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    • 专利摘要:
    aqueous pharmaceutical formulation containing methionine, its use and medicine for the treatment of diabetes mellitus. the present invention relates to an aqueous pharmaceutical formulation with an insulin, an insulin analogue or a derivative of insulin and methionine; as well as its preparation, its use for the treatment of diabetes mellitus and a medicine for the treatment of diabetes mellitus.
    公开号:BR112012000177B1
    申请号:R112012000177-9
    申请日:2010-07-02
    公开日:2021-06-01
    发明作者:Julia Schnieders；Christiane Fuerst；Walter Kamm；Isabell Schoettle；Annika Hagendorf；Gerrit Hauck；Verena Siefke-Henzler
    申请人:Sanofi-Aventis Deutschland Gmbh；
    IPC主号:
    专利说明:

    Description
    [0001] The present invention relates to an aqueous pharmaceutical formulation with an insulin, an insulin analogue or a derivative of insulin and methionine; as well as its preparation, use for the treatment of diabetes mellitus, and a medicine for the treatment of diabetes mellitus.
    [0002] Worldwide an increasing number of people suffer from diabetes mellitus. Among them, many have the so-called type I diabetes, for which, at the moment, the only possible therapy is to replace the deficient endocrine insulin secretion. Those who are affected are dependent on insulin injections for life, often several times a day. Unlike type I diabetes mellitus, in type II diabetes there is not always a lack of insulin, however in a large number of cases, especially in the advanced stage, treatment with insulin, if appropriate in combination with an oral antidiabetic agent, is considered a more advantageous form of therapy. In healthy individuals, insulin release from the pancreas is strongly linked to blood glucose concentration. Elevated blood glucose levels, such as those that occur after meals, are quickly offset by a corresponding increase in insulin secretion. In fasting, the plasma insulin level drops to a basal level value (base "line value"), which is sufficient to ensure a continuous supply of glucose to insulin-sensitive organs and tissues and to keep hepatic glucose production low. during the night. The replacement of endogenous insulin secretion by exogenous insulin application, mostly subcutaneous application, as a rule does not approach the quality of physiological regulation described above. Blood glucose often "goes off the rails" (toggles) up or down, which in its more severe forms can be fatal. In addition, high blood glucose levels for many years without initial symptoms pose a considerable health risk. The large-scale DCCT study in the US (The Diabetes Control and Complications Trial Research Group (1993), N. Engl. J. Med. 329, 977986) has clearly pointed out that chronic high blood glucose levels are responsible for the emergence of diabetic complications late. Delayed diabetic complications are microvascular and macrovascular diabetic complications that manifest, under certain circumstances, as retinopathies, nephropathies or neuropathies and lead to blindness, renal failure, as well as loss of extremities and are also associated with an increased risk of cardiovascular disorders . From this, it can be inferred that improved diabetes therapy should be aimed primarily at keeping the blood level as close as possible within the physiological range. According to the concept of intensified insulin therapy, this must be achieved by several daily injections of fast-acting and slow-acting insulin preparations. Fast-acting formulations are indicated with meals to compensate for the postprandial rise in blood glucose. Slow-acting basal insulins are intended to ensure insulin delivery, especially at night, without leading to hypoglycaemia.
    [0003] Insulin is a polypeptide of 51 amino acids, which are divided into two chains of amino acids: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are linked together by 2 disulfide bridges. Insulin preparations have been used for many years in diabetes therapy. Thus, not only naturally occurring insulin, but also, more recently, insulin derivatives and insulin analogues are employed.
    [0004] Insulin analogues are naturally occurring insulin analogues, namely human insulin or animal insulin, which differ by replacement of at least one naturally occurring amino acid radical and/or by addition/deletion of at least one amino acid radical corresponding to, or identical to, naturally occurring insulin. Amino acids can also be non-naturally occurring amino acids.
    [0005] Insulin derivatives are naturally occurring insulin derivatives or insulin analogues that are obtained by chemical modification. The chemical modification can consist, for example, of the addition of one or more chemical groups determined on one or more amino acids. As a rule, insulin derivatives and insulin analogues have a slightly altered activity compared to human insulin.
    [0006] Insulin analogues with an accelerated entry into action are described in EP 0 214 826, EP 0 375 437 and in EP 0 678 522. EP 0 124 826 relates, among others, to substitutions of B27 and B28. EP 0 678 522 describes insulin analogues which have, at position B29, several amino acids, preferably proline, but not glutamic acid.
    [0007] EP 0 375 437 discloses insulin analogues with lysine or arginine in B28, which can optionally be further modified also in B3 and/or A21.
    [0008] In EP 0 419 504 insulin analogues are disclosed, which are protected against chemical modifications by modification of asparagine in B3 and of at least one other amino acid in positions A5, A15, A18 or A21.
    [0009] As a rule, insulin derivatives and insulin analogues have a slightly altered effect compared to human insulin.
    [00010] In WO 92/00321 insulin analogues are described, in which at least one amino acid in positions B1-B6 has been replaced by lysine or arginine. According to WO 92/00321, such insulins have a prolonged action. A delayed effect is also exhibited in the insulin analogues described in EP-A 0 368 187. The concept of intensive insulin therapy seeks to reduce the health risk by seeking to stabilize blood sugar control through an early administration of basal insulins. An example of a common basal insulin is the drug Lantus® (active ingredient: insulin glargine = Gly (A21), Arg (B31), Arg (B32) human insulin). It is generally a goal of developing new improved basal insulins to minimize the number of hypoglycemic events. An ideal basal insulin works safely in each patient for at least 24 hours. Ideally, the onset of insulin effect is delayed and has as flat a time/activity profile as possible, thus visibly minimizing the danger of short-term sugar undersupply and thus allowing the application of even an early food intake. A good supply of basal insulin is effective when insulin activity is kept constant for as long as possible, that is, the body is supplied with a constant amount of insulin. Thus the risk of hypoglycemic events and a patient-specific variability per day are minimized. The pharmacokinetic profile of an ideal basal insulin should then be characterized by a delay in entry into action and a delayed action, that is, a long-lasting action.
    [00011] Insulin preparations that are found on the market, of totally natural origin, for insulin replacement, differ in the origin of insulin (for example, from calf, pig and human insulin), as well as its composition, with what the activity profile (entry into action and duration of action) can be influenced. By combining different insulin preparations, the most different action profiles and adjustments in blood sugar levels as physiologically as possible can be obtained. Recombinant DNA technology now makes it possible to prepare such modified insulins. Included here are insulin glargine (Gly(A21)-Arg(B31)-Arg(B32) human insulin), with a prolonged time of action. Insulin glargine is injected as an acidic, clear solution and, due to its dissolution properties, is precipitated in the physiological pH range of the subcutaneous tissue as a stable association of hexamers. Insulin glargine is injected once a day and is distinguished from other long-acting insulins by its flat serum profile and the reduced risk of nocturnal hypoglycemia associated with it (Schubert-Zsilavecz et al., 2:125-130 (2001)). Specific preparation of insulin glargine, which leads to prolonged duration of action, unlike other preparations described so far, is characterized by a clear solution with an acidic pH. Specifically with an acidic pH index, insulins, however, show reduced stability and a high tendency to aggregation under thermal and physico-mechanical load, which can be noticed in the form of turbidity and precipitation (particle formation) (Brange et al. ., J. Ph. Sci 86:517525 (1997)).
    [00012] Such insulin analogues have been found to lead to desirable basal time/efficacy profiles when insulin analogues are characterized by the following characteristics, wherein • the B-chain termination consists of an amidated basic amino acid radical, such as lysine or arginine amide, ie, in the basic amino acid radical amidated at the end of the B chain, the carboxyl group of the terminal amino acid is in its amidated form, and the N-terminal amino acid radical of the insulin A chain is a radical. lysine or an arginine radical, and• the A8 amino acid position is occupied by a histidine radical, and• the A21 amino acid position is occupied by a glycine radical, and• there are two neutral amino acid substitutions for acidic amino acids, two additions of negatively charged amino acid radicals or such substitution and such addition respectively at positions A5, A15, A18, B-1, B0, B1, B2, B3, and B4.
    [00013] Common to all aqueous formulations of insulins, insulin analogues, and insulin derivatives is that the mentioned proteins are not completely chemically stable, but rather depending on the time, storage temperature, and movement at which the formulation is subject, and much more, there are a number of molecular processes that can occur, affecting insulins, insulin analogues and insulin derivatives, which are detrimental to the quality of the formulation. A substance that impairs the chemical stability of insulins, insulin analogues and insulin derivatives is oxygen, whose contact with the formulations in question due to its presence in the air - particularly in package formulations for multiple administration - cannot be avoided. It is assumed, among others, that the oxidative potential of oxygen brings the deficiencies in chemical stability.
    [00014] It was then found, surprisingly, that the addition of the amino acid methionine in formulations of insulins, insulin analogues and insulin derivatives, leads to an improved stability of these proteins.
    [00015] An object of the invention is therefore an aqueous pharmaceutical formulation containing an insulin, an insulin analogue or an insulin derivative, or a pharmacologically tolerable salt thereof, and methionine.
    [00016] Another object of the invention is a pharmaceutical formulation as described above, where insulin is selected from a group containing human insulin, porcine insulin, and bovine insulin.
    [00017] Another object of the invention is a pharmaceutical formulation as described above, where 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 an insulin analogue of 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 bond chemistry;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,
    [00018] where two amino acid radicals from the group containing A5, A15, A18, B-1, B0, B1, B2, B3, and B4, simultaneously and independently of each other, are Asp or Glu, in particular in which the analogue of insulin is selected from a group containing: 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 a,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), A rg (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.
    [00019] Another object of the invention is a pharmaceutical formulation as described above, the insulin analogue being selected from a group containing an insulin analogue of the formula IIs s1 5 I 10 I 15 20A-1 AO Al IVE A5 CCHSTCSLY A15 LE A18 YC A21I chain A(SEQ. ID NO: 3)SS SI 1B —1 BO B1 V B3 B4 HLCGSHLVEALYLVCGERGFFY1 5 10 15 20 25T P B29 B30 B31 B32 (SEQ. ID NO: 4) chain B 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 Gln;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 containing amino acids selected from the group comprising amino acids such as 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 bond chemical; B32 is Arg-amide or Lys-amide,
    [00020] where no more than two amino acid radicals from the group containing A5, A15, A18, B-1, B1, B2, and B4, simultaneously and independently of each other, is Asp or Glu, in particular being the analogue of insulin is selected from a group comprising: 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) - human NH2 insulin, Arg (A-1), Arg (A0), Glu (A15), His (A8 ), Gly (A21), Arg (B30) - human NH2insulin, Arg (A-1), Arg (A0), Glu (A15), His (A8), Gly (A21), Lys (B30) - human NH2insulin, Arg (A-1), Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B30) - human NH2 insulin, Arg (A-1), Arg (A0), Asp (A18 ), His (A8), Gly (A21), Arg (B30) - human NH 2 insulin, Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B0), Arg (B30 ) - human NH2 insulin, Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B0), Lys (B30) - human NH2 insulin, Arg (A-1), Arg (A0 ), His (A8), Gly (A21), Asp (B3), Arg (B30) - NH2insuli in human, Arg (A-1), Arg (A0), His (A8), Gly (A21), Asp (B3), Lys (B30) - human NH2 insulin, Arg (A-1), Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B30) - human NH2 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) - NH 2 human insulin, Arg (A0), Glu (A5), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (A0 ), Glu (A5), His (A8), Gly (A21), Arg (B31), Lys (B32) - human NH2 insulin, Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B31), Arg (B32) - human NH2insulin, Arg (A0), Asp (A18), His (A8), Gly (A21), Arg (B31), Lys (B32) - human NH2insulin, 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 ( THE 0), 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) - human NH 2 insulin, Arg (A0), His (A8), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - human NH 2 insulin, Arg ( A0), His (A8), Gly (A21), Glu (B0), Arg (B31), Arg (B32) - human NH2 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.
    [00021] Another object of the invention is a pharmaceutical formulation as described above, in which 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 human insulin, B30-N-palmitoyl-ThrB29LysB30 human insulin, B29-N-(N-palmitoyl-Y-glutamyl)-des(B39) human insulin, B29-N-(N-litocholyl-Y-glutamyl)-des(B30) insulin human, B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin, and B29-N-(w-carboxyheptadecanoyl) human insulin.
    [00022] Another object of the invention is a pharmaceutical formulation as described above, which comprises 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, and containing a pH of 5 or less.
    [00023] Another object of the invention is a pharmaceutical formulation as described above, which comprises a preservative selected from a group containing phenol, m-cresol, chlorocresol, benzyl alcohol and paraben.
    [00024] Another object of the invention is a pharmaceutical formulation as described above, which comprises an isotonicity agent selected from a group containing mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride and glycerol.
    [00025] Another object of the invention is a pharmaceutical formulation as described above, with a pH in the range of pH 2.5 - 4.5, preferably pH 3.0 - 4.0, more preferably in the region of pH 3, 75.
    [00026] Another object of the invention is a pharmaceutical formulation as described above, where insulin, insulin analogue and/or insulin derivative is present at a concentration of 240 -3000 nmol/ml.
    [00027] Another object of the invention is a pharmaceutical formulation as described above, in which glycerin is present in a concentration of 20 to 30 mg/ml.
    [00028] Another object of the invention is a pharmaceutical formulation as described above, in which glycerin is present at a concentration of 25 mg/ml.
    [00029] Another object of the invention is a pharmaceutical formulation as described above, in which m-cresol is present in a concentration of 1 to 3 mg/ml, preferably 2 mg/ml.
    [00030] Another object of the invention is a pharmaceutical formulation as described above, in which zinc is present in a concentration of 0.01 or 0.03 or 0.08 mg/ml.
    [00031] Another object of the invention is a pharmaceutical formulation as described above, in which is additionally contained a glucagon-like peptide-1 (GLP1) or an analogue or derivative thereof, or exendin-3 and/or exendin-4 or a analogue or derivative thereof, preferably exendin-4.
    [00032] Another object of the invention is a pharmaceutical formulation as described above, in which an analogue of exendin-4 is selected from a group containing 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 in which an analogue of exendin-4 is selected from the group containing 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 one thereof pharmaceutically tolerable salt.
    [00033] Another object of the invention is a pharmaceutical formulation as described above, in which the peptide Lys6-NH2 is added to the C-termini of the analogs of exendin-4.
    [00034] Another object of the invention is a pharmaceutical formulation as described above, in which an analogue of exendin-4 is selected from the group comprising 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, desPro36, 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 Pro 36, Pro37, Pro38 exendin-4(1-39) -NH2, H-(Lys)6- des Pro36, Pro 37, 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, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39) -NH2,H-Asn-(Glu) 5- des Pro36, Pro37, Pro38 [Met(O)14, Asp28] exendin-4(1-39) -NH2, des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin - 4(1-39)- (Lys)6-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]exendin-4(1-39) -(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] exendin-4(1-39)-(Lys) 6-NH2, or a pharmaceutically tolerable salt thereof.
    [00035] Another object of the invention is a pharmaceutical formulation as described above, which further comprises Arg34, Lys26 (Nε(Y-glutamyl(Nα-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a salt thereof pharmaceutically tolerable.
    [00036] Another object of the invention is a pharmaceutical formulation as described above, comprising methionine in a concentration range of up to 10 mg/ml, preferably up to 3 mg/ml.
    [00037] Another object of the invention is a pharmaceutical formulation as described above, which comprises (a) introducing the components into an aqueous solution and (b) adjusting the pH.
    [00038] Another object of the invention is a pharmaceutical formulation as described above for the treatment of diabetes mellitus.
    [00039] Another object of the invention is a medicine for the treatment of diabetes mellitus, composed of a formulation as described above.
    [00040] In the following, the patent application will be described by means of some examples, which will in no way have a restrictive effect.Legends of the figures: figure 1: blood sugar lowering effect of new insulin analogues according to formula I in ratsfigure 2: blood sugar lowering effect of new insulin analogues according to formula I in dogs figure 3: blood sugar lowering effect of YKL205 in dogs figure 4: zinc dependence to the hypoglycemic effect of YKL205 in dogsfigure 5: blood sugar lowering effect of new insulin analogues according to formula II in ratsfigure 6: blood sugar lowering effect of insulin glargine in ratsExamples:
    [00041] The following examples should thoroughly clarify the concept of the invention, without any restrictive effect. Example 1: Studies for filling the solution using nitrogen, oxygen and filling under normal conditions.
    [00042] The preparation of the solution takes place by introducing about 25% 0.1 M HCl and adding 0.2% of polysorbate 20 stock solution. In succession SAR161271 and the chloride stock solution are added and stirred of zinc. SAR161271 is dissolved by adding 1M HCl at a pH index of pH 2. The solution is stirred, then 1M NaOH is added to adjust the pH index to pH 4.0. Water for use in injection is used to complete up to 90% of the application size (dose). 85% glycerin and m-cresol are added to the solution under stirring in succession. Water for use in injection is used to reach the desired final weight. The solution is filtered using a filter fitted with a syringe. The preparation was divided into three parts: non-aerated (as a reference), aerated with nitrogen and aerated with oxygen (as a positive control). The gasification took place under the mattress of the gas in question.UntreatedQuantity of SAR1612711 M + 5°C: 3.67 mg/ml1 M + 25°C: 3.46 mg/ml1 M + 37°C: 3.41 mg/mlImpurities1 M + 5°C: 3.0%1 M + 25°C: 3.6%1 M + 37°C: 5.6%High molecular weight proteins1 M + 5°C: 0.2%1 M + 25°C: 0.3%1 M + 37°C: 1.4% Treated with Nitrogen Amount of SAR1612711 M + 5°C: 3.73 mg/ml1 M + 25°C: 3.50 mg/ml1 M + 37°C: 3.35 mg/ml Impurities1M + 5°C: 3.1%1M + 25°C: 3.5%1M + 37°C: 5.2%High molecular weight proteins1M + 5°C: 0.2%1 M + 25°C: 0.3%1 M + 37°C: 1.2% Treated with Oxygen Amount of SAR1612711 M + 5°C: 3.54 mg/ml1 M + 25 °C: 3.34 mg/ml1 M + 37°C: 3.26 mg/mlImpurities1 M + 5°C: 3.2%1M + 25°C: 3.9%1M + 37°C: 7 .2% High molecular weight proteins 1 M + 5°C: 0.2% 1 M + 25°C: 0.5%1 M + 37°C: 2.9%
    [00043] The filling with the employment of nitrogen after 1 month showed no visible reduction of impurities compared to the untreated sample. The filling with the use of oxygen showed slightly higher impurities and proteins with slightly higher molecular mass. Based on these results, filling under normal conditions was selected.Example 2: Study of stability with 3 different antioxidants
    [00044] The solution was prepared as described in example 1. Additionally between the addition of 85% glycerin and m-cresol, the antioxidants methionine or glutathione or ascorbic acid were added to the formulation to reduce the level of oxidative by-product. Formulations containing either glutathione (0.183 mg/ml) or ascorbic acid (0.105 mg/ml) showed a distinct discoloration after only 3 months of storage. The formulation containing methionine (0.089 mg/ml) showed no discoloration and was stable after 1 month storage at 5°C. Amount of SAR1612711 M + 5°C: 3.43 mg/ml1 M + 25°C: 3, 43 mg/ml1 M + 37°C: 3.53 mg/mlImpurities1 M + 5°C: 2.9%1M + 25°C: 3.4%1M + 37°C: 5.7% highest molecular weight 1 M + 5°C: 0.2% 1 M + 25°C: 0.3% 1 M + 37°C: 1.1% Example 3: Formulation of amidated insulin derivatives
    [00045] Examples 3 to 7 are only for the determination of biological, pharmacological and physicochemical properties of insulin analogues according to formula I, in which first formulations (Example 3) of them were prepared and then the tests were carried out correspondents (Examples 4 to 7). A solution was prepared with the compounds as follows. The insulin analogue according to 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).
    [00046] The following compositions were used as dissolution media: a) 1 mM hydrochloric acid b) 1 mM hydrochloric acid, 5 μg/ml zinc (added as zinc chloride or hydrochloric acid) c) 1 mM hydrochloric acid , 10 μg/ml zinc (added as zinc chloride or hydrochloric acid)d) 1 mM hydrochloric acid, 15 μg/ml zinc (added as zinc chloride or hydrochloric acid) e) 1 mM hydrochloric acid, 30 μg/ml zinc (added as zinc chloride or hydrochloric acid)f) 1 mM hydrochloric acid, 80 μg/ml zinc (added as zinc chloride or hydrochloric acid)g) 1 mM hydrochloric acid, 120 μg/ml of zinc (added as zinc chloride or hydrochloric acid)
    [00047] For this was weighed, first, an amount of material freeze-dried around 30% greater than the amount needed due to molecular weight and target concentration. Afterwards, the existing concentration was determined by means of analytical HPLC and the solution was then prepared with 5 mM hydrochloric acid and 80 μg/ml of zinc to achieve the necessary volume to obtain the target concentration. If necessary, the pH index was readjusted to 3.5 ± 0.1. After the final HPLC analysis to ensure a target concentration of 240 ± 5 μM, the ready-made solution was transferred by means of a syringe containing a 0.2 μm filter, to a sterile flask which was closed with a septum and a cap. snap. For the short-term single test of the insulin derivatives of the invention, there was no optimization of the formulations in relation, for example, to the addition of isotonic agents, preservatives or buffer substances. new insulin analogues in rats
    [00048] The blood sugar lowering effect of selected new insulin analogues is tested in healthy, normoglycemic male Wistar rats. Male rats receive a subcutaneous injection of a 9 nmol/kg dose of an insulin analogue. Immediately before the invention of the insulin analogue, and at regular intervals of up to eight hours after the injection, blood samples were taken from the animals, and their blood sugar content was determined. The experiment clearly shows (see figure 1) that the insulin analogue according to the invention leads to a significantly delayed entry into action and a longer and more uniform duration of effect. of the new insulin analogues in dogs
    [00049] The blood sugar lowering effect of selected new insulin analogues is verified in healthy, normoglycemic male beagle dogs. Male animals received a dose of a subcutaneous injection of an insulin analogue of 6 nmol/kg. Immediately prior to injection of the insulin analogue, and at regular intervals up to forty-eight hours after injection, blood samples were taken from animals, and their blood sugar content determined. The experiment clearly shows (compare with figure 2) that the insulin analogue employed according to the invention leads to a noticeably delayed entry into action and a longer, more uniform duration of effect.Example 6: evaluation of the reducing action of blood sugar in dogs with a dose increased twice.
    [00050] The blood sugar lowering effect of selected new insulin analogues is verified in healthy, normoglycemic male Beagle dogs. Male animals received a subcutaneous injection dose of 6 nmol/kg and 12 nmol/kg of an insulin analogue. Immediately before injection of the insulin analogue and at regular intervals up to forty-eight hours after injection, blood samples were taken from the animals, and their blood sugar content was determined. The experiment clearly shows (compare with figure 3) that the insulin analogue according to the invention that is employed has a dose-dependent effect, but despite the twice-increased dose, the effect profile is flat, ie not there is a pronounced low point (Nadir). It can be concluded from this that the insulins according to the invention, in comparison with the known delay insulins, very clearly lead to fewer hypoglycemic events.Example 7: Evaluation of the blood sugar lowering action in dogs with different concentrations of zinc in the formulation
    [00051] The experiments were performed as described in example 35. Figure 4 shows the result. According to her, the time/activity curve of the insulin analogue according to the invention can be influenced by the amount (content) of zinc ions in the formulation with the same concentration of insulin, so that it is verified in zero or one low zinc content, a rapid onset of action and the action persists for 24 hours, whereas with a higher zinc content, a flat onset is observed and the insulin effect persists for much longer than 24 hours.Example 8 : Formulation of amidated insulin derivatives
    [00052] Examples 8 to 10 are only for the determination of biological, pharmacological and physicochemical properties of insulin analogues according to formula II, firstly their formulations were prepared (Example 8) and then the tests were performed correspondents (Examples 9 and 10). The insulin analogue according to 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). For this, the freeze-dried material was first weighed in an amount 30% greater than the amount required due to the molecular weight and the required target concentration. After that, the existing concentration was determined by means of analytical HPLC and the solution was then prepared with 5 mM hydrochloric acid with 80 μg/ml of zinc to obtain the necessary volume to reach the target concentration. If necessary, the pH value was readjusted to 3.5 ± 0.1. After the final HPLC analysis to ensure a target concentration of 240 ± 5 µM, the completed solution was transferred, using a syringe containing a 0.2 µm filter element, into a sterile vial that was closed with a septum and a cap. of fence. For a unique short-term verification of the insulin derivatives according to the invention, no optimization of the formulations was carried out, considering, for example, an addition of isotonic agents, preservatives or buffer substances.Example 9: evaluation of the action blood sugar reduction of new insulin analogues in rats.
    [00053] The blood sugar lowering effect of selected new insulin analogues is tested in healthy, normoglycemic male Wistar rats. Male rats received a dose of 9 nmol/kg of an insulin analogue injected subcutaneously. Immediately before the injection of the insulin analogue, and at regular intervals up to 8 hours after the injection, the animals' blood samples were taken, and from them the blood sugar content was checked. The experiment clearly shows (compare with figure 5) that the insulin analogue according to the invention led to a visible delayed entry into action and led to a longer, more uniform duration of action.Example 10: evaluation of the reducing action of blood sugar of new insulin analogues in dogs
    [00054] The blood sugar lowering effect of selected new insulin analogues is tested in male, normoglycemic beagle dogs. Male animals received a subcutaneous injection dose of 6 nmol/kg of an insulin analogue. Immediately before injection of the insulin analogue, at regular intervals for up to forty-eight hours after injection, blood samples were taken from animals, and their blood sugar content was determined. The experiment clearly showed that the insulin analogues according to the invention lead to a noticeably delayed entry into flat action, and to a longer and more uniform duration of action.
    权利要求:
    Claims (20)
    [0001]
    1. Aqueous pharmaceutical formulation, characterized in that it comprises Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine), or a pharmaceutically tolerable salt thereof, and methionine, said pharmaceutical formulation having a pH in the range of pH 2.5 - 4.5.
    [0002]
    2. Pharmaceutical formulation according to claim 1, characterized in that it has a pH in the range of pH 3.0 - 4.0.
    [0003]
    3. Pharmaceutical formulation according to claim 1 or 2, characterized in that it has a pH of pH 3.75.
    [0004]
    4. Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that it comprises 0.001 to 0.2 mg/ml of zinc, 0.1 to 5.0 mg/ml of a preservative, and 5.0 at 100 mg/ml of an isotonicity agent.
    [0005]
    5. Pharmaceutical formulation according to any one of claims 1 to 4, characterized in that it comprises a preservative selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol and parabens.
    [0006]
    6. Pharmaceutical formulation according to any one of claims 1 to 5, characterized in that it comprises an isotonicity agent selected from the group consisting of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride and glycerol.
    [0007]
    7. Pharmaceutical formulation according to any one of claims 1 to 6, characterized in that insulin glargine is present at a concentration of 240 - 3000 nmol/ml.
    [0008]
    8. Pharmaceutical formulation according to any one of claims 1 to 7, characterized in that it comprises glycerol in a concentration of 20 to 30 mg/ml.
    [0009]
    9. Pharmaceutical formulation according to any one of claims 1 to 8, characterized in that it comprises glycerol in a concentration of 25 mg/ml.
    [0010]
    10. Pharmaceutical formulation according to any one of claims 1 to 9, characterized in that it comprises m-cresol in a concentration of 1 to 3 mg/ml.
    [0011]
    11. Pharmaceutical formulation according to any one of claims 1 to 10, characterized in that it comprises m-cresol at a concentration of 2 mg/ml.
    [0012]
    12. Pharmaceutical formulation according to any one of claims 1 to 11, characterized in that it comprises zinc in a concentration of 0.01 or 0.03 or 0.08 mg/ml.
    [0013]
    13. Pharmaceutical formulation according to any one of claims 1 to 12, characterized in that it further comprises exendin-4, or a pharmaceutically acceptable salt thereof.
    [0014]
    14. Pharmaceutical formulation according to any one of claims 1 to 12, characterized in that it further comprises H-desPro36-exendin-4-Lys6-NH2, or a pharmaceutically acceptable salt thereof.
    [0015]
    15. Pharmaceutical formulation according to any one of claims 1 to 12, characterized in that it further comprises Arg34, Lys26 (Nε(Y-glutamyl(Nα-hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof.
    [0016]
    16. Pharmaceutical formulation according to any one of claims 1 to 15, characterized in that it comprises methionine in a concentration range of up to 10 mg/ml.
    [0017]
    17. Pharmaceutical formulation according to any one of claims 1 to 16, characterized in that it comprises methionine in a concentration range of up to 3 mg/ml.
    [0018]
    18. Process for preparing a formulation as defined in any one of claims 1 to 17, characterized in that it comprises introducing the insulin analogue and methionine of the pharmaceutical formulation as defined in claim 1 into an aqueous solution, and( b) adjust the pH.
    [0019]
    19. Use of a formulation as defined in any one of claims 1 to 17, characterized in that it is in the preparation of a drug to treat diabetes mellitus.
    [0020]
    20. Medicine to treat diabetes mellitus, characterized in that it comprises a formulation as defined in any one of claims 1 to 17.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS6033474B2|1978-05-11|1985-08-02|Fujisawa Pharmaceutical Co|
    DE3316363C2|1983-05-05|1991-10-17|Deutsche Babcock Anlagen Ag, 4200 Oberhausen, De|
    PH25772A|1985-08-30|1991-10-18|Novo Industri As|Insulin analogues, process for their preparation|
    DK257988D0|1988-05-11|1988-05-11|Novo Industri As|NEW PEPTIDES|
    DE3837825A1|1988-11-08|1990-05-10|Hoechst Ag|NEW INSULIN DERIVATIVES, THEIR USE AND A PHARMACEUTICAL PREPARATION CONTAINING THEM|
    AU641631B2|1988-12-23|1993-09-30|Novo Nordisk A/S|Human insulin analogues|
    IL93282A|1989-02-09|1995-08-31|Lilly Co Eli|Insulin analogs|
    DK155690D0|1990-06-28|1990-06-28|Novo Nordisk As|NEW PEPTIDES|
    US5272135A|1991-03-01|1993-12-21|Chiron Ophthalmics, Inc.|Method for the stabilization of methionine-containing polypeptides|
    WO1999034821A1|1998-01-09|1999-07-15|Novo Nordisk A/S|Stabilised insulin compositions|
    US6365177B1|1998-06-05|2002-04-02|Insotech Ltd.|Insulin supplemented infant formula|
    JP2007204498A|1999-03-01|2007-08-16|Chugai Pharmaceut Co Ltd|Long-term stabilized formulations|
    EP1076066A1|1999-07-12|2001-02-14|Zealand Pharmaceuticals A/S|Peptides for lowering blood glucose levels|
    WO2001024814A1|1999-10-04|2001-04-12|Chiron Corporation|Stabilized liquid polypeptide-containing pharmaceutical compositions|
    US6852694B2|2001-02-21|2005-02-08|Medtronic Minimed, Inc.|Stabilized insulin formulations|
    DE10114178A1|2001-03-23|2002-10-10|Aventis Pharma Gmbh|Zinc-free and low-zinc insulin preparations with improved stability|
    CA2463908A1|2001-10-18|2003-04-24|Bristol-Myers Squibb Company|Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions|
    BR0215216A|2001-12-21|2004-11-16|Novo Nordisk Healthcare Ag|Liquid aqueous composition, method for preparing a liquid aqueous composition of a factor vii polypeptide, use of a liquid aqueous composition, and method for treating a factor vii response syndrome|
    DE10227232A1|2002-06-18|2004-01-15|Aventis Pharma Deutschland Gmbh|Sour insulin preparations with improved stability|
    JP2007537981A|2003-09-19|2007-12-27|ノボ　ノルディスク　アクティーゼルスカブ|Novel plasma protein affinity tag|
    US20080090753A1|2004-03-12|2008-04-17|Biodel, Inc.|Rapid Acting Injectable Insulin Compositions|
    US20090142338A1|2005-03-04|2009-06-04|Curedm, Inc.|Methods and Compositions for Treating Type 1 and Type 2 Diabetes Mellitus and Related Conditions|
    US20070191271A1|2006-02-10|2007-08-16|Dow Pharmaceutical Sciences|Method for stabilizing polypeptides lacking methionine|
    WO2007098479A2|2006-02-21|2007-08-30|University Of Medicine And Dentistry Of New Jersey|Localized insulin delivery for bone healing|
    TW200806317A|2006-03-20|2008-02-01|Wyeth Corp|Methods for reducing protein aggregation|
    DE102006031962A1|2006-07-11|2008-01-17|Sanofi-Aventis Deutschland Gmbh|Amidated insulin glargine|
    WO2008124522A2|2007-04-04|2008-10-16|Biodel, Inc.|Amylin formulations|
    DK2157967T3|2007-04-23|2013-04-08|Intarcia Therapeutics Inc|Suspension formulations of insulinotropic peptides and applications thereof|
    SI2219607T1|2007-11-01|2012-09-28|Merck Serono Sa|Liquid LH formulations|
    NZ586590A|2008-01-09|2012-06-29|Sanofi Aventis Deutschland|Insulin analogues or derivatives having an extremely delayed time-action profile|
    TWI394580B|2008-04-28|2013-05-01|Halozyme Inc|Super fast-acting insulin compositions|
    EP3228320B1|2008-10-17|2019-12-18|Sanofi-Aventis Deutschland GmbH|Combination of an insulin and a glp-1 agonist|
    JP2009091363A|2008-11-21|2009-04-30|Asahi Kasei Pharma Kk|Stabilized aqueous injectable solution of pth|
    TW201113032A|2009-07-06|2011-04-16|Sanofi Aventis Deutschland|Slow-acting insulin preparations|
    PT2498802E|2009-11-13|2015-04-13|Sanofi Aventis Deutschland|Pharmaceutical composition comprising a glp-1 agonist, an insulin, and methionine|
    RU2573995C2|2009-11-13|2016-01-27|Санофи-Авентис Дойчланд Гмбх|Pharmaceutical composition containing glp-1 agonist and methionine|
    AU2011202239C1|2010-05-19|2017-03-16|Sanofi|Long-acting formulations of insulins|NZ586590A|2008-01-09|2012-06-29|Sanofi Aventis Deutschland|Insulin analogues or derivatives having an extremely delayed time-action profile|
    EP3228320B1|2008-10-17|2019-12-18|Sanofi-Aventis Deutschland GmbH|Combination of an insulin and a glp-1 agonist|
    TW201113032A|2009-07-06|2011-04-16|Sanofi Aventis Deutschland|Slow-acting insulin preparations|
    PT2498802E|2009-11-13|2015-04-13|Sanofi Aventis Deutschland|Pharmaceutical composition comprising a glp-1 agonist, an insulin, and methionine|
    RU2573995C2|2009-11-13|2016-01-27|Санофи-Авентис Дойчланд Гмбх|Pharmaceutical composition containing glp-1 agonist and methionine|
    EP2611458B1|2010-08-30|2016-09-21|Sanofi-Aventis Deutschland GmbH|Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2|
    US9821032B2|2011-05-13|2017-11-21|Sanofi-Aventis Deutschland Gmbh|Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin|
    EP2720712B1|2011-06-17|2016-03-02|Halozyme, Inc.|Stable formulations of a hyaluronan-degrading enzyme|
    AU2012300978B2|2011-08-29|2017-04-27|Sanofi-Aventis Deutschland Gmbh|Pharmaceutical combination for use in glycemic control in diabetes type 2 patients|
    AR087744A1|2011-09-01|2014-04-16|Sanofi Aventis Deutschland|PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OF A NEURODEGENERATIVE DISEASE|
    AR094821A1|2012-07-25|2015-09-02|Hanmi Pharm Ind Co Ltd|LIQUID FORMULATION OF AN INSULINOTROPIC PEPTIDE CONJUGATE OF PROLONGED ACTION|
    US10441665B2|2012-07-25|2019-10-15|Hanmi Pharm. Co., Ltd.|Liquid formulation of long acting insulinotropic peptide conjugate|
    WO2014071405A2|2012-11-05|2014-05-08|Case Western Reserve University|Long-acting single-chain insulin analogues|
    MX360420B|2012-12-19|2018-10-31|Wockhardt Ltd|A stable aqueous composition comprising human insulin or an analogue or derivative thereof.|
    TW201927333A|2013-02-04|2019-07-16|法商賽諾菲公司|Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives|
    US10130288B2|2013-03-14|2018-11-20|Cell and Molecular Tissue Engineering, LLC|Coated sensors, and corresponding systems and methods|
    US10405961B2|2013-03-14|2019-09-10|Cell and Molecular Tissue Engineering, LLC|Coated surgical mesh, and corresponding systems and methods|
    AR098168A1|2013-10-25|2016-05-04|Sanofi Sa|STABLE FORMULATION OF GLULISINE INSULIN|
    KR20160101195A|2014-01-09|2016-08-24|사노피|Stabilized pharmaceutical formulations of insulin aspart|
    WO2015104314A1|2014-01-09|2015-07-16|Sanofi|Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives|
    SG11201604708VA|2014-01-09|2016-07-28|Sanofi Sa|Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives|
    MA41138A|2014-12-12|2017-10-17|Sanofi Aventis Deutschland|FORMULATION CONTAINING A FIXED INSULIN GLARGINE / LIXISENATIDE RATIO|
    EA034940B1|2015-03-13|2020-04-09|Санофи-Авентис Дойчланд Гмбх|Treatment of type 2 diabetes mellitus patients|
    TW201705975A|2015-03-18|2017-02-16|賽諾菲阿凡提斯德意志有限公司|Treatment of type 2 diabetes mellitus patients|
    法律状态:
    2020-08-25| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-09-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-12-08| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-12-29| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-04-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-01| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 02/07/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |
    优先权:
    申请号 | 申请日 | 专利标题
    DE102009031748.1|2009-07-06|
    DE102009031748|2009-07-06|
    DE102010013134|2010-03-27|
    DE102010013134.2|2010-03-27|
    PCT/EP2010/059436|WO2011003822A2|2009-07-06|2010-07-02|Insulin preparations containing methionine|
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