EP2451472A1 - Heat- and vibration-stable insulin preparations - Google Patents

Heat- and vibration-stable insulin preparations

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Publication number
EP2451472A1
EP2451472A1 EP20100730441 EP10730441A EP2451472A1 EP 2451472 A1 EP2451472 A1 EP 2451472A1 EP 20100730441 EP20100730441 EP 20100730441 EP 10730441 A EP10730441 A EP 10730441A EP 2451472 A1 EP2451472 A1 EP 2451472A1
Authority
EP
Grant status
Application
Patent type
Prior art keywords
arg
nh
asp
insulin
glu
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20100730441
Other languages
German (de)
French (fr)
Inventor
Anja Pfenninger
Norbert Tennagels
Christiane Fuerst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi-Aventis Deutschland GmbH
Original Assignee
Sanofi-Aventis Deutschland GmbH
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/28Insulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Abstract

The invention relates to a method for producing an aqueous, pharmaceutical formulation comprising an insulin, an insulin analog, or an insulin derivative, wherein the ready-made formulation takes place directly by dissolving the insulin, the insulin analog, or the insulin derivative as a solid in a suitable solvent mixture.

Description

description

Heat and schüttelstabile insulin preparations The invention relates to a process for preparing an aqueous pharmaceutical formulation comprising an insulin, an insulin analog or an insulin derivative wherein the ready to use formulation of the immediately by dissolving the insulin,

Insulin analog or insulin derivative as a solid with a suitable

done solvent mixture.

Worldwide an increasing number of people suffering from diabetes mellitus. Among them are many so-called type I diabetics, for whom the substitution of the missing

endocrine insulin secretion is the only currently possible therapy. The

Concerned for life, usually several times a day, dependent on insulin injections. In contrast to Type I diabetes II diabetes is the type not fundamentally a lack of insulin, however, treatment with insulin is used in a variety of cases, especially in the advanced stage, possibly in

Combination with an oral antidiabetic, is viewed as the most favorable form of therapy. In healthy people, the release of insulin by the pancreas strictly to the

Concentration in blood glucose coupled. Elevated blood glucose levels, such as occur after meals, with a corresponding increase in

Insulin quickly compensated. In the fasting state of the drops

Plasma insulin levels to a basal value which is sufficient to ensure a continuous supply of insulin-sensitive organs and tissue with glucose and to keep hepatic glucose production low during the night. The replacement of the endogenous insulin secretion by exogenous, mostly subcutaneous administration of insulin usually the quality of the physiological regulation of blood glucose described above does not approximate. There is often lapses in blood glucose up or down, which can be life-threatening in its most severe forms. However, in addition also for years to elevated blood glucose levels without initial symptoms a significant health risk. The large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) demonstrated clearly that chronically elevated blood glucose levels are substantially responsible for the development of late diabetic complications. Diabetic late damage is micro- and macrovascular damage, which may manifest as retinopathy, nephropathy, or neuropathy and leads to blindness, kidney failure and loss of limbs and beyond with an increased risk for heart / circulatory diseases

accompanied. It can be deduced that an improved therapy of diabetes must be aimed primarily to keep the blood glucose as closely as possible in the physiological range. According to the concept of intensified insulin therapy, this should acting from fast and slow by multiple daily injections

Insulin preparations have been achieved. Rapid-acting formulations are given at meals in order to compensate the postprandial rise in blood glucose. Slow-acting basal insulins should ensure the basic supply of insulin especially during the night without leading to hypoglycemia.

Insulin is a polypeptide of 51 amino acids spread into 2 amino acid chains: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are connected to one another by 2 disulfide bridges. Insulin preparations have been employed for diabetes therapy for many years. Not only naturally occurring insulins are used, but recently also insulin derivatives and analogs.

Insulin analogs are analogs of naturally occurring insulins, namely

Human insulin or animal insulins, which an amino acid residue naturally occurring with other amino acids and / or addition / removal differ by substitution of at least of at least one amino acid residue from the corresponding, otherwise identical naturally occurring insulin same. These may also be amino acids which do not occur naturally. Insulin derivatives are derivatives of naturally occurring insulin or an

Insulin analog which are obtained by chemical modification. The chemical modification may, for example, in the addition of one or more specific chemical groups to one or more amino acids. As a rule, insulin derivatives and insulin analogues versus human insulin have a slightly altered effect. Insulin analogs having an accelerated onset of action are described in EP 0,214,826,

EP 0375437 and EP 0678522 described. EP 0124826 inter alia relates to substitutions of B27 and B28. EP 0,678,522 describes insulin analogs which have in the position B29 various amino acids, preferably proline, but not glutamic acid.

EP 0375437 includes insulin analogs with lysine or arginine in B28, which can optionally be additionally modified in B3 and / or A21.

In EP 0419504 insulin analogs are disclosed to chemical

Modifications are protected, in which asparagine in B3 and another amino acid in the positions A5, A15, A18 or A21 are modified at least.

As a rule, insulin derivatives and insulin analogues versus human insulin have a slightly altered effect. In WO 92/00321, insulin analogs are described in which an amino acid of the positions B1 -B6 is replaced by lysine or arginine at least. Such insulins have according to WO 92/00321 for a prolonged effect. A sustained action also have the insulin analogs described in EP-A 0,368,187. The concept of intensive insulin therapy attempts mitigate the health risk by a stable control of blood sugar level is desired by early administration of basal insulin. An example of a common basal insulin is the medicine Lantus ® (active substance: insulin glargine = Gly (A21), Arg (B31), Arg (B32) human insulin). In general, it is important to minimize the development of new, improved basal insulins, the number of hypoglycemic events. An ideal basal insulin acts safe in each patient at least 24 hours. Ideally, sets the

delayed insulin action and comprising a flat possible time / action profile, so that the risk of short-term blood sugar is considerably reduced and the application can be done even without ingestion of foods. A good supply of basal insulin is given when the effect of insulin consistently continues as long as possible, ie, the body is supplied with a constant amount of insulin. Thus the risk of hypoglycemic events is low and minimizes patient and day-specific variability. The pharmacokinetic profile of an ideal basal insulin should thus by a delayed onset of action and by that be marked long-lasting and uniform effect delayed.

The insulin preparations of naturally occurring insulins on the market for insulin substitution differ in the origin of the insulin (for example, bovine, porcine, human insulin), as well as the composition, whereby the profile of action (onset of action and duration of action) can be influenced. by combining

various insulin preparations can achieve a wide variety of profiles of action and adjust physiological possible blood glucose levels. The recombinant DNA

Today technology allows the production of such modified

Insulins. To this end, insulin glargine is one (Gly (A21) Arg (B31) Arg (B32) human insulin) with a prolonged duration of action. Insulin glargine is injected as an acidic, clear solution and falls due to its dissolution characteristics in the physiological pH range of the

Subcutaneous tissue from a stable Hexamerassoziat. Insulin glargine is injected once a day and is distinguished from other long-acting insulins by its flat serum profile and the associated reduction of the risk of nocturnal hypoglycaemia from (Schubert Zsilavecz et al., 2: 125-130 (2001)). The specific preparation of insulin glargine that leads to prolonged duration of action is in

Contrary to previously described preparations characterized by a clear solution having an acidic pH. Especially at acidic pH, however, show insulins a reduced stability and an increased tendency to aggregate under thermal and physico-mechanical stress that is in the form of cloudiness and

can make precipitations (particle formation) felt (Brange et al, J. Ph Be 86:.. 517-525 (1997)).

Liquid insulin preparations have a shelf life of about two years when stored at 2-8 ° C. The durability in use allows for storage at up to 25 ° C and is given as 4 weeks, mechanical stress (shaking) should be avoided. Patients must be careful to generally ensure that the insulin preparation is a clear solution, as it can cause precipitation of insulin in exceptional cases, in part, by the formation of so-called "fibrils". This creates the danger that a sufficient dose of the drug is not guaranteed.

There is therefore a need to heat and schüttelstabilen stable insulins or heat and schüttelstabilen stable insulin formulations for the treatment of type 2 and type 1 diabetes to develop. This is done as part of the invention described herein. The two-component lnsulinzubereitungen invention differ from conventional through their heat stability and stability to mechanical stess. Unlike present on the market liquid insulin formulations, the heat and Schüttelstabilität based on the retention of insulin as a solid until shortly before administration. It could be shown that insulin-resistant under heat stress to degradation (changes in the molecular structure) is more stable than dissolved. Furthermore precipitated dissolved insulin; this represents a biophysical process, which can not take place in the solid state. As a result, heat stress is comparable with more bioavailable insulin an insulin preparation is available, when the release operation takes place after the heat stress.

An aqueous insulin preparations continue to show at mechanical stress (shaking) the tendency to precipitate insulin. The amount of bioavailable insulin after Schüttelstreß is therefore unknown and represents an impairment of

Patient safety. In addition, there is thus out of heat-stable insulin preparations need for such, also to mechanical stress (eg shaking) are stable. It could be shown that insulin-resistant against shaking is more stable than dissolved insulin. The biophysical process of precipitating at Schüttelstreß takes place exclusively in dissolved insulin. In the sequence is at a comparable Schüttelstreß bioavailable insulin in unimpaired amount available if the releasing operation takes place after the Schüttelstreß. Typically, insulin in aqueous systems, the auxiliaries and additives, such as antibacterials, isotonizing agents, buffering agents, and / or surfactants (= hereinafter "solvent" referred to) available on the market. The dissolution of insulin for the manufacture of a pharmacological composition is in generally ensured by the fact that the insulin is first dissolved acidic to then be adjusted to the required concentration and pH of the solution in the further steps (the Wellcome Foundation Limited te London,

Octrooiraad Nederland, Octrooiannnvrage No. 6506714, 05.26.1965 "Werkwijze voor het bereiden van insulinepreparaten").

Alternatively, a partial dissolution of insulins in an alkaline medium, followed by pH-value setting is described along with a slightly increased stability of the insulin preparations (WO 2004/096266). Thus, a multi-stage process for the preparation of a ready insulin preparation for the required, which includes, inter alia, the adjustment of the pH.

It has now been found that ready-made

can be prepared by a one step process insulin preparations in which the insulin (or an analogue or derivative thereof) with a buffer solution

is combined and by dissolving the insulin (or analogue or derivative thereof) the ready-insulin composition is formed within a few minutes. Thus, the dissolution process of the solid insulin can be done on site by the patient or his caregivers, for example, in a two-chamber ampoule or other suitable devices. Corresponding tests, insulin in the appropriate solvents and concentrations in an adequate time (~ 10 min) to dissolve completely, are successful. Essentially this success by suitable pH value of the solvent depends. The basic composition of the

Solvents (aids, additives, etc.) not not necessarily different from the already on the market or formulations. Heat and mech. stress stable and insulins thus offer the following advantages:

- Necessary cold chain is obsolete

- storage provision simplified in warm countries

- Improved drug safety for the patient

- General extended shelf life of the drug

- Reduced return of vials of insulin precipitated

The two-component lnsulinzubereitungen invention offer advantages mentioned above. Patients with no or that lack access to suitable cooling devices can thus hold appropriate amounts of insulin available; also is the

Use of such preparations in countries with warm climates particularly advantageous. and the amount of insulin solution at Patienen can be so reduced by suitable ampules sizes in terms of the 2-component inventive insulin preparations that the necessary storage time can be reduced in use to a minimum level. This allows the addition of antimicrobial

Additives such as m-cresol or other phenols reduced or even become obsolete.

The preparations can for all known insulins, insulin analogues and

Insulin derivatives are prepared. This includes preparations with desirable basal time /

Effect profiles, where insulin analogs are characterized by the features that

• the B chain end of an amidated basic amino acid residue such as lysine or

Arginine amide, ie at the amidated basic amino acid residue at the B chain end is the carboxyl group of the terminal amino acid in its amidated

Form, and • the N-terminal amino acid residue of the insulin A-chain, a lysine or arginine residue, and

• amino acid position A8 is occupied by a histidine residue, and

• is the amino acid position A21 occupied by a glycine residue, and

• two substitutions of neutral amino acids with acidic amino acids, two

Addition of negatively charged amino acid residues or each such substitution and such addition at the positions A5, A15, A18, B1, BO, B1, B2, B3 and B4 are carried out. An object of the invention is therefore a process for preparing an aqueous pharmaceutical formulation comprising an insulin, an insulin analog or an insulin derivative or a pharmacologically tolerable salt thereof, wherein the

formulation ready for use directly by dissolving the insulin, the

Insulin analog or insulin derivative as a solid with a suitable

occurs solvent mixture, preferably wherein the composition of the suitable solvent mixture is determined by

(A) solvent mixtures varying pH with concentrations of

Excipients are prepared, which correspond containing the final concentration of the excipients of the formulation, an insulin, an insulin analog or an insulin derivative, and

(B) that of the solvent mixture is determined by dissolving the desired insulin, insulin analog or insulin derivative represented by dissolving the solid of insulin, insulin analog or insulin derivative is the desired pH of the

produces ready-made formulation.

Another object of the invention is a method as described above, wherein the insulin, the insulin analog or the insulin derivative is present as a crystalline or amorphous solid. An object of the invention is a method as described above wherein the

Insulin is selected from a group consisting of human insulin, porcine insulin and bovine insulin. Another object of the invention is as described above, a method wherein the insulin analog is selected from a group comprising Gly (A21), Arg (B31), Arg (B32) -human insulin, Lys (B3), Glu (B29) human insulin, Asp (B28) human insulin, Lys (B28) Pro (B29) human insulin and Des (B30) human insulin.

Another object of the invention is a method according to one or more of claims 1 to 3, wherein the insulin analog is selected from a group consisting of an insulin analog of the formula I

SS

1 5 | 10 | 15 20

AO GIVE A5 CCHSICSLY A15 A18 LE YCG

I (SEQ ID NO: 1) \ A-chain

BI BO Bl B2 B3 B4 HLCGSHLVEALYLVCGERGFF Y

1 5 10 15 20 25

TP B29 B30 B31 B32 (SEQ ID NO: 2)

B chain

30 wherein

AO is Lys or Arg; A5 is Asp, Gln or Glu;

A15 is Asp, Glu or Gln;

A18 is Asp, Glu or Asn;

B-1 Asp, Glu or an amino group;

BO Asp, Glu or a chemical bond; B1 Asp, Glu or Phe;

B2 Asp, Glu or Val;

B3 is Asp, GIu or Asn;

B4 Asp, Glu or Gln; B29 is Lys or a chemical bond; B30 is Thr or a chemical bond;

B31 Arg, Lys, or a chemical bond;

B32 Arg-amide, Lys-amide, or one amino group corresponding to said two amino acid residues of the group consisting of A5, A15, A18, B1, BO, B1, B2, B3 and B4 simultaneously and independently Asp or Glu

correspond, or a pharmacologically tolerable salt thereof, preferably, wherein the insulin analog is selected from a group comprising:

Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Asp (A18), Gly ( A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Lys (B32 ) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B3), Arg ( B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 human insulin , Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His ( A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Asp (B3 ), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31) , Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu ( A15), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (B4 ), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (BO), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (BO), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), (His A8 ), Asp (A18), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21) , Glu (BO), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg ( AO), His (A8), Glu (A15), Gly (A21), Asp (B1), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15 ), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B1) , Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Asp (B1), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Arg ( B31) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Lys (B31) - NH 2 human insulin.

Another object of the invention is a method as described above, wherein the insulin analog is selected from a group comprising

an insulin analog of the formula Il SS

5 I 10 I 15 20

Al AO Al IVE CCHSICSLY A5 A15 A21 LE Al 8 YC

A chain

II

BI BO Bl V B3 B4 HLCGSHLVEALYLVCGERGFF Y

1 5 10 15 20 25

TP B29 B30 B31 B32 (SEQ ID NO: 4) B-chain

30 wherein

A-1 Lys, Arg, or an amino group;

AO is Lys, Arg or a chemical bond;

A1 Arg or Gly; A5 is Asp, Glu or Gln;

A15 is Asp, Glu or Gln;

A18 is Asp, Glu or Asn;

A21 Ala, Ser, Thr or Gly;

B-1 Asp, Glu or an amino group; BO Asp, Glu or a chemical bond;

B1 Asp, Glu, Phe or a chemical bond; B3 is Asp, GIu or Asn;

B4 Asp, Glu or Gln;

B29 Arg, Lys or an amino acid selected from a group consisting of the amino acids Phe, Ala, Thr, Ser, VaI, Leu, Glu, or Asp, or a chemical bond;

B30 is Thr or a chemical bond; B31 Arg, Lys, or a chemical bond; B32 Arg-Lys-amide or amide corresponding, wherein no more than one amino acid residue of the group consisting of A5, A15, A18, B1, BO, B1, B2, B3 and B4 correspond simultaneously and independently Asp or Glu, and preferably in the the insulin analog is selected from a group comprising:

Arg (A-1), Arg (AO), Glu (A5), His (A8), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Glu ( A5), His (A8), Gly (A21), Lys (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Glu (A15), His (A8), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Glu (A15), His (A8), Gly (A21), Lys (B30) - NH 2 human insulin, Arg (A-1) , Arg (AO), Asp (A18), His (A8), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Asp (A18), His (A8 ), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Glu (BO), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Glu (BO), Lys (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Asp (B3), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Asp (B3) , Lys (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Glu (B4), Arg (B30) - NH 2 human insulin, Arg (A- 1), Arg (AO), His (A8), Gly (A21), Glu (B4), Lys (B3 0) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin,

Arg (AO), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin,

Arg (AO), Glu (A5), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), Glu (A5), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), Asp (A18), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), Asp (A18), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), Glu (A15), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), Glu (A15), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO ), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Arg (B30) - NH 2 - human insulin,

Arg (AO), His (A8), Gly (A21), Lys (B30) - NH 2 - human insulin,

Arg (A-1), Arg (AO), His (A8), Gly (A21), Arg (B30) - NH 2 - human insulin,

Arg (A-1), Arg (AO), His (A8), Gly (A21), Lys (B30) - NH 2 - human insulin,

Arg (AO), Arg (A1), His (A8), Gly (A21), Arg (B30) - NH 2 - human insulin,

Arg (AO), Arg (A1), His (A8), Gly (A21), Lys (B30) - NH 2 - human insulin,

His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin. Another object of the invention is a method according to one or more of claims 1 to 3, wherein the insulin derivative is selected from a group comprising B29-N-myristoyl-des (B30) human insulin, B29-N-palmitoyl-des (B30) human insulin , B29-N-myhstoyl human insulin, B29-N-palmitoyl human insulin, B28-N-myristoyl Lys B28 Pro B29 human insulin, B28-N-palmitoyl-Lys B28 Pro B29 human insulin, B30-N-myhstoyl-Thr B29 Lys B3 ° human insulin , B30-N-palmitoyl- Thr B29 Lys B30

Human insulin, B29-N- (N-palmitoyl-Y-glutamyl) -des (B39) human insulin, B29-N- (N-lithocholyl-Y-glutamyl) -des (B30) human insulin, B29-N- (ω-carboxyheptadecanoyl ) - des (B30) human insulin and B29-N- (ω-carboxyheptadecanoyl) human insulin. Another object of the invention is a method as described above wherein the formulation contains a preservative selected from a group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, parabens is present.

Another object of the invention is as described above, a method, wherein the formulation in an isotonizing agent selected from a group comprising mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol is present.

Another object of the invention is a method as described above, wherein the insulin, the insulin analog and / or the insulin derivative in a concentration of 240 - 3000 present nmol / ml

Another object of the invention is a method as described above, wherein in the formulation in addition, a glucagon-like peptide-1 (GLP-1) or an analogue or derivative thereof, or exendin-3 or -4 or an analogue or derivative thereof is contained , preferably wherein an analogue of exendin-4 is selected from a group comprising

H-DESpro 36 -Exendin-4-Lys 6 -NH 2,

H-des (Pro 36 37) -Exendin-4-l_ys 4 -NH 2, and

H-des (Pro 36 37) -Exendin-4-Lys 5 -NH 2,

or a pharmacologically tolerable salt thereof.

Another object of the invention is as described above, a method in which an analogue of exendin-4 is selected from a group comprising DESpro 36 [Asp 28] exend in-4 (1 -39)

DESpro 36 [isoasp 28] exend in-4 (1 -39)

DESpro 36 [Met (O) 14, Asp 28] exend in-4 (1 -39)

DESpro 36 [Met (O) 14, isoasp 28] exend in-4 (1 -39)

DESpro 36 [Trp (O2) 25, Asp 28] exend in-2 (1 -39)

DESpro 36 [Trp (O2) 25, isoasp 28] exend in-2 (1 -39)

DESpro 36 [Met (O) 14 Trp (O2) 25, Asp 28] exend in-4 (1 -39) and

DESpro 36 [Met (O) 14 Trp (O2) 25, isoasp 28] exend in-4 (1-39), or a pharmacologically tolerable salt thereof, preferably in which the C-termini of exendin-4 analogs of the is peptide -Lys6-NH 2 is added.

Another object of the invention is a pharmaceutical formulation as described above, wherein an analogue of exendin-4 is selected from a group comprising

H- (Lys) 6 - des Pro 36 [Asp 28] Exendin-4 (1 -39) -Lys 6 -NH 2

of Asp 28 Pro 36, Pro 37, Pro 38 exendin-4 (1 -39) -NH 2,

H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) -NH 2,

H-Asn- (Glu) 5 of the Pro 36, Pro 37, Pro 38 [Asp 28] exend in-4 (1 -39) -NH 2,

of Pro 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,

H- (Lys) 6 - Pro of 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,

H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,

H- (Lys) 6 - des Pro 36 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -Lys 6 -NH 2,

H- the Asp 28 Pro 36, Pro 37, Pro 38 [Trp (O2) 25] exend in-4 (1 -39) -NH 2,

H- (Lys) 6 - Pro of 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -NH 2,

H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -NH2, the Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH 2,

H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2, H-Asn- (Glu ) 5 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH2, H- (Lys) 6 - 36 of the Pro [Met (O) 14, Asp 28] exendin-4 (1 -39) -Lys 6 -NH 2,

the Met (O) 14 Asp 28 Pro 36, Pro 37, Pro 38 exendin-4 (1 -39) -NH 2,

H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) -NH 2,

H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) -NH2, the Pro 36, Pro 37, Pro 38 [ Met (O) 14, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH 2,

H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) -Lys 6 -NH 2,

H-Asn- (Glu) 5 of the Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH2, H- (Lys) 6 - des Pro 36 [Met (O) 14, Trp (O2) 25, Asp 28] exendin-4 (1 -39) -Lys 6 -NH 2,

of Asp 28 Pro 36, Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25] Exendin-4 (1 -39) -NH 2,

H- (Lys) 6 - des Pro 36 'Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -NH2, H-Asn- ( Glu) 5 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] exendin-4 (1 -39) -NH2, the Pro 36, Pro 37, Pro 38 [Met (O) 14 , Trp (O2) 25, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH2, H- (Lys) 6 - des Pro 36 'Pro 37, Pro 38 [Met (O) 14 , Trp (O2) 25, Asp 28] exend in-4 (1 -39) - (Lys) 6 - NH 2,

H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25, Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,

or a pharmacologically tolerable salt thereof.

Another object of the invention is a method as described above, wherein in the formulation additionally Arg 34, Lys 26 (N ε (γ-glutamyl (N α -hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof is contained.

Another object of the invention is a method as described above wherein the formulation contains a zinc salt is still contained.

Another object of the invention is the use of a method as described above for the large scale production of an insulin, insulin analog or insulin derivative.

Another object of the invention is a two-piece set of containers in which one of the containers, an insulin, an insulin analog or an insulin derivative as a solid and the other container a mixed solvent of a specific pH-value with the final concentration of the excipients of a desired formulation of an insulin, an insulin analog or an insulin derivative comprises; to heat and schüttelstabilen storage of insulin, the insulin analog or

Insulin derivative for the subsequent manufacture of a ready formulation by dissolving the solid in the solvent mixture as described above.

Another object of the invention is a dual-chamber injection system, in which a chamber, an insulin, an insulin analog or an insulin derivative as a solid and the other chamber

a mixed solvent of a specific pH-value with the final concentration of the excipients of a desired formulation of an insulin, an insulin analog or an insulin derivative comprises; as described above for heat and schüttelstabilen storage of insulin, the insulin analog or the Insulindehvats for the subsequent manufacture of a ready formulation by dissolving the solid in the solvent mixture. In this description, the terms "formulation" and "preparation" are used synonymously.

Figure legend:

Fig. 1: Hypoglycemic effect of novel insulin analogues according to formula I in rats

Fig. 2: Blood glucose-lowering effect of novel insulin analogues according to formula I in

dog

Fig. 3: Hypoglycemic effect of YKL205 in the dog

Fig. 4: Zinc dependency of the hypoglycemic effect of YKL205 in the dog

Fig. 5: Hypoglycemic effect of insulin analogues of the invention

Formula Il in rats

Fig. 6: Blood glucose-lowering effect of insulin glargine in rats

Examples:

The following examples are intended to illustrate the inventive concept in more detail, without being restrictive. Example 1: Simplified dissolving insulin in a step (dissolution test)

Typically, insulin in aqueous systems, the auxiliaries and additives, such as antibacterials, isotonizing agents, buffering agents, and / or surfactants (= hereinafter "solvent" referred to) available on the market. The dissolution of insulin for the manufacture of a pharmacological composition is in generally ensured by the fact that the insulin is first dissolved acidic to then be adjusted to the required concentration and pH of the solution in the further steps (the Wellcome Foundation Limited te London,

Octrooiraad Nederland, Octrooiannnvrage No. 6506714, 05.26.1965 "Werkwijze voor het bereiden van insulinepreparaten"). Alternatively, a partial dissolution of insulins in an alkaline medium is described along with a slightly increased stability of the insulin preparations (WO 2004/096266

PCT / DK2004 / 000300, "Improved Physical Stability of Insulin Formulations").

Dissolution test:

To the complicated procedure of dissolving insulins to escape (see above), was tested whether it is possible insulins as solids dissolve so that their on the market formulation is achieved in one step. The goal was the

maintain composition of the market formulation, ie taking into account the concentration of all auxiliaries and additives and the pH.

There were studied:

a. Lantus ® (auxiliaries and additives, zinc chloride, m-cresol, glycerol, pH 4) b. Insuman ® (auxiliaries and additives Nathumhydrogenphosphat, m-cresol, glycerol, pH 7.3)

There were prepared various solvent mixtures, which corresponded to the final concentration of the excipient for the two Lantus ® and Insuman ®. Here, the pH of the solvent was varied. a. Lantus ® required a pH value of the solvent of pH 2.85 in order to achieve a complete resolution with the required final pH value of pH. 4 The

Dissolution rate (final volume 1 mL) was below 10min. b. Insuman ® required a pH value of the solvent from pH 7.6 to achieve a complete resolution with the required final pH value of pH 7.3. The

Dissolution rate (final volume 1 mL) was below 10min. LC-UV / MS analysis of the samples following the simplified resolution with subsequent evaluation of the UV chromatogram showed the

Market formulations identical spectra (UV-signal of the m-cresol and the respective insulin regard to retention time and peak area).

Conclusion: It is possible to release insulin in one step, ie without prior dissolving in the acid or alkaline pH. adjusting the pH of the solvent to the concentration to be achieved in each case as well as the pH of the finished product as a function of the intrinsic identified the pH-changing properties of the insulins to be solved. was a key factor Under

Adaptation of this empirically determined parameters of the pulping process for the insulins in a reasonable time frame could be realized (<10 min).

Example 2: Heat stability of solids (heat stress test, the shaking, amorphous solids)

The heat stability of aqueous insulin preparations is the subject of numerous studies (literature:. A. Krogh, AM Hemmingsen, Biochem J. (1928) 22, 1231 -1238 "The destructive action of heat on insulin Solutions").

It is known that additives contribute differently to the thermal stability of the dissolved insulin, for example (the zinc concentration or the pH of NR

Stephenson, RG novel; Journal of Pharmacy and Pharmacology (1960) 12 372- 376 "Thermal Stability of insulin made from Zinc Insulin Crystals").

PB Porter identified as the main cause of the loss of biologically active insulin material (BV Fisher, - in the study of heat stability of in-house, market-ready solutions containing all auxiliaries and additives, the precipitation was in own studies - in addition to the formation of degradation products ;.. J Pharm Pharmacol (1981), 33203-206 "Stability of bovine insulin"). Based on these observations the Hitzestabiliät of insulin solid was checked, and were used in the following brand names used the finished aqueous formulations for the respective insulin solids (active ingredients):

Heat stress test:

I) insulin Various solids were stored for two weeks at different temperatures (50 0 C, 60 0 C and 80 ° C) (absence of light). a. Lantus ® (crystalline); b. Insuman ® (crystalline); c. Apidra ® (amporph)

II) Various insulin solids were at 60 0 C of different lengths

stored (14 days, 1 month, 2 months, 3 months).

a. Lantus ® (crystalline); b. Insuman ® (crystalline); c. Apidra ® (amporph)

III) solids of Arg (Ao), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg

(B31), Arg (B32) Humaninsulinamid and Lantus ®, both in the amorphous state were stored at 60 ° C for two weeks. After completion of the heat stress phases the solids were dissolved, so that an identical concentration as the market formulations yielded.

As comparative samples, were dissolved insulin solutions with the same concentration directly before the measurement.

In addition, Lantus ®, Insuman ® and Apidra ® were market-ready preparations /

Containers (Source: Production) stressed for 14 days at 60 ° C. As comparative samples were stored containers from the same production batch at 4 ° C and analyzed along with the stressed samples. Conclusion: The heat stability of insulins when stored as solid for 14 days was found to be temperature dependent. The degree of stability was insulin dependent. Storage as a solid proved to be heat stable than the storage in market-ready solution.

(I) LC-UV / MS analysis of the samples followed by analysis of the UV-chroma tograms gave the following values:

Conclusion: The heat stability of insulins when stored as solid for 14 days was found to be temperature dependent. The degree of stability warinsulinabhängig. Storage as a solid proved to be heat stable than the storage in

market-ready solution. (II) LC-UV / MS analysis of the samples followed by analysis of the UV-chroma tograms gave the following values:

Lantus ®:

Insuman ®.

Apidra ®:

Conclusion: The heat stability of insulins when stored as a solid at 60 0 C proved to be time-dependent. The degree of stability was insulin dependent. (III) LC-UV / MS analysis of the samples followed by analysis of the UV-chroma tograms gave the following values:

Conclusion: The heat stability of insulins when stored as a solid at 60 ° C proved to be time-dependent. The degree of stability was insulin dependent. Both studied long-acting insulins have also been found in amorphous state as relatively heat-stable.

shaking test:

It is known that aqueous insulin preparations against shaking are unstable (A. Oliva, JB Farina, M. Llabres;. Int J. of Pharmaceutics (1996) 143143-170

"Influence of temperature and shaking on stability of insulin preparations: degradation kinetics"). Several insulin formulations were shaken at room temperature (absence of light) 100h at 1400rpm. a) Lantus ®, Insuman ® and Apidra ® into marketable finished preparations / containers (Source: Production)

Lantus (cartridge without Polysorbate 20, no polysorbate vial 20, vial with

Polysorbate 20), Insuman ® (cartridge vial), Apidra ® (cartridge vial) b) Lantus ®, Insuman ® and Apidra ® (shaken as a solid separately: Solvent for direct dissolution in one step, see "Direct dissolving

Insulin solid ").

After completion of the Schüttelphase the solids (sample b) were dissolved, so that an identical concentration as the market formulations yielded. c) As comparative samples, the corresponding market formulations were stored under exclusion of light at room temperature and 100h.

LC-UV / MS analysis of the samples followed by analysis of the UV-chroma tograms gave the following values ​​(Reference: Sample c):

Conclusion: Mechanical stress caused by shaking of insulin solutions an Prezipitation of insulin. The degree is insulin dependent Insuman ® case showed the greatest instability.

Mechanical stress pointed to insulin solid no negative impact: the solid then allowed to dissolve 100%, even if the solutions were mitgeschüttelt separately. Example 3: Possible applications (industrial scale preparation of

Insulin preparations, heat and schüttelstabile dosage form in a two-component system) Large-scale preparation of insulin formulations:

At a resolution in one step is a simplified procedure with the following advantages: There are fewer steps with fewer analyzes (eg pH) to create, ie the preparation of the insulin preparations can be made faster. Moreover, the production is less complicated, a simplified training of employees brings with it (less complicated SOPs). In addition, fewer containers must be cleaned, which in turn saves time and material.

Heat and Schüttelstabile dosage form in a two-component system: It was found that solid insulins - even over a longer period - at

Heat stress are more stable than dissolved. There was a small extent degradation, however, a loss by precipitation accounted for so that consequently more bioavailable insulin stood at comparable heat stress available when the release operation took place only after the heat stress. Precipitation and degradation induced by vigorous shaking of the fixed insulins, could not be observed.

An administration in solid form can therefore be described as its safer than general temperature stable and more resistant to shaking and in a row. Moreover provides administration of insulin in solid form (powder) to the additional advantage that an accidental freezing by the patient may cause any complication; solid insulins are known to be stored in the frozen state.

Possible applications: Insulin powders instead of dissolved insulins are (with suitable solvents generally aqueous systems, the auxiliaries and additives, such as

for example, antibacterials, isotonizing agents, buffering agents, and / or surfactants = hereinafter "solvent" referred to) offered in a two-component system. A two-chamber system is described for example in WO2007 / 038773 A1. Thus, the tolerable increases temperature range (both towards lower and higher temperatures). in addition, the stability increases to mechanical stress such as strong vibrations. as a result, longer shelf lives, lower costs for storage and transport and a safer drug use are expected.

By the simplified dissolution in a step, the applicability is ensured by the patient.

Example 4: Formulation of amidated Indulinderivate

Examples 4 to 8 are used only for determining the biological, pharmacological and physicochemical properties of insulin analogues according to formula I by formulations were provided which initially (Example 4) and then appropriate tests were carried out (Examples 5 to 8). It was prepared from the compounds a solution as follows: The insulin analogue according to the invention was dissolved at a target concentration of 240 ± 5 uM in 1 mM hydrochloric acid at 80 ug / ml of zinc (as zinc chloride). As a solution medium following compositions were used:

a) 1 mM hydrochloric acid,

b) 1 mM hydrochloric acid, 5 ug / ml of zinc (as zinc chloride or hydrochloric acid) c) 1 mM hydrochloric acid, 10 ug / ml of zinc (as zinc chloride or hydrochloric acid) d) 1 mM hydrochloric acid, 15 ug / ml of zinc (as zinc chloride or hydrochloric acid) e) 1 mM hydrochloric acid, 30 ug / ml of zinc (added as zinc chloride or hydrochloric acid) f) 1 mM hydrochloric acid, 80 ug / ml of zinc (as zinc chloride or hydrochloric acid), g) 1 mM hydrochloric acid, 120 ug / mL zinc (added as zinc chloride or hydrochloric acid)

To this was added of the freeze-dried material is initially a higher amount than about 30% due to the molecular weight and the desired

Concentration required weighed. Thereafter, the present concentration was determined by analytical HPLC and the solution is then made up to the required volume to achieve the target concentration of 5 mM hydrochloric acid at 80 ug / mL zinc. When necessary, the pH was readjusted to 3.5 ± 0.1. After the final analysis by HPLC to hedge

Target concentration of 240 ± 5 uM was the final solution through a syringe with a 0.2 micron filter attachment in a with a septum and a crimp cap

sealed sterile vial transferred. For the short term, one-time testing of the insulin derivatives of the invention no optimization of formulations, for example, was made as an addition of isotonic agents, preservatives or buffers.

Example 5: Evaluation of the glucose-lowering effect of new insulin analogues in rats The blood glucose lowering effect of selected novel insulin analogues is tested in healthy male, normoglycemic Wistar rats. Male rats is injected a dose of 9 nmol / kg of an insulin analogue subcutaneously. Immediately prior to injection of the insulin analog and at regular intervals up to eight hours after the injection the animals, blood samples are taken and it determines the blood sugar content. The experiment clearly shows (see. Fig. 1), that the insulin analog used according to the invention in a significantly delayed

Onset of action and a longer, uniform duration of action leads.

Example 6: Evaluation of the glucose-lowering effect of new insulin analogues dog

The blood glucose lowering effect of selected novel insulin analogues is tested in healthy male, normoglycemic Beagle dogs. Male rats is injected subcutaneously with a dose of 6 nmol / kg of an insulin analog. Immediately prior to injection of the insulin analog and at regular intervals up to eight hours after the injection the animals, blood samples are taken and it determines the blood sugar content. The experiment clearly shows (see. Fig. 2), that the insulin analog used according to the invention clearly a

delayed onset of action and a longer, uniform duration of action leads.

Example 7: Evaluation of the glucose-lowering effect in the dog at

doubly increased dose

The blood glucose lowering effect of selected novel insulin analogues is tested in healthy male, normoglycemic Beagle dogs. Male rats is injected subcutaneously with a dose of 6 nmol / kg and 12nmol / kg of an insulin analog. Immediately prior to injection of the insulin analog and at regular intervals up to eight hours after the injection the animals, blood samples are taken and it determines the blood sugar content.

The experiment clearly shows (see. Fig. 3) such that the insulin analog used according to the invention acts dose-dependent, but that is flat in spite of two-fold increased dose time course of action, ie no pronounced low point (nadir) is observed. This suggests that insulin according to the invention result in comparison with known delay insulins to significantly fewer hypoglycemic events.

Example 8: Evaluation of the glucose-lowering effect in dogs with various concentrations of zinc in the formulation

The experiments were carried out as described in Example 35th Figure 4 shows the result. Thereafter, the time can be - response curve of the insulin analogue according to the invention by the content of zinc ions in the formulation at the same concentration of insulin influence in such a way that one observes a rapid onset at zero or low zinc content and stops the action of over 24 hours, while at higher zinc content shallow onset of action is observed and the insulin effect lasts much longer than 24 hours. Example 9: Formulation of the insulin derivatives amidated

Examples 9 to 11 are used only for determination of biological,

pharmacological and physicochemical properties of insulin analogues according to formula Il by formulations were provided which initially

(Example 9) and then appropriate tests were carried out (Examples 10 and 11). The insulin analogue according to the invention was dissolved at a target concentration of 240 ± 5 uM in 1 mM hydrochloric acid at 80 ug / ml of zinc (as zinc chloride). To this was weighed required by the freeze-dried material is initially a higher amount than about 30% due to the molecular weight and the desired concentration. Thereafter, the present concentration was determined by analytical HPLC and the solution is then made up to the required volume to achieve the target concentration of 5 mM hydrochloric acid at 80 ug / mL zinc. When necessary, the pH was readjusted to 3.5 ± 0.1. After the final analysis by HPLC to secure the target concentration of 240 ± 5 .mu.M, the finished solution was transferred via syringe with a 0.2 micron filter attachment in a sealed with a septum and a crimp cap sterile vial. For the short term, one-time testing of the insulin derivatives of the invention no optimization of formulations, for example, was made as an addition of isotonic agents, preservatives or buffers.

Example 10: Evaluation of the glucose-lowering effect of new insulin analogues in the rat

The blood glucose lowering effect of selected novel insulin analogues is tested in healthy male, normoglycemic Wistar rats. Male rats is injected a dose of 9 nmol / kg of an insulin analogue subcutaneously. Immediately prior to injection of the insulin analog and at regular intervals up to eight hours after the injection the animals, blood samples are taken and it determines the blood sugar content. The experiment clearly shows (see. Fig. 5) that insulin analogue according to the invention leads to a significantly delayed onset of action and a prolonged, uniform duration of action.

Example 11: Evaluation of the glucose-lowering effect of new insulin analogues dog

The blood glucose lowering effect of selected novel insulin analogues is tested in healthy male, normoglycemic Beagle dogs. Male rats is injected subcutaneously with a dose of 6 nmol / kg of an insulin analog. Immediately prior to injection of the insulin analog and at regular intervals up to eight hours after the injection the animals, blood samples are taken and it determines the blood sugar content. The experiment clearly shows that insulin analogue according to the invention leads to a significantly delayed onset of action and a longer flat, uniform duration of action.

Claims

claims:
1. A process for preparing an aqueous pharmaceutical formulation comprising an insulin, an insulin analog or an insulin derivative, or a
pharmacologically tolerable salt thereof, wherein the formulation is ready to use directly by dissolving the insulin, the insulin analog or the insulin derivative as a solid with a suitable solvent mixture.
2. The method of claim 1, wherein the composition of the appropriate Lösem ittelgemischs is determined by
(A) solvent mixtures varying pH with concentrations of
Excipients are prepared, which correspond containing the final concentration of the excipients of the formulation, an insulin, an insulin analog or an insulin derivative, and
(B) that of the solvent mixture is determined by dissolving the desired insulin, insulin analog or insulin derivative represented by dissolving the solid of insulin, insulin analog or insulin derivative is the desired pH of the
produces ready-made formulation.
3. The method according to one or more of claims 1 or 2, wherein the insulin, the insulin analog or the insulin derivative is present as a crystalline or amorphous solid.
4. The method according to one or more of claims 1 to 3, wherein the insulin is selected from a group consisting of human insulin, porcine insulin and bovine insulin.
5. The method according to one or more of claims 1 to 3, wherein the
Insulin analog is selected from a group comprising Gly (A21), Arg (B31), Arg (B32) -human insulin, Lys (B3), Glu (B29) human insulin, Asp (B28) human insulin, Lys (B28) Pro (B29 ) human insulin and Des (B30) human insulin.
6. The method according to one or more of claims 1 to 3, wherein the insulin analog is selected from a group comprising
an insulin analog of the formula I
s
1 5 | 10 | 15 20
AO GIVE A5 CCHSICSLY A15 A18 LE YCG
I (SEQ ID NO: 1) \ A-chain
BI BO Bl B2 B3 B4 HLCGSHLVEALYLVCGERGFF Y
1 5 10 15 20 25
TP B29 B30 B31 B32 (SEQ ID NO: 2)
B chain
30
in which
AO is Lys or Arg;
A5 is Asp, Gln or Glu;
A15 is Asp, Glu or Gln; A18 is Asp, Glu or Asn;
B-1 Asp, Glu or an amino group;
BO Asp, Glu or a chemical bond;
B1 Asp, Glu or Phe;
B2 Asp, Glu or Val; B3 is Asp, GIu or Asn;
B4 Asp, Glu or Gln;
B29 is Lys or a chemical bond;
B30 is Thr or a chemical bond; B31 Arg, Lys, or a chemical bond; B32 Arg-amide, Lys-amide, or one amino group corresponding to said two amino acid residues of the group consisting of A5, A15, A18, B1, BO, B1, B2, B3 and B4 simultaneously and independently Asp or Glu
correspond to, or which a pharmacologically tolerable salt.
7. The method according to claim 6, wherein the insulin analog is selected from a group comprising:
Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Asp (A18), Gly (A21), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Asp (A18), Gly ( A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Asp (A18), Gly (A21), Arg (B31), Lys (B32 ) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Glu (A15), Gly (A21), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B3), Arg ( B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 human insulin , Arg (AO), His (A8), Glu (A15), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His ( A8), Gly (A21), Asp (B3), Glu (B4), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Asp (B3 ), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31) , Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu ( A15), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (B4 ), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Glu (BO), A rg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15), Gly (A21), Glu (BO), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), (His A8 ), Asp (A18), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21) , Glu (BO), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A5), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg ( AO), His (A8), Glu (A15), Gly (A21), Asp (B1), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Glu (A15 ), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B1) , Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), G Iy (A21), Glu (BO), Asp (B1), Arg (B31), Arg (B32) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Asp (B1), Arg (B31), Lys (B32) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Arg ( B31) - NH 2 human insulin, Arg (AO), His (A8), Asp (A18), Gly (A21), Asp (B3), Arg (B30), Lys (B31) - NH 2 human insulin.
8. The method according to one or more of claims 1 to 3, wherein the
Insulin analog is selected from a group comprising
an insulin analog of the formula Il SS
1 5 | 10 I 15 20 Al AO Al IVE CCHSICSLY A5 A15 A18 LE YC A21
A chain
II
BI BO Bl V B3 B4 HLCGSHLVEALYLVCGERGFF Y
1 5 10 15 20 25 TP B29 B30 B31 B32 (SEQ ID NO 4) B-chain
30 VV -;
in which
A-1 Lys, Arg, or an amino group;
AO is Lys, Arg or a chemical bond;
A1 Arg or Gly;
A5 is Asp, Glu or Gln;
A15 is Asp, Glu or Gln;
A18 is Asp, Glu or Asn;
A21 Ala, Ser, Thr or Gly;
B-1 Asp, Glu or an amino group;
BO Asp, Glu or a chemical bond; B1 Asp, Glu, Phe or a chemical bond; B3 is Asp, GIu or Asn; B4 Asp, Glu or Gln;
B29 Arg, Lys or an amino acid selected from a group consisting of the amino acids Phe, Ala, Thr, Ser, VaI, Leu, Glu, or Asp, or a chemical bond;
B30 is Thr or a chemical bond;
B31 Arg, Lys, or a chemical bond; B32 Arg-Lys-amide or amide corresponding, wherein no more than one amino acid residue of the group consisting of A5, A15, A18, B1, BO, B1, B2, B3 and B4 correspond simultaneously and independently Asp or GIu.
9. The method according to claim 6, wherein the insulin analog is selected from a group comprising:
Arg (A-1), Arg (AO), Glu (A5), His (A8), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Glu ( A5), His (A8), Gly (A21), Lys (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Glu (A15), His (A8), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Glu (A15), His (A8), Gly (A21), Lys (B30) - NH 2 human insulin, Arg (A-1) , Arg (AO), Asp (A18), His (A8), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), Asp (A18), His (A8 ), Gly (A21), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Glu (BO), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Glu (BO), Lys (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Asp (B3), Arg (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Asp (B3) , Lys (B30) - NH 2 human insulin, Arg (A-1), Arg (AO), His (A8), Gly (A21), Glu (B4), Arg (B30) - NH 2 human insulin, Arg (A- 1), Arg (AO), His (A8), Gly (A21), Glu (B4), Lys (B 30) - NH 2 human insulin, Arg (AO), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin,
Arg (AO), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin,
Arg (AO), Glu (A5), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), Glu (A5), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), Asp (A18), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), Asp (A18), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), Glu (A15), His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), Glu (A15), His (A8), Gly (A21), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Asp (B3), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Asp (B3), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (B4), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (B4), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO), Arg (B31), Arg (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Glu (BO ), Arg (B31), Lys (B32) - NH 2 - human insulin, Arg (AO), His (A8), Gly (A21), Arg (B30) - NH 2 - human insulin,
Arg (AO), His (A8), Gly (A21), Lys (B30) - NH 2 - human insulin,
Arg (A-1), Arg (AO), His (A8), Gly (A21), Arg (B30) - NH 2 - human insulin,
Arg (A-1), Arg (AO), His (A8), Gly (A21), Lys (B30) - NH 2 - human insulin,
Arg (AO), Arg (A1), His (A8), Gly (A21), Arg (B30) - NH 2 - human insulin,
Arg (AO), Arg (A1), His (A8), Gly (A21), Lys (B30) - NH 2 - human insulin,
His (A8), Gly (A21), Arg (B31), Arg (B32) - NH 2 - human insulin.
10. The method according to one or more of claims 1 to 3, wherein the
insulin derivative is selected from a group comprising B29-N-myristoyl-des (B30) human insulin, B29-N-palmitoyl-des (B30) human insulin, B29-N-myhstoyl
Human insulin, B29-N-palmitoyl human insulin, B28-N-myhstoyl Lys B28 Pro B29
Human insulin, B28-N-palmitoyl-Lys B28 Pro B29 human insulin, B30-N-myristoyl
Thr B29 Lys B30 human insulin, B30-N-palmitoyl- Thr B29 Lys B30 human insulin, B29-N- (N-palmitoyl-Y-glutamyl) -des (B39) human insulin, B29-N- (N-lithocholyl-Y-glutamyl ) - des (B30) human insulin, B29-N- (ω-carboxyheptadecanoyl) -des (B30) human insulin and B29-N- (ω-carboxyheptadecanoyl) human insulin.
11. The method according to one or more of claims 1 to 10, wherein the formulation contains a preservative selected from a group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, parabens is present.
12. The method according to any one of claims 1 to 11, wherein the formulation in an isotonizing agent selected from a group comprising mannitol, sorbitol,
Lactose, dextrose, trehalose, sodium chloride, glycerol is present.
13. The method according to any one of claims 1 to 12, wherein the insulin that
Insulin analog and / or the insulin derivative in a concentration of 240 - 3000 present nmol / ml
14. The method according to one or more of claims 1 to 13, wherein included in the formulation in addition, a glucagon-like peptide-1 (GLP-1) or an analogue or derivative thereof, or exendin-3 or -4 or an analogue or derivative thereof is.
15. The method of claim 14, wherein an analogue of exendin-4 is selected from a group comprising
H-DESpro 36 -Exendin-4-Lys 6 -NH 2,
H-des (Pro 36 37) -Exendin-4-l_ys 4 -NH 2, and
H-des (Pro 36 37) -Exendin-4-Lys 5 -NH 2,
or a pharmacologically tolerable salt thereof.
16. The method according to claim 14, wherein an analogue of exendin-4 is selected from a group comprising
DESpro 36 [Asp 28] exend in-4 (1 -39)
DESpro 36 [isoasp 28] exend in-4 (1 -39), DESpro 36 [Met (O) 14, Asp 28] exend in-4 (1 -39)
DESpro 36 [Met (O) 14, isoasp 28] exend in-4 (1 -39)
DESpro 36 [Trp (O2) 25, Asp 28] exend in-2 (1 -39)
DESpro 36 [Trp (O2) 25, isoasp 28] exend in-2 (1 -39)
DESpro 36 [Met (O) 14 Trp (O2) 25, Asp 28] exend in-4 (1 -39) and
DESpro 36 [Met (O) 14 Trp (O2) 25, isoasp 28] exend in-4 (1 -39)
or a pharmacologically tolerable salt thereof.
17. The method according to claim 16, in which the C-termini of exendin-4 analogs of the peptide is -Lys 6 -NH 2 is added.
18. A pharmaceutical formulation according to claim 14, wherein an analogue of exendin-4 is selected from a group comprising
H- (Lys) 6 - des Pro 36 [Asp 28] Exendin-4 (1 -39) -Lys 6 -NH 2
of Asp 28 Pro 36, Pro 37, Pro 38 exendin-4 (1 -39) -NH 2,
H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) -NH 2,
H-Asn- (Glu) 5 of the Pro 36, Pro 37, Pro 38 [Asp 28] exend in-4 (1 -39) -NH 2,
of Pro 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,
H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,
H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Asp 28] exend in-4 (1 -39) - (Lys) 6 -NH 2,
H- (Lys) 6 - des Pro 36 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -Lys 6 -NH 2,
H- the Asp 28 Pro 36, Pro 37, Pro 38 [Trp (O2) 25] exend in-4 (1 -39) -NH 2,
H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -NH 2,
H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -NH2, the Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH 2,
H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2, H-Asn- (Glu ) 5 - des Pro 36, Pro 37, Pro 38 [Trp (O2) 25, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH2, H- (Lys) 6 - 36 of the Pro [Met (O) 14, Asp 28] exendin-4 (1 -39) -Lys 6 -NH 2,
the Met (O) 14 Asp 28 Pro 36, Pro 37, Pro 38 exendin-4 (1 -39) -NH 2,
H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) -NH 2,
H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) -NH2, the Pro 36, Pro 37, Pro 38 [ Met (O) 14, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH 2,
H- (Lys) 6 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) -Lys 6 -NH 2,
H-Asn- (Glu) 5 of the Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH2, H- (Lys) 6 - des Pro 36 [Met (O) 14, Trp (O2) 25, Asp 28] exendin-4 (1 -39) -Lys 6 -NH 2,
of Asp 28 Pro 36, Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25] Exendin-4 (1 -39) -NH 2,
H- (Lys) 6 - des Pro 36 'Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25, Asp 28] Exendin-4 (1 -39) -NH2, H-Asn- ( Glu) 5 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Asp 28] exendin-4 (1 -39) -NH2, the Pro 36, Pro 37, Pro 38 [Met (O) 14 , Trp (O2) 25, Asp 28] exendin-4 (1 -39) - (Lys) 6 -NH 2,
H- (Lys) 6 - des Pro 36 'Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25, Asp 28] exend in-4 (1 -39) - (Lys) 6 - NH 2 .
H-Asn- (Glu) 5 - des Pro 36, Pro 37, Pro 38 [Met (O) 14, Trp (O2) 25, Asp 28] Exendin-4 (1 -39) - (Lys) 6 -NH 2,
or a pharmacologically tolerable salt thereof.
19. The method of claim 14, wherein 26 (N ε (γ-glutamyl (N α -hexadecanoyl))) GLP-1 (7-37) [liraglutide] or a pharmacologically tolerable salt thereof contained in the formulation in addition Arg 34, Lys is.
20. The method according to one or more of claims 1 to 19, wherein in the formulation is still contain a zinc salt.
21. Use of a method according to one or more of claims 1 to 20 in the large-scale production of an insulin, insulin analog or
Insulin derivative.
22. Two-piece set of containers in which a container of an insulin, a
An insulin analog or an insulin derivative as a solid and the other container contains a solvent mixture of a specific pH-value with the final concentration of the excipients of a desired formulation of an insulin, an insulin analog or an insulin derivative; to heat and schüttelstabilen storage of insulin, the insulin analog or the insulin derivative for the subsequent manufacture of a ready formulation by dissolving the solid in the solvent mixture according to one or more of claims 1 to twentieth
23 two-chamber injection system in which a chamber insulin, a
An insulin analog or an insulin derivative as a solid and the other compartment contains a solvent mixture of a specific pH-value with the final concentration of the excipients of a desired formulation of an insulin, an insulin analog or an insulin derivative; to heat and schüttelstabilen storage of insulin, the insulin analog or the insulin derivative for the subsequent manufacture of a ready formulation by dissolving the solid in the solvent mixture according to one or more of claims 1 to twentieth
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