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HK1166266B - Aqueous preparations comprising methionine - Google Patents

Aqueous preparations comprising methionine Download PDF

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Publication number
HK1166266B
HK1166266B HK12106953.8A HK12106953A HK1166266B HK 1166266 B HK1166266 B HK 1166266B HK 12106953 A HK12106953 A HK 12106953A HK 1166266 B HK1166266 B HK 1166266B
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HK
Hong Kong
Prior art keywords
arg
human insulin
asp
glu
lys
Prior art date
Application number
HK12106953.8A
Other languages
German (de)
French (fr)
Chinese (zh)
Other versions
HK1166266A (en
Inventor
Isabell Schoettle
Annika Hagendorf
Christiane Fuerst
Gerrit Hauck
Verena Siefke-Henzler
Walter Kamm
Julia Schnieders
Original Assignee
Sanofi-Aventis Deutschland Gmbh
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Application filed by Sanofi-Aventis Deutschland Gmbh filed Critical Sanofi-Aventis Deutschland Gmbh
Publication of HK1166266A publication Critical patent/HK1166266A/en
Publication of HK1166266B publication Critical patent/HK1166266B/en

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Description

The invention relates to an aqueous pharmaceutical formulation containing insulin, an insulin analogue or an insulin derivative and methionine, and their manufacture, use for the treatment of diabetes mellitus and a medicinal product for the treatment of diabetes mellitus.
A growing number of people worldwide are suffering from diabetes mellitus. Among them are many so-called type I diabetics, for whom the replacement of the missing endocrine insulin secretion is the only currently possible therapy. The affected are dependent on insulin injections throughout life, usually several times a day. Unlike type I diabetes, type II diabetes does not basically have a lack of insulin, but in a large number of cases, especially in the advanced stage, treatment with insulin, possibly in combination with an oral anti-diabetes medication, is considered the most favorable therapy.The replacement of the body's own insulin secretion by exogenous, mostly subcutaneous, insulin administration usually does not achieve the physiological regulation of blood glucose described above. Frequently, upward or downward spikes in blood glucose can be life threatening in their most severe forms. However, even over the years without the onset of symptoms, elevated blood glucose can pose a significant health risk.The large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N.Eng. J. Med. 329, 977-986) clearly demonstrated that chronically elevated blood glucose levels are a major factor in the development of diabetic late-onset diabetes. Diabetic late-onset diabetes is micro- and macrovascular damage, which may manifest as retinoid, nephro- or neuropathy and lead to blindness, renal failure and loss of extremities, and is also associated with an increased risk of cardiovascular disease.Fast-acting formulations are given with meals to compensate for the postprandial rise in blood glucose. slow-acting basal insulins are intended to ensure basic insulin supply, especially during the night, without causing hypoglycaemia.
Insulin is a polypeptide of 51 amino acids, which are distributed on 2 amino acid chains: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are connected by 2 disulfide bridges. Insulin preparations have been used for many years for diabetes therapy.
Insulin analogues are analogues of naturally occurring insulins, namely human or animal insulins, which are distinguished by substitution of at least one naturally occurring amino acid residue with other amino acids and/or addition/removal of at least one amino acid residue from the corresponding otherwise identical naturally occurring insulin.
Insulin derivatives are derivatives of naturally occurring insulin or an insulin analog obtained by chemical modification. The chemical modification may consist, for example, in the addition of one or more specific chemical groups to one or more amino acids.
Accelerated-acting insulin analogues are described in EP 0 214 826, EP 0 375 437 and EP 0 678 522. EP 0 214 826 refers to substitutions of B27 and B28. EP 0 678 522 describes insulin analogues that contain various amino acids, preferably proline, in position B29, but not glutamic acid. EP 0 375 437 includes insulin analogues with lysine or arginine in B28 which may optionally be modified further in B3 and/or A21.
In EP 0 419 504 insulin analogues protected against chemical modification are disclosed in which asparagine is modified into B3 and at least one other amino acid in positions A5, A15, A18 or A21.
As a rule, insulin derivatives and insulin analogues have a slightly different effect than human insulin.
US 6 852 694 shows a stabilized insulin composition containing a mixture of insulin species, in which heterodimeric complexes are formed from the two insulin species, which are more stable than homodimeric complexes in compositions containing only one insulin species.
WO 2008/133908 discloses suspension formulations of insulinotropic peptides such as GLP-1 or Exendin-4. The suspension formulations shall comprise a particle formula consisting of an insulinotropic peptide, a disaccharide, methionine and a buffer and a non-aqueous suspension carrier comprising one or more pyrrolidone polymers and one or more solvents.
US 2006/0093576 reveals a stabilized interleukin-2 formulation produced by bringing the interleukin-2 into contact with an amino acid and a buffer. The amino acid is selected from arginine, lysine, aspartic acid and glutamic acid. The formulation may additionally contain methionine in an amount to inhibit the oxidation of at least one methionine residue in the interleukin-2.
WO 99/62558 reveals a powdered or liquid formulation for children's nutrition supplemented with insulin to reduce the risk of children developing diabetes.
WO 2009/048959 reveals fast-acting injectable insulin formulations.
WO 2008/124522 reveals compositions which include an insulin, a zinc chelator and a solvent in combination with a GLP-1 mimetic or GLP-1 analogue.
The concept of intensified insulin therapy aims to reduce the health risk by aiming at stable control of blood sugar levels through early administration of basal insulins. An example of a common basal insulin is the medicine Lantus® (active ingredient: Glargin = Gly (A21), Arg (B31), Arg (B32)). In the development of new basal insulin products, it is necessary to minimise the number of basal insulin hypoglycaemic events.Ideally, the insulin action is delayed and with a time/ action profile as flat as possible, so that the risk of short-term hypoglycaemia is significantly minimised and the application can be done even without prior food intake. A good basal insulin supply is provided when the insulin action is maintained for as long as possible, i. e. the body is provided with a constant amount of insulin. This minimises the risk of hypoglycaemic events and patient and day-specific variability.This means that it is characterized by a long-lasting and uniform effect.
Recombinant DNA technology now allows the production of such modified insulin products, including the insulin origin (e.g. bovine, porcine, human insulin) and the composition that can affect the profile of action (start of action and duration of action). Combining different insulin preparations allows for a wide range of action profiles and a possible physiological adjustment of blood glucose levels. Recombinant DNA technology now allows the production of such modified insulin products. These include the insulin origin (e.g. bovine, pig, human insulin) and the composition that can affect the profile of action (start of action and duration of action). Insulin production is more pronounced as a clear, clear solution. The effect of insulin is more pronounced as a solution (e.g. ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph ph
It has been found that such insulin analogues lead to the desired baseline time/effect profile described when the insulin analogues are characterised by the B-chain end being composed of an amidated basic amino acid residue such as lysine or arginine amide, i.e. the amidated basic amino acid residue at the B-chain end is the carboxyl group of the final amino acid in its amidated form, and the N-terminal amino acid residue of the insulin A-chain is a lysine or arginine, and the amino acid position A8 is occupied by a histidine, and the amino acid position A21 is occupied by a glycine, and two neutral substitutions are followed by two negative amino acid substitutions, namely amino acids A1, A2, A5, A5, A5, B1, B1, B1, B2, B1, B1, B2, B1, B1, B8, and B1 in each such addition.
All aqueous formulations of insulins, insulin analogues and insulin derivatives have in common that the proteins mentioned are not completely chemically stable, but that depending on the time, storage temperature, motion to which the formula is subjected, etc., a number of molecular processes may occur in the insulins, insulin analogues and insulin derivatives which are detrimental to the quality of the formula. A substance which affects the chemical stability of insulins, insulin analogues and insulin derivatives is oxygen, which cannot be prevented from coming into contact with the corresponding formulations by its presence in the air - especially in formulations in multi-dose packaging.
Surprisingly, it has now been found that the addition of the amino acid methionine to formulations of insulins, insulin analogues and insulin derivatives leads to improved stability of these proteins.
The invention therefore relates to an aqueous pharmaceutical formulation containing an insulin, an insulin analogue or an insulin derivative, or a pharmacologically tolerable salt thereof, and methionine, the pH of the formulation being 4.5 or less.
In the pharmaceutical formulation such as As described above, the insulin analogue is selected from a group containing Gly (A21), Arg (B31), Arg (B32) human insulin, Lys (B3), Glu (B29) human insulin, Asp (B28) human insulin, Lys (B28) Pro (B29) human insulin, Des (B30) human insulin and one insulin analogue of formula I Other wherein A0Lys or Arg;A5Asp, Gln or Glu;A15Asp, Glu or Gln;A18Asp, Glu or Asn;B-1Asp, Glu or an amino group;B0Asp, Glu or a chemical bond;B1Asp, Glu or Phe;B2Asp, Glu or Val;B3Asp, Glu or Asn;B4Asp, Glu or Gln;B29Lys or a chemical bond;B30Thr or a chemical bond;B31Arg, Lys or a chemical bond;B32Arg-Amide, Lys-Amide or an amino group corresponding to two amino acid residues of the group containing A5, A15, A18, B-1, B0, B1, B2, B3 and B4 corresponding simultaneously and independently to Asp or Glu,where the insulin analogue is selected from a group containing in particular: The following are the functional groups of the active substance: (i) human insulin, (ii) human insulin, (iii) human insulin, (iv) human insulin, (v) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human insulin, (vi) human (vi) human (vi) human (vi) human insulin, (vi) human (vi) human (vi) human insulin, (vi) human (vi) human (vi) human (vi) human (vi) human (vi) human (vi) humanThe following are the functional groups of the active substance: human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, human insulin, as well as well as well as the human, human, human, human, human, human, and all human, and all human, and all, and all, and all, and all, and allThe following are the functional groups of the active substance: acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, aceticThe following equation is used to determine the concentration of the active substance in the test chemical: (i) the concentration of the active substance in the test chemical, (ii) the concentration of the active substance in the test chemical, (iii) the concentration of the active substance in the test chemical, (iv) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the concentration of the active substance in the test chemical, (v) the test chemical, (v) the concentration of the active substance in the test chemical, (v) the test chemical, (v) the concentration in the test chemical, (v) the test chemical, the concentration in the test chemical, the test chemical, the test substance in the test chemical, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test, the test,The following are the functional groups of the active substance: arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenic, arsenThe following are the functional groups of the active substance: aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic acid, aspartic, aspartic, aspartic, aspartic, aspartic, aspartic
In the pharmaceutical formulation such as The insulin analogue described above is alternatively selected from a group containing an insulin analogue of formula II. wherein A1Lys, Arg or an amino group;A0Lys, Arg or a chemical bond;A1Arg or Gly;A5Asp, Glu or Gln;A15Asp, Glu or Gln;A18Asp, Glu or Asn;A21Ala, Ser, Thr or Gly;B1Asp, Glu or an amino group;B0Asp, Glu or a chemical bond;B1Asp, Glu, Glu, Phe or a chemical bond;B3Asp, Glu or Asn;B4Asp, Glu or Lysn;B29Arg, or an amino acid selected from a group containing the amino acids Phe, Thr, Leu, Val, Glu or Asn; or a chemical bond;B30BT or a chemical bond;B31Asp, Glu or Asn;B32Asp, Glu or Lys; or a chemical bond; is equivalent to, and contains not more than one amino acid residue of group A5,A15, A18, B-1, B0, B1, B2, B3 and B4 correspond simultaneously and independently to Asp or Glu, the insulin analogue being selected from a group comprising: The following are the active substances which are to be classified in the additive:The following are the functional groups of the active substance, as defined in point (a) of Article 1 of Directive 2001/18/EC:The following equation is used to determine the concentration of the active substance in the test chemical:The following are the functional groups of the active substance: (i) the active substance, (ii) the active substance, (iii) the active substance, (iv) the active substance, (v) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi) the active substance, (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi), (vi, (vi), (vi), (vi, (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi), (vi, (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi, (vi), (vi), (vi), (vi, (vi), (vi, (vi), (vi, (vi), (vi, (vi), (vi), (vi, (vi), (vi, (The following are the active substances which may be used in the manufacture of the active substance:
In another alternative, the insulin derivative is selected from a group containing 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 LysB28ProB29 human insulin, B28-N-palmitoyl-LysB28ProB29 human insulin, B30-N-myristoyl-ThrB29LysB30 humanins, B30-N-palmitoyl-Th-B29LysB30 humanins, B29-N-N-N-myl-glutamyl-glutamyl-hypnoxy (B3 (B3) humanins, B29-N-chol-N-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-Human-N-N-Human-N-Human-N-N-Human-N-Human-N-N-Human-N-Human-N-N-Human-N-N-Human-N-N-Human-N-N-Human-N-N-Human-N-N-Human-N-N-N-N-Human-N-N-N-Human-N-N-N-Human-N-N-N-N-N-Human-N-N-N-N-N-Human-N-N-N-N-N-Human-N-N-N-N-N-N-N-N-N-N-N-N-Human-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-
The invention also relates to a pharmaceutical formulation as described above, which is capable of being used in the manufacture of a 0,001 to 0,2 mg/ml of zinc, 0,1 to 5,0 mg/ml of preservative and It contains between 5,0 and 100 mg/ml of an isotonic agent.
A further subject matter of the invention is a pharmaceutical formulation as described above, in which a preservative selected from a group containing phenol, m-cresol, chlorcresol, benzyl alcohol, parabens is present.
The invention also relates to a pharmaceutical formulation as described above, in which an isotonic agent is present, selected from a group containing mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol.
A further subject matter of the invention is a pharmaceutical formulation as described above, with a pH in the range of pH 2,5 to 4,5, preferably pH 3,0 to 4,0, especially preferably pH 3,75.
The invention also relates to a pharmaceutical formulation as described above, in which the insulin, insulin analogue and/or insulin derivative is present at a concentration of 240-3000 nmol/ml.
The invention also relates to a pharmaceutical formulation described above, which contains glycerol in a concentration of 20 to 30 mg/ml.
The invention also relates to a pharmaceutical formulation described above, which contains glycerol at a concentration of 25 mg/ml.
Another subject matter of the invention is a pharmaceutical formulation as described above, in which m-cresol is present at a concentration of 1 to 3 mg/ml, preferably 2 mg/ml.
The invention also relates to a pharmaceutical formulation as described above, in which zinc is present at a concentration of 0.01 or 0.03 or 0.08 mg/ml.
A further subject matter of the invention is a pharmaceutical formulation as described above, which additionally contains a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, or exendin-3 or -4 or an analogue or derivative thereof, preferably containing exendin-4.
Another subject matter of the invention is a pharmaceutical formulation as described above, in which an analogue of Exendin-4 is selected from a group containing: a width of not more than 15 mm, a width of not more than 50 mm, a width of not more than 50 mm, or a pharmacologically tolerable salt thereof, or an analogue of Exendin-4 is selected from a group containing The following shall be reported for the product: The test chemical is a chemical that is used to determine the concentration of a substance in a solution. The test chemical is a chemical that is used to determine the concentration of a substance in a solution. The test chemical is a chemical that is used to determine the concentration of a substance in a solution. The test chemical is a chemical that is used to determine the concentration of a substance in a solution. The test chemical is a chemical that is used to determine the concentration of a substance in a solution. a width of not more than 50 mm, The test chemical is a chemical that is used to determine the concentration of a substance in a solution. or a pharmacologically tolerable salt of it.
Another subject matter of the invention is a pharmaceutical formulation as described above, in which the peptide -Lys6-NH2 is added to the C-terminus of the exendin-4 analogues.
Another subject matter of the invention is a pharmaceutical formulation as described above, in which an analogue of Exendin-4 is selected from a group containing: H- ((Lys) 6- of Pro36 [Asp28]Exendin-4 ((1-39)-Lys6-NH2 a thickness of not more than 0,05 mm, The following is added to the list of active substances: H-Asn- ((Glu) 5 of Pro36, Pro37, Pro38 [Asp28]Exendin-4 ((1-39) -NH2, a thickness of not more than 0,05 mm, The test chemical is a chemical that is used to determine the concentration of a substance in a solution. The following substances are to be classified in the same heading as the active substance: The test chemical is a chemical that is used to determine the concentration of a substance in a solution. H- of Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]Exendin-4(1-39 -NH2, whether or not in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the solution in the form of a solution in the form of a solution in the solution in the form of a solution in the form of a solution in the solution in the solution in the form of a solution in the solution in the solution in the form of an solution in the solution in the solution in the solution in the solution in the solution in the form of an accident in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the situation in the The following is added to the list of substances which are to be classified in the additive: The following is added to the list of substances which are to be classified in Annex I to Regulation (EC) No 1907/2006 as additives to the active substance: The following substances are to be classified in the same category as the active substance: The test chemical is a chemical that is used to determine the concentration of a substance in a solution. The following substances are to be classified in the same heading as the active substance: The test chemical is a chemical that is used to determine the concentration of a substance in a solution. a thickness of not more than 0,05 mm, The following is added to the list of substances which are to be classified in the additive: H-Asn- ((Glu) 5- of Pro36, Pro37, Pro38 [Met(O) 14], Asp28] Exendin-4 ((1-39) -NH2, a thickness of not more than 0,05 mm, The following substances are to be classified in the same heading as the active substance: The following substances are to be classified in the same heading as the product: The test chemical is a chemical that is a mixture of two or more of the following: The following substances are to be classified in the same category as the active substance: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] H-Asn- ((Glu) 5- of Pro36, Pro37, Pro38 [Met(O) 14], Asp28] Exendin-4 ((1-39) -NH2, The following substances are to be classified in the same category as the active substance: The chemical composition of the product is determined by the following equation: It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.] or a pharmacologically tolerable salt of it.
Another subject matter of the invention is a pharmaceutical formulation as described above, which additionally contains Arg34, Lys26 (Nε ((γ-glutamyl ((Nα-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof.
Another subject of the invention is a pharmaceutical formulation as described above, in which methionine is present in the concentration range up to 10 mg/ml, preferably up to 3 mg/ml.
The invention also relates to a process for producing a formulation as described above, in which the (a) the components are introduced into an aqueous solution and (b) the pH is adjusted.
The invention also relates to the use of a formulation as described above for the treatment of diabetes mellitus.
Another subject matter of the invention is a medicinal product for the treatment of diabetes mellitus, consisting of a formulation as described above.
The following is a description of the notification using a few examples which are not intended to be restrictive.
The character legend: Fig. 1: Blood glucose lowering effect of new insulin analogues of formula I in ratsFig. 2: Blood glucose lowering effect of new insulin analogues of formula I in dogsFig. 3: Blood glucose lowering effect of YKL205 in dogsFig. 4: Zinc dependence of the hypoglycaemic effect of YKL205 in dogsFig. 5: Blood glucose lowering effect of the inventive insulin analogues of formula II in ratsFig. 6: Blood glucose lowering effect of insulin glargine in rats
Examples:
The following examples are intended to explain the idea of the invention in more detail without being restrictive.
Example 1: Studies to refill the solution using nitrogen, oxygen and refilling under normal conditions
The solution is prepared by introducing approximately 25 % 0.1 M HCl and adding 0.2% polysorbate 20 stock solution. SAR161271 and the zinc chloride stock solution are added and stirred successively. 1 M HCl is added at a pH of 2 to dissolve SAR161271. The solution is stirred, then 1 M NaOH is added to set the pH to 4.0. Water for injection is added to 90 % of the stock size. Glycerol 85 % and m-cresol are added successively to the solution under tubing. Water for injection is added to the desired final weight. Untreated Content SAR161271 The following is the list of substances which are to be classified in the Annex to this Regulation: 1 M + 5° C: 3.0 %1 M + 25° C: 3.6 %1 M + 37° C: 5.6 %High molecular weight proteins The following table shows the data for the year 2000:
Nitrogen treated Content SAR161271 The following is the list of substances which are to be classified in the Annex to this Regulation: M + 5° C: 3.1 % 1 M + 25° C: 3.5 % 1 M + 37° C: 5.2 % High molecular weight proteins The temperature of the water is measured at the temperature of the water.
Oxygenated Content SAR161271 The following is the list of substances which are to be classified as 'compounds' in the Annex to Regulation (EC) No 1907/2006 of the European Parliament and of the Council: The following table shows the data for the year 2000:
The nitrogen filling showed no significant reduction in impurities after 1 month compared to the untreated sample. The oxygen filling showed slightly higher impurities and higher molecular proteins. On the basis of these results, the normal filling was selected.
Example 2: Stability study with 3 different antioxidants
The solution was prepared as described in example 1.In addition, between the addition of 85% glycerol and m-cresol, the antioxidants methionine or glutathione or ascorbic acid were added to the formulation to reduce the oxidative byproduct.The formulations containing either glutathione (0.183 mg/ml) or ascorbic acid (0.105 mg/ml) showed significant discoloration after 3 months of storage.The formulations containing methionine (0.089 mg/ml) showed no discoloration and were stable at 5°C after 1 month of storage. Content SAR161271 The following is the list of substances which are to be classified in the Annex to this Regulation: The following is the list of active substances in the feed additive: The following table shows the data for the year 2000:
Example 3: Formulation of the amidized indulin derivatives
Examples 3 to 7 are intended only to determine the biological, pharmacological and physicochemical properties of insulin analogues according to formula I by first providing formulations (examples 3) and then testing them (examples 4 to 7). A solution was obtained from the compounds as follows: The insulin analogue of the invention was dissolved in 1 mM saline acid with 80 μg/mL zinc (as zinc chloride) at a target concentration of 240 ± 5 μM.
The following formulations were used as solvent: (a) 1 mM hydrochloric acid, 5 μg/mL zinc (as zinc chloride or hydrochloric acid added) (c) 1 mM hydrochloric acid, 10 μg/mL zinc (as zinc chloride or hydrochloric acid added) (d) 1 mM hydrochloric acid, 15 μg/mL zinc (as zinc chloride or hydrochloric acid added) (e) 1 mM hydrochloric acid, 30 μg/mL zinc (as zinc chloride or hydrochloric acid added) (f) 1 mM hydrochloric acid, 80 μg/mL Z (as zinc chloride or hydrochloric acid added) (g) 1 mM hydrochloric acid, 120 μg/mL hydrochloric acid added)
To this end, the freeze-dried material was weighed at a level approximately 30% higher than the level required by molecular weight and concentration, and the concentration was determined by analytical HPLC and the solution was then filled to the volume required to reach the target concentration with 5 mM hydrochloric acid with 80 μg/mL zinc, adjusting the pH to 3.5 ± 0,1 if necessary. After final HPLC analysis to ensure the target concentration of 240 ± 5 μM, the finished solution was injected with a 0.2 μm filter in a septic tank containing a septum and a capsule containing a closed slit. For short-term testing, no isotope or preservative was added to the solution.
Example 4: Evaluation of the blood glucose lowering effect of new insulin analogues in the rat
The blood glucose lowering effect of selected novel insulin analogues is investigated in male, healthy, normoglycaemic wisteria rats. Male rats are injected with a dose of 9 nmol/kg of an insulin analogue subcutaneously. Immediately before the injection of the insulin analogue and at regular intervals up to eight hours after the injection, blood samples are taken from the animals and blood glucose levels are determined. The experiment clearly shows (see Figure 1) that the insulin analogue of the invention used results in a significantly delayed effect and a longer, uniform duration of action.
Example 5: Evaluation of the blood glucose lowering effect of new insulin analogues in dogs
The blood glucose lowering effect of selected novel insulin analogues is investigated in male, healthy, normoglycemic beagles. Male animals are injected with a dose of 6 nmol/kg of an insulin analogue subcutaneously. Immediately before the injection of the insulin analogue and at regular intervals up to 48 hours after the injection, blood samples are taken from the animals and blood glucose levels are measured. The experiment clearly shows (see Fig. 2) that the insulin analogue of the invention used results in a significantly delayed onset of insulin and a longer, uniform duration of action.
Example 6: Evaluation of the blood glucose lowering effect in the dog at twice the dose
The blood glucose lowering effect of selected novel insulin analogues is being studied in male, healthy, normoglycaemic beagles. Male animals are injected with a dose of 6 nmol/ kg and 12 nmol/ kg of an insulin analogue subcutaneously. Blood samples are taken and blood glucose levels are measured immediately before the insulin analogue is injected and at regular intervals up to 48 hours after the injection. The experiment clearly shows (see Fig. 3) that the insulin analogue of the invention used is dose-dependent, but that despite a twice increased dose the course of action is flat, i.e. no marked trough (Nadir) is observed.
Example 7: Evaluation of blood glucose lowering effects in dogs at different zinc concentrations in the formulation
The experiments were carried out as described in example 5 and the result is shown in Figure 4 where the time curve of action of the insulin analogue of the invention can be influenced by the zinc ion content of the formula at the same insulin concentration in such a way that a rapid onset of action is observed at zero or low zinc content and the effect lasts for 24 hours, whereas at a higher zinc content a shallow onset of action is observed and the insulin effect lasts for significantly longer than 24 hours.
Example 8: Formulation of the amidized insulin derivatives
Examples 8 to 10 are intended only to determine the biological, pharmacological and physicochemical properties of insulin analogues according to formula II by first providing formulations of these (Examples 8) and then performing appropriate tests (Examples 9 and 10). The insulin analogue of the invention was dissolved at a target concentration of 240 ± 5 μM in 1 mM hydrochloric acid with 80 μg/mL zinc (as zinc chloride). To this end, the freeze-dried material was first inhaled at a concentration approximately 30% higher than the target concentration due to molecular weight and the desired concentration. The concentration was then finalised by means of a spray capsule and the solution was then determined to achieve a concentration of 240 ± 5 μm in a solution of 80 μm zinc (as zinc chloride).
Example 9: Evaluation of the blood glucose lowering effect of new insulin analogues in the rat
The blood glucose lowering effect of selected novel insulin analogues is investigated in male, healthy, normoglycemic wisteria rats. Male rats are injected with a dose of 9 nmol/kg of an insulin analogue subcutaneously. Immediately before the injection of the insulin analogue and at regular intervals up to eight hours after the injection, blood samples are taken from the animals and the blood glucose levels are determined. The experiment clearly shows (see Figure 5) that the insulin analogue of the invention results in a significantly delayed onset of action and a longer, uniform duration of action.
Example 10: Evaluation of the blood glucose lowering effect of new insulin analogues in dogs
The blood glucose lowering effect of selected novel insulin analogues is being investigated in male, healthy, normoglycemic beagles. A dose of 6 nmol/kg of an insulin analogue is injected subcutaneously into male animals. Blood samples are taken from the animals immediately before the insulin analogue is injected and at regular intervals up to 48 hours after the injection and the blood glucose is measured. The experiment clearly shows that the insulin analogue of the invention results in a significantly delayed, shallow onset of action and a longer, uniform duration of action.

Claims (16)

  1. An aqueous pharmaceutical formulation comprising an insulin analog or insulin derivative, or a pharmacologically tolerable salt thereof, and methionine, the pH of the formulation being 4.5 or less, and
    (I) the insulin analog being selected from the group consisting of Gly(A21), Arg(B31), Arg(B32) human insulin, Lys(B3), Glu(B29) human insulin, Asp(B28) human insulin, Lys(B28) Pro(B29) human insulin, Des(B30) human insulin and an insulin analog of the formula I where
    A0 is Lys or Arg;
    A5 is Asp, Gln or Glu;
    A15 is Asp, Glu or Gln;
    A18 is Asp, Glu or Asn;
    B-1 is Asp, Glu or an amino group;
    B0 is Asp, Glu or a chemical bond;
    B1 is Asp, Glu or Phe;
    B2 is Asp, Glu or Val;
    B3 is Asp, Glu or Asn;
    B4 is Asp, Glu or Gln;
    B29 is Lys or a chemical bond;
    B30 is Thr or a chemical bond;
    B31 is Arg, Lys or a chemical bond;
    B32 is Arg-amide, Lys-amide or an amino group,
    where two amino acid residues of the group consisting of A5, A15, A18, B-1, B0, B1, B2, B3, and B4, simultaneously and independently of one another, are Asp or Glu, and the insulin analog being selected in particular from the group consisting of:
    Arg (A0), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu(A5), Glu (A15), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His(A8), Glu (A5), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His(A8), Glu (A5), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His(A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B0), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Gly (A21), Glu (B0), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B0), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Glu (B0), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B0), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Glu (B0), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B1), Arg (B31), Arg(B32) - NH2 human insulin,
    Arg (A0), His (A8), Glu (A15), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B1), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Glu (B0), Asp (B1), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Glu (B0), Asp (B1), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Arg (B31) - NH2 human insulin,
    Arg (A0), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Lys (B31) - NH2 human insulin,
    (II) the insulin analog being selected from the group consisting of an insulin analog of the formula II where
    A-1 is Lys, Arg or an amino group;
    A0 is Lys, Arg or a chemical bond;
    A1 is Arg or Gly;
    A5 is Asp, Glu or Gln;
    A15 is Asp, Glu or Gin;
    A18 is Asp, Glu or Asn;
    A21 is Ala, Ser, Thr or Gly;
    B-1 is Asp, Glu or an amino group;
    B0 is Asp, Glu or a chemical bond;
    B1 is Asp, Glu, Phe or a chemical bond;
    B3 is Asp, Glu or Asn;
    B4 is Asp, Glu or Gln;
    B29 is Arg, Lys or an amino acid selected from the group consisting of the amino acids Phe, Ala, Thr, Ser, Val, Leu, Glu or Asp, or a chemical bond;
    B30 is Thr or a chemical bond;
    B31 is Arg, Lys or a chemical bond;
    B32 is Arg-amide or Lys-amide,
    where not more than one amino acid residue from the group consisting of A5, A15, A18, B-1, B0, B1, B2, B3 and B4, simultaneously and independently of one another, is Asp or Glu, and the insulin analog being selected in particular from a group consisting of:
    Arg (A-1), Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), Glu (A5), His (A8), Gly (A21), Lys (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), Glu (A15), His (A8), Gly (A21), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), Glu (A15), His (A8), Gly (A21), Lys (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B0), Lys (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Asp (B3), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Asp (B3), Lys (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B4), Lys (B30) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), Glu (A15), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), Glu (A15), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B31), Arg (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B31), Lys (B32) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Arg (B30) - NH2 human insulin,
    Arg (A0), His (A8), Gly (A21), Lys (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Arg (B30) - NH2 human insulin,
    Arg (A-1), Arg (A0), His (A8), Gly (A21), Lys (B30) - NH2 human insulin,
    Arg (A0), Arg (A1), His (A8), Gly (A21), Arg (B30) - NH2 human insulin,
    Arg (A0), Arg (A1), His (A8), Gly (A21), Lys (B30) - NH2 human insulin,
    His (A8), Gly (A21), Arg (B31), Arg (B32) - NH2 human insulin, or
    (III) the insulin derivative being 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 LysB28ProB29 human insulin, B28-N-palmitoyl-LysB28ProB29 human insulin, B30-N-myristoyl-ThrB29LysB30 human insulin, B30-N-palmitoyl- ThrB29LysB30 human insulin, B29-N-(N-palmitoyl-Υ-glutamyl)-des(B39) human insulin, B29-N-(N-lithocholyl-Υ-glutamyl)-des(B30) human insulin, B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin, and B29-N-(ω-carboxyheptadecanoyl) human insulin.
  2. The pharmaceutical formulation as claimed in claim 1, comprising 0.001 to 0.2 mg/ml of zinc, 0.1 to 5.0 mg/ml of a preservative, and 5.0 to 100 mg/ml of an isotonicity agent.
  3. The pharmaceutical formulation as claimed in claim 1 or 2, comprising a preservative selected from a group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, and parabens and/or an isotonicity agent selected from a group consisting of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.
  4. The pharmaceutical formulation as claimed in one or more of claims 1 to 3, having a pH in the range of pH 2.5 - 4.5, preferably in the range of pH 3.0 - 4.0, and more preferably in the region of pH 3.75.
  5. The pharmaceutical formulation as claimed in one or more of claims 1 to 4, the insulin analog and/or insulin derivative being present in a concentration of 240 - 3000 nmol/ml.
  6. The pharmaceutical formulation as claimed in one or more of claims 1 to 5, comprising glycerol at a concentration of 20 to 30 mg/ml, preferably at a concentration of 25 mg/ml.
  7. The pharmaceutical formulation as claimed in one or more of claims 1 to 6, comprising m-cresol at a concentration of 1 to 3 mg/ml, preferably at a concentration of 2 mg/ml.
  8. The pharmaceutical formulation as claimed in one or more of claims 1 to 7, comprising zinc at a concentration of 0.01 or 0.03 or 0.08 mg/ml.
  9. The pharmaceutical formulation as claimed in one or more of claims 1 to 8, further comprising a glucagon-like peptide-1 (GLP1) or an analog or derivative thereof, or exendin-3 and/or -4 or an analog or derivative thereof.
  10. The pharmaceutical formulation as claimed in claim 9, comprising:
    (i) exendin-4,
    (ii) an analog of exendin-4 selected from a group consisting of H-desPro36-exendin-4-Lys6-NH2, H-des(Pro36,37)-exendin-4-Lys4-NH2 and H-des(Pro36,37)-exendin-4-Lys5-NH2, or a pharmacologically tolerable salt thereof, or
    (iii) an analog of exendin-4 selected from a group consisting of desPro36 [Asp28]exendin-4 (1-39), desPro36 [IsoAsp28]exendin-4 (1-39), desPro36 [Met(O)14, Asp28]exendin-4 (1-39), desPro36 [Met(O)14, IsoAsp28]exendin-4 (1-39), desPro36 [Trp(O2)25, Asp28]exendin-2 (1-39), desPro36 [Trp(O2)25 IsoAsp28]exendin-2 (1-39), desPro36 [Met(O)14Trp(O2)25, Asp28]exendin-4 (1-39) and desPro36 [Met(O)14Trp(O2)25, IsoAsp28]exendin-4 (1-39), or a pharmacologically tolerable salt thereof, the peptide Lys6-NH2 optionally being attached to the C-termini of the analogs of exendin-4.
  11. The pharmaceutical formulation as claimed in claim 9, in which the analog of exendin-4 is selected from the group consisting of H-(Lys)6- des Pro36 [Asp28]exendin-4(1-39)-Lys6-NH2 des Asp28Pro36, Pro37, Pro38 exendin-4(1-39) -NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39) -NH2, H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5- des Pro36, Pro37, Pro38 [Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36 [Trp(O2)25, Asp28]exendin-4(1-39)-Lys6-NH2, H- des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]exendin-4(1-39) -NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39) -NH2, H-Asn-(Glu)5- des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5- des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36 [Met(O)14, Asp28]exendin-4(1-39)-Lys6-NH2, des Met(O)14 Asp28 Pro36, Pro37, Pro38 exendin-4(1-39) -NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met(O)14, Asp28]exendin-4(1-39) -NH2, H-Asn-(Glu)5- des Pro36, Pro37, Pro38 [Met(O)14, Asp28] exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Met(O)14, Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met(O)14, Asp28]exendin-4(1-39)-Lys6-NH2, H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39)-Lys6-NH2, des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]exendin-4(1-39) -NH2, H-(Lys)6- des Pro36, Pro17, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39) -NH2, H-Asn-(Glu)5- des Pro36, Pro37, Pro38 [Met(O)14, Asp28] exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6- des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39)-(Lys)6-NH2, H-Asn-(Glu)5- des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] exendin-4(1-39)-(Lys)6-NH2, or a pharmacologically tolerable salt thereof.
  12. The pharmaceutical formulation as claimed in claim 9, further comprising Arg34, Lys26 (Nε(γ-glutamyl(Nα-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof.
  13. The pharmaceutical formulation as claimed in one or more of claims 1 to 12, comprising methionine in the concentration range of up to 10 mg/ml, preferably of up to 3 mg/ml.
  14. A process for preparing a formulation as claimed in one or more of claims 1 to 13, which comprises
    (a) introducing the components into an aqueous solution and
    (b) adjusting the pH.
  15. The use of a formulation as claimed in one or more of claims 1 to 13 for producing a medicament for treating diabetes mellitus.
  16. A medicament for use in treating diabetes mellitus, composed of a formulation as claimed in one or more of claims 1 to 13.
HK12106953.8A 2009-07-06 2010-07-02 Aqueous preparations comprising methionine HK1166266B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009031748.1 2009-07-06
DE102010013134.2 2010-03-27

Publications (2)

Publication Number Publication Date
HK1166266A HK1166266A (en) 2012-10-26
HK1166266B true HK1166266B (en) 2017-09-01

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