DE102008051834A1 - Drug, useful e.g. for treating diabetes, preferably type-I or II and for controlling fasting, postprandial and/or postabsorptive plasma glucose concentration, comprises insulin and glucagon-like peptide-1 agonist - Google Patents

Abstract

Drug comprises at least insulin and at least one glucagon-like peptide-1 (GLP-1) agonist. The drug is formulated and/or confectioned in such a manner that it contains the insulin and GLP-1 agonist in a predetermined amount and is administered with respect to the need of a patient. Independent claims are also included for: (1) a kit comprising the drug; (2) a combination of Gly(A21)-Arg(B31)-Arg(B32)-human insulin and desPro 3>6>-exendin-4(1-39)-Lys 6-NH 2and/or their salts; (3) treating a patient with the drug and kit, comprising (a) selecting a dose of insulin, (b) selecting a dose of GLP-1-agonsit, (c) selecting a composition from a first-, second- and optionally a further composition of the drug, which contains the doses of (a) and (b) in a concentration, so that the doses of (a) and (b) are present in the same volume, and (d) determining and administering an amount, which corresponds to the doses of (a) and (b); and (4) preparing the drug comprising formulating and/or confectioning so that the drug contains the insulin and the GLP-1-agonist in a predetermined amount and is administered with respect to the need of a patient. ACTIVITY : Antidiabetic; Anorectic. Test details are described but no results given. MECHANISM OF ACTION : Glucagon-like peptide-1 agonist.

Description

The The invention relates to a pharmaceutical composition comprising at least one insulin and at least one GLP-1 agonist, wherein the drug is so formulated and / or formulated that it is the insulin and contains the GLP-1 agonist at a predetermined dose and in each case adapted to the needs of a patient dose can be administered.

Worldwide About 250 million people suffer from diabetes mellitus. For the type I diabetic is the substitution of the missing endocrine insulin secretion the only currently possible Therapy. Those affected are lifelong, usually several times a day, dependent on insulin injections. Unlike type I diabetes There is not a basic shortage of type II diabetes to insulin, however, is used in a variety of cases especially in the advanced stage, treatment with insulin, optionally in combination with an oral antidiabetic, as considered most favorable form of therapy.

In healthy individuals, insulin release through the pancreas is strictly linked to the concentration of blood glucose. Increased blood glucose levels, as they occur after meals, are rapidly compensated by a corresponding increase in insulin secretion. In the fasting state, the plasma insulin level drops to a basal level sufficient to ensure a continuous supply of insulin-sensitive organs and tissues with glucose and to keep hepatic glucose production low at night. The replacement of the body's insulin secretion by exogenous, usually subcutaneous administration of insulin generally does not approach the above-described quality of the physiological regulation of blood glucose. Often, derailments of blood glucose go up or down, which can be life threatening in their most severe forms. In addition, however, elevated levels of blood glucose for years without initial symptoms, a significant health risk for blood glucose levels without initial symptoms, represents a significant health risk. The large-scale DCCT study in the US ( The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986 ) clearly demonstrated that chronically elevated blood glucose levels are significantly responsible for the development of diabetic late damage. Diabetic late damage is micro- and macrovascular damage, which may be u. Manifest as retinopathy, nephropathy or neuropathy and lead to blindness, renal failure and loss of extremities and also go along with an increased risk of cardiovascular disease. From this it can be deduced that an improved therapy of diabetes must first and foremost aim to keep the blood glucose as close as possible to the physiological range. According to the concept of intensified insulin therapy, this should be achieved by injections of fast-acting and slow-acting insulin preparations several times a day. Quick-acting formulations are given at mealtimes to offset the postprandial increase in blood glucose. Slow-acting basal insulins should ensure the basic supply of insulin, especially at night, without leading to hypoglycaemia.

insulin is a polypeptide of 51 amino acids, based on 2 amino acid chains distribute: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are through 2 disulfide bridges connected with each other. Insulin preparations have been around for many years used for diabetes therapy. It will not only be natural occurring insulins, but more recently also insulin derivatives and analogues.

insulin analogues are analogues of naturally occurring insulins, viz Human insulin or animal insulin, which is replaced by substitution at least one naturally occurring amino acid residue with other amino acids and / or addition / removal at least an amino acid residue from the corresponding, otherwise same to distinguish naturally occurring insulin. These may also be amino acids that are not natural occurrence.

the insulin derivatives are derivatives of naturally occurring insulin or a Insulin analog obtained by chemical modification. The chemical modification may, for. B. in the addition of one or several specific chemical groups to one or more amino acids consist. Usually have insulin derivatives and insulin analogues a slightly different from human insulin Effect.

Insulin analogues with accelerated onset of action are EP 0 214 826 . EP 0 375 437 and EP 0 678 522 described. EP 0 214 826 refers inter alia to substitutions of B27 and B28. EP 0 678 522 describes insulin analogs that have different amino acids in position B29, preferably proline, but not glutamic acid. EP 0 375 437 includes insulin analogues with lysine or arginine in B28, which may optionally be additionally modified in B3 and / or A21. An accelerated effect is also evident in the EP-A-0 885 961 described insulin analogues.

In the EP 0 419 504 discloses insulin analogues protected against chemical modification by using asparagine in B3 and at least another amino acid in the positions A5, A15, A18 or A21 are changed.

In the WO 92/00321 Insulin analogs are described in which at least one amino acid of positions B1-B6 is replaced by lysine or arginine. Such insulins have according to WO 92/00321 a prolonged effect on. A delayed effect also show in the EP-A 0 368 187 and those in the German Patent Applications No. 10 2008 003 568.8 and 10 2008 003 566.1 described insulin analogues.

The insulin preparations on the market of naturally occurring insulins for insulin substitution differ in the origin of insulin (eg beef, pork, human insulin) and the composition, with which the effect profile (action and duration of action) can be influenced. By combining different insulin preparations, a wide variety of active profiles can be achieved and physiological blood sugar levels adjusted as far as possible. Recombinant DNA technology nowadays enables the production of such modified insulins. These include insulin glargine (Gly (A21) Arg (B31) Arg (B32) human insulin) with a prolonged duration of action. Insulin glargine is injected as an acidic, clear solution and precipitates as a stable hexamer associate due to its solubility in the physiological pH range of the subcutaneous tissue. Insulin glargine is injected once daily and is distinguished from other long-acting insulins by its low serum profile and the associated reduction in the risk of nocturnal hypoglycaemia ( Schubert-Zsilavecz et al., 2: 125-130 (2001) ).

The specific preparation of insulin glargine, which prolonged to Duration of action leads through a clear solution characterized by acidic pH.

Glucagon-like peptide 1 (GLP-1) is an endocrine hormone that increases the insulin response after ingestion of glucose or fat. GLP-1 generally lowers glucagon levels, slows gastric emptying, stimulates (pro) insulin biosynthesis, increases insulin sensitivity, and stimulates insulin-independent glycogen biosynthesis ( Holst (1999), Curr. Med. Chem. 6: 1005 . Nauck et al. (1997) Exp Clin Endocrinol Diabetes 105: 187 . Lopez-Delgado et al. (1998) Endocrinology 139: 2811 ).

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

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

Exendin-3, exendin-4 and exendin agonists have been proposed for the treatment of diabetes mellitus and the prevention of hyperglycemia, reducing gastric motility and depletion ( US 5,424,286 and WO98 / 05351 ).

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

Combinations of insulin and GLP-1 are out WO 2004/005342 known for the treatment of diabetes.

In In clinical practice, the amount of insulin to be administered becomes adjusted to the individual needs of individual diabetes patients. Individual patients usually need different ones each Amounts of insulin or / and GLP-1 agonist. Usually The predetermined dose is administered by a certain amount a composition of defined concentration. It follows that a composition containing insulin and GLP-1 contains at the same time, the administration of only one certain 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 needs of the patient. Because in practice the correct setting of the administered amount of Insulin is essential, it is assumed that when administered from a specific ratio of insulin to GLP-1's GLP-1 agonist is either under- or overdosed and possibly coincidentally correct.

Of the The present invention was therefore based on the object, a drug to provide the above-described disadvantages of the prior art at least partially overcomes the technology. Furthermore, should be achieved, if possible, only one administration per day.

• • Höhere Wirksamkeit aufgrund der Kombination der komplementären Wirkungen auf die nüchternen und postprandialen Glukosewerte, welche sich ergänzen (Beispiele 2 und 3). Die Kombination zeigt eine Senkung der postprandialen Glukosekonzentration (= verbesserte Glukosetoleranz) wie ein GLP-1-Agonist allein und zusätzlich die postabsorptiven Glukosesenkung wie ein Insulin (Beispiel 9).
• • Verminderung des Risikos einer Hypoglykämie (Beispiele 2–4).
• • Bessere Anpassung der Blutglukosekonzentration an normoglykämische Werte (Beispiel 8).
• • Verbesserte Glukosetoleranz und Absenkung der postabsorptiven Glukosekonzentrationen (Beispiel 9).
• • Die synergistischen Wirkungen der Kombination auf die Glukosekonzentration werden in einem Konzentrationsbereich des GLP-1-Agonisten von einer Größenordnung (Faktor 10) beobachtet. (Beispiel 6 verglichen mit den Beispielen 4 und 2). Erst bei kleineren GLP-1-Dosen bzw. größeren Verhältnissen von Insulin zu GLP-1 überwiegen die Wirkungen des Insulins.
• • Erhalt der Funktion der β-Zellen (Beispiel 10).
• • Gewichtsverlust/Verminderung der Gewichtszunahme.
• • Alle Beispiele zeigen, dass GLP-1-Agonisten und Insuline keine negativen Wechselwirkungen zeigen.
• • Durch die Wirkungen auf die nüchternen, postprandialen und postabsorptiven Blutglukosekonzentrationen wird ein möglich, die Zahl der Verabreichungen der Kombination auf einmal täglich zu reduzieren.

It has surprisingly been found that the combination of an insulin with a GLP-1 agonist has synergistic effects in the regulation of blood glucose in the postprandial and postabsorptive phase compared to the use of insulin or the GLP-1 agonist alone:

• • Greater efficacy due to the combination of complementary effects on fasting and postprandial glucose levels that complement each other (Examples 2 and 3). The combination shows a reduction in postprandial glucose concentration (= improved glucose tolerance) as a GLP-1 agonist alone and in addition the postabsorptive glucose lowering as an insulin (Example 9).
• • Reduction of the risk of hypoglycaemia (Examples 2-4).
• • Better adjustment of blood glucose concentration to normoglycemic levels (Example 8).
• • Improved glucose tolerance and lowering postabsorptive glucose concentrations (Example 9).
• • The synergistic effects of the combination on the glucose concentration are observed in a concentration range of the GLP-1 agonist of one order of magnitude (factor 10). (Example 6 compared to Examples 4 and 2). Only with smaller GLP-1 doses or larger ratios of insulin to GLP-1 outweigh the effects of insulin.
• • Maintaining the function of β-cells (Example 10).
• • Weight loss / reduction of weight gain.
• • All examples show that GLP-1 agonists and insulins show no negative interactions.
• • Effects on fasting, postprandial and postabsorptive blood glucose levels will make it possible to reduce the number of administrations of the combination once a day.

One Subject of the invention is a drug comprising at least one insulin and at least one GLP-1 agonist, wherein the drug is formulated or / and formulated such that it insulin and the GLP-1 agonist in a predetermined each Contains quantity and in each one to the need of one Patients adjusted dose can be administered.

The Medicaments according to the invention are in particular used for the treatment of patients with diabetes mellitus, in particular of patients with Type I or Type II diabetes.

By the medicament of the invention may be the blood glucose concentration in patients with diabetes, especially diabetes type I or type II, better adapted to normoglycemic values.

Prefers It is used to recruit the sober, the postprandial and / or the postabsorptive plasma glucose concentration of patients used with diabetes, especially by patients with diabetes Type I or Type II. More preferred is the invention Medicinal products for postprandial and / or postabsorptive treatment Plasma glucose concentration used by patients with diabetes especially used by patients with diabetes type I or type II. Adjustment in this context means that normoglycemic blood glucose concentrations be achieved in essence or at least an approximation this is achieved. In particular, under normoglycemic values Blood glucose concentrations within the normal range (fluctuation range 60-140 mg / dl corresponding to 3.3 to 7.8 mM / L). This fluctuation range includes blood glucose levels in fasting conditions, postprandial and postabsorptive conditions.

postprandial and postabsorptive are those skilled in the field of diabetology common terms. Under postprandial is particular herein the phase after a meal or / and after a glucose load referred to in the experiment. This phase is especially healthy by an increase and a decrease in the glucose concentration marked in the blood. As a postabsorptive or postabsorptive phase This is especially the phase following the postprandial phase designated. The postprandial phase typically ends up 4 h after the meal and / or glucose load. The postabsorptive Phase typically lasts up to 8 to 16 h.

As well the drug according to the invention is preferred to improve glucose tolerance in treating a patient used with diabetes, especially with diabetes type I or type II. Under improvement of the glucose tolerance is understood that by the drug according to the invention the postprandial Plasma glucose concentration is lowered. Likewise, under improvement the glucose tolerance understood that by the inventive Medicines lowered the postabsorptive plasma glucose concentration becomes. Reduction means in particular that the plasma glucose concentration Normoglycemic values are essentially achieved or at least is approximated.

The Medicament according to the invention may be the risk reduce hypoglycemia, which z. B. in the postabsorptive Phase can occur. The medicament according to the invention is preferred for the prevention of hypoglycemia in the treatment of a patient with diabetes, especially one Diabetes type I or type II, hypoglycemia being used especially in the postabsorptive phase.

The Medicaments according to the invention can function of the pancreatic β-cells. The invention Medicines are preferred for the prevention of a loss of function of β-cells of the pancreas in a patient with diabetes, especially used with type I or type II diabetes. Of the Functional loss of β-cells may be due in particular to apoptosis be caused.

Further the medicament of the invention may be a weight loss cause and / or to prevent weight gain in patients with diabetes, especially Type I or II. In diabetes patients, especially type II, weight gain and overweight are common problems. So that can the administration of the medicament according to the invention support a therapy to treat obesity.

It it is understood that the medicament of the invention can be used to treat a patient with diabetes, in particular with diabetes type I or II, more than any of those described herein to treat preferred indications. Therefore, from the present Invention includes not only the individual preferred indications, but also any combinations of indications. The invention Medicines may therefore be used to treat one or more of the indications described herein in patients with diabetes, in particular used by patients with Type I or Type II diabetes, e.g. As for the adjustment of the sober, the postprandial or / and the postabsorptive plasma glucose concentration, for improvement glucose tolerance, for the prevention of hypoglycaemia, for the prevention of a loss of function of β-cells of the pancreas, for weight loss and / or for prevention a weight gain can be used. Preferred is the setting the fasting, the postprandial and / or the postabsorptive Plasma glucose concentration, improving glucose tolerance or / and the prevention of hypoglycemia.

The Medicaments according to the invention may also be used for Preparation of a medicament for the treatment of one or more the indications described herein are used, e.g. B. for Attitude of the sober, the postprandial or / and the postabsorptive plasma glucose concentration, for improvement glucose tolerance, for the prevention of hypoglycaemia, for the prevention of a loss of function of β-cells of the pancreas, for weight loss and / or for prevention a weight gain can be used.

The at least one insulin and the at least one GLP-1 agonist also for the manufacture of a medicament for the treatment of one or several of the indications described herein are used z. As for the adjustment of the sober, the postprandial or / and the postabsorptive plasma glucose concentration, to improve the Glucose tolerance, for the prevention of hypoglycaemia, for the prevention of a loss of function of β-cells of the pancreas, for weight loss and / or for prevention a weight gain can be used.

Of the at least one GLP-1 agonist and the at least one insulin be provided together in a pharmaceutical composition. Here, a first, a second composition and optionally at least one further pharmaceutical composition is provided, which each contain the insulin and the GLP-1 agonist. Therefore an article of the invention is a drug comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one another pharmaceutical composition, each at least include an insulin and at least one GLP-1 agonist and that at least one insulin and / or the at least one GLP-1 agonist in different proportions by weight based on the total weight of the composition.

In in the present application means "optionally at least another pharmaceutical composition "that the Medicaments according to the invention in addition to the first and the second pharmaceutical composition at least one may comprise further pharmaceutical composition. The medicament according to the invention So z. B. 3, 4, 5, 6, 7, 8, 9, 10 or more inventive pharmaceutical compositions.

Prefers are medicaments which are a first and a second according to the invention containing pharmaceutical composition.

As well are preferred drugs, which are a first, a second and a third pharmaceutical composition according to the invention contain.

As well are preferred drugs, which a first, a second, a third and a fourth pharmaceutical according to the invention Composition included.

As well are preferred drugs, which a first, a second, a third, fourth and fifth pharmaceutical compositions contain.

The weight proportions of the at least one Insulin and the at least one GLP-1 agonist may be selected in the first pharmaceutical composition, the second pharmaceutical composition and optionally at least one further pharmaceutical composition such that the pharmaceutical compositions have different ratios of insulin to the GLP-1 agonist Contained by weight.

in this connection the first composition can be the smallest ratio and the second composition the next larger one Ratio included. If at least one other composition is present, this may be the next larger one Ratio included. If still another composition is present, this in turn next larger Ratio included. The compositions could that is, from the first to the second and optionally further compositions Increasing ratios of insulin to the GLP-1 agonist based included on the weight fraction.

Of the Weight fraction of one of the two active ingredients, so at least an insulin or the at least one GLP agonist, in the first pharmaceutical Composition, the second pharmaceutical composition and the optionally at least one further pharmaceutical composition is preferably each selected so that by administration a certain volume of the first, the second or / and the at least another composition the predetermined dose of this drug can be administered. Particularly preferred is this active ingredient the at least one insulin.

Of the Weight fraction of the other of the two active ingredients, so at least an insulin or the at least one GLP-1 agonist in which first pharmaceutical composition, the second pharmaceutical Composition and optionally at least one other pharmaceutical composition is preferably selected that the ratios of insulin to the GLP-1 agonist related on the weight fraction from the first to the second and optionally increase further compositions. This is particularly preferred Active ingredient of at least one GLP-1 agonist.

About that In addition, the proportion by weight of the other of the two active ingredients determined in the pharmaceutical compositions such that one of the pharmaceutical compositions are selected That can be the dose to be administered of the first of the two active ingredients and the dose of the second active ingredient to be administered in one certain volumes are given. This will be a pharmaceutical Composition selected which the desired Contains ratio.

Theoretically could be therapeutically desired for every single one Ratio of the proportions by weight of at least one insulin for at least one GLP-1 agonist a pharmaceutical composition be provided to an optimal needs-based dosage to achieve both agents for each patient.

In The present invention is a certain number of pharmaceutical compositions adequate to the dosages required in practice for to capture both active ingredients. It will be for every patient a certain dosage range within a therapeutically meaningful one Interval determined for each of the two active ingredients. The dose to be administered is intended for a given dose Patients vary substantially within this dosage range, without overdosing or underdosing.

Surprisingly, it has been found that the synergistic effects of the combination of at least one insulin and at least one GLP-1 agonist on glucose concentration in the blood plasma in a concentration range of the GLP-1 agonist of the order of magnitude (factor 10). Since primarily the amount of insulin needs to be adjusted and precisely dosed to the individual patient, the synergistic concentration range of the GLP-1 agonist allows for a pharmaceutical composition of the invention having a specific ratio of at least one insulin to the at least one GLP-1 agonist includes a therapeutic range of insulin dosages concurrent with the associated synergistic amount of GLP-1 agonist. The ratio may be selected so that for each insulin dosage desired, a dosage of the at least one GLP-1 agonist corresponding to within the desired range, e.g. B. the synergistic range lies. As stated above, the ratios of the first, second and optionally at least one further composition of the medicament can furthermore be selected so that the ratios increase from the first to the second and optionally at least one further composition. If the dosage of the GLP-1 agonist at the desired insulin dosage of one composition (e.g., the first composition) is outside (usually above) the desired dosage range of the GLP-1 agonist, 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 in which the amount of the GLP-1 agonist in the desired insulin dose is within the desired range. The ratios of the first, second, and optionally at least one further composition of the drug may be further selected such that the portions of insulin dosages corresponding to the desired dosages of the at least one GLP-1 agonist are contiguous and / or overlapping. Preferably, the areas overlap. In particular, overlap means that at least two compositions can be selected which, at the desired dosage of the at least one insulin, each contain an amount of the at least one GLP-1 agonist which is within the desired dosage range.

For example suffice 3 compositions to the dose of at least an insulin for an individual patient on one Value selected from the range of 15 to 80 units Insulin and at the same time the GLP-1 agonist with a Dosage within the range of 10 to 20 μg (see Example 11).

As well can provide a pharmaceutical according to the invention can be in which the ratio can be selected will do that at any desired dosage of the GLP-1 agonist a dosage of the at least one insulin corresponds, which within the desired range, e.g. B. the synergistic Area, lies. The relationships of the first, second and optionally at least one further composition of the medicament can also be chosen so that the areas dosages of the GLP-1 agonist which are among the desired Dosages of at least one insulin correspond, adjoin one another and / or overlap each other. Preferably overlap the areas. Overlapping means in this context in particular, that at least two compositions selected which can be at the desired dosage of at least one GLP-1 agonist each a quantity of the at least one Contain insulins which are within the desired dosage range.

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

The Compositions according to the invention can the at least one insulin in each case identical or different Contain by weight. For example, at least two of the inventive compositions which at least an insulin in a substantially identical proportion by weight contain.

It it is preferred that the first, second and optionally further Composition the at least one insulin in a substantially identical Contain by weight and the at least one GLP-1 agonist contained in different proportions by weight.

The Compositions according to the invention can the at least one GLP-1 agonist in each case identical or contain various proportions by weight. For example, you can at least two of the compositions of the invention the at least one GLP-1 agonist in a substantially identical one Contained by weight.

It It is also preferred that the first, second and optionally further composition the at least one GLP-1 agonist in one contain substantially identical weight fraction and that at least contain an insulin in different proportions by weight.

Next the first, second and optionally at least one other Composition may be the drug of the invention contain at least one further pharmaceutical composition, which either at least one insulin or at least one GLP-1 agonist contains. Likewise, the inventive Pharmaceuticals at least one further pharmaceutical composition containing at least one insulin and at least one GLP-1 agonist in a ratio of parts by weight such as herein described first, second or optionally further pharmaceutical Composition contains.

One Another object of the invention is a pharmaceutical comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition is at least one insulin and the second pharmaceutical composition comprises at least comprises a GLP-1 agonist and wherein the drug is an independent Administration of the first and second pharmaceutical compositions formulated and / or confectioned.

Another subject of the invention is a kit comprising a pharmaceutical composition according to the invention. The kit according to the invention may be intended for use by medical personnel or by medical laypersons, in particular the patient himself or assistants such as relatives. In the kit according to the invention, the individual pharmaceutical compositions comprising the medicament according to the invention are combined in separate packages, so that the patient in each case to the current need select a suitable composition and administer a needs-based amount. The kit according to the invention comprises, for example, the medicament according to the invention in the form of a set of syringes, glass ampoules and / or pins which contain a composition according to the invention.

"Packaging" is a term which is known to the person skilled in the art and in pharmacology Final treatment, z. B. Portioning and packaging, of medicines designated for use by the end user. In the present Registration means "made-up" or "packaging" in particular, that the pharmaceutical compositions of the invention packaged in a therapeutically effective amount in a suitable manner are the selection of at least one of the Compositions of the medicament according to the invention to the desired dosage of the at least one insulin and of the at least one GLP-1 agonist. Especially Parenteral administration, preferably an injection, is more pronounced preferably for subcutaneous injection. A suitable packaging is z. As a syringe or a glass jar with a suitable closure, from which, if necessary, individual therapeutically effective doses can be removed. As well suitable are injection pens ("pens", "pens") for administration of insulin containing a container (e.g. B. a cartridge), which is an inventive containing pharmaceutical composition.

Is "formulating" or "formulation" a term known to those skilled in the art and in the art Pharmacology, the manufacture of medicines and pharmaceutical compositions and the preparation referred to as excipients. In the present Registration means "formulate" or "formulation" in particular, that the composition of the invention in a suitable form, which is an administration of a therapeutically effective amount of the active ingredients allows. In particular, a formulation for parenteral administration, preferred for injection, more preferably for subcutaneous Injection, provided.

In In the present invention, the term "GLP-1 agonist" includes GLP-1, Analogs and derivatives thereof, exendin-3 and analogs and derivatives thereof, Exendin-4 and analogs and derivatives thereof. The invention Compositions include one or more independently selected 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. Further, substances including the biological activity of GLP-1 exhibit.

GLP-1 analogs and derivatives are e.g. B. in the WO 98/08871 Exendin-3, analogues and derivatives of exendin-3, exendin-4 and analogues and derivatives of exendin-4 can be described in WO 01/04156 . WO 98/30231 . US 5,424,286 , in the EP Application 99 610043.4 , in WO 2004/005342 and WO 04/035623 being found. These documents are incorporated herein by reference. The exendin-3, exendin-4 and analogs and derivatives thereof described therein can be used in the compositions of the present invention as GLP-1 agonists. Likewise, any combinations of the exendin-3, exendin-4 and the analogs and derivatives described therein may be used as GLP-1 agonists.

Of the at least one GLP-1 agonist is preferably independent selected from the group consisting of exendin-4, analogs and derivatives of exendin-4 and pharmacologically tolerable salts from that.

Another preferred GLP-1 agonist is an analog of exendin-4 selected from a group consisting of:
H-desPro ³⁶ -Exendin-4-Lys ₆ -NH ₂ ,
H-des (Pro ^36,37) -Exendin-4-Lys ₄ -NH _2,
H-des (Pro ^36,37) -Exendin-4-Lys ₅ -NH ₂ and pharmacologically tolerable salts thereof.

Another preferred GLP-1 agonist is an analog of exendin-4 selected from a group consisting of:
desPro ³⁶ [Asp ²⁸ ] exendin-4 (1-39),
desPro ³⁶ [IsoAsp ²⁸ ] exendin-4 (1-39),
DESpro ³⁶ [Met (O) ^14, Asp ^28] Exendin-4 (1-39),
desPro ³⁶ [Met (O) ¹⁴ , IsoAsp ²⁸ ] Exendin-4 (1-39),
desPro ³⁶ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-2 (1-39),
desPro ³⁶ [Trp (O ₂ ) ²⁵ , IsoAsp ²⁸ ] Exendin-2 (1-39),
desPro ³⁶ [Met (O) ¹⁴ Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39),
desPro ³⁶ [Met (O) ¹⁴ Trp (O ₂ ) ²⁵ , IsoAsp ²⁸ ] Exendin-4 (1-39) and pharmacologically tolerable salts thereof.

Another preferred GLP-1 agonist is an analog of exendin-4 selected from a group as described in the previous paragraph, in which the C-termini of the analogs of exendin-4 is added with the peptide Lys ₆ -NH ₂ .

Another preferred GLP-1 agonist is an analog of exendin-4 selected from a group consisting of:
H- (Lys) ₆ -desPro ³⁶ [Asp ²⁸ ] Exendin-4 (1-39) -Lys ₆ -NH ₂
desAsp ²⁸ Pro ³⁶ , Pro ³⁷ , Pro ₃₈ exendin-4 (1-39) -NH ₂ ,
H- (Lys) ₆ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Asp ²⁸ ] Ex din-4 (1-39) -NH ₂ ,
H-Asn- (Glu) ₅ desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H- (Lys) ₆ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H-Asn- (Glu) ₅ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,

H- (Lys) ₆ -desPro ³⁶ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) -Lys ₆ -NH ₂ ,
H-des Asp ²⁸ Pro ³⁶ , Pro ³⁷ , Pro ³⁸ [Trp (O ₂ ) ²⁵ ] Exendin-4 (1-39) -NH ₂ ,
H- (Lys) ₆ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
H-Asn- (Glu) ₅ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H- (Lys) ₆ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H-Asn- (Glu) ₅ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H- (Lys) ₆ -desPro ³⁶ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) -Lys ₆ -NH ₂ ,
DeSmet (O) ¹⁴ Asp ²⁸ Pro ^36, Pro ^37, Pro ³⁸ exendin-4 (1-39) -NH _2,
H- (Lys) ₆ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
H-Asn- (Glu) ₅ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H- (Lys) ₆ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) -Lys ₆ -NH ₂ ,
H-Asn- (Glu) ₅ desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,

H- (Lys) ₆ -desPro ³⁶ [Met (O) ¹⁴ , Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) -Lys ₆ -NH ₂ ,
desAsp ²⁸ Pro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Trp (O ₂ ) ²⁵ ] Exendin-4 (1-39) -NH ₂ ,
H- (Lys) ₆ -desPro ^36, Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
H-Asn- (Glu) ₅ -desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Asp ²⁸ ] Exendin-4 (1-39) -NH ₂ ,
desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H- (Lys) ₆ -desPro ^36, Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ ,
H-Asn- (Glu) _5- desPro ³⁶ , Pro ³⁷ , Pro ³⁸ [Met (O) ¹⁴ , Trp (O ₂ ) ²⁵ , Asp ²⁸ ] Exendin-4 (1-39) - (Lys) ₆ -NH ₂ and pharmacologically tolerable salts thereof.

Another preferred GLP-1 agonist is selected from a group consisting of Arg ³⁴ , Lys ²⁶ (N ^ε (γ-glutamyl (N ^α -hexadecanoyl)), GLP-1 (7-37) [liraglutide] and a pharmacologically tolerable Salt of it.

Another preferred GLP-1 agonist is AVE0010. AVE0010 assigns the sequence:
desPro ³⁶ exendin-4 (1-39) -Ly ₆ -NH ₂
on. This substance is shown as SEQ ID NO: 93 in WO 01/04156 released. Also, pharmacologically tolerable salts of AVE0010 are preferred.

Of the Term "at least one GLP-1 agonist" Combinations of the GLP-1 agonists described herein which used in the compositions of the invention be, for. Any combinations of two or more GLP-1 agonists selected from the GLP-1 agonists described herein.

The at least one GLP-1 agonist is also preferably independently selected from exendin-4, Pro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ and Arg ³⁴ , Lys ²⁶ (N ^ε (γ-glutamyl (N ^α hexadecanoyl))) GLP-1 (7-37) [liraglutide] and pharmacologically tolerable salts thereof.

The Contain compositions of the invention the GLP-1 agonist in an amount of 10 μg / ml to 20 mg / ml, preferably 25 μg / ml to 15 mg / ml. For the acidic to neutral dissolved GLP-1 agonists is preferred 20 μg / ml to 300 μg / ml and for the neutral to basic, preferably 500 μg / ml to 10 mg / ml. For Exendin-4 analogues preferably 20 μg / ml to 150 μg / ml.

In In the present application, the term "insulin" does not encompass only unmodified insulins, but also insulin analogs, insulin derivatives and insulin metabolites. The compositions of the invention include one or more independently selected from the group consisting of insulins (eg unmodified insulins), Insulin analogues, insulin derivatives and insulin metabolites and any Combinations of it.

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

Further An insulin according to the invention can be independent be selected from unmodified insulins, in particular from bovine insulins, porcine insulins and human insulins.

The at least one insulin may be independently selected from the group consisting of bovine insulins, porcine insulins and human insulins. More preferably, this is at least one insu lin independently selected from human insulins. An insulin according to the invention may be selected from unmodified insulins, in particular from bovine insulins, porcine insulins and human insulins.

invention Insulin derivatives are derivatives of a naturally occurring one Insulin or / and an insulin analogue, which are obtained by chemical modification to be obtained. The chemical modification may, for. In addition one or more particular chemical groups to one or more Amino acids exist.

Insulin analogues which are in EP 0 214 826 . EP 0 375 437 . EP 0 678 522 . EP 0 885 961 . EP 0 419 504 . WO 92/00321 , the German Patent Applications No. 10 2008 003 568.8 and no. 10 2008 003 566.1 and EP-A 0 368 187 may be part of the compositions of the invention. The documents EP 0 214 826 . EP 0 375 437 . EP 0 678 522 . EP 0 419 504 . WO 92/00321 and EP-A 0 368 187 are incorporated herein by reference.

A preferred insulin analog 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) -humaninsulinamide, Lys (B3) -Glu (B29) -human insulin; Lys ^B28 Pro ^B29 human insulin (insulin lyspro), B28Asp human insulin (insulin aspart), human insulin in which proline at position B28 has been substituted by Asp, Lys, Leu, Val or Ala and where in position B29Lys may be substituted by Pro; AlaB26 human insulin; Des (B28-B30) human insulin; Des (B27) -human insulin or B29Lys (□ -tetradecanoyl), (B30) -human insulin (insulin detemir).

A preferred insulin derivative according to the invention can 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 ^B28 Pro ^B29 human insulin, B28-N-palmitoyl-Lys ^B28 Pro ^B29 human insulin, B30-N-myristoyl-Thr ^B29 Lys ^B30 human insulin, B30-N-palmitoyl-Thr ^B29 Lys ^B30 human insulin, B29-N - (N-palmitoyl-Y-glutamyl) des (B30) human insulin, B29-N- (N-lithocholyl-Y-glutamyl) -des (B30) human insulin, B29-N- (ω-carboxyheptadecanoyl) -des (B30 ) Human insulin and B29-N- (ω-carboxyheptadecanoyl) human insulin.

A more preferred insulin derivative of the invention is selected from the group consisting of Gly (A21) -Arg (B31) -Arg (B32) human insulin, Lys ^B28 Pro ^B29 human insulin (insulin Lyspro), B28Asp human insulin (insulin aspart), B29Lys (ε- tetradecanoyl), B30 human insulin (insulin detemir).

Of the Term "at least one insulin" includes combinations the insulins described herein, analogs, derivatives and metabolites thereof, which are used in the compositions of the invention be, for. For example, any combinations of two or more are selected from the insulins described herein, analogs, derivatives and metabolites.

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

in the 2- to 10-, preferably 3 to 5, pens-cover-all concept are the Compositions in the range of 20 μg / ml GLP-1 agonist and 100 U / ml insulin to 300 μg / ml GLP-1 agonist and 500 U / ml insulin. The following concentration ranges are preferred: 25 μg / ml and 100 U / ml, 33 μg / ml and 100 U / ml, 40 μg / ml and 100 U / ml, 66 μg / ml and 100 U / ml and 75 μg / ml and 100 U / ml.

Of the desired dosage range of insulin is particular a dosage with synergistic effect. Here are the values at 5 to 100 U, preferably at 15 to 80 U. For the GLP-1 Agonists include the values for the dosage range 5 μg to 2 mg, preferably 10 μg to 1.8 mg, especially preferred at 10 μg to 30 μg.

[Here are even more detailed information on the quantities used and dosages]

The preferred dosage form of the pharmaceutical compositions The present invention relates to liquid compositions which especially for parenteral administration, more preferred for injection, most preferably for subcutaneous injection are suitable. In particular, the pharmaceutical compositions of the present invention for injection once a day suitable.

The Pharmaceutical composition of the present invention can have an acidic or physiological pH. An acidic pH range is preferably in the range of pH 1-6.8, stronger preferably pH 3.5-6.8, even more preferably pH 3.5-4.5, most preferably at a pH of about 4.0-4.5. A physiological pH is preferably in the Range of pH 4.0-8.5, more preferably pH 5.0 to 8.5, more preferably pH 6.0 to 8.5.

The composition of the invention may contain a suitable preservative. Suitable preservatives are, for. Phenol, m-cresol, benzyl alcohol and / or p-hydroxybenzoic acid esters.

Further the composition according to the invention can be a contain suitable buffer. As buffer substances, in particular for adjusting a pH between about 4.0 and 8.5 z. As sodium acetate, sodium citrate, sodium phosphate, etc. used become. Otherwise, to adjust the pH also physiological safe dilute acids (typically HCl) or alkalis (typically NaOH). Preferred concentrations the buffer and corresponding salts are in the range of 5-250 mM, more preferably in the range of 10-100 mM.

The Composition according to the invention may be zinc ions contain. The concentration of zinc ions is preferably in the Range from 0 μg / ml to 500 μ / ml, stronger preferably from 5 μg to 200 μg zinc / ml.

Furthermore, the composition according to the invention may contain suitable isotonizing agents. Suitable z. Glycerol, dextrose, lactose, sorbitol, mannitol, glucose, NaCl, calcium or magnesium compounds such as CaCl _2, etc. Glycerol, dextrose, lactose, sorbitol, mannitol and glucose are usually in the range of 100-250 mM, NaCl in a concentration of up to 150 mM.

Further can the composition of the invention a Containing surfactant. A surfactant can increase the stability of acidic Greatly increase insulin compositions. With that you can even compositions are made that have several Months with temperature stress the superior stability over guarantee hydrophobic aggregation germs.

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, polyols; wherein the partial and fatty acid ester are selected and ethers of glycerol and sorbitol from a group comprising clamping ^®, Tween ^®, Myrj ^®, Brij ^®, Cremophor ^®; wherein the polyols are selected from the group consisting of polypropylene glycols, polyethylene glycols, poloxamers, polysorbates, Pluronics, Tetronics. Preferred concentrations of the surfactants are in the range of 5-200 μg / ml, preferably 5-120 μg / ml and more preferably 20-75 μg / ml.

Further the composition according to the invention can be further Additives such. B. salts containing the release retard the at least one insulin.

A particularly preferred subject of the invention is a drug as described herein comprising at least one insulin independently selected from Lys ^B28 Pro ^B29 human insulin (insulin Lyspro), B28Asp human insulin (insulin aspart), B29Lys (□ tetradecanoyl), B30 human insulin (insulin detemir), and Insulin glargine (Gly (A21) Arg (B31) Arg (B32) human insulin) and comprising AVE0010 or / and a pharmacologically tolerable salt thereof. Another particularly preferred article is a drug as described herein comprising insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin) and AVE0010 (desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ ) or / and a pharmacologically tolerable salt thereof. The compositions of these particularly preferred drugs preferably have an acidic pH of 1-6.8, more preferably pH 3.5-6.8, even more preferably pH 3.5-5.0, most preferably at a pH of about 4 , 0 to 4.5. Further, the compositions of these particularly preferred drugs may contain a surfactant as described herein.

A further subject of the invention is a combination of insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin) and AVE0010 (desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ ) or / and a pharmacologically tolerable salt thereof.

One Another subject of the invention is a method for the treatment of a patient with an inventive Drug or kit as described herein.

The inventive method for treating a Patients include the administration of a method according to the invention Medicament comprising at least one insulin and at least one GLP-1 agonist, wherein the drug is formulated or / and formulated, that it contains the insulin and the GLP-1 agonist in each case Contains quantity and in each one to the need of one Patients adjusted dose can be administered.

• (a) Auswählen einer Dosis des wenigstens einen Insulins, welche verabreicht werden soll,
• (b) Auswählen einer Dosis des wenigstens einen GLP-1-Agonisten, welche verabreicht werden soll,
• (c) Auswählen einer Zusammensetzung aus der ersten, zweiten und gegebenenfalls wenigstens einen weiteren Zusammensetzung des Arzneimittels, welche die Dosen aus (a) und (b) in einer Konzentration enthält, so dass die Dosen aus (a) und (b) in gleichem Volumen vorliegen, und
• (d) Bestimmen und Verabreichen einer Menge, welche den Dosen aus (a) und (b) entspricht.

In particular, the method comprises administering a pharmaceutical composition 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 containing at least one insulin and / or the at least containing a GLP-1 agonist in different proportions by weight based on the total weight of the composition, the method comprising:

• (a) selecting a dose of the at least one Insulin, which should be administered
• (b) selecting a dose of the at least one GLP-1 agonist to be administered,
• (c) selecting a composition of the first, second and optionally at least one further composition of the medicament containing the doses of (a) and (b) in a concentration such that the doses of (a) and (b) are the same Volume present, and
• (d) determining and administering an amount corresponding to the doses of (a) and (b).

The The treatment method according to the invention can in particular for the treatment of patients with diabetes, especially with diabetes Type I or II can be used. The process is preferred for Attitude of the sober, the postprandial or / and the postabsorptive plasma glucose concentration, for improvement glucose tolerance, for the prevention of hypoglycaemia, for the prevention of a loss of function of β-cells of the pancreas, for weight loss and / or for prevention used a weight gain.

The Determination of the dose after step (a) or / and step (b) takes place according to the individual needs of the patients.

step (c) the treatment method according to the invention can be done on the basis of a table. this table may be part of the medicament of the invention be. Example 11 contains an example of one Inventive table.

One Another object of the invention is a Process for the preparation of an inventive Pharmaceutical comprising formulation and / or packaging, so that it contains the insulin and the GLP-1 agonist in each case Contains quantity and in each one to the need of one Patients adjusted dose can be administered. It is preferred In the manufacturing process, the drug is formulated and formulated, that one of the invention described herein Medicaments can be obtained, for example, an inventive A pharmaceutical composition comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least one further pharmaceutical composition which at least one insulin and at least one GLP-1 agonist and at least one insulin and / or at least a GLP-1 agonist in different proportions by weight on the total weight of the composition.

The Invention is by the following figures and the following Example illustrates without this in any of the invention Restrict the way.

Legends to the pictures

1 : Study design for the oral glucose tolerance test.

2 : OGTT in dogs: effect of Lantus versus placebo.

3 : OGTT in dogs: Effect of AVE0010 versus placebo.

4 : OGTT in dogs: Effect of an AVE0010-Lantus combination on blood glucose levels.

5 : OGTT in dogs: Effect of an AVE0010-Lantus combination on plasma insulin and c-peptide levels.

6 : OGTT in the dog: effect of a dose reduction of AVE0010 with different ratios to Lantus in the combination formulation.

7 : Model: Diabetic insulin-resistant db / db mouse.

8th : Effect of an AVE0010-Lantus combination on blood glucose in the diabetic db / db mouse.

9 : Effect of an AVE0010-Lantus combination in the oral glucose tolerance test in the diabetic db / db mouse.

10 : Effect of the AVE0010-Lantus combination on cytokine and lipotoxicity-induced β-cell apoptosis in vitro.

11 : The "3 pens cover all" concept.

Examples

example 1

Model: oral glucose tolerance test (OGTT) in healthy dogs: comparison of the combination Lantus-AVE0010 with the two individual active ingredients.

animals

• • Male normoglycemic Beagles
• • Body weight: ~ 15 kg
• • Number per group: n = 6

Study design (see 1 )

• • Single subcutaneous injections of Placebo or test formulation at time 0
• • 2 oral glucose dosages of 2 g glucose / kg body weight at the time of 30 min and 5 h
• • Blood samples are used to determine blood glucose, Plasma insulin and c-peptide taken

Group classification (n = 6)

• • Placebo (= Lantus placebo formulation without API)
• • Lantus (0.3 IU / kg s.c., equivalent to 1.8 nmol / kg). Lantus is Gly (A21) -Arg (B31) -Arg (B32) human insulin.
• • AVE0010 (10 μg / kg sc in Lantus placebo formulation, equivalent to 2 nmol / kg). AVE0100 is desPro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ .
• • AVE0010-Lantus combination (10 μg / kg AVE0010 / 0.3 IU / kg Lantus s. c.)

Example 2

OGTT in dogs: effect of Lantus versus placebo

• • wiederholter OGTT (2 g/kg p. o.)
• • männl. Beagle, n = 6
• • MW ± Sem
• • Placebo = Lantus-Placebo
• • Lantus (0.3 U/kg s. c.)

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

• Repeated OGTT (2 g / kg po)
• • Male Beagle, n = 6
• • MW ± sem
• • Placebo = Lantus placebo
• Lantus (0.3 U / kg sc)

Result: The data is in 2 shown. The sole administration of Lantus does not prevent the OGTT-induced increase in blood glucose. Lantus potentiates the expected delayed decrease in plasma glucose concentration in the postabsorptive phase.

Example 3

OGTT in dogs: effect of Lantus versus placebo

• • wiederholter OGTT (2 g/kg p. o.)
• • männl. Beagle, n = 6
• • MW ± Sem
• • Placebo = Lantus-Placebo
• • AVE0010 (10 μg/kg s. c.)

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

• Repeated OGTT (2 g / kg po)
• • Male Beagle, n = 6
• • MW ± sem
• • Placebo = Lantus placebo
• • AVE0010 (10 μg / kg sc)

Result: The data is in 3 shown. AVE0010 almost completely prevents the OGTT-induced postprandial increase in blood glucose. There is no effect on the glucose concentration in the postabsorptive phase. This example demonstrates that the effect of AVE0010 on the OGTT-induced postprandial increase in blood glucose is complementary to the hypoglycemic effect of Lantus in the postabsorptive phase.

Example 4

OGTT in the dog: effect of an AVE0010-Lantus combination on the blood glucose level

• • wiederholter OGTT (2 g/kg p. o.)
• • männl. Beagle, n = 6
• • MW ± Sem
• • Placebo = Lantus-Placebo
• • AVE0010 (10 μg/kg s. c.)
• • Lantus (0.3 U/kg s. c.)
• • AVE + Lan (= Prämix von 10 μg/kg und 0.3 U/kg Lantus in einer Formulierung)

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

• Repeated OGTT (2 g / kg po)
• • Male Beagle, n = 6
• • MW ± sem
• • Placebo = Lantus placebo
• • AVE0010 (10 μg / kg sc)
• Lantus (0.3 U / kg sc)
• • AVE + Lan (= premix of 10 μg / kg and 0.3 U / kg Lantus in one formulation)

Result: The data is in 4 shown. The combination affects the postprandial glucose increase like AVE0010 (see example 3). The hypoglycemic effect of Lantus in the postabsorptive phase is also present but attenuated (see Example 2). This is a synergistic effect of Lantus and AVE0010, as AVE0010 alone has no effect on glucose levels after glucose administration, and Lantus alone has no effect on postprandial glucose levels.

Example 5

OGTT in the dog: effect of an AVE0010-Lantus combination on plasma insulin and c-peptide levels

• • wiederholter OGTT (2 g/kg p. o.)
• • männl. Beagle, n = 6
• • MW ± Sem
• • Placebo = Lantus-Placebo
• • AVE0010 (10 μg/kg s. c.)
• • Lantus (0.3 U/kg s. c.)
• • AVE + Lan (= Prämix von 10 μg/kg und 0.3 U/kg Lantus in einer Formulierung)

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

• Repeated OGTT (2 g / kg po)
• • Male Beagle, n = 6
• • MW ± sem
• • Placebo = Lantus placebo
• • AVE0010 (10 μg / kg sc)
• Lantus (0.3 U / kg sc)
• • AVE + Lan (= premix of 10 μg / kg and 0.3 U / kg Lantus in one formulation)

The C-peptide is released in the conversion of proinsulin into insulin and serves as a marker of insulin secretion of β-cells of the pancreas. As part of a glucose load test, you can use the c-peptide determines the responsiveness of the pancreas become.

Result: The data is in 5a and 5b shown. In the combination group, there is an increased following on the postprandial insulin reduction postabsorptive lantuce level. C-peptide levels of the combination correspond to the insulin curve of AVE0010 during the prandial phases and Lantus during the postabsorptive phase.

Example 6

OGTT in dogs: effect of dose reduction of AVE0010 with different ratios to Lantus in the Combination formulation.

• • wiederholter OGTT (2 g/kg p. o.)
• • männl. Beagle, n = 11/6/6/6
• • MW ± Sem
• • Kontrolle = Lantus-Placebo
• • AVE + Lan (= Prämix von 0.15 bis 1.0 μg/kg und 0.3 U/kg Lantus in einer Formulierung). In den Beispielen 2 bis 5 wurden AVE0010-Konzentrationen von 10 μg/kg verwendet.

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

• Repeated OGTT (2 g / kg po)
• • male Beagle, n = 11/6/6/6
• • MW ± sem
• • Control = Lantus placebo
• • AVE + Lan (= premix of 0.15 to 1.0 μg / kg and 0.3 U / kg Lantus in one formulation). In Examples 2 to 5, AVE0010 concentrations of 10 μg / kg were used.

Result: The data is in 6 shown. A reduction of the AV0010 dose from 10 μg / kg (see in particular Example 4) to 1 μg / kg (ie by a factor of 10) and the resulting increase in the ratio of Lantus to AVE0010 does not affect the synergistic activity of the Combination AVE0010 with Lantus (see in particular Example 4). Only at significantly lower doses of AVE0010 does the effect of the combination approach the effect of Lantus alone (cf. 2 ). Thus, the AVE0010 dose can be varied at least within an order of magnitude (ie at least a factor of 10) without losing the synergistic effect.

Example 7

Model: Diabetic insulin-resistant db / db mouse: Comparison of the combination Lantus-AVE0010 with the two individual active ingredients.

animals

• • Female db / db mouse
• • Age: 10-11 weeks
• • Number per group: n = 10

study design

• • Single subcutaneous injection of Placebo or the test formulation
• • Taking blood samples to determine blood glucose

grouping

• • Placebo (= Lantus placebo formulation without API)
• • AVE0010 (10 μg / kg s.c.)
• • Lantus (5 IU / kg s. C.)
• • AVE0010-Lantus combination (premix of 10 μg / kg AVE0010 plus 5 IU / kg Lantus s. c.)

Example 8

Effect of an AVE0010-Lantus combination on the blood glucose in the diabetic db / db mouse

• • Weibliche db/db-Maus, 10 Wochen
• • n = 10, MW ± Sem
• • Vehikel = Lantus-Placebo
• • AVE0010 (10 μg/kg sc)
• • Lantus (5 U/kg sc)
• • AVE0010-Lantus (= Prämix von AVE0010 10 μg/kg und Lantus 5 U/kg in einer Formulierung)

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

• • Female db / db mouse, 10 weeks
• • n = 10, MW ± sem
• Vehicle = Lantus placebo
• • AVE0010 (10 μg / kg sc)
• Lantus (5 U / kg sc)
• • AVE0010-Lantus (= premix of AVE0010 10 μg / kg and Lantus 5 U / kg in one formulation)

Result: The data is in 7 shown. The AVE0010-Lantus combination resulted in a faster and greater decrease in blood glucose concentration in diabetic db / db mice compared to the two single agents. Thus, the combination diabetic db / db mice closer to normoglycemia than each of the two drugs alone.

Example 9

Effect of an AVE0010-Lantus combination in the oral glucose tolerance test in the diabetic db / db mouse

• • Weibliche db/db-Maus, 11 Wochen
• • n = 10, MW ± Sem
• • Kontrolle = Lantus-Placebo
• • AVE0010 (10 μg/kg sc)
• • Lantus (5 U/kg sc)
• • AVE0010-Lantus (= Prämix von AVE0010 10 μg/kg und Lantus 5 U/kg in einer Formulierung)

The experiment was carried out according to the protocol described in Example 7. In addition, an OGTT (2 g / kg po @ 30 min) was performed.

• • Female db / db mouse, 11 weeks
• • n = 10, MW ± sem
• • Control = Lantus placebo
• • AVE0010 (10 μg / kg sc)
• Lantus (5 U / kg sc)
• • AVE0010-Lantus (= premix of AVE0010 10 μg / kg and Lantus 5 U / kg in one formulation)

Result: The data is in 8th shown. The AVE0010-Lantus co-combination leads to significantly improved glucose tolerance and lower postabsorptive glucose levels.

Example 10

Effect of the AVE0010-Lantus combination on cytokine and lipotoxicity induced □ cell apoptosis in vitro

• Insulinoma cell line INS-1 of the rat
• • Incubation with the test compound for 5 H
• • Further incubation with a cytokine mix for 22 h (1 ng / mL IFN-□ + 4 ng / mL IL-1β) or
• • Further incubation with 0.5 mM FFA for 18 h (palmitates: BSA 3: 1)

When The measure of apoptosis is caspase-3 activity and the fragmentation of cell nuclei used with apoptosis correlate.

Result: The data is in 9 shown. AVE0010 or Lantus (= glargine, glar) alone prevent apoptosis by ~ 40-50%. The combination AVE0010 and Lantus significantly better prevent apoptosis. The combination provides increased protection against cytokine and lipotoxicity-induced apoptosis due to this synergistic effect.

Example 11

The "3 pens cover all" concept ( 11 )

• • 3 premix pens (premix pens) with 3 different predefined ratios: - mix A: 100 U Lantus + 66.66 μg AVE0010 per mL - mix B: 100 U Lantus + 40 μg AVE0010 per mL - mix C: 100 U Lantus + 25 μg AVE0010 per mL
• • Use of the 3 premix pens: The example table in 10 assumes a therapeutic range of 15 to 80 U per dose of Lantus and 10 to 20 μg of AVE0010. For a particular patient, a dose of Lantus to be administered is established or predetermined. The predetermined dose is visited in the left column. If a corresponding AVE0010 dose in the range between 10 and 20 μg is mentioned in columns MIX A-MIX C, the corresponding MIX is selected, dosed and administered. The areas are overlapping: z. For example, for a need of 26 to 30 U, Lantus Mix A or MIX B (with a higher dose of AVE0010) could be chosen. The same applies to MIX B and C. If, for example, a dose of 50 U insulin is determined, then 0.5 ml of MIX B or MIX C should be dosed. This dose contains 20 μg (MIX B) or 12.5 μg (MIX C) AVE0010.
• • Conclusion: Assuming that a probable AVE0010 effect between 10 and 15 μg and achieved a therapeutic effect of between 15 and 22 μg Almost all patients taking Lantus doses of Take 15-80 U, as well as therapeutic doses of AVE0010 between 10 and 20 μg if they are one of the three Use premix pens that contain three different Lantus: AVE001 ratios (Mix A, B or C). Due to the wide range of possible Ratios of Lantus to AVE0010 (See Example 6) with synergistic effects can the conditions be matched in the pens so that for each dose from Lantus in at least one pen a synergistic dose of AVE0010 is included.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - EP 0214826 [0007, 0007, 0076, 0076]
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Claims (25)

Medicament comprising at least one insulin and at least one GLP-1 agonist, wherein the drug is so formulated and / or is made up that it is the insulin and the GLP-1 agonist in a respective predetermined amount and in each case be administered to the needs of a patient adapted dose can. Medicament according to claim 1 for Attitude of the sober, the postprandial or / and the postabsorptive plasma glucose concentration in diabetic patients. A pharmaceutical according to claim 1 or 2 to improve glucose tolerance. Medicament according to one of the preceding Claims for the prevention of hypoglycemia. Medicament according to one of the preceding Claims for the prevention of a loss of function of β-cells of the pancreas. Medicament according to one of the preceding Claims for weight loss and / or prevention a weight gain. Medicament according to one of the preceding Claims comprising a first pharmaceutical composition and a second pharmaceutical composition and optionally at least another pharmaceutical composition, each at least include an insulin and at least one GLP-1 agonist and that at least one insulin and / or the at least one GLP-1 agonist in different proportions by weight based on the total weight of Composition included. Medicament according to claim 7, wherein the weight proportions of the at least one insulin and the at least a GLP-1 agonist in the first pharmaceutical composition, the second pharmaceutical composition and optionally selected at least one further pharmaceutical composition be that the pharmaceutical compositions different Ratios of insulin to GLP-1 agonist based on contain the weight fraction. Medicament according to claim 7 or 8, wherein the first, second and optionally further composition the at least one insulin in a substantially identical one Contain by weight and the at least one GLP-1 agonist contained in different proportions by weight. Medicament according to claim 7 or 8, wherein the first, second and optionally further composition the at least one GLP-1 agonist in a substantially identical one Contain by weight and the at least one insulin in different Contain by weight. Medicament according to one of the claims 1 to 6 comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition at least one insulin comprises and the second pharmaceutical composition at least comprises a GLP-1 agonist and wherein the drug is an independent Administration of the first and second pharmaceutical compositions formulated and / or confectioned. Medicament according to one of the preceding Claims, wherein the at least one insulin is independent is selected from human insulins, analogs, derivatives and Metabolites thereof. The pharmaceutical composition according to claim 12, wherein said at least one insulin is independently selected from the group consisting of Gly (A21) -Arg (B31) -Arg (B32) human insulin, Lys ^B28 Pro ^B29 human insulin, B28Asp human insulin and B29Lys (ε-tetradecanoyl) , desB30 human insulin. Medicament according to one of the preceding Claims, wherein the at least one GLP-1 agonist is independent is 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 from that. The pharmaceutical composition of claim 14, wherein said at least one GLP-1 agonist is independently selected from the group consisting of exendin-4, pro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ [AVE0010], and Arg ³⁴ , Lys ²⁶ (N ^ε (γ-glutamyl (N ^α -hexadecanoyl))) GLP-1 (7-37) [liraglutide] and pharmacologically tolerable salts thereof. Medicament according to claim 15, wherein the at least one GLP-1 agonist is independently selected is from the group consisting of exendin-4, analogs, derivatives and pharmacologically tolerable salts thereof. The pharmaceutical composition of claim 16, wherein the at least one GLP-1 agonist of the Pro ^{36 is} exendin-4 (1-39) -Ly ₆ -NH ₂ . A pharmaceutical composition according to any one of the preceding claims wherein the insulin is Gly (A21) Arg (B31) Arg (B32) human insulin and the GLP-1 agonist of Pro ³⁶ exendin-4 (1-39) -Lys ₆ -NH ₂ or a pharmaceutically acceptable salt thereof. A kit comprising a medicament according to any one of Claims 1 to 16. Combination of Gly (A21) -Arg (B31) -Arg (B32) human insulin and the Pro ³⁶ exendin-4 (1-39) Lys ₆ -NH ₂ or / and a pharmaceutically acceptable salt thereof. Use of at least one insulin and at least a GLP-1 agonist for the manufacture of a medicament for treatment a patient with diabetes, especially diabetes type I or II, for the adjustment of the sober, the postprandial or / and the postabsorptive plasma glucose concentration, for improvement glucose tolerance, for the prevention of hypoglycaemia, for the prevention of a loss of function of β-cells of the pancreas, for weight loss and / or for prevention a weight gain. Method for treating a patient with a A pharmaceutical composition according to claim 7 or a kit comprising such a medicament comprising (a) Select a dose of the at least one insulin administered should, (b) selecting a dose of the at least one GLP-1 agonist, which should be administered (c) selecting one Composition of the first, second and optionally at least another composition of the drug containing the doses from (a) and (b) in a concentration such that the doses of (a) and (b) are in the same volume, and (D) Determining and administering an amount corresponding to the doses of (a) and (b) corresponds. A method according to claim 22 to Attitude of the sober, the postprandial and / or the postabsorptive plasma glucose concentration, to improve the Glucose tolerance, for the prevention of hypoglycaemia, for the prevention of a loss of function of β-cells of the pancreas, for weight loss and / or for prevention a weight gain. A method according to claim 22 or 23, wherein step (c) is performed on the basis of a table becomes. Process for the preparation of a medicament according to of claims 1 to 18, comprising formulation and / or Make up, making it the insulin and the GLP-1 agonist in a predetermined amount each contains and in one each dose adapted to the needs of a patient can be.