Combination of an insulin and a glp-1 agonist.

(54) Title: COMBINATION OF AN INSULIN AND A GLP-1 AGONIST.

(54) Title: COMBINATION OF AN INSULIN AND A GLP-1 AGONIST.

(57) Summary

The present invention relates to a medicament for treating a patient with type 1 or type 2 diabetes, to adjust the concentration of fasting, postprandial and / or postabsorptive blood glucose, to improve glucose tolerance, to prevent hypoglycemia, for weight loss and / or to prevent weight gain, said medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, the first pharmaceutical composition comprises Gly (A21) -Arg (B31) -Arg (B32) human insulin and the second pharmaceutical composition comprises Gly (A21) Arg (B31) -Arg (B32) human insulin and desPro36exendina-4 (1-39 ) -Lys6-NH2 or one of its pharmacologically tolerable salts.

(57) Abstract

The invention relates to a drug comprising at least one insulin and at least one GLP-1 receptor agonist.

<img file="MX344293B_D0001.tif" />

<img file="MX344293B_D0002.tif" />

PATENT TITLE NO. 344293

Headlines)

SANOFI - AVENTIS DEUTSCHLAND GMBH

Home;

Denomination;

Classification:

Inventor (s):

Number:

Mexican Institute of Industrial Property

Brüningstrasse 50, 65929, Frankfurtam Main, GERMANY

COMBINATION OF AN INSULIN AND A GLP-1 AGONIST.

Int.CI.8: A61K38 / 26; A61K38 / 28; A61P3 / 04; A61P3 / 10

ULRICH WERNER; BARBEL ROTTHAUSER; CHRISTOPHER JAMES SMITH

REQUEST

International filing date:

MX / a / 2011/003804 October 2009

PRIORITY

Country;

Date:

Number:

DF DE

DE October 2008 October 2008 August 2009

2008 051 834.4

2008 053 048.4

2009 038 210.0

Validity: Twenty years

Expiration Date: October 9, 2029

The reference patent is granted based on articles 1^or, 2^or section V, 6th section III, and 59 of the Industrial Property Law. t&gt; e in accordance with article 23 · # β the Industrial Property Law, this patent has a non-extendable term of twenty years, counted from the date of filing of the international application and will be subject to the payment of the fee for keep the rights in force.

Whoever subscribes to this title does so based on the provisions of article * β · sections III and 7^or bis 2 of the Industrial Property Law (Official Federation Certificate (DOF) 06/27/1991, amended on 10/25/1996, 12/26/1 ^ 7, 05/17/1999,

01/26/2004, 06/16/2005, 01/25/2006, 06/05/2009, 06/01/20/20, 06/18/2010 06/28/2010, ZV 04/09/2012) ; articles 1 ?, 3^or fraction V subsection a), 4^or and 12th work I and: III of the Regulations of the Institute⁷®etoaBB.dt.to- Industrial (DOF 14/12 / 199®, reformed the

07/01/2002, 07/15/2004; , 07/28/2004 and 09/07/2007); items 1^or, 3°, 4°, 5^or fraction V subsection a), 16 sections I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999, amended on 10/10/2002, 09/07/2004, 08/04/2004 and 09/13/2007), 1st, 3^orand 5th paragraph a) of the Agreement that delegates powers to the Deputy Directors General, Coordinator, Divisional Directors, Head of the Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

<img file="MX344293B_D0003.tif" />

<img file="MX344293B_D0004.tif" />

Issue Date: December 13, 2016

THE DIVISIONAL DIRECTOR OF PATENTS

<img file="MX344293B_D0005.tif" />

NAHANNY CANAL REYES

<img file="MX344293B_D0006.tif" />

<img file="MX344293B_D0007.tif" />

<img file="MX344293B_D0008.tif" />

INSTÍTUTOÍMEXICAN »·

OF INDUSTRIAL PROPERTY

<img file="MX344293B_D0009.tif" />

COMBINATION OF AN INSULIN AND AGONISY Ub GLP-1

The invention relates to a medicament comprising at least one insulin and at least one GLP-1 receptor agonist, hereinafter referred to as a GLP-1 agonist, wherein the medicament is formulated and / or forms a compound in such a manner comprising insulin and GLP-1 agonist each in a predetermined amount and can be administered in a dose tailored to a patient's individual requirement.

The invention more particularly relates to a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, and, optionally, at least one other pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist and it contains the at least one insulin and / or the at least one GLP-1 agonist in different fractions with respect to the total weight of the composition.

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

Some 250 million people worldwide suffer from

IMPB

MEXICAN INSTITUTE I OF INDUSTRIAL PROPERTY diabetes mellitus. Among them, for type 1 diabetics, the only current possible therapy is replacement of poor endocrine insulin secretion. Those affected depend on insulin injections throughout their lives, usually several times a day. Type 2 diabetes contrasts with type 1 diabetes in that there is not always insulin deficiency, but in a large number of cases, especially in the advanced stage, insulin treatment, when appropriate in combination with an oral antidiabetic agent, is considered most advantageous form of therapy.

In healthy individuals, the release of insulin by the pancreas is strictly coupled to the blood glucose concentration. Elevated blood glucose levels, such as those that occur after meals, are quickly offset by a corresponding increase in insulin secretion. On an empty stomach, the plasma insulin level drops to a baseline level that is sufficient to ensure a continuous supply of glucose to insulin-sensitive organs and tissues, and to maintain low hepatic glucose production overnight. The replacement of endogenous insulin secretion by exogenous, usually subcutaneous, insulin administration generally does not come close to the above-described quality of physiological regulation of blood glucose. There are often instances when blood glucose leaks out of the channel, either up or down, and in its most severe forms, this can be life threatening. However, blood glucose levels that have been elevated for many years, with no initial, exogenous symptoms, also constitute a considerable health risk. The large-scale study DCCT in the United States (The Diabetes Control and Complications Trial Research Group

<img file="MX344293B_D0010.tif" />

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

<img file="MX344293B_D0011.tif" />

(1993) N. Engl. J. Med. 329, 977-986) unambiguously demonstrated that chronically elevated blood glucose levels are responsible for the development of late diabetic complications. Late diabetic complications are micro and macrovascular damage that manifest in certain circumstances, such as retinopathy, kidney disease, or neuropathy and lead to blindness, kidney failure, and limb loss, and are also associated with an increased risk of cardiovascular disorders. From this it can be inferred that an improved diabetes therapy should be aimed primarily at keeping blood glucose as close as possible within the physiological range. In accordance with the concept of intensified insulin therapy, it should be achieved by injections, several times a day, of fast-acting and slow-acting insulin preparations. Fast acting formulations are given at meal times to compensate for the postprandial increase in blood glucose. Basal slow-acting insulins are intended to ensure basic insulin supply, especially at night, without leading to hypoglycemia.

Insulin is a polypeptide composed of 51 amino acids divided into two chains of 2 amino acids: the A chain, with 21 amino acids, and the B chain, with 30 amino acids. The chains are linked together by two disulfide bridges. Insulin preparations have been used for many years for diabetes therapy. Such preparations use not only insulins found in nature, but also, more recently, insulin derivatives and insulin analogues.

Insulin analogues are analogs of insulins that are

IMPI &amp;

MEXICAN INSTITUTE

INDUSTRIAL PROPERTY G ** found in nature, namely human insulin or animal insulins, which differ by replacing at least one naturally occurring amino acid residue with another amino acid and / or adding / removal of at least one amino acid residue from the corresponding insulin found in nature, otherwise identical. The amino acids in question can also be amino acids that are not found in nature.

Insulin derivatives are derivatives of insulin found in nature or of an insulin analog that is obtained by chemical modification. Chemical modification may consist, for example, of the addition of one or more defined chemical groups and one or more amino acids. In general, the activity of insulin derivatives and insulin analogues is altered in part, compared to human insulin.

Insulin analogues with accelerated onset of action are described in EP 0 214 826, EP 0 375 437, and EP 0 678 522. EP 0 214 826 relates, inter alia, to replacements for B27 and B28 . EP 0 678 522 describes insulin analogues having different amino acids at position B29, preferably proline, but not glutamic acid. EP 0 375 437 covers insulin analogues with lysine or arginine in B28, which optionally can also be modified in B3 and / or A21. Accelerated activity is also exhibited with the insulin analogues described in EP-A-0 885 961.

EP 0 419 504 describes insulin analogues that are protected against chemical modifications by modification of

IMPIfS

INSTITUTO MEXICANí '· DE LA PROFIEDAL C INDUSTRIAL ^xasparagm at B3 and from at least one other amino acid at positions A5, A15, A18 or A21.

WO 92/00321 describes insulin analogues in which at least one amino acid at positions B1-B6 has been replaced by lysine or arginine. Said insulins, according to WO 92/00321, have prolonged activity. The insulin analogues described in EP-A 0 368 187 and the insulin analogues described in Germany patent applications 10 2008 003 568.8 and 10 2008 003 566.1 also exhibit delayed activity.

Insulin preparations from insulin found in nature for insulin replacement, which are on the market differ in the origin of insulin (eg bovine, porcine, human insulin) and also in its composition, therefore, the action profile may be influenced by it (start of action and duration of action). By combining different insulin products it is possible to obtain a wide variety of action profiles and to set blood sugar levels that are as close to physiological as possible. Currently, recombinant DNA technology enables the production of such modified insulins. These include insulin glargine (human insulin Gly (A21) -Arg (B31) -Arg (B32)), with long duration of action. Insulin glargine is injected as a limpid acid solution and, due to its properties in solution in the physiological pH range of subcutaneous tissue, it precipitates as a stable hexamer partner. Insulin glargine is injected once a day and is notable compared to other long-acting insulins for its flat serum profile and the associated reduction in the risk of nocturnal hypoglycemia (Schubert-Zsilavecz et al., 2: 125-130 (2001) ).

MEXICAN INSTITUTE

Df. THE PROPERTY -Jn:

INDUSTRIAL 'esa-J

The specific insulin glargiiTS preparation which led to a long duration of action is characterized by being a clear solution with an acidic pH.

Glucagon-like peptide 1 (GLP-1) is an endocrine hormone that increases the insulin response after oral intake of glucose or fat. GLP-1 generally regulates 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, LopezDelgado 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) amide and GLP-1 (7-37).

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

Exendin-3, exendin-4, and exendin agonists have

IMPW

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL have been proposed for the treatment of diabetes mellitus and the prevention of hyperglycemia; reduce gastric motility and gastric emptying (US 5,424,286 and WO98 / 05351).

Exendin analogs can be characterized by amino acid replacements and / or C-terminal truncation of the natural exendin-4 sequence. Exendin analogs of this type are described in WO 99/07404, WO 99/25727, WO 99/25728.

The combinations of insulin and GLP-1 are known from WO 2004/005342 for the treatment of diabetes.

In clinical practice, the amount of insulin to be administered is adjusted to the individual requirements of each patient with diabetes. Each individual patient generally needs different amounts of insulin and / or GLP-1 agonist. Generally, the predetermined dose is administered by administering a defined amount of a composition having a defined concentration. This results in a composition comprising insulin and GLP-1 at the same time allowing the administration of only a particular proportion of insulin and GLP-1. This implies that only one of the two amounts of insulin and GLP-1 can be optimally adapted to the requirement of the patients. Given that correct adjustment of the amount of insulin administered is essential in practice, it is assumed that, when a particular proportion of insulin to GLP-1 is administered, the GLP-1 agonist is in insufficient or excessive doses and in the best case is by chance correct.

Various systems are known for injecting a combination of active compounds. The active compounds can be formulated in

IMPT ΐΝνπτυΤΟ MEXICANO rrI.Á industrial property a composition and supply in a device, for example in a pre-filled syringe. Such a system allows dosing of the combination, but only in a fixed portion of the active compounds, as presented in the composition. As stated there, this is a disadvantage for the combination of an insulin with a GLP-1 agonist, since different amounts of the insulins and the GLP-1 agonist must be administered, according to the therapeutic requirement.

It is also possible to administer two active compounds in two separate formulations, each comprising one of the two active compounds, which are injected independently of each other, each with a device (eg prefilled syringes). In the case of injection therapy such as insulin injection, for example, patient compliance is a key prerequisite for successful therapy. In general, in the case of injection therapy, pain, phobia of needles, and ease of transporting the injection apparatus represent a problem that can lead to reduced compliance. If the patient must use two different devices for injection, these problems multiply.

A single device for insulin delivery and a GLP-1 agonist is advantageous with respect to the use of two different devices for administering insulin and a GLP-1 agonist for the patient / user. In addition, the use of a single device instead of two devices can reduce the number of steps the patient / user must complete, which reduces the frequency of errors in use. This reduces the risk of unwanted side effects.

<img file="MX344293B_D0012.tif" />

<img file="MX344293B_D0013.tif" />

MÍXiCANd INSTITUTE OF. INDUSTRIAL PROPERTY

<img file="MX344293B_D0014.tif" />

Documents US 4,689,042, US 5,478,323, US 5,253,785 and

WO 01/02039 describe devices for the simultaneous administration of two injectable products to a patient. These devices comprise two containers, each containing a composition. In these devices, the two compositions are injected through a needle. This allows to overcome the disadvantages produced by the use of two separate devices. As a result of the mixing process, there is a dilution of the concentrations of the two active compounds. This can have an adverse impact on pharmacokinetics.

The pharmacokinetics of insulin, particularly insulin glargine, is influenced by the dilution of insulin in the administered composition. In order to ensure reliable activity of a particular dose of insulin, therefore, the insulin concentration should be kept constant as much as possible. Dosing must take place essentially through the volume of the insulin composition administered. This also applies to the administration of a combination of insulin and a GLP-1 agonist. When a combination of insulin and a GLP-1 agonist is administered, this condition can only be met if both substances are dosed in a fixed proportion to each other in a composition. When both substances are supplied in separate compositions and mixed for injection in a suitable device (for example, according to WO 01/02039), then a constant concentration of insulin can only be obtained if the insulin composition is not substantially diluted by the composition of the GLP-1 agonist. This imposes limits on the possibility of insulin and agonist independent dosing of GLP-1.

<img file="MX344293B_D0015.tif" />

A possible solution would be to supply the deüSLFM— ~ agonist in a concentration high enough so that the dosed addition of the GLP-1 agonist does not produce significant dilution of the insulin composition (eg, not more than 10%). Polypeptides such as insulins (eg insulin glargine, Lantus®) or GLP-1 agonists cannot be concentrated ad infinitum. First, the solubility of proteins is limited, and high protein concentrations can alter the flow characteristics of the solution. The most important problem with the use of solutions with a high concentration of active compound is the precision of the dose. In high concentrations it would be necessary to administer small volumes or to perform the dosing in a different solution. Devices are known that accurately dose small or very small volumes. However, such devices have a high cost and, based on their operation, are only intended for use by trained personnel, such as the laboratory. Since patients generally inject themselves alone with GLP-1 insulins and / or agonists, the use of such devices to deliver GLP-1 insulins and / or agonists is ruled out. The devices described, for example, in US 4,689,042, US 5,478,323, US 5,253,785 and WO 01/02039, which allow patients to inject themselves with solutions of active compound, are unsuitable for dosing small or very small volumes.

The problems caused by the injection of a combination of an insulin and a GLP-1 agonist are the following: • The proportion of the active compounds must be variable;

MEXICAN PROPERTY INSTITUTE • The pharmacokinetics of at least one of the compounds cKifF &amp; óé (leF --- insulin) is influenced by the concentration / dilution; ~ • The pharmacokinetics of at least one other active compound (the GLP-1 agonist) is not influenced or is not substantially influenced by concentration / dilution.

Accordingly, one of the objectives of the present invention is to provide a medicament which at least in part overcomes the previously described disadvantages of the prior art. Another intention is that whenever possible there is only one administration per day.

Surprisingly, it was found that the combination of an insulin with a GLP-1 agonist exhibits synergistic effects on the regulation of blood glucose in the postprandial and postabsorptive passages, compared to the use of insulin or the GLP-1 agonist alone:

• Increased activity based on the combination of complementary activities of fasting and postprandial glucose levels, which complement each other (examples 2 and 3). The combination exhibits a reduction in postprandial glucose concentration (i.e., greater glucose tolerance) than the GLP-1 agonist alone, and also exhibits postabsorptive glucose reduction similar to that of insulin (Example 9).

• Reduced risk of hypoglycemia (examples 2-4).

• Greater adaptation of the blood glucose concentration with respect to the normoglycemic levels (example 8).

IMPI

MEXICAN INSTITUTE OF PROPERTY

Greater glucose tolerance and reduced condSFiHStÜone

<img file="MX344293B_D0016.tif" />

postabsorptive glucose (example 9).

• The synergistic activities of the combination on the glucose concentration are observed in the concentration range of the GLP-1 agonist of an order of magnitude (factor 10). (Example 6 compared to examples 4 and 2). Only in the case of relatively low doses of GLP-1 and / or relatively large proportions of insulin to GLP-1, do insulin activities predominate.

• Maintains the function of β cells (example 10).

• Weight loss / reduction in weight gain.

• All examples demonstrate that GLP-1 agonists and insulins do not exhibit adverse interactions.

• As a result of activities on fasting, postprandial, and postabsorptive blood glucose levels, it is possible to reduce the number of administrations of the combination to once per day.

The invention provides a medicament comprising at least one insulin and at least one GLP-1 agonist, wherein the medicament is formulated and / or composed such that it comprises the insulin and the GLP-1 agonist, each in a predetermined amount and can be administered in a dose adapted to the individual requirement of a patient.

The medicament of the invention is used in particular to treat patients with diabetes mellitus, more particularly patients with type 1 or type 2 diabetes.

<img file="MX344293B_D0017.tif" />

MEXICAN INSTITUTE r »cia ao'xttm.

OF THE INDUSTRIAL PROPERTY

<img file="MX344293B_D0018.tif" />

The medicament of the invention makes it possible to adapt the blood glucose concentration more effectively to normoglycemic levels in the case of patients with diabetes, more particularly type 1 or type 2 diabetes.

The medicament is preferably used to adjust the fasting, postprandial and / or postabsorptive blood glucose concentration of patients with diabetes, more particularly patients with type 1 or type 2 diabetes. More preferably, the medicament of the invention is used to adjust the postprandial and / or postabsorptive blood glucose concentration of patients with diabetes, more particularly patients with type 1 or type 2 diabetes. In this context, adjustment means that normoglycemic concentrations of blood glucose or at least one approximation are substantially achieved. Normoglycemic levels are more particularly meant blood glucose concentrations in the normal range (fluctuation width 60 - 140 mg / dl, corresponding to 3.3 to 7.8 mmol / l). This range of fluctuation encompasses blood glucose concentrations under fasting conditions, postprandial conditions, and postabsorptive conditions.

Postprandial and postabsorptive are terms known to those skilled in the art of diabetes. Postprandial is used herein to refer more particularly to the phase after a meal and / or after a glucose load in an experiment. This phase is characterized more particularly in a healthy individual by an increase and decrease in the concentration of glucose in the blood. Post-absorbent, or post-absorptive phase, is used herein to refer

MIXICAN INSTITUTE OF INDUSTRIAL PORTAL more particularly to the phase that follows the postprandial phase. The postprandial phase generally ends around 4 h after a meal and / or glucose load. The postabsorptive phase generally lasts up to 8 a

h.

The medicament of the invention is also preferably used to improve glucose tolerance in the treatment of a patient with diabetes, more particularly with type 1 or type 2 diabetes. Improving glucose tolerance means that the medicament of the invention decreases the postprandial concentration of blood glucose. Improving glucose tolerance is also taken with the meaning that the drug of the invention lowers the post-absorptive concentration of blood glucose. Decreasing more particularly means that the concentration of blood glucose substantially reaches or at least approaches normoglycemic values. The medicament of the invention is capable of reducing the risk of hypoglycemia, which can occur, for example, in the post-absorptive phase. The medicament of the invention is preferably used to prevent hypoglycemia in the treatment of a patient with diabetes, more particularly with type 1 or type 2 diabetes, where it is possible for hypoglycemia to occur more particularly in the postabsorptive phase.

The medicament of the invention can maintain the function of the β cells of the pancreas. The medicament of the invention is preferably used to prevent loss of pancreatic β-cell function in a patient with diabetes, more particularly with type 1 or type 2 diabetes. Loss of β-cell function may be more particularly caused by apoptosis.

MEXICAN INSTITUTE

OF THE PROPERTY

In addition, the medicine of the invention can pdfS ^ Ec / Cfear

<img file="MX344293B_D0019.tif" />

weight loss and / or prevent weight gain in patients with diabetes, more particularly type I or II. In patients with diabetes, especially type 2 diabetes, weight gain and excessive weight are common problems. Consequently, the administration of the medicine of the invention can endorse a therapy for the treatment of excess weight.

It will be appreciated that the medicament of the invention can be used for the purpose of treating more than one of the preferred indications described therein in a patient with diabetes, more particularly with type 1 or 2 diabetes. Accordingly, the present invention encompasses not only the preferred individual indications, but also arbitrary combinations of indications. The medicament of the invention accordingly can be used to treat one or more of the indications described herein in patients with diabetes, more particularly in patients with type 1 or type 2 diabetes, for the purpose, for example, of adjusting the concentration fasting blood glucose, postprandial and / or post-absorptive, to improve glucose tolerance, to prevent hypoglycemia, to prevent loss of pancreatic β-cell function, for weight loss and / or to prevent weight gain. Adjusting the fasting, postprandial and / or postabsorptive blood glucose concentration, improving glucose tolerance and / or preventing hypoglycemia are preferred.

The medicament of the invention can also be used to produce a medicinal product to treat one or more of the indications described herein, such as, for example, to adjust fasting, postprandial and / or fasting blood glucose concentration.

IMPI

MEXICAN INSTITUTE

Ot the coldness

INDUSTRIAL

<img file="MX344293B_D0020.tif" />

post-absorptive, to improve glucose tolerance, to prevent hypoglycemia, to prevent a loss of pancreatic β-cell function, for weight loss and / or to prevent weight gain.

The at least one insulin and the at least one GLP-1 agonist can also be used to produce a medicinal product to treat one or more of the indications described herein, such as for example to adjust fasting blood glucose concentration , postprandial and / or postabsorptive, to improve glucose tolerance, to prevent hypoglycemia, to prevent loss of pancreatic β cell function, for weight loss and / or to prevent weight gain.

The at least one GLP-1 agonist and the at least one insulin can be provided together in a pharmaceutical composition. In this case, a first and a second composition and, optionally, at least one other pharmaceutical composition are provided, where each comprises insulin and the GLP-1 agonist. Accordingly, the invention provides a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, and, optionally, at least one other pharmaceutical composition, wherein each comprises at least one insulin and at least one GLP-1 agonist, and containing the at least one insulin and / or the at least one GLP-1 agonist in different fractions by weight with respect to the total weight of the composition.

In the present specification optionally, at least one other pharmaceutical composition means that the medicament of the invention, in addition to the first and second compositions

IMPI SU

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY pharmaceuticals, may comprise at least one other pharmaceutical composition. 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 drugs are those that comprise a first and a second pharmaceutical composition of the invention.

Equally preferred are the drugs comprising a first, a second and a third pharmaceutical composition of the invention.

Equally preferred are the drugs comprising a first, a second, a third and a fourth pharmaceutical composition of the invention.

Equally preferred are drugs comprising a first, a second, a third, a fourth, and a fifth pharmaceutical composition.

The weight fractions of the at least one insulin and of the at least one GLP-1 agonist can be selected in the first pharmaceutical composition, the second pharmaceutical composition, and, when used, in the at least one other pharmaceutical composition. such that the pharmaceutical compositions contain different proportions of insulin to GLP-1 agonist, based on the weight fraction.

In this case, the first composition can contain the lowest proportion and the second composition, the next highest proportion. When at least one other composition is present, it may contain the next highest proportion. When another is also present

<img file="MX344293B_D0021.tif" />

composition, may contain the next highest proportion in turn. Accordingly, the compositions may contain proportions of insulin to GLP-1 agonist, based on weight fraction, increasing from the first to the second and, when used, the following compositions.

The weight fraction of one of the two active compounds, that is, of the at least one insulin or of the at least one GLP-1 agonist, in the first pharmaceutical composition, the second pharmaceutical composition, and, when used, the at least one other pharmaceutical composition is preferably selected in each case such that the predetermined dose of this active compound can be administered by administration of a defined volume of the first, the second and / or at least one other composition. With particular preference, this active compound in the at least one insulin.

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, when used, the at least one other pharmaceutical composition is preferably selected such that the ratios of insulin to GLP-1 agonist, based on weight fraction, increases from the first to the second and, when used, other compositions . With particular preference, this active compound is the at least one GLP-1 agonist.

Furthermore, the weight fraction of the other of the two active compounds in the pharmaceutical compositions is determined such that one of the pharmaceutical compositions can be selected from

<img file="MX344293B_D0022.tif" />

<img file="MX344293B_D0023.tif" />

INSTITUTO MtXíCANO DF. INDUSTRIAL PROPERTY such 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 given in a defined volume. Thus, a pharmaceutical composition containing the desired ratio is selected.

In theory, it should be possible to provide a pharmaceutical composition for each therapeutically desired individual proportion of the weight fractions of the at least one insulin to the at least one GLP-1 agonist, in order to obtain an optimal dose, tailored to the requirements , for both active compounds for each patient.

In the present invention, a particular amount of pharmaceutical compositions is sufficient to cover the doses necessary to practice the two active compounds. For each patient, a dosage range is defined within a therapeutically rational range for each of the two active compounds. The dose that is administered should thus fluctuate essentially within the dosage range for a particular patient, without any excess and defective doses.

Surprisingly, it was found that the synergistic effects of the combination of at least one insulin and at least one GLP-1 agonist on the concentration of glucose in the blood plasma occurs in a concentration range of the GLP-1 agonist of an order of magnitude (factor 10). Since it is primarily the amount of insulin that must be precisely tailored and dosed for each individual patient, the synergistic concentration range of the GLP-1 agonist produces a pharmaceutical composition of the invention that contains a defined proportion of at least one insulin regarding the at least one agonist of

MEXICAN INSTITUTE

OF THE INDUSTRIAL MONEDAD

GLP-1 to cover the therapeutic range of insulin doses simultaneously with the associated synergistic amount of GLP-agonist

one. The ratio can be selected such that each desired dose of insulin has its corresponding dose of the at least one GLP-1 agonist, which is within the desired range, eg, the synergistic range. As stated above, the proportions of the first, the second, and, when used, at least one other composition of the drug can also be chosen such that the proportions increase from the first to the second and, when they use, the at least one other composition. If the dose of the GLP-1 agonist at the desired dose of insulin in one composition (eg, the first composition) is outside (generally higher) than the desired dosage range of the GLP-1 agonist, then the next composition ( for example, the second composition) or another composition with a higher 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 dose of insulin is within the desired range. The proportions of the first, second, and, when used, at least one other drug composition can also be chosen such that the insulin dose ranges corresponding to the desired doses of the at least one LPG agonist -1 limit each other and / or overlap each other. The ranges preferably overlap. Overlap more particularly means that it is possible to select at least two compositions that, in the desired dose of the at least one insulin, each contain an amount of the at least one GLP-1 agonist that is within the desired dose range.

IΜ ΡI 015¾

INSTtTtn Μ

ΠΕ LA FKÍFFIEOkb

For example, three compositions are sufficient to 'adjust the dose of the at least one insulin for a patient' Tñ ^ MdüáTen'eTriivel selected from the range of 15 to 80 insulin units and at the same time dose the GLP-1 agonist with a amount within the range of 10 to pg (see example 11).

It is also possible to provide a medicament of the invention in which the ratio is selected such that for each desired dose of the GLP-1 agonist there is a corresponding dose of the at least one insulin that is within the desired range, for example , the synergistic range. The proportions of the first, second, and, when used, at least one other drug composition can also be chosen such that the ranges of GLP-1 agonist doses that correspond to the desired doses from al minus one insulin limit each other and / or overlap each other. The ranges preferably overlap. In this context, overlap more particularly means that it is possible to select at least two compositions that, in the desired dose of the at least one GLP-1 agonist, each contain an amount of the at least one insulin that is within the range desired dose.

Preferably the medicament of the invention contains not more than 10 pharmaceutical compositions as defined above, more preferably not more than 5, not more than 4, not more than 3 or 2 pharmaceutical compositions.

The compositions of the invention may contain the at least one insulin in identical or different weight fractions. For example, at least two of the compositions of the invention can

<img file="MX344293B_D0024.tif" />

²² ΙΜΡΙ

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL contain the at least one insulin in a substantially identical weight fraction.

Preferably, the first, second, and, when used, other compositions contain the at least one insulin in a substantially identical weight fraction and the at least one GLP-1 agonist in different weight fractions.

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

It is also preferred that the first, second, and, when used, other compositions contain the at least one GLP-1 agonist in a substantially identical weight fraction and the at least one insulin in different weight fractions.

In addition to the first, the second, and, when using, at least one other composition, the medicament of the invention may comprise at least one other 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 other pharmaceutical composition containing at least one insulin and at least one GLP-1 agonist in a proportion of the weight fractions similar to those described above as first, second or, when Another pharmaceutical composition is used.

The invention also provides a medicament comprising a first pharmaceutical composition and a second composition.

IMPI »

MEXICAN INSTITUTE

Dt THE PROPERTY

INDUSTRIAL - Pharmaceutical, wherein the first pharmaceutical composition comprises at least one insulin and the second pharmaceutical composition comprises at least one GLP-1 agonist, wherein the medicament is formulated and / or forms a compound for independent administration of the first and the second pharmaceutical composition.

Example 12 shows how a combination of two or more active compounds can be formulated such that when two or more compositions are combined, both active compounds can be administered in any desired amount and in any desired proportion to each other. This takes into account the fact that at least one of the active compounds must not be diluted as a result of the combination (for example, by 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 other active compound, wherein these active compounds are provided in a first, a second, and, optionally, at least one another composition. The first active compound is present in all compositions. The second active compound is present in the second formulation, and the at least one other active compound, when used, is present in the optionally at least one other composition. Thus the second and each of the other compositions comprise the first active compound in combination with another active compound.

The present invention accordingly also provides a medicament comprising a first pharmaceutical composition and

IMPI

<img file="MX344293B_D0025.tif" />

a second pharmaceutical composition, and optionally at least one other pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one first active compound, and the second pharmaceutical composition comprises at least one first active compound and at least one second active compound, and the at least one other pharmaceutical composition comprises at least a first and at least one other active compound. The active compounds here can be any of the desired active compounds.

The first composition preferably comprises as active compound only the at least one first active compound .

The first, the second, and, when used, at least one other composition may comprise the first active compound in a substantially identical weight fraction or in different weight fractions relative to the total weight of the composition.

It is preferred that the first pharmaceutical composition, the second pharmaceutical composition, and, when used, the at least one other pharmaceutical composition comprise the first active compound in substantially identical weight fractions relative to the total weight of the composition. In this way, it is possible to ensure that any desired proportion of the first and second composition can be used and, where applicable, any desired proportion of the first and at least one other composition, where the dose of the first active compound takes place at through the total amount of the administered compositions. Through the ratio of the two compositions it is possible to increase steplessly the amount of the active compound found only in the second composition and, where appropriate, in the al

<img file="MX344293B_D0026.tif" />

²⁵ IMPI

INSTITUTO Mexicano r&gt; f LA PROPIIOAD INDISTRIAL minus one other composition. Thus, accordingly, it is easily possible to dose any desired amount and any desired ratio of the first to the second active compound and, where appropriate, the first active compound to another active compound, without altering the concentration of the first active compound.

The first active compound can be at least one insulin. The second active compound can be at least one GLP-1 agonist. A medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one other pharmaceutical composition, is preferred, wherein the first pharmaceutical composition comprises at least one insulin, and the second pharmaceutical composition comprises at least one insulin and at least one GLP-1 agonist, and the at least one other pharmaceutical composition comprising at least one insulin and at least one other active compound.

The first composition preferably comprises as active compound only the at least one insulin.

The other active compound can be any desired active compound. More particularly, the other active compound is an active compound that is used to treat patients with diabetes mellitus (type 1 and / or type 2), including active compounds to also treat concomitant disorders of diabetes.

The first, the second, and, when used, at least one other composition may comprise insulin in a substantially equal weight fraction or in different weight fractions relative to the total weight of the composition.

It is preferred that the first pharmaceutical composition, the

IMPI

<img file="MX344293B_D0027.tif" />

second pharmaceutical composition, and, when used, the at least one other pharmaceutical composition comprise insulin in fractions by weight substantially equal to the total weight of the composition.

In this way it is possible to ensure that any desired proportion of the first and second composition can be used and, where applicable, any desired proportion of the first and at least one other composition, the dose of insulin that is made through the amount total of the administered compositions. Through the ratio of the two compositions it is possible to steplessly increase the amount of the active compound found only in the second composition and, where appropriate, in the at least one other composition. Accordingly, it is thus easily possible to dose any desired amount and any desired ratio of insulin to the GLP-1 agonist and, where appropriate, insulin to another active compound, without altering the concentration of the at least one Insulin.

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

The first active compound can also be at least one GLP-1 agonist. The second active compound can be at least one insulin. A medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one other pharmaceutical composition, is preferred, wherein the first pharmaceutical composition comprises at least one agonist of

IMPI

WSTfTUTt · MEXICAN.DE&gt; .A MOFIEDAI *

GLP-1, and the second pharmaceutical composition I bought^leil m

<img file="MX344293B_D0028.tif" />

a GLP-1 agonist and at least one insulin, and where ~ an other pharmaceutical composition comprises at least one GLP-1 agonist and at least one other active compound.

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

The first, the second, and, when used, at least one other composition may comprise the GLP-1 agonist in a substantially equal weight fraction or in different weight fractions relative to the total weight of the composition. It is preferred that the first pharmaceutical composition, the second pharmaceutical composition and, when used, the at least one other pharmaceutical composition comprise the at least one GLP-1 agonist in substantially equal weight fractions relative to the total weight of the composition.

Accordingly, the present invention provides a medicament that exhibits numerous advantages over prior art compositions, comprising separate compositions each containing an active compound, more particularly an insulin or a GLP-1 agonist, wherein such advantages include the following:

• The ratio of the first active compound to the second active compound and, where applicable, the first active compound to at least one other active compound can be freely chosen by the user.

• Since the first active compound is present in all compositions, more particularly in equal weight fractions, this active compound is not diluted when the first composition is

IMPI

<img file="MX344293B_D0029.tif" />

INSTITUTO MEXICANO DE LA PROHBDAD INDUSTRIAL mixes with the second and, when appropriate, other compositions. This is important for active compounds such as insulin, for example, in which the pharmacokinetics are influenced by the concentration / dilution.

• The injection volume is reduced (see example 12). Consequently there is a reduction in the dilution of the second active compound (eg, a GLP-1 agonist) and, where appropriate, of another active compound.

The invention also provides a kit comprising a medicament of the invention. The kit of the invention may be intended for use by a medical team or by persons without specialist medical training, more particularly by patients or auxiliaries such as family members. In the kit of the invention, the individual pharmaceutical compositions comprising the medicament of the invention are prepared in separate packages, and consequently the patient can select the composition appropriate to the current requirement and administer an amount corresponding to that requirement. The kit of the invention comprises, for example, the medicament of the invention in the form of a set of syringes, glass ampoules and / or packages comprising a composition of the invention.

The medicament of the invention can be administered in various known ways. The drug can be administered parenterally. The drug can be injected, with the possible use of injection systems with or without needles. In addition, the drug can be administered by inhalation. In this case it is possible that

IMPI

MSXJCANO INSTITUTE

OF. IA INDUSTRIALITY Liquid compositions are inhaled, or the compositions are inhaled in the powder form. Furthermore, the medicament of the invention can be administered as a spray, more particularly as a nasal spray. Furthermore, the medicine of the invention can be administered by a transdermal system. The skilled operator knows these administration methods and is capable of formulating the medicament of the invention in such a way that it can be effectively administered by one of these administration methods. The compositions of the medicament of the invention are preferably liquid. Furthermore, it is preferred that the medicament of the invention is administered parenterally, more particularly by injection.

The present invention also provides a device for administering the medicament of the invention. This device comprises the pharmaceutical compositions that are covered by the medicament of the invention, in separate containers, and allows the pharmaceutical compositions to be dosed independently of each other. The device of the invention can be a device for parenteral administration. The device of the invention can be a device for injection with or without needles. Furthermore, the device can be an inhalation device, in which case liquid compositions are inhaled, or the compositions can be inhaled in the powder form. Furthermore, the device may be a device for administering a spray, more particularly a nasal spray. Furthermore, the device can be a transdermal delivery system. It is preferred that the device of the invention is a device for parenteral administration, more particularly a device for injection.

<img file="MX344293B_D0030.tif" />

MEXICAN INSTITUTE

OF THE PWOFIEDAU INDUSTRIAL

<img file="MX344293B_D0031.tif" />

"Compound packaging" is a term known to the skilled operator and which in pharmacology identifies termination treatment, such as portion preparation and packaging, for example, of drugs for use by the end user. In the present specification, "compound packaging" or "compound packaging" means more particularly that the pharmaceutical compositions of the invention are suitably packaged in a therapeutically effective amount to allow for the selection described herein of at least one of the compositions of the medicament of the invention for the desired dose of the at least one insulin and of the at least one GLP-1 agonist. More particularly, a parenteral administration, preferably an injection, more preferably a subcutaneous injection is intended. The suitable packaging is, for example, a syringe or a glass container with a suitable closure, from which, as required, individual therapeutically active doses can be drawn. Similarly, injection containers for insulin administration are also suitable, comprising a container (eg, a reel) which contains a pharmaceutical composition of the invention.

"Formulating" or "formulation" is a term known to those skilled in the art and which in the field of pharmacology refers to the production of drugs and drug compositions, and their preparation with excipients. In the present specification "formulating" or "formulation" means more particularly that the composition of the invention is provided in a suitable form that allows the administration of a therapeutically effective amount of the active compounds. Plus

IMPI (á? INSTITUTO MEXICANO VíSfi DE LA FROMEDAD

INDUSTRIAL particularly, a formulation is for parenteral administration, preferably for injection, more preferably for subcutaneous injection.

In the present invention, the term "GLP-1 agonist" includes GLP-1, its analogs and derivatives, exendin-3 and its analogs and derivatives, and exendin-4 and its analogs and derivatives. The compositions of the invention comprise one or more selected independently of one another from the group consisting of glucagon-like peptide 1 (GLP-1), GLP-1 analogs and derivatives, exendin-3, exendin-3 analogs and derivatives, exendin -4, analogs and derivatives of exendin-4, and its pharmacologically tolerable salts. Also included are substances that exhibit the biological activity of GLP-1.

Analogues and derivatives of

GLP-1 are described in WO 98/08871, for example; exendin-3, exendin-3 analogs and derivatives, and exendin-4 and exendin-4 analogs and derivatives can be found in WO 01/04156,

WO 98/30231, US 5,424,286, in EP application 61 61 043.4, in WO 2004/005342 and WO 04/035623. These documents are included herein by reference. The exendin-3 and exendin-4 described in these documents, and their analogs and derivatives described therein, can be used in the compositions of the present invention as GLP-1 agonists. It is also possible to use any desired combination of exendin-3 and exendin-4 described in these documents, and the analogs and derivatives described therein as GLP-1 agonists. The at least one GLP-1 agonist is preferably independently selected from the group consisting of exendin-4, analogs and derivatives

IMPI

<img file="MX344293B_D0032.tif" />

of exendin-4, and its pharmacologically tolerable salts.

Another preferred GLP-1 agonist is an exendin-4 analog selected from the group consisting of: H-desPro³⁶-exendin-4-Lyse-NH2, H-des (Pro^36,37) -exend¡na-4-Lys4-NH2, H-des (Pro^36,37) -exendina-4-Lys5-NH2, and their pharmacologically tolerable salts.

Another preferred GLP-1 agonist is an exendin-4 analog selected from the group consisting of: desPro³⁶ [Asp²⁸] exendin-4 (1-39), desPro³⁶ [lsoAsp²⁸] exendin-4 (1-39), desPro³⁶ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39), desPro³⁶ [Me to)¹⁴, lsoAsp²⁸] exendin-4 (1-39), desPro³⁶ [Trp (O2)²⁵, Asp²⁸] exendin-2 (1-39), desPro³⁶ [Trp (O2)²⁵, lsoAsp²⁸] exendin-2 (1-39), desPro³⁶ [Me to)¹⁴Trp (O₂)²⁵, Asp²⁸] exendin-4 (1-39), desPro³⁶ [Me to)¹⁴Trp (O2)²⁵, lsoAsp²⁸] exendin-4 (1-39), and its pharmacologically tolerable salts.

Another preferred GLP-1 agonist is an exendin-4 analog selected from a group as described in the previous paragraph, where the -Lys peptide₆-NH₂ has been attached to the C-termini of exendin-4 analogs.

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

H- (Lys)₆- des Pro³⁶ [Asp²⁸] exendin-4 (1-39) -Lys6-NH2 des Asp²⁸Pro³⁶, Pro³⁷, Pr038 exendin-4 (1-39) -NH2,

IMPI »

INSTITUTO Mt&gt; UCAN &lt;: OF THE PROPERTY ----^:Ptl _{or &lt;5} o-, oo non-INDUSTRIAL

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

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

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

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

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

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

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

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

H- (Lys) 6- des Pro³⁶ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) -Lys6-NH₂, des Met (O)¹⁴ Asp²⁸ Pro ³⁶, Pro³⁷, Pro³⁸ exendin-4 (1-39) -NH₂,

H- (Lys)₆- des Pro³⁶, Pro ³⁷, Pro³⁸ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) -NH2, H-Asn- (Glu) 5- des Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) NH2, des Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) - (Lys) 6-NH₂,

H- (Lys)₆- des Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) -Lys₆NH₂,

H-Asn- (Glu)₅ from Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) (Lys)₆-NH₂,

H- (Lys)₆- des Pro³⁶ [Me to)¹⁴, Trp (O2)²⁵, Asp²⁸] exend¡na-4 (1-39) -Lys6-NH₂,

IMPI

<img file="MX344293B_D0033.tif" />

des Asp²⁸ Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Trp (O2)²⁵] exendin-4 (1-39) -NH2,

H- (Lys)₆- des Pro³⁶'Pro³⁷, Pro³⁸ [Me to)¹⁴, Trp (O₂)²⁵, Asp²⁸] exendin-4 (1

39) -NH₂,

H-Asn- (Glu)₅- des Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Asp²⁸] exendin-4 (1-39) NH₂, from Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Trp (O2)²⁵, Asp²⁸] exendin-4 (1-39) - (Lys) 6NH₂,

H- (Lys)₆- des Pro^36, Pro³⁷, Pro³⁸ [Me to)¹⁴, Trp (O2)²⁵, Asp²⁸] exendin-4 (139) - (Lys) 6-NH₂,

H-Asn- (Glu)₅- des Pro³⁶, Pro³⁷, Pro³⁸ [Me to)¹⁴, Trp (O2)²⁵, Asp²⁸] exendin4 (1-39) - (Lys) 6-NH₂, and its pharmacologically tolerable salts.

Another preferred GLP-1 agonist is selected from a group consisting of Arg³⁴, Lys²⁶(N^and(y-glutamyl (N^to-hexadecane!))) GLP-1 (7-37) [liraglutide] and one of its pharmacologically tolerable salts.

Another preferred GLP-1 agonist is AVE0010. AVE0010 has the Pro sequence³⁶exendin-4 (1-39) -Lys6-NH₂. This substance is published as SEQ ID No: 93 in WO 01/04156. The pharmacologically tolerable salts of AVE0010 are also preferred.

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

The at least one GLP-1 agonist is also preferably independently selected from exendin-4, Pro³⁶exendin-4 (1-39) Lys₆-NH₂, _and Arg³⁴, Lys²⁶(N^£(Y-glutamyl (N^to-hexadecanoyl))) GLP-1 (7-37)

IMPI

MEXICAN INSTITUTE i __&gt;

'OF THE MOF1EPAP

INDUSTRIAL - «n --- [liraglutide], and its pharmacologically tolerable salts.

The compositions of the invention contain the agonist of

GLP-1 in an amount of 10 pg / ml to 20 mg / ml, preferably 25 pg / ml to 15 mg / ml. For GLP-1 agonists dissolved in acid or neutral medium, the figures are preferably 20 pg / ml to 300 pg / ml, and for agonists dissolved in neutral to basic medium, they are preferably

500 pg / ml to 10 mg / ml. For exendin-4 analogs, 20 pg / ml to 150 pg / ml are preferred.

In the present specification, the term "insulin" encompasses not only unmodified insulins, but also insulin analogues, insulin derivatives, and insulin metabolites. The compositions of the invention comprise one or more selected independently from the group consisting of insulins (eg, unmodified insulins), insulin analogues, insulin derivatives, and insulin metabolites, and any of their desired combinations.

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

Furthermore, an insulin of the invention can be selected independently from unmodified insulins, more particularly from bovine insulins, porcine insulins, and human insulins.

The at least one insulin can be selected

<img file="MX344293B_D0034.tif" />

<img file="MX344293B_D0035.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY regardless of the group consisting of bovine insulins, porcine insulins, and human insulins. More preferably, the at least one insulin is independently selected from human insulins. An insulin of the invention can be selected from unmodified insulins, more particularly from bovine, porcine insulins, and human insulins.

The insulin derivatives of the invention are derivatives of naturally occurring insulins and / or an insulin analog, which is obtained by chemical modification. The chemical modification may consist, for example, of the addition of one or more defined chemical groups in one or more amino acids.

The insulin analogues described in EP 0 214 826, EP 0 375 437, EP 0 678 522, EP 0 885 961, EP 0 419 504, WO 92/00321, German patent applications 10 2008 003 568.8 and 10 2008 003 566.1, and EP-A 0 368 187 can be part of the compositions of the invention. 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 included herein by reference.

A preferred insulin analog of the invention can 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^B29 human insulin (insulin lyspro), B28 Asp human insulin (insulin aspart), human insulin in which proline at position B28 has been replaced by Asp, Lys, Leu, Val or Ala and where Lys at position B29 can be replaced by Pro; AlaB26 insulin

IMPIOUS ^ηΕ INDUSTRIAL human; des (B28-B30) human insulin; des (B27) human insulin or

B29Lys (e-tetradecanoyl), des (B30) human insulin (insulin detemir).

<img file="MX344293B_D0036.tif" />

A preferred insulin derivative of 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^B28Pro^B29 human insulin, B28-N-palmitoyl-Lys^B28Pro^B29 human insulin, B30-N-myristoyl-Thr^B29Lys^B3° human insulin, B30-N-paImitoilThr^B29Lys^B3° human insulin, B29-N- (N-palmitoyl-Y-glutamyl) -des (B30) human insulin, B29-N- (N-litocolyl-Y-glutamyl) -des (B30) human insulin, B29- N- (w-carboxyheptadecanoyl) -des (B30) human insulin, and Β29-Ν- (ωcarboxyheptadecanoyl) human insulin.

A more highly preferred insulin derivative of the invention is selected from the group consisting of Gly (A21) -Arg (B31) Arg (B32) human insulin, Lys^B28Pro^B29 human insulin (lyspro insulin),

B28 Asp human insulin (insulin aspart), B29Lys (s tetradecanoyl), desB30 human insulin (insulin detemir).

The term "at least one insulin" includes the combinations of the insulins described herein, their analogues, derivatives, and metabolites that are used in the compositions of the invention, for example, any desired combination of two or more insulins selected from the Described herein, their analogues, derivatives, and metabolites.

The compositions of the invention contain 60-6000 nmol / ml, preferably 240-3000 nmol / ml, of an insulin as defined herein. Depending on the insulin used, a concentration of 240ΙΜΡΙ

<img file="MX344293B_D0037.tif" />

3000 nmol / ml corresponds approximately to a concentration of 1_4 -____ mg / ml or 40-500 units / ml.

In 2 to 10 full coverage systems, preferably 3 to 5, the compositions are in the range of 20 pg / ml GLP1 agonist and 100 U / ml insulin to 300 pg / ml GLP-1 agonist and 500 U / ml of insulin. The following concentration ranges are preferred: 25 pg / ml and 100 U / ml, 33 pg / ml and 100 U / ml, 40 pg / ml and 100 U / ml, 66 pg / ml and 100 U / ml, and 75 pg / ml and 100 U / ml.

The desired dosage range of insulin is in particular a dosage with synergistic effect. Here the values ​​are from 5 to 100 U, preferably from 15 to 80 U. For the GLP-1 agonist, the values ​​for the dosage range are from 5 pg to 2 mg, preferably 10 pg to 1.8 mg, more preferably 10 pg to 30 pg.

[More precise details here on the quantities used and on the dosages]

The preferred embodiment of the pharmaceutical compositions of the present invention consists of liquid compositions suitable particularly for parenteral administration, more preferably for injection, most preferably for subcutaneous injection. In particular, the pharmaceutical composition of the present invention is suitable for injection once a day.

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, more preferably pH 3.5 - 6.8, even more preferably pH 3.5 - 4.5, most preferably in a pH

IMPI

<img file="MX344293B_D0038.tif" />

of about 4.0 - 4.5. A physiological pH ran prAfprpnr.ia in the range of pH 4.0 - 8.5, more preferably pH 5.0 to 8.5, even more preferably pH 6.0 to 8.5.

The composition of the invention can comprise a suitable preservative. Examples of suitable preservatives include phenol, m-cresol, benzyl alcohol, and / or p-hydroxybenzoic esters.

The composition of the invention may also comprise a suitable buffer. Buffer substances that can be used, particularly to fix a pH level between about 4.0 and 8.5, include, for example, sodium acetate, sodium citrate, sodium phosphate, etc. On the other hand, dilute acids without physiological objections (generally HCI) or alkalis (generally NaOH) are suitable for fixing the pH level. The preferred concentrations of the buffers and also of the corresponding salts are in the range of 5-250 mM, more preferably in the range of 10-100 mM.

The composition of the invention can comprise zinc ions. The concentration of zinc ions is preferably in the range of 0 pg / ml to 500 pg / ml, more preferably 5 pg to 200 pg of zinc / ml.

The composition of the invention may also comprise suitable isotonicity agents. Suitable examples include glycerol, dextrose, lactose, sorbitol, mannitol, glucose, NaCl, calcium compounds, or magnesium compounds such as CaCh, etc. Glycerol, dextrose, lactose, sorbitol, mannitol, and glucose are generally in the range of 100-250 mM, NaCl in a concentration of up to 150 mM.

The composition of the invention may also comprise a surfactant. A surfactant can greatly increase

IMPIg ^ í

INSTITUTE .MEXICAíMi.

OF THE INDUSTRIAL PROFIEDAL 'measured the stability of acidic insulin compositions. By using the surfactant it is even possible to prepare compositions that guarantee the superior stability with respect to the hydrophobic aggregation nuclei for many months before exposures at elevated temperature.

The surfactant is preferably selected from the group consisting of partial esters and of fatty acids and ethers of polyhydric alcohols such as glycerol and sorbitol, and polyols, wherein the partial esters and fatty acids and the ethers of glycerol and of sorbitol are selected from a group containing Span®, Tween®, Myrj®, Brij® and Cremophor®; and where the polyols are selected from the group of polypropylene glycols, polyethylene glycols, poloxamers, polysorbates, pluronics, and tetronics. Preferred concentrations of the surfactants are in the range of 5-200 pg / ml, preferably 5-120 pg / ml and more preferably 20-75 pg / ml.

The composition of the invention may also comprise other additives such as, for example, salts, which retard the release of at least one insulin.

A particularly preferred object of the invention is a medicament as described herein comprising at least one insulin independently selected from Lys^B28Pro^B29human insulin (insulin lyspro), B28 Asp human insulin (insulin aspart), B29Lys (s-tetradecanoyl), desB30 human insulin (insulin detemir), and insulin glargine (Gly (A21) -Arg (B31) -Arg (B32) insulin human), and comprising AVE0010 and / or one of its pharmacologically tolerable salts. Another particularly preferred object is a

IMPI

MEXICAN INSTITUTE

FROM THE PtOrifDAP

IN DUSTKíAL

<img file="MX344293B_D0039.tif" />

medicament as described herein which includes insnlina.

glargine (Gly (A21) -Arg (B31) -Arg (B32) human insulin) and AVE0010 (des Pro³⁶exendin-4 (1-39) -Lys6-NH2) and / or one of its pharmacologically tolerable salts. 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 a pH from about 4.0 to 4.5. Furthermore, the compositions of these particularly preferred drugs may comprise a surfactant as described herein.

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

The invention also 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, wherein the medicament is formulated and / or compounded such that it contains insulin and GLP-1 agonist, each in a predetermined amount and can be administered in a dose tailored to a patient's individual requirement.

More particularly, the method comprises administering a medicament comprising a first pharmaceutical composition and a second pharmaceutical composition, and, optionally,

<img file="MX344293B_D0040.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX344293B_D0041.tif" />

at least one other pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and comprising the at least one insulin and / or the at least one GLP-1 agonist in different fractions in weight with respect to the total weight of the composition, wherein said method comprises:

(a) Select a dose of the at least one insulin to be administered, (b) select a dose of the at least one GLP-1 agonist to be administered, (c) select a composition of the first, second, and , when used, at least one other composition of the medicament comprising the doses of (a) and (b) in a concentration such that the doses of (a) and (b) are present in the same volume, and (d) determining and administering an amount corresponding to the doses of (a) and (b).

The dose according to step (a) and / or step (b) is determined according to the individual requirement of the patients.

Step (c) of the treatment method of the invention can be carried out on the basis of a table. This table may be part of the medication of the Invention. Example 11 contains an example of a table of the invention.

The method of treating a patient may more particularly comprise the administration of a medicament, wherein the medicament comprises a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one other pharmaceutical composition, wherein the first composition

IMPI

<img file="MX344293B_D0042.tif" />

Pharmaceutical comprises at least one first active compound ...... and ...

second pharmaceutical composition comprises at least one first active compound and at least one second active compound, wherein the at least one other pharmaceutical composition comprises at least one first active compound and at least one other active compound, and wherein the method comprises the following steps :

(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, when used, at least one other composition, such that the selected dose of the at minus a first active compound is present in the total amount, (I) 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, (Ii) where appropriate, select a dose of the at least one other active compound to be administered, and determining the amount of the at least one other composition such that the selected dose of the at least one other active compound is present in the amount of the at least one other composition, (iv) administering an amount of the first composition to the patient , where the administered amount corresponds to the total amount according to step (i) minus the amount of the second composition according to step (ii), and, when applicable, minus the amount of the at least one other composition according to step (iii), and

IMPI, * 3;

^{, NST}'T'^r'T&gt; MKlCANO

ROI&gt; Industrial RROUSIMC (v) administer the amount of the second composition that was determined in step (ii), and, when applicable, the amount of the at least one other composition that was determined in step (iii), to patient.

The first active compound can be an insulin, and the second active compound can be a GLP-1 agonist. Accordingly, the method of treating a patient may more particularly comprise the administration of a medicament, wherein the medicament comprises a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one other pharmaceutical composition, wherein the first composition pharmaceutical comprises at least one insulin, and the second pharmaceutical composition comprises at least one insulin and at least one GLP-1 agonist, and wherein the at least one other pharmaceutical composition comprises at least one insulin and at least one other active compound, and the method comprises the steps of:

(i) select a dose of the at least one insulin to be administered, and determine the total amount of the first, the second, and, when used, at least one other 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) when appropriate, select a dose from the at least one other

<img file="MX344293B_D0043.tif" />

MEXICAN INSTITUTE OF THE INDUSTRIAL PkOPltDAL

<img file="MX344293B_D0044.tif" />

active compound to be administered, and determining the amount of the at least one other composition such that the selected dose of the at least one other active compound is present in the amount of the at least one other composition, (iv) administering a amount of the first composition to the patient, where the amount administered corresponds to the total amount according to step (i) minus the amount of the second composition according to step (ii), and, when applicable, minus the amount of the at least one other composition according to step (ii), and (v) administering the amount of the second composition that was determined in step (i), and, when appropriate, the amount of the al minus one other composition that was determined in step (ii), to the patient.

The first active compound can be a GLP-1 agonist, and the second active compound can be an insulin. Accordingly, the method of treating a patient may more particularly comprise the administration of a medicament, wherein the medicament comprises a first pharmaceutical composition and a second pharmaceutical composition, and optionally at least one other pharmaceutical composition, wherein the first composition pharmaceutical composition comprises at least one GLP-1 agonist, and the second pharmaceutical composition comprises at least one GLP-1 agonist and at least one insulin, and wherein the at least one other pharmaceutical composition comprises at least one GLP-1 agonist and at least one other active compound, and the method comprises the steps of:

(i) select a dose of the at least one GLP-1 agonist to be administered, and determine the total amount of the first, the

<img file="MX344293B_D0045.tif" />

IMPI iNSTmm&gt; Mexican GIVE PROPERTY

INDUSTRIAL second and, when using, at least one other composition, such that the selected dose of the at least one agonist of

GLP-1 is present in the total amount, (¡i) (¡v) select a dose of the at least one insulin to be administered and determine the amount of the second composition such that the selected dose of the at least an insulin is present in the amount of the second composition, when appropriate, select a dose of the at least one other active compound to be administered, and determining the amount of the at least one other composition such that the selected dose of the at least one other active compound is present in the amount of the at least one other composition, administering an amount of the first composition to the patient, wherein the amount administered corresponds to the total amount according to step (i) minus the amount of the second composition according to step (i), and, when applicable, minus the amount of the at least one other composition according to step (iii), and administering the amount of the second composition that was determined in step (ii), and, when applicable, the amount of the at least one other composition that in stage (iii), the patient was determined.

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

The treatment method of the invention can be used more particularly to treat patients with diabetes, more particularly

IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY with type I or II diabetes. Preferably the method is used to adjust the fasting, postprandial and / or postabsorptive blood glucose concentration, to improve glucose tolerance, to prevent hypoglycemia, to prevent loss of pancreatic β cell function, for loss weight and / or to prevent weight gain.

The invention also provides a method of preparing a medicament of the invention, which comprises formulating and / or preparing the compound such that it contains insulin and the GLP-1 agonist, each in a predetermined amount and that can be administered. in a dose adapted to the individual requirement of a patient. In the method of preparation the drug is preferably formulated and prepared in such a way that one of the drugs of the invention described in the, for example, a drug of the invention comprising a first pharmaceutical composition and a second pharmaceutical composition can be obtained. , and optionally at least one other pharmaceutical composition, each comprising at least one insulin and at least one GLP-1 agonist, and comprising the at least one insulin and / or the at least one GLP-1 agonist in different fractions by weight with respect to the total weight of the composition.

The invention is illustrated in the following figures and the following example, which in no way restrict the invention.

Key to the figures

Fig. 1: Study design for the oral glucose tolerance test.

Fig. 2: OGTT in the dog: effect of insulin glargine compared to placebo.

<img file="MX344293B_D0046.tif" />

Fig. 3: OGTT in the dog: effect of AVE0010 with respect to placebo.

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX344293B_D0047.tif" />

Fig. 4: OGTT in the dog: effect of a combination of AVEOOlO / insulin glargine on the level of blood glucose.

Figs. 5a and 5b: OGTT in the dog: effect of a combination of AVEOOlO / insulin glargine on the level of plasma insulin and peptide c.

Fig. 6: OGTT in the dog: effect of a dose that reduces AVE0010 with different proportions with respect to insulin glargine in the combined formulation.

Fig. 7: Effect of a combination of AVEOOlO / insulin glargine on blood glucose in the db / db diabetic mouse.

Fig. 8: Effect of a combination of AVEOOlO / insulin glargine in the oral glucose tolerance test in the db / db diabetic mouse.

Fig. 9: Effect of a combination of AVEOOlO / insulin glargine on cytokine-induced β-cell apoptosis and lipotoxicity in vitro.

Fig. 10: The “full coverage with 3 packages” system.

Examples

Example 1

Model: Oral glucose tolerance test (OGTT) in healthy dogs: comparison of the insulin glargine / AVEOOlO combination with the two individual active compounds.

Animals

IMPI

INSTITUTO méXICAN · · n »la nmin *» INDUSTRIAL

<img file="MX344293B_D0048.tif" />

• Male normoglycemic beagle dogs • Body weight: -15 kg • Quantity per group: n = 6

Study design (see fig. 1) • individual subcutaneous injections of placebo or test formulation at time 0 • 2 oral administrations of glucose, at 2 g glucose / kg of body weight, at times 30 min and 5 h • Blood samples are taken to determine blood glucose, plasma insulin, and c-peptide.

Division of groups (n = 6) • Placebo (Lantus placebo formulation without API) • Insulin glargine (0.3 Ul / kg sc, equivalent to 1.8 nmol / kg). Insulin glargine is Gly (A21) -Arg (B31) -Arg (B32) human insulin.

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

• AVE0010 / insulin glargine combination (10 pg / kg AVE0010 / 0.3

Ul / kg insulin glargine sc)

Example 2

OGTT in the dog: effect of insulin glargine compared to placebo

ΙΜΡΙ

OFFSTUTC MÜX1CAN4

D € THE PROPERTY

INDUSTRIAL

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

• OGTT repeat (2 g / kg po) • Male beagles, n = 6 • Mean ± Sem • placebo = placebo Lantus • insulin glargine (0.3 U / kg sc)

Results: the data is shown in fig. 2. Single administration of insulin glargine does not prevent OGTT-induced increase in blood glucose. Insulin glargine reinforces the expected reduction in blood glucose concentration in the postabsorptive phase.

Example 3

OGTT in the dog: effect of AVE0010 compared to placebo

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

• Repeated OGTT (2 g / kg po) • Male beagles, n = 6 • mean ± Sem • placebo = Lantus placebo • AVE0010 (10 pg / kg sc)

<img file="MX344293B_D0049.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Results: The data is shown in fig. 3. AVE0010 prevents OGTT-induced postprandial increase in blood glucose almost completely. There is no effect on 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 blood sugar lowering effect of insulin glargine in the postabsorptive phase.

Example 4

OGTT in the dog: effect of a combination of AVE0010 / insulin glargine on the level of blood glucose

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

• Repeated OGTT (2 g / kg po) • Male beagles, n = 6 • mean ± Sem • placebo = Lantus placebo • AVE0010 (10 pg / kg sc) • Insulin glargine (0.3 U / kg sc) • AVE + Lan (= premix of 10 pg / kg AVE0010 and 0.3 U / kg insulin glargine in a formulation)

<img file="MX344293B_D0050.tif" />

IMPIAS

MEXICAN INSTITUTE

Dg LA FROfíSDAD C * «* | industrial

Results: the data is shown in fig. 4. The combination has the same action on postprandial glucose increase as AVE0010 (cf. example 3). The hypoglycemic effect of insulin glargine in the postabsorptive phase is similarly present, but attenuated (cf. example 2). This is a synergistic effect of insulin glargine and AVE0010, since AVE0010 alone has no effect on glucose level, which decreased again after glucose administration, and insulin glargine itself has no effect on postprandial level. glucose

Example 5

OGTT in the dog: effect of a combination of AVE0010 / insulin glargine on plasma insulin and c-peptide level

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

• Repeated OGTT (2 g / kg po) • Male beagles, n = 6 • mean ± Sem • placebo = Lantus placebo • AVE0010 (10 pg / kg sc) • Insulin glargine (0.3 U / kg sc) • AVE + Lan (= premix 10 pg / kg AVE0010 and 0.3 U / kg insulin glargine in a formulation)

INSTITUTO MKXICANC DF. THE INDUSTRIAL PROPERTY

<img file="MX344293B_D0051.tif" />

Peptide c is released in the course of proinsulin to insulin conversion, and serves as a marker for insulin secretion by pancreatic β cells. In a glucose load test, the peptide c can be used to determine the responsiveness of the pancreas.

Results: the data is shown in figs. 5a and 5b. In the combination group, the postprandial reduction in insulin is followed by an increase in the level of postabsorptive glargine insulin. The levels of c-peptide for the combination correspond to the insulin curve of AVE0010 during the prandial | es passages, and of insulin glargine during the postabsorptive phase.

Example 6

OGTT in the dog: effect of a decrease in the dose of AVE0010 with different proportions with respect to insulin glargine in the combined formulation.

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

• Repeated OGTT (2 g / kg po) • Male beagles, n = 11/6/6/6 • mean ± Sem control = placebo Lantus

AVE + Lan (= premix of 0.15 to 1.0 pg / kg of AVE0010 and 0.3 U / kg of

IMPI0 fNSTJTinc MÍXICANC 'Z Cl LA rtOt &lt;tO_AUINDUSTRIAL insulin glargine in a formulation). In Examples 2 to 5, AVE0010 concentrations of 10 pg / kg were used.

Results: the data is shown in fig. 6. The reduction of the dose of AVE0010 from 10pg / kg (cf. particularly example 4) to 1 pg / kg (ie, by a factor of 10), and the resulting increase in the ratio of insulin glargine to AVE0010 , has no effect on the synergistic activity of the combination of AVE0010 with insulin glargine (cf. in particular example 4). Only with significantly lower doses of AVE0010, the effect of the combination approximates the effect of insulin glargine alone (cf. in particular fig. 2). Accordingly, the AVE0010 dose should be varied at least within an order of magnitude (ie, by a factor of at least 10) without loss of synergistic effect.

Example 7

Model: db / db insulin resistant diabetic mouse: comparison of the insulin glargine / AVE0010 combination with the two individual active compounds.

Animals • Female db / db mice • Age: 10-11 weeks

Quantity per group: n = 10

IMPI 05 ^ mmican institute,;

OE LA PRORIÍDAD V \ a—

INDUSTRIAL

Study Design • Individual subcutaneous placebo injection or test formulation • Blood sampling to determine blood glucose

Group division • Placebo (= Lantus placebo formulation without API) • AVE0010 (10 pg / kg sc) • Insulin glargine (5 lU / kg sc) • AVEOOlO / insulin glargine combination (10 pg / kg premix

AVE0010 plus 5 lU / kg insulin glargine sc)

Example 8

Effect of a combination of AVEOOlO / insulin glargine on blood glucose in the db / db diabetic mouse

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

• Female db / db mice, 10 weeks • n = 10, mean ± Sem • Vehicle = placebo Lantus • AVE0010 (10 pg / kg se) • Lantus (5 U / kg se) • AVEOOlO / insulin glargine (= premix AVE0010 10 pg / kg and insulin glargine 5 U / kg in one formulation)

IMPI

MEX PROJECT OF UA PROnWAÜ INDUSTRIAL

Results: the data is shown in fig. 7. In db / db diabetic mice, where the AVE0010 / insulin glargine combination produced a faster and more pronounced decrease in blood glucose concentration, compared to the two individual active compounds. Consequently, the combination brings diabetic db / db mice closer to normoglycemia than either of the two active compounds alone.

Example 9

Effect of a combination of AVE0010 / insulin glargine on the oral glucose tolerance test in the db / db diabetic mouse

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 mice, 11 weeks • n = 10, mean ± Sem • Control = placebo Lantus • AVE0010 (10 pg / kg se) • Insulin glargine (5 U / kg se) • AVE0010 / insulin glargine (= premix of AVE0010 10 pg / kg and insulin glargine 5 U / kg in one formulation)

MEXICAN INSTITUTE

OF LA IEUAD iMourrmAt.

Results: the data is shown in fig. 8. The AVE0010 / insulin giargine combination leads to significantly improved glucose tolerance and lower post-absorptive glucose levels.

Example 10

Effect of the AVE0010 / insulin giargine combination on cytokine-induced β cell apoptosis and lipotoxicity in vitro • Insulinoma cell line INS-1, rat • Incubation with test compound for 5 h • Subsequent incubation with a mixture of cytokines for 22 h (1 ng / mL IFN-y + 4 ng / mL Ιί-1β) ο • Further incubation with 0.5 mM FFA for 18 h (palmitates: BSA 3: 1)

The measures used for apoptosis are caspase-3 activity and fragmentation of cell nuclei, which are correlated with apoptosis.

Results: the data is shown in fig. 9. AVE0010 or insulin giargine (giargine, Glar) alone prevent apoptosis by ~ 40-50%. The combination of AVE0010 and insulin giargine prevents apoptosis significantly better. Based on this synergistic effect, the combination produces increased protection against cytokine-induced apoptosis and lipotoxicity.

Example 11

The “3-pack full coverage” system (fig. 10) • 3 pre-mix packs with 3 different predetermined proportions:

- Mix A: 100 U of insulin glargine + 66.66 pg of AVE0010 per mL

- Mix B: 100 U of insulin glargine + 40 pg of AVE0010 per mL

- Mix C: 100 U of insulin glargine + 25 pg of AVE0010 per mL • Use of the 3 premix containers: the table in fig. 10, which represents an example, starts from the therapeutic range of 15 to 80 U per dose of insulin glargine and 10 to 20 pg of AVE0010. For a particular patient, a dose of insulin glargine is specified or determined to be administered. The default dose is found in the left column. When the MIX A-MIX C columns specify a corresponding dose AVE0010 in the range 10-20 pg, the corresponding MIX is selected, dosed, and administered. The ranges overlap: for example, in the case of a requirement of 26 to 30 U of insulin glargine, it will be possible to choose MIX A or MIX B (with a higher dose of AVE0010). The same applies to MIX B and C. For example, if a 50 U dose of insulin is intended, then 0.5 ml of MIX B or MIX C can be dosed. This dose contains 20 pg (MIX B) or 12.5 pg (MIX C) of AVE0010 .

• Conclusion: on the presumption that a probable effect of AVE0010 is obtained between 10 and 15 pg, and a therapeutic effect between 15 and 22 pg, almost all patients receiving insulin glargine doses of 15-80 U

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY can also obtain therapeutic doses of AVE0010 between 10 and

<img file="MX344293B_D0052.tif" />

eg if they use one of the three premix packs containing three different proportions of insulin glargine: AVE0010 (MIX A, B or C).

Based on the wide range of possible proportions of insulin glargine with respect to AVE0010 (cf. example 6) with a synergistic effect, the proportions of the packages can be adjusted in such a way that for each insulin glargine dose there is a synergistic dose of AVE0010 in at least one container.

Example 12

This example shows how a combination of two or more active compounds can be formulated such that, when two or more compositions are combined, both active compounds can be administered in any desired amount and in any desired proportion to each other. Here it is taken into account that at least one of the active compounds must not be diluted as a consequence of the combination (for example, by direct mixing before administration).

In this example, the designations active A and active B represent any active compound of interest. In particular, Active A is an insulin and Active B is a GLP-1 agonist. Active A can also be a GLP-1 agonist, and Active B can also be an insulin.

one. Comparative example

IMPI

<img file="MX344293B_D0053.tif" />

For a combination therapy with an active A (eg, insulin) and an active B (eg, a GLP-1 agonist), container 1 is provided with a composition with active A in a concentration of a mg / ml, and a container 2 with an active B composition in a concentration of b mg / ml.

For the administration of a combination of the two assets, a volume Vi mi of container 1 and a volume V are mixed₂ my from container 2.

For the dosage of the two active ingredients in certain concentrations a and b, the volumes Vi _and V₂ to be managed are selected depending on the amount of assets A and B to be managed. Volumes Vi_and V₂ of the two assets are determined based on the amount of asset, as follows:

Amount of asset A: Vi a mg

Amount of asset B: V₂ b mg

The concentrations of actives A and B in the mixture of the two compositions are determined as follows.

Active A: x mg / mL = Vi · a / (Vi + V₂)

Active B: y mg / mL = V₂ B / (Vi + V₂)

Vi + V₂ is the total volume administered. This means that the two assets dilute each other. Consequently, with this system, it is not possible to maintain, for example, the concentration of active A (for example, insulin) at a predetermined level in the case of varying amounts of active B.

IMPI

<img file="MX344293B_D0054.tif" />

2. Example of the invention

In this example, for a combination therapy with an active A (eg, insulin) and an active B (eg, a GLP-1 agonist), container 1 is provided with a composition with active A in a concentration a mg / ml, and a container 2 with a composition with active A in a concentration of a mg / ml and with active B in a concentration of b mg / ml. The concentration of active A is accordingly the same in both compositions.

For the administration of a combination of the two assets, a volume V is mixed₃ mi of container 1 and a volume V₂ my from container 2.

For the dosage of the two active ingredients, in certain concentrations a and b, the volumes V_{3 and} V₂ to be managed are selected depending on the amount of assets A and B to be managed. Volumes V_{3 and} V₂ of the two assets are determined based on the amount of asset, as follows:

Amount of asset A: (V₃ A + V₂) to (mg))

Amount of asset B: V₂ B mg

The concentrations of assets A and B are determined as follows.

Active A: a mg / mL = (V₃ a + V₂ a) / (V₃ + V₂)

Active B: z mg / mL = V₂ b / (V₃ + V₂)

V₃ + V₂ is the total volume administered. From the previous calculation it is evident that the concentration of active A is always at mg / ml, that is, it is constant, regardless of the proportion of volume V₃/ V₂ That

MEXICAN INSTITUTE

DF. 1.A ^ ROPIEPAÍ INI ilKTRlA | dosa. __

Comparison of the comparative example (see section 1) with the present example of the invention, it is apparent that, for an equal dosage amount of actives A and B, the total volume required in the example of the invention is less.

For a given dose (amount of active compound) of active A, the figure in the comparative example is:

V- | to mg

In the example of the invention it is: (V₃ a + V₂ A) mg

Since the amount of active compound must be equal in both cases, (V₃ a + V₂ a) = \ Λι a (V₃ + V₂) A = XA a and V₃ + V₂ = Vi or V₃ = Vj - V₂

Here, volume V₂ in which asset B is administered is the same in both cases.

The total volume in the comparative example is V₁ + V₂

The total volume in the example of the invention is

V₃ + V₂

According to the previous equation, for the example of the invention, the case is: V₃+ V₂= V! -V₂+ V₂ = Vj

This volume V-ι is less than the volume Vi + V₂ of the comparative example.

As a result of mixing the composition with the assets

IMPIft

ΪΤνΊ \&gt; MLAiuni '·'&gt;. OF INDUSTRIAL PROPERTY

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

b&gt; zb&gt; V₂ b / (V₃ + V₂) b&gt; b V₂ / (V₃ + V₂), Where v₂ / (V₃ + V₂) is &lt;1, yz&gt; y

V₂ b / (V₃ + V₂)&gt; V₂ b / (Vi + V₂) / (V₃ + V₂)&gt; 1 / (Vi + V₂) / (Vt - V₂ + V₂)&gt; 1 / (Vi + V₂) / Vi&gt; 1 / (Vi + V₂)

Accordingly, the dosage system of the invention for administering varying doses of active A (eg, insulin) and B (eg, a GLP-1 agonist) has three advantages over the comparative system:

• The concentration of active A (for example, an insulin) can be kept constant at a predetermined level. • When the doses of active A and B to be administered are the same, the total volume to be administered is less.

• The dilution of active B (for example, the GLP-1 agonist) is lower than that of the comparative experiment. Consequently, the concentration of active B can more easily be kept within a predetermined range.

The present example can easily be extended to drugs with three or more active compounds, where the first or * IMPI

MEXICAN INSTITUTE

OF '.A FROWFBA »' NDfP. ^ IAl active compound is present in all compositions (preferably in equal weight fractions) and where there is at least one other active compound in every other composition. The first composition can be mixed with each other composition in the same proportion without diluting the concentration of the active compound in the first composition.

<img file="MX344293B_D0055.tif" />

<img file="MX344293B_D0056.tif" />

I