additional active compound may be any desired active compound. More specifically, the further active compounds are active compounds for the treatment of patients with diabetes mellitus (type 1 and/or type 2), including also active compounds for the treatment of concomitant disorders of diabetes mellitus.

The first, second, and in case of use at least one further composition may comprise insulin in substantially equal weight fractions or in different weight fractions relative to the total weight of the composition.

The first pharmaceutical composition, the second pharmaceutical composition, and, where used, the at least one further pharmaceutical composition preferably comprise a substantially equal weight fraction of insulin relative to the total weight of the composition. This means that it is possible to ensure that dosing of insulin can occur via the total amount of composition administered using any desired ratio of the first and second compositions and, where appropriate, any desired ratio of the first and at least one further composition. Via the ratio of the two compositions, it is possible to steplessly increase the amount of active compound present only in the second composition and, where appropriate, in at least one further composition. Thus, in this way it is easily possible to dose any desired amount and any desired ratio of insulin to GLP-1 agonist and, where appropriate, insulin to another active compound without changing the concentration of the at least one insulin.

In the present invention, a "substantially equal weight fraction" of active compound in both compositions means that one of the two compositions contains a weight fraction of active compound that is higher than its weight fraction in the other composition, for example by not more than 10%, not more than 5%, not more than 1% or not more than 0.1%.

The first active compound can also be at least one GLP-1 agonist. The second active compound may be at least one insulin. Preferably a medicament comprising a first pharmaceutical composition comprising at least one GLP-1 agonist and a second pharmaceutical composition comprising at least one GLP-1 agonist and at least one insulin, and optionally at least one further pharmaceutical composition comprising at least one GLP-1 agonist and at least one further active compound.

Preferably, the first composition comprises only at least one GLP-1 agonist as active compound.

The first, second, and where used, at least one additional pharmaceutical composition may comprise a substantially equal weight fraction or a different weight fraction of the GLP-1 agonist relative to the total weight of the composition. The first pharmaceutical composition, the second pharmaceutical composition, and, where used, the at least one further pharmaceutical composition preferably comprise a substantially equal weight fraction of the at least one GLP-1 agonist relative to the total weight of the composition.

Thus, the present invention provides a medicament exhibiting a number of advantages over prior art compositions, including separate compositions each containing one active compound, more specifically insulin or a GLP-1 agonist, including the following:

● the ratio of first active compound to second active compound and, where appropriate, first active compound to at least one further active compound can be freely selected by the user.

● because the first active compound is present in all compositions, more particularly in equal weight fractions, this active compound is not diluted when mixing the first composition with the second and, where appropriate, further compositions. This is important for active compounds such as insulin, for example in cases where pharmacokinetics is affected by concentration/dilution.

● the injection volume is reduced (see example 12). Thus, there is a reduction in dilution of the second active compound (e.g., a GLP-1 agonist) and, where appropriate, the additional active compound.

In addition, the present invention provides a kit comprising the medicament of the present invention. The kit of the invention may be intended for use by medical staff or by persons without expert medical training, more particularly by the patient himself or by helpers such as relatives. In the kit of the present invention, the individual pharmaceutical compositions constituting the medicament of the present invention are assembled in separate packages, and therefore, the patient can select a composition suitable for the current requirements and administer an amount in accordance with the requirements. The kit of the invention comprises a medicament of the invention, for example in the form of a set of syringes, glass ampoules and/or pens comprising a composition of the invention.

There are a variety of ways in which the agents of the invention may be administered. The medicament may be administered parenterally. The medicament may be injected, wherein it is possible to use an injection system with or without a needle. In addition, the drug may be administered by inhalation. In this case, it is possible to inhale the liquid composition, or the composition may be inhaled in the form of powder. Furthermore, the medicament of the present invention may be administered as a spray, more particularly as a nasal spray. In addition, the medicament of the present invention may be administered by a transdermal system. The skilled person is aware of these methods of administration and can formulate the medicament of the invention in such a way that it can be effectively administered by one of these methods of administration. Preferably, the pharmaceutical composition of the invention is a liquid. Furthermore, it is preferred to administer the medicament of the invention parenterally, more particularly by injection.

The invention further provides a device for administering the medicament of the invention. This device contains the pharmaceutical compositions covered by the medicaments of the invention in separate containers and allows dosing the pharmaceutical compositions independently of each other. The device of the present invention may be a device for parenteral administration. The device of the present invention may be a device for injection with or without a needle. Furthermore, the device may be a device for inhalation, in which case a liquid composition is inhaled, or the composition may be inhaled in powder form. Furthermore, the device may be a device for applying a spray, more particularly a nasal spray. Additionally, the device may be a transdermal administration system. The device of the invention is preferably a device for parenteral administration, more particularly an injection device.

"mixing" is a term known to the skilled person and which pharmacologically identifies the finished treatment, such as dispensing and packaging, of a drug, for example, for use by an end user. In the present specification, "mixing" more specifically means packaging the pharmaceutical compositions of the invention in a therapeutically effective amount in a suitable manner to allow selection of at least one composition of the invention as described herein for the desired dosing of at least one insulin and at least one GLP-1 agonist. More specifically, parenteral administration, preferably injection, more preferably subcutaneous injection, is intended. For example, a suitable package is a syringe or glass container with a suitable cap from which an individual therapeutically active dose can be withdrawn as desired. Also suitable is an injection pen for administering insulin comprising a container (e.g. a cartridge) containing the pharmaceutical composition of the invention.

"formulation" is a term known to the skilled person and in the field of pharmacology that refers to the production of drugs and pharmaceutical compositions, and their preparation using excipients. In the present specification, "formulating" more specifically means providing the composition of the invention in a suitable form that allows the administration of a therapeutically effective amount of the active compound. More specifically, the formulation is intended for parenteral administration, preferably for injection, more preferably for subcutaneous injection.

In the present invention, the term "GLP-1 agonist" includes GLP-1, analogues and derivatives thereof, exendin-3 and analogues and derivatives thereof, and exendin-4 and analogues and derivatives thereof. The composition of the invention comprises one or more items selected independently of each other from the group consisting of: glucagon-like peptide-1 (GLP-1), analogs and derivatives of GLP-1, exendin-3, analogs and derivatives of exendin-3, exendin-4, analogs and derivatives of exendin-4, and pharmacologically tolerable salts thereof. Also included are substances that exhibit GLP-1 biological activity.

GLP-1 analogs and derivatives are described, for example, in WO 98/08871; exendin-3, analogues and derivatives of Exendin-3, and analogues and derivatives of Exendin-4 and Exendin-4 can be found in WO01/04156, WO98/30231, US5,424,286, EP application 99610043.4, WO2004/005342 and WO 04/035623. These documents are included herein by reference. The exendin-3 and exendin-4 described in these documents, and the analogues and derivatives thereof described therein, may be used as GLP-1 agonists in the compositions of the present invention. It is also possible to use any desired combination of exendin-3 and exendin-4 and the analogues and derivatives described therein as GLP-1 agonists as described in these documents. Preferably, the at least one GLP-1 agonist is independently selected from the group consisting of: exendin-4, analogues and derivatives of Exendin-4, and pharmacologically tolerable salts thereof.

Further preferred GLP-1 agonists are exendin-4 analogues selected from the group consisting of:

H-desPro³⁶Exendin-4-Lys₆-NH₂，

H-des(Pro^36,37) Exendin-4-Lys₄-NH₂,

H-des(Pro^36,37) Exendin-4-Lys₅-NH₂And pharmacologically tolerable salts thereof.

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),

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

desPro³⁶[Met(O)¹⁴Trp(O₂)²⁵，IsoAsp²⁸]exendin-4 (1-39), and pharmacologically tolerable salts thereof.

Another preferred GLP-1 agonist is an exendin-4 analogue selected from the group as described in the preceding paragraph, wherein the peptide-Lys₆-NH₂Have been attached to the C-terminus of exendin-4 analogues.

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)₅des 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 Asp²⁸Pro³⁶、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)₆-NH₂，

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

des Met(O)¹⁴Asp²⁸Pro³⁶、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)₅des Pro³⁶、Pro³⁷、Pro³⁸[Met(O)¹⁴，Asp²⁸]Exendin-4 (1-39) -Lys₆-NH₂，

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

des Asp²⁸Pro³⁶、Pro³⁷、Pro³⁸[Met(O)¹⁴、Trp(O₂)²⁵]Exendin-4 (1-39) -NH₂，

H-(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-NH₂And pharmacologically tolerable salts thereof.

Further preferred GLP-1 agonists are selected from the group consisting of:

Arg³⁴，Lys²⁶(N^ε(Gamma-glutamyl (N)^α-hexadecanoyl))) GLP-1(7-37) [ liraglutide](liraglutide) and pharmacologically tolerable salts thereof.

Another preferred GLP-1 agonist is AVE 0010. AVE0010 has the sequence Pro³⁶Exendin-4 (1-39) -Lys₆-NH₂. This substance is disclosed in WO01/04156 as SEQ ID No: 93. Pharmacologically tolerable salts of AVE0010 are also preferred.

The term "at least one GLP-1 agonist" includes combinations of GLP-1 agonists described herein as used in the compositions of the invention, examples being any desired combination of two or more GLP-1 agonists selected from the GLP-1 agonists described herein.

Further preferably, the at least one GLP-1 agonist is independently selected from the group consisting of exendin-4, Pro³⁶Exendin-4 (1-39) -Lys₆-NH₂And Arg³⁴、Lys²⁶(N^ε(Gamma-glutamyl (N)^α-hexadecanoyl))) GLP-1(7-37) [ liraglutide]And pharmacologically tolerable salts thereof.

The composition of the invention contains the GLP-1 agonist in an amount of 10 μ g/ml to 20mg/ml, preferably 25 μ g/ml to 15 mg/ml. For acidic to neutral soluble GLP-1 agonists the numbers are preferably 20 to 300. mu.g/ml, whereas for neutral to basic agonists they are preferably 500 to 10 mg/ml. For exendin-4 analogues, 20 μ g/ml to 150 μ g/ml are preferred.

In the present specification, the term "insulin" covers not only unmodified insulin but also insulin analogues, insulin derivatives, and insulin metabolites. The composition of the present invention comprises one or more independently selected from the group consisting of: insulin (e.g., unmodified insulin), insulin analogs, insulin derivatives, and insulin metabolites, and any desired combinations thereof.

The at least one insulin may be independently selected from the group consisting of: bovine insulin, analogs, derivatives, and metabolites thereof, porcine insulin, analogs, derivatives, and metabolites thereof, and human insulin, analogs, derivatives, and metabolites thereof. Preferably, the at least one insulin is independently selected from human insulin, analogs, derivatives, and metabolites thereof.

Furthermore, the insulin of the present invention may be independently selected from unmodified insulins, more specifically bovine insulin, porcine insulin, and human insulin.

The at least one insulin may be independently selected from the group consisting of: bovine insulin, porcine insulin, and human insulin. More preferably, at least one insulin is independently selected from human insulin. The insulin of the invention may be selected from unmodified insulins, more specifically bovine insulin, porcine insulin, and human insulin.

The insulin derivatives of the present invention are derivatives of naturally occurring insulin and/or insulin analogues, which are obtained by chemical modification. For example, a chemical modification may consist in adding one or more defined chemical groups to one or more amino acids.

Insulin analogues described in EP0214826, EP0375437, EP0678522, EP0885961, EP0419504, WO92/00321, German patent applications 102008003568.8 and 102008003566.1, and EP-A0368187 may be part of the composition of the present invention. The documents EP0214826, EP0375437, EP0678522, EP0419504, WO92/00321, and EP-A0368187 are included herein by reference.

A preferred insulin analogue of the invention may be selected from the group consisting of: gly (a21) -Arg (B31) -Arg (B32) human insulin (insulin glargine, Lantus); arg (A0) -His (A8) -Glu (A15) -Asp (A18) -Gly (A21) -Arg (B31) -Arg (B32) human insulin amide, Lys (B3) -Glu (B29) human insulin; lys^B28Pro^B29Human insulin (insulin lyspro), B28Asp human insulin (insulin aspart), human insulin in which the proline in position B28 has been replaced with Asp, Lys, Leu, Val or Ala and the Lys in position B29 may be replaced with Pro; AlaB26 human insulin; des (B28-B30) human insulin; des (B27) human insulin or B29Lys (. epsilon. -tetradecanoyl group), des (B30) human insulin (insulin detemir).

Preferred insulin derivatives of the invention may be selected from the group consisting of: B29-N-myristoyl-des (B30) human insulin, B29-N-palmitoyl-des (B30) human insulin, B29-N-myristoyl human insulin, B29-N-palmitoyl human insulin, B28-N-myristoyl Lys^B28Pro^B29Human insulin, B28-N-palmitoyl-Lys^B28Pro^B29Human insulin, B30-N-myristoyl-Thr^B29Lys^B30Human insulin, B30-N-palmitoyl-Thr^B29Lys^B30Human insulin, B29-N- (N-palmitoyl-Y-glutamyl) -des (B30) human insulin, B29-N- (N-lithocholyl-Y-glutamyl) -des (B30) human insulin, B29-N- (omega-carboxyheptadecanoyl) -des (B30) human insulin, and B29-N- (omega-carboxyheptadecanoyl) human insulin.

More highly preferred insulin derivatives of the invention are selected from the group consisting of: gly (A21) -Arg (B31) -Arg (B32) human insulin, Lys^B28Pro^B29Human insulin (insulin lyspro), B28Asp human insulin (insulin aspart), B29Lys (. epsilon. -tetradecanoyl), desB30 human insulin (insulin detemir).

The term "at least one insulin" includes combinations of insulin, analogs, derivatives, and metabolites thereof described herein used in the compositions of the present invention, e.g., any desired combination of two or more selected from the group consisting of insulin, analogs, derivatives, and metabolites described herein.

The compositions of the invention contain from 60 to 6000nmol/ml, preferably 240-3000nmol/ml of insulin as defined herein. Depending on the insulin used, a concentration of 240-3000nmol/ml corresponds approximately to a concentration of 1.4-35mg/ml or 40-500 units/ml.

In 2 to 10, preferably 3 to 5 pens covering all systems, the composition ranges from 20 μ g/ml GLP-1 agonist and 100U/ml insulin to 300 μ g/ml GLP-1 agonist and 500U/ml insulin. The following concentration ranges are preferred: 25. mu.g/ml and 100U/ml, 33. mu.g/ml and 100U/ml, 40. mu.g/ml and 100U/ml, 66. mu.g/ml and 100U/ml, and 75. mu.g/ml and 100U/ml.

In particular, the desired dosage range of insulin is a dosage that has a synergistic effect. Here, the value is 5 to 100U, preferably 15 to 80U. For GLP-1 agonists, the dose range values are 5 μ g to 2mg, preferably 10 μ g to 1.8mg, more preferably 10 μ g to 30 μ g.

[ more precise details regarding the amounts and dosages used herein ]

Preferred presentation forms of the pharmaceutical composition of the invention are liquid compositions particularly suitable for parenteral administration, more preferably injection, more preferably subcutaneous injection. In particular, the pharmaceutical composition of the present invention is suitable for once-a-day injection.

The pharmaceutical compositions of the invention may have an acidic or physiological pH. The acidic pH range is preferably in the range of pH1-6.8, more preferably pH3.5-6.8, even more preferably pH3.5-4.5, most preferably at a pH of about 4.0-4.5. The physiological pH is preferably in the range of pH4.0-8.5, more preferably pH5.0 to 8.5, even more preferably pH6.0 to 8.5.

The compositions of the present invention may contain a suitable preservative. Examples of suitable preservatives include phenol, m-cresol, benzyl alcohol and/or parabens.

The compositions of the present invention may further comprise a suitable buffering agent. Particularly useful buffering substances for setting the pH level between about 4.0 and 8.5 include, for example, sodium acetate, sodium citrate, sodium phosphate, and the like. In other cases, physiologically objectionable dilute acids (typically HCl) or bases (typically NaOH) are suitable for setting the pH level. Preferred concentrations of the buffer and also of the corresponding salts are in the range of 5-250mM, more preferably in the range of 10-100 mM.

The compositions of the present invention may comprise zinc ions. The concentration of zinc ions is preferably in the range of 0 to 500. mu.g/ml, more preferably 5 to 200. mu.g zinc/ml.

The compositions of the present invention may further comprise a suitable isotonic/isotonicity agent. Suitable examples include glycerol, dextrose, lactose, sorbitol, mannitol, glucose, NaCl, calcium compounds or magnesium compounds such as CaCl₂And the like. Glycerol, dextrose, lactose, sorbitol, mannitol, and glucose are typically in the range of 100-.

The composition of the present invention may further comprise a surfactant. Surfactants can greatly enhance the solubility of acidic insulin compositions. With the use of surfactants, it is even possible to prepare compositions which guarantee excellent stability in terms of hydrophobic aggregated cores over many months of temperature exposure.

The surfactant is preferably selected from the group consisting of: partial and fatty acid esters and ethers of polyhydric alcohols such as glycerol and sorbitol, and polyhydric alcohols, glycerolThe oil and sorbitol moieties and fatty acid esters and ethers are selected from the group consisting of:andand the polyol is selected from the group consisting of: polypropylene glycol, polyethylene glycol, poloxamers, polysorbates, Pluronic, and Tetronic. Preferred concentrations of the surfactant are in the range of 5-200. mu.g/ml, preferably 5-120. mu.g/ml and more preferably 20-75. mu.g/ml.

The composition of the invention may further comprise other additives such as, for example, salts that delay the release of at least one insulin.

A particularly preferred subject of the present invention is a medicament as described herein, comprising an amino acid independently selected from Lys^B28Pro^B29At least one insulin selected from human insulin (insulin lyspro), B28Asp human insulin (insulin aspart), B29Lys (. epsilon. -tetradecanoyl), desB30 human insulin (insulin detemir), and insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin), and further comprises AVE0010 and/or a pharmacologically tolerable salt thereof. Another particularly preferred subject matter is a medicament as described herein, comprising insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin) and AVE0010(des Pro³⁶Exendin-4 (1-39) -Lys₆-NH₂) And/or a pharmacologically tolerable salt thereof. These particularly preferred pharmaceutical compositions preferably have an acidic pH of 1-6.8, more preferably a pH of 3.5-6.8, even more preferably a pH of 3.5-5.0, most preferably a pH of about 4.0 to 4.5. In addition, the compositions of these particularly preferred medicaments may comprise a surfactant as described herein.

Further subjects of the invention are insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin) and AVE0010(des Pro³⁶Exendin-4 (1-39) -Lys₆-NH₂) And/or a pharmacologically tolerable salt thereof.

The invention further provides a method of treating a patient with a kit or medicament of the invention as described herein.

The method of the invention for treating a patient comprises administering a medicament of the invention comprising at least one insulin and at least one GLP-1 agonist, the medicament being formulated and/or mixed such that it contains insulin and GLP-1 agonist each in predetermined amounts and can be administered at a dosage appropriate to the individual requirements of the patient.

More specifically, the method comprises administering a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one further pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and comprising a different weight fraction of the at least one insulin and/or the at least one GLP-1 agonist relative to 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, where used, at least one other composition of the drug, which comprises the doses from (a) and (b) in concentrations such that the doses from (a) and (b) are present in the same volume, and

(d) determining and administering an amount corresponding to the dose from (a) and (b).

Determining the dose according to step (a) and/or step (b) according to the individual requirements of the patient.

Step (c) of the therapeutic method of the present invention may be carried out based on a table. This table may be part of the medicament of the invention. Example 11 contains an example of a table according to the invention.

More specifically, a method of treating a patient may comprise administering a medicament comprising a first pharmaceutical composition comprising at least one first active compound and a second pharmaceutical composition comprising at least one first active compound and at least one second active compound, and optionally at least one additional pharmaceutical composition comprising at least one first active compound and at least one additional active compound, and the method comprises the steps of:

(i) selecting a dose of the at least one first active compound to be administered and determining the total amount of the first, second, and, where used, the at least one additional composition, such that the selected dose of the at least one first active compound is present in the total amount,

(ii) selecting a dose of the at least one second active compound to be administered and determining the amount of the second composition such that the selected dose of the at least one second active compound is present in the amount of the second composition,

(iii) selecting, where appropriate, a dose of the at least one additional active compound to be administered, and determining the amount of the at least one additional composition such that the selected dose of the at least one additional active compound is present in the amount of the at least one additional composition,

(iv) (iv) administering to the patient an amount of the first composition corresponding to the total amount according to step (i) minus the amount of the second composition according to step (ii) and, where appropriate, the amount of the at least one further composition according to step (iii), and

(v) (iv) administering to the patient the amount of the second composition determined in step (ii), and where appropriate the amount of at least one additional composition determined in step (iii).

The first active compound may be insulin and the second active compound may be a GLP-1 agonist. Thus, more specifically, a method of treating a patient may comprise administering a medicament comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist, and optionally at least one additional pharmaceutical composition comprising at least one insulin and at least one additional active compound, and the method comprises the steps of:

(i) selecting a dose of at least one insulin to be administered and determining the total amount of the first, second, and, in the case of use, the at least one additional composition, such that the selected dose of the at least one insulin is present in the total amount,

(ii) selecting a dose of the at least one GLP-1 agonist to be administered and determining the amount of the second composition such that the selected dose of the at least one GLP-1 agonist is present in the amount of the second composition,

(iv) (iv) administering to the patient an amount of the first composition corresponding to the total amount according to step (i) minus the amount of the second composition according to step (ii) and, where appropriate, the amount of at least one further composition according to step (iii), and

The first active compound may be a GLP-1 agonist and the second active compound may be insulin. Thus, more specifically, a method of treating a patient may comprise administering a drug comprising a first pharmaceutical composition comprising at least one GLP-1 agonist and a second pharmaceutical composition comprising at least one GLP-1 agonist and at least one insulin, and optionally at least one additional pharmaceutical composition comprising at least one GLP-1 agonist and at least one additional active compound, and the method comprises the steps of:

(i) selecting a dose of the at least one GLP-1 agonist to be administered and determining the total amount of the first, second, and, where used, the at least one additional composition, such that the selected dose of the at least one GLP-1 agonist is present in said total amount,

(ii) selecting a dose of at least one insulin to be administered and determining an amount of the second composition such that the selected dose of the at least one insulin is present in the amount of the second composition,

Steps (i), (ii) and/or (iii) may be carried out based on at least one table, which may be part of a drug. For each of steps (i), (ii), and (iii) independently of each other, a table may be provided.

More specifically, the treatment methods of the present invention can be used to treat diabetic, more specifically type 1 or type II diabetic, patients. Preferably, the methods of use are for regulating fasting, postprandial, and/or post-absorption blood glucose concentrations, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of pancreatic beta-cell function, for weight loss, and/or for preventing weight gain.

The invention further provides a method of preparing a medicament of the invention, comprising formulating and/or mixing such that it contains insulin and a GLP-1 agonist, each in predetermined amounts, and can be administered in a dosage appropriate to the individual requirements of the patient. In the method of preparation, the medicaments are preferably formulated and mixed such that one of the medicaments of the invention described herein, such as for example a medicament of the invention comprising a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one further pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and comprising a different weight fraction of said at least one insulin and/or said at least one GLP-1 agonist relative to the total weight of the composition, can be obtained.

The invention is illustrated by the following figures and examples, which are not intended to limit the invention in any way whatsoever.

Brief Description of Drawings

FIG. 1: study design for oral glucose tolerance testing.

FIG. 2: OGTT in dogs: effect of insulin glargine relative to placebo.

FIG. 3: OGTT in dogs: effect of AVE0010 relative to placebo.

FIG. 4: OGTT in dogs: effect of AVE 0010/insulin glargine combination on blood glucose levels.

Fig. 5a and 5 b: OGTT in dogs: effect of AVE 0010/insulin glargine combination on plasma insulin and c-peptide levels.

FIG. 6: OGTT in dogs: the dose-reducing effect of AVE0010 was found to be different ratios in the combination formulation compared to insulin glargine.

FIG. 7: effect of AVE 0010/insulin glargine combination on blood glucose in diabetic db/db mice.

FIG. 8: effect of AVE 0010/insulin glargine combination in oral glucose tolerance test in diabetic db/db mice.

FIG. 9: effect of AVE 0010/insulin glargine combination on cytokine and lipotoxicity induced apoptosis of beta cells in vitro.

FIG. 10: the "3 pens cover all" systems.

Examples

Example 1

Model: oral Glucose Tolerance Test (OGTT) in healthy dogs: the glargine insulin/AVE 0010 combination was compared to the two active compounds alone.

Animal(s) production

● beagle dog with normal blood sugar in male

● weight: about 15kg

● number of groups: n =6

Research design (see figure 1)

● Subcutaneous injection of placebo or test formulation at time 0

● glucose was administered orally at 2g glucose/kg body weight 2 times at 30 minutes and 5 hours

● blood samples were collected for determination of blood glucose, plasma insulin, and c-peptide

Grouping (n =6)

● placebo (Lantus placebo formulation without API)

● insulin glargine (0.3 IU/kg s.c., equal to 1.8 nmol/kg). Insulin glargine is Gly (A21) -Arg (B31) -Arg (B32) human insulin.

● AVE0010 (10. mu.g/kg s.c. in Lantus placebo formulation, equal to 2 nmol/kg). AVE0010 is des Pro³⁶Exendin-4 (1-39) -Lys₆-NH₂。

● AVE 0010/insulin glargine combination (10 μ g/kg AVE0010/0.3 IU/kg insulin glargine s.c.).

Example 2

OGTT in dogs: effect of insulin glargine relative to placebo

The experiment was carried out according to the protocol described in example 1.

● repeated OGTT (2g/kg p.o.)

● male beagle dog, n = 6.

● mean ± Sem

● placebo = Lantus placebo

● insulin glargine (0.3U/kg s.c.)

As a result: the data are shown in figure 2. A single administration of insulin glargine does not prevent OGTT-induced elevation of blood glucose. Insulin glargine enhances the expected delayed reduction of blood glucose concentration in the post-absorption phase.

Example 3

OGTT in dogs: effect of AVE0010 relative to placebo

● repeat OGTT (2g/kg p.o.)

● Male beagle dog, n =6

● mean ± Sem

● placebo = Lantus placebo

●AVE0010(10μg/kg s.c.)

As a result: the data are shown in figure 3. AVE0010 almost completely prevented OGTT-induced postprandial elevation of blood glucose. There was no effect on glucose concentration during the post-absorption phase. This example shows that the effect of AVE0010 on OGTT-induced postprandial elevation of blood glucose is complementary to the blood glucose lowering effect of insulin glargine in the post-absorption phase.

Example 4

OGTT in dogs: effect of AVE 0010/insulin glargine combination on blood glucose levels

● repeat OGTT (2g/kg p.o.)

● Male beagle dog, n =6

● mean ± Sem

● placebo = Lantus placebo

●AVE0010(10μg/kg s.c.)

● insulin glargine (0.3U/kg s.c.)

●AVE+Lan（=A kind ofPremixed 10 μ g/kg AVE0010 and 0.3U/kg insulin glargine in formulation

As a result: the data are shown in figure 4. The combination had the same effect as AVE0010 on postprandial glucose elevation (see example 3). The hypoglycemic effect of insulin glargine in the post-absorption stage is also present but diminished (see example 2). This is a synergistic effect of insulin glargine and AVE0010, since AVE0010 alone has no effect on glucose levels, which again drop after administration of glucose, whereas insulin glargine alone has no effect on postprandial glucose levels.

Example 5

OGTT in dogs: effect of AVE 0010/insulin glargine combination on plasma insulin and c-peptide levels

● repeat OGTT (2g/kg p.o.)

● Male beagle dog, n =6

● mean ± Sem

● placebo = Lantus placebo

●AVE0010(10μg/kg s.c.)

● insulin glargine (0.3U/kg s.c.)

The C-peptide is released during the conversion of proinsulin to insulin and serves as a marker for insulin secretion by pancreatic β -cells. In the glucose loading test, c-peptide can be used to determine the responsiveness of the pancreas.

As a result: the data is shown in fig. 5a and 5 b. In the combination group, a postprandial decrease in insulin was followed by an increase in insulin glargine levels after absorption. The combined C-peptide levels correspond to the insulin profile of AVE0010 during the meal phase and of insulin glargine during the post-absorption phase.

Example 6

OGTT in dogs: with varying proportions of AVE0010 in the combined formulation.

● repeat OGTT (2g/kg p.o.)

● Male beagle dog, n =11/6/6/6

● mean ± Sem

● control = Lantus placebo

●AVE+Lan（=A kind of0.15 to 1.0 μ g/kg AVE0010 and 0.3U/kg insulin glargine pre-mixed in the formulation). In examples 2 to 5, AVE0010 concentrations of 10. mu.g/kg were used.

As a result: the data are shown in figure 6. A reduction of the dose of AVE0010 from 10 μ g/kg (specific comparative example 4) to 1 μ g/kg (i.e. 10-fold) and the resulting increase in the ratio of insulin glargine to AVE0010 had no effect on the synergistic activity of the combination of AVE0010 and insulin glargine (specific comparative example 4). The effect of the combination does approach that of insulin glargine alone only at the significantly smaller dose of AVE0010 (compare in particular figure 2). Thus, the dose of AVE0010 can be varied by at least an order of magnitude (e.g., at least 10-fold) without loss of synergy.

Example 7

Model: diabetic, insulin resistant db/db mice: the glargine insulin/AVE 0010 combination was compared to the two active compounds alone.

Animal(s) production

● female db/db mouse

● age: 10-11 weeks

● number of groups: n =10

Design of research

● subcutaneous injection of placebo or test formulation

● blood sample is collected to determine blood glucose

Grouping

● placebo (= Lantus placebo formulation without API)

●AVE0010(10μg/kg s.c.)

● insulin glargine (5 IU/kg s.c.)

● AVE 0010/insulin glargine combination (premixed 10 μ g/kg AVE0010 and 5 IU/kg insulin glargine s.c.)

Example 8

Effect of AVE 0010/insulin glargine combination on blood glucose in diabetic db/db mice

The experiment was carried out according to the protocol described in example 7.

● female db/db mice, 10 weeks old

● n =10, mean ± Sem

● vehicle = Lantus placebo

●AVE0010(10μg/kg sc)

● Lantus (5U/kg sc)

● AVE 0010/insulin glargine (= insulin glargine)A kind ofAVE001010 μ g/kg and insulin glargine 5U/kg premixed in formulation

As a result: the data are shown in figure 7. In diabetic db/db mice, the AVE 0010/insulin glargine combination produces a faster and more pronounced decrease in blood glucose concentration compared to the two active compounds alone. Thus, the combination brings diabetic db/db mice closer to euglycemia than either of the two active compounds alone.

Example 9

Effect of AVE 0010/insulin glargine combination in oral glucose tolerance test in diabetic db/db mice

The experiment was carried out according to the protocol described in example 7. In addition, OGTT (2g/kg p.o. at 30 min) was performed.

● female db/db mice, 11 weeks old

● n =10, mean ± Sem

● control = Lantus placebo

●AVE0010(10μg/kg sc)

● insulin glargine (5U/kg sc)

● AVE 0010/insulin glargine (= inA kind ofAVE001010 μ g/kg and insulin glargine 5U/kg premixed in formulation

As a result: the data are shown in figure 8. The AVE 0010/insulin glargine combination results in significantly improved glucose tolerance and lower post-absorption glucose levels.

Example 10

Effect of AVE 0010/insulin glargine combination on cytokine and lipotoxicity induced apoptosis of beta cells in vitro

● insulinoma cell line INS-1, rat

● incubation with test Compounds for 5 hours

● incubated with cytokine mixture for an additional 22 hours (1 ng/mL IFN-. gamma. +4 ng/mLIL-1. beta.)Or

● incubated with 0.5mM FFA for a further 18 hours (palmitate: BSA3: 1)

Measurements for apoptosis are caspase-3 activity and fragmentation of the nucleus, which is associated with apoptosis.

As a result: the data are shown in fig. 9. AVE0010 or glargine (Glar) alone prevented apoptosis by about 40-50%. AVE0010 and insulin glargine in combination significantly better prevented apoptosis. Based on this synergistic effect, the combination elicits increased protection against cytokine and lipotoxicity induced apoptosis.

Example 11

'3 pens all' system (fig. 10)

● there were 3 different pre-mix pens in 3 different predetermined ratios:

-mixture a: 100U of insulin glargine per mL + 66.66. mu.g AVE0010

-mixture B: 100U of insulin glargine per mL + 40. mu.g AVE0010

-mixture C: 100U of insulin glargine per mL + 25. mu.g AVE0010

● use 3 premix pens: the table in figure 10 (which represents an example) starts with a treatment range of 15 to 80U of insulin glargine and 10 to 20 μ g AVE0010 per dose. The dose of insulin glargine to be administered is prescribed or predetermined for a particular patient. The left hand column is consulted for the predetermined dose. In the case where column mixture a-mixture C specifies a corresponding dose of AVE0010 in the range between 10 and 20 μ g, the corresponding mixture is selected, dosed, and administered. The ranges overlap: for example, in the case of insulin glargine requiring 26 to 30U, it would be possible to select either mixture a or mixture B (with a higher dose of AVE 0010). It applies to mixtures B and C. If, for example, a dose of 50U of insulin is intended, 0.5ml of mixture B or mixture C can be dosed. This dose contained 20. mu.g (mixture B) or 12.5. mu.g (mixture C) of AVE 0010.

● conclusion: assuming that a possible AVE0010 effect is obtained between 10 and 15 μ g and a therapeutic effect is obtained between 15 and 22 μ g, almost all patients taking 15-80U doses of insulin glargine can also obtain a therapeutic dose of AVE0010 between 10 and 20 if they use one of three pre-mix pens containing three different insulin glargine to AVE0010 ratios (mixture A, B, C). Based on the wide range of possible ratios of insulin glargine to AVE0010 with synergistic effects (comparative example 6), the ratio in the pen can be adapted such that for each insulin glargine dose there is a synergistic dose of AVE0010 in at least one pen.

Example 12

This example shows how a combination of two or more active compounds can be formulated in such a way that, when two or more compositions are combined, the two active compounds can be administered in any desired amount and in any desired ratio to each other. The present invention contemplates that at least one of the active compounds must not be diluted by the combination (e.g., via direct mixing prior to administration).

In this example, the designations "activity a" and "activity B" represent any desired active compound. Specifically, active A is insulin and active B is a GLP-1 agonist. Active A may also be a GLP-1 agonist, and active B may also be insulin.

1. Comparative examples

For combination therapy with active A (e.g. insulin) and active B (e.g. GLP-1 agonist) there is provided a container 1 containing a composition with an active A concentration of a mg/ml and a container 2 containing a composition with an active B concentration of bmg/ml.

For the administration of a combination of two activities, the volume V from the container 1 is mixed₁ml and volume V from container 2₂ml。

For dosing of both activities at given concentrations a and B, the volume V to be administered is selected depending on the amount of the activities A and B to be administered₁And V₂. The volume V of the two activities was determined based on the amount of activity as follows₁And V₂：

Amount of active A: v₁·a mg

Amount of active B: v₂·b mg

The concentration of activities a and B in the mixture of the two compositions was determined as follows.

Activity A: x mg/mL = V₁·a/(V₁+V₂)

Activity B: y mg/mL = V₂·b/(V₁+V₂)

V₁+V₂Is the total volume administered. This means that the two activities are diluted with each other. Thus, with this system it is not possible to maintain e.g. the concentration of activity a (e.g. insulin) at a predetermined level in case of different amounts of activity B.

2. Illustrative embodiments of the invention

In this example, for a combination therapy with active A (e.g. insulin) and active B (e.g. a GLP-1 agonist), a container 1 containing a composition with an active A concentration of a mg/ml and a container 2 containing a composition with an active A concentration of a mg/ml and an active B concentration of B mg/ml are provided. Thus, the concentration of active a is in both compositions.

For the administration of a combination of two activities, the volume V from the container 1 is mixed₃ml and volume V from container 2₂ml。

For dosing of both activities at given concentrations a and B, the volume V to be administered is selected depending on the amount of the activities A and B to be administered₃And V₂. The volume V of the two activities was determined based on the amount of activity as follows₃And V₂：

Amount of active A: (V)₃·a+V₂·a)mg

Amount of active B: v₂·b mg

The concentrations of activities a and B were determined as follows.

Activity A: a mg/mL = (V)₃·a+V₂·a)/(V₃+V₂)

Activity B: z mg/mL = V₂·b/(V₃+V₂)

V₃+V₂Is the total volume administered. From the above calculations it is clear that the concentration of active A is always a mg/ml, i.e. constant, regardless of the dose administered, in what volume ratio V₃/V₂。

Comparing the comparative example (see section 1) with the inventive example, it is apparent that the total volume required in the inventive example is lower for the same dosed amounts of activity a and B.

For a given dose of active a (amount of active compound), the numbers in the comparative examples are: v₁·a mg。

In an inventive embodiment, it is: (V)₃·a+V₂·a)mg

Since the amount of active compound should be the same in both cases,

(V₃·a+V₂·a)=V₁·a

(V₃+V₂)·a=V₁·a

and V₃+V₂=V₁

Or V₃=V₁-V₂

Here, the volume V of the activity B administered₂The same in both cases.

The total volume in the comparative example is V₁+V₂

Total volume in the inventive example is V₃+V₂

In accordance with the above equation, for the inventive embodiment, the fact is:

V₃+V₂=V₁-V₂+V₂=V₁

this volume V₁Volume V less than comparative example₁+V₂。

Activity B is diluted as a result of mixing the composition with activity a and B with the composition with activity a. This dilution was less than the dilution of active B in the comparative example (i.e. concentration B > concentration z > concentration y):

b>z

b>V₂·b/(V₃+V₂)

b>b·V₂/(V₃+V₂) In which V is₂/(V₃+V₂)<1, and

z>y

V₂·b/(V₃+V₂)>V₂·b/(V₁+V₂)

1/(V₃+V₂)>1/(V₁+V₂)

1/(V₁–V₂+V₂)>1/(V₁+V₂)

1/V₁>1/(V₁+V₂)

thus, the dosing system of the present invention for administering different doses of active a (e.g. insulin) and B (e.g. GLP-1 agonist) has three advantages over the comparative system:

● the concentration of active A (e.g. insulin) can be kept constant at a predetermined level

● the total volume to be administered is smaller with the same dose of activity A and B to be administered.

● dilution of active B (e.g., GLP-1 agonist) is less than in the comparative examples. Thus, the concentration of active B can be more easily maintained within a predetermined range.

This embodiment can be easily extended to drugs having three or more active compounds, the first active compound being present in all compositions (preferably in equal weight fractions), and at least one additional active compound in each additional composition. The first composition may be mixed with each of the additional compositions in the same ratio without diluting the concentration of the active compound in the first composition.

The present invention relates to the following items.

1. A medicament comprising at least one insulin and at least one GLP-1 agonist, said medicament being formulated and/or mixed in such a way that it comprises a predetermined amount of each of said insulin and said GLP-1 agonist and can be administered at a dose suitable for the requirements of a patient individual.

2. A medicament as claimed in item 1 for regulating fasting, postprandial and/or post-absorption blood glucose concentration in a diabetic patient.

3. The medicament as claimed in item 1 or 2, which is used for improving glucose tolerance.

4. A medicament as claimed in any one of the preceding claims, for use in the prevention of hypoglycaemia.

5. A medicament as claimed in any one of the preceding claims for use in preventing loss of function of pancreatic β -cells.

6. A medicament as claimed in any one of the preceding claims for use in weight reduction and/or prevention of weight gain.

7. A medicament as claimed in any one of the preceding claims, comprising a first and a second pharmaceutical composition, and optionally at least one further pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and containing a different weight fraction of said at least one insulin and/or said at least one GLP-1 agonist relative to the total weight of the composition.

8. The medicament as claimed in item 7, the weight fractions of the at least one insulin and the at least one GLP-1 agonist in the first pharmaceutical composition, in the second pharmaceutical composition, and in case of use in the at least one further pharmaceutical composition being selected such that the pharmaceutical compositions contain different ratios of insulin to GLP-1 agonist based on the weight fractions.

9. The medicament as claimed in item 7 or 8, said first, second and, where used, further composition comprising substantially the same weight fraction of said at least one insulin and a different weight fraction of said at least one GLP-1 agonist.

10. The medicament as claimed in item 7 or 8, said first, second and, where used, further composition comprising substantially the same weight fraction of said at least one GLP-1 agonist and a different weight fraction of said at least one insulin.

11. A medicament as claimed in any one of claims 1 to 6, comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one GLP-1 agonist, said medicament being formulated and/or mixed for separate administration of said first and second pharmaceutical compositions.

12. A medicament as claimed in any one of claims 1 to 6, comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist, and optionally at least one further pharmaceutical composition comprising at least one insulin and at least one further active compound.

13. A medicament as claimed in item 12, said first pharmaceutical composition, said second pharmaceutical composition, and, where used, said at least one additional composition, comprising substantially the same weight fraction of said insulin relative to the total weight of said compositions.

14. A medicament as claimed in any one of the preceding claims, said at least one insulin being independently selected from: human insulin, analogs, derivatives, and metabolites thereof.

15. A medicament as claimed in item 14, the at least one insulin is independently selected from the group consisting of: gly (A21) -Arg (B31) -Arg (B32) human insulin, Lys^B28Pro^B29Human insulin, B28Asp human insulin, and B29Lys (. epsilon. -tetradecane)Acyl), desB30 human insulin.

16. A medicament as claimed in any one of the preceding claims, said at least one GLP-1 agonist being independently selected from the group of: GLP-1, analogs and derivatives thereof, exendin-3, analogs and derivatives thereof, exendin-4, analogs and derivatives thereof, and pharmacologically tolerable salts thereof.

17. A medicament as claimed in item 16, said at least one GLP-1 agonist being independently selected from the group consisting of: exendin-4, desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂[AVE0010]And Arg³⁴,Lys²⁶(N^ε(Gamma-glutamyl (N)^α-hexadecanoyl))) GLP-1(7-37) [ liraglutide]And pharmacologically tolerable salts thereof.

18. A medicament as claimed in item 17, said at least one GLP-1 agonist being independently selected from the group consisting of: exendin-4, analogs, derivatives, and pharmacologically tolerable salts thereof.

19. The medicament as claimed in item 18, wherein the at least one GLP-1 agonist is desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂。

20. A medicament as claimed in any one of the preceding claims, said insulin being Gly (A21) -Arg (B31) -Arg (B32) human insulin and said GLP-1 agonist being desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂Or a pharmacologically tolerable salt thereof.

21. A kit comprising a medicament as claimed in any one of items 1 to 18.

Gly (A21) -Arg (B31) -Arg (B32) human insulin and desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂And/or a pharmacologically tolerable salt thereof.

23. Use of at least one insulin and at least one GLP-1 agonist for the preparation of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or 2 diabetic patients, for the regulation of fasting, postprandial and/or post-absorption blood glucose concentrations, for the improvement of glucose tolerance, for the prevention of hypoglycemia, for the prevention of loss of function of pancreatic β -cells, for weight loss and/or for the prevention of weight gain.

24. A method of treating a patient with a medicament as claimed in item 7 or with a kit comprising such a medicament, comprising:

(a) selecting a dose of the at least one insulin to be administered,

(b) selecting a dose of the at least one GLP-1 agonist to be administered,

25. A method as claimed in item 24 for regulating fasting, postprandial and/or post-absorption blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of pancreatic β -cell function, for weight loss and/or for preventing weight gain.

26. A method as claimed in item 24 or 25, step (c) being carried out on the basis of a table.

27. A method of treating a patient with a medicament as claimed in claim 13, or with a kit comprising such a medicament, the medicament comprising:

(i.) selecting a dose of the at least one insulin to be administered and determining a total amount of the first, second, and, if used, at least one additional composition, such that the selected dose of the at least one insulin is present in the total amount,

(ii.) selecting a dose of the at least one GLP-1 agonist to be administered and determining the amount of the second composition such that the selected dose of the at least one GLP-1 agonist is present in the amount of the second composition,

(iii) where appropriate, selecting a dose of the at least one additional active compound to be administered and determining the amount of the at least one additional composition such that the selected dose of the at least one additional active compound is present in the amount of the at least one additional composition,

(iv) administering to the patient an amount of the first composition corresponding to the total amount according to step (i) minus the amount of the second composition according to step (ii) and, where appropriate, the amount of the at least one further composition according to step (iii), and

(v.) administering to the patient the amount of the second composition determined in step (ii), and where appropriate the amount of the at least one additional composition determined in step (iii).

28. A method as claimed in item 27 for regulating fasting, postprandial and/or post-absorption blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for preventing loss of pancreatic β -cell function, for weight loss and/or for preventing weight gain.

29. A method as claimed in item 27 or 28, steps (i), (ii) and/or (iii) being carried out on a table basis.

30. A method of preparing a medicament as claimed in any one of items 1 to 20, comprising formulating and/or mixing such that it comprises a predetermined amount of each of said insulin and said GLP-1 agonist and can be administered at a dosage appropriate to the individual requirements of the patient.

31. A device comprising a medicament as claimed in any one of items 1 to 20 or a kit as claimed in item 21, the device comprising pharmaceutical compositions of the medicament in separate containers and allowing the pharmaceutical compositions to be dosed independently of one another.

32. A device as claimed in item 31 for injection.

Claims

1. Use of a medicament comprising a first and a second pharmaceutical composition, and optionally at least one further pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and containing different weight fractions of the at least one insulin and/or the at least one GLP-1 agonist, relative to the total weight of the composition, for the manufacture of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or type 2 diabetic, for regulating fasting, postprandial and/or post-absorption blood glucose concentrations, for improving glucose tolerance, for preventing hypoglycaemia, for weight loss and/or for preventing weight gain.

2. The use as claimed in claim 1, the weight fractions of said at least one insulin and said at least one GLP-1 agonist in said first pharmaceutical composition, in said second pharmaceutical composition, and in case of use in said at least one further pharmaceutical composition being selected such that said pharmaceutical compositions contain different ratios of insulin to GLP-1 agonist based on said weight fractions.

3. The use as claimed in claim 1 or 2, said first, second and, where used, further composition comprising substantially the same weight fraction of said at least one insulin and a different weight fraction of said at least one GLP-1 agonist.

4. The use as claimed in claim 1 or 2, said first, second and, where used, further composition comprising substantially the same weight fraction of said at least one GLP-1 agonist and a different weight fraction of said at least one insulin.

5. Use of a medicament comprising a first pharmaceutical composition comprising at least one insulin and a second pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist and optionally at least one further pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist, for the manufacture of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or type 2 diabetic, for regulating fasting, postprandial and/or post-absorption blood glucose concentration, for improving glucose tolerance, for the prevention of hypoglycaemia, for weight loss and/or for preventing weight gain.

6. The use as claimed in claim 5, said first pharmaceutical composition, said second pharmaceutical composition, and, where used, said at least one further composition, comprising substantially the same weight fraction of said insulin relative to the total weight of said composition.

7. The use as claimed in any one of claims 1 to 6, said at least one insulin being independently selected from the group consisting of: gly (A21) -Arg (B31) -Arg (B32) human insulin, Lys^B28Pro^B29Human insulin, B28Asp human insulin, and B29Lys (. epsilon. -tetradecanoyl), desB30 human insulin.

8. The use as claimed in any one of claims 1 to 7, said at least one GLP-1 agonist being independently selected from the group consisting of: GLP-1, analogs and derivatives thereof, exendin-3, analogs and derivatives thereof, exendin-4, analogs and derivatives thereof, and pharmacologically tolerable salts thereof.

9. The use as claimed in claim 8, said at least one GLP-1 agonist being independently selected from the group consisting of: exendin-4, desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂[AVE0010]And Arg³⁴,Lys²⁶(N^ε(Gamma-glutamyl (N)^α-hexadecanoyl))) GLP-1(7-37) [ liraglutide]And pharmacologically tolerable salts thereof.

10. The use as claimed in claim 9, said at least one GLP-1 agonist being independently selected from the group consisting of: exendin-4, analogs, derivatives, and pharmacologically tolerable salts thereof.

11. The use as claimed in claim 10, saidAt least one GLP-1 agonist is desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂。

12. The use as claimed in any one of claims 1 to 11, said insulin being Gly (a21) -Arg (B31) -Arg (B32) human insulin and said GLP-1 agonist being desPro³⁶Exendin-4 (1-39) -Lys₆-NH₂Or a pharmacologically tolerable salt thereof.

13. Use of a kit comprising a medicament as defined in any one of claims 1 to 12 for the preparation of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or type 2 diabetic, for regulating fasting, postprandial and/or post-absorption blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for weight loss and/or preventing weight gain.

Use of a combination of Gly (a21) -Arg (B31) -Arg (B32) human insulin and liraglutide and/or a pharmacologically tolerable salt thereof for the preparation of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or 2 diabetic patients, for regulating fasting, postprandial and/or post-absorption blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for weight loss and/or for preventing weight gain.

15. Use of a medicament as defined in any one of claims 1 to 4, or a kit comprising said medicament, for the preparation of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or type 2 diabetic patients, for the regulation of fasting, postprandial and/or post-absorption blood glucose concentrations, for the improvement of glucose tolerance, for the prevention of hypoglycemia, for weight loss and/or prevention of weight gain, by a method comprising the steps of:

(a) selecting a dose of the at least one insulin to be administered,

(b) selecting a dose of the at least one GLP-1 agonist to be administered,

16. The use as claimed in claim 15, step (c) being carried out on the basis of a table.

17. Use of a medicament as defined in claim 6, or a kit comprising said medicament, for the preparation of a pharmaceutical product for the treatment of diabetic, more particularly type 1 or type 2 diabetic patients, for the regulation of fasting, postprandial and/or post-absorption blood glucose concentrations, for the improvement of glucose tolerance, for the prevention of hypoglycemia, for weight loss and/or prevention of weight gain, by a method comprising the steps of:

18. The use as claimed in claim 17, steps (i), (ii) and/or (iii) being carried out on the basis of a table.

19. A method of preparing a medicament as defined in any one of claims 1 to 12, comprising formulating and/or mixing such that it comprises a predetermined amount of each of said insulin and said GLP-1 agonist and can be administered at a dose suitable for the individual requirements of the patient.

20. Use of a device comprising a medicament as defined in any one of claims 1 to 12, a kit as defined in claim 13, or a combination as defined in claim 14, for the manufacture of a pharmaceutical product for treating diabetic, more particularly type 1 or type 2 diabetic, for regulating fasting, postprandial and/or post-absorption blood glucose concentration, for improving glucose tolerance, for preventing hypoglycemia, for weight loss and/or preventing weight gain, the device comprising a pharmaceutical composition of the medicament in separate containers and allowing the pharmaceutical compositions to be dosed independently of each other.

21. The use as claimed in claim 20, wherein the device is for injection.