DK162255B - AURAL INSULIN PREPARATION AND APPLICATION OF A COMBINATION OF STABILIZING PHYSIOLOGICALLY ACCEPTABLE AGENTS FOR PREPARATION - Google Patents

Abstract

1. Pulsation damper (10) for elastically disposed objects (26), including a damper housing which is at least partially filled with 3 viscose damping medium (12) and which is open at the top relative to its installation position ; a hollow plunger pipe (17) which is open at the bottom relative to its installation position and continuously conically formed and which can be moved up and down into the damper medium (12) ; a top plate (16), linked with the plunger pipe (17), for receiving the object (26), in which respect the plunger pipe (17) is connected with the top plate (16) by its smaller diameter (28), and its larger diameter (29) is emersed into the damper medium (12), characterised in that the interior of the plunger pipe (17) is divided into two chambers by a sealing plate (22) ; that a buffer plate (24) including passages (33) is disposed in the larger diameter (29) at the bottom of the plunger pipe (17) which plate carries a plurality of interior pipes (21) which extend into the plunger pipe (17), the upper ends of the interior pipes (21) being at a distance (35) from the sealing plate (22), and the plunger pipe (17) has a plurality of peripheral bores (19) in the casing surface below the sealing plate (22).

Description

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The invention relates to an aqueous insulin preparation for use in automatic dosing devices with an insulin concentration greater than one unit of insulin per day. ml and a content of stabilizing physiologically acceptable agents. Furthermore, the invention relates to the use of a combination of stabilizing physiologically acceptable agents for the preparation of the present composition.

It is well known that special requirements are required for parenteral substitution therapy with insulin. In particular, 10 are considered the issue of delayed pharmacokinetics, which allows to set the diabetic with one or a few injections per day. day. To achieve such depot effects, there are some clinically suitable principles, including the use of zinc or protamine sulfate as depot auxiliaries.

These known deposition principles depend on the physical effect of the slow redissolution of a highly soluble form of the insulin present at physiological pH, e.g. in the form of the zinc (II) crystal. Thus, if the composition already has a neutral pH value, which in terms of the chemical stability is an advantage of long storage time, these preparations are thus suspensions which, prior to dosing, must be very carefully shaken homogeneously to avoid misdosing.

The previously known insulin repository compositions also have extremely specific action profiles that can only be varied within certain limits by the addition of dissolved insulin. There are always patients for whom alternative efficacy profiles are desirable, e.g. where the impact sets in somewhat slower but stays about 30 for as long. Thus, if the doctor has such preparations available, he can go into the diabetic's specific habits and characteristics. If, on the other hand, the patient were required to change his or her habits, this would result in the patient compliancy problem, which ultimately affects the good treatment result to a significant degree.

Kr aegen et al. describes in Brit. With. J. 3., 464-466

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2 (1975), a stabilizing effect of the addition of up to 3.5% Haemaccel to highly diluted insulin solutions (0.04 I.E./ ml). can prevent the adsorption of the insulin on the storage vessel and the tubing system into infusion systems.

It has now been found that an aqueous insulin preparation having an insulin concentration greater than one unit of insulin per day. and a content of stabilizing physiologically acceptable agents surprisingly has a synergistically improved physical stability and other improved properties, for example with respect to the action profile, when it has a viscosity of at least 1.75 mPa * s at 4 ° C. and as stabilizing physiologically acceptable agents contain a combination of A) a physiologically acceptable thickener of the type crosslinked gelatin partial hydrolysates and / or dextran with B) a physiologically acceptable surfactant selected from 20 B1) ethylene glycol propylene glycol blend polymerate or block polymeris however, with at least half of the chain links being 1,2-propylene units, B2) lecithin and B3) polyoxyethylene-23-lauryl ether.

This preparation is particularly well stabilized against mechanical stress, especially at elevated temperature, e.g. against shaking and pumping movements. especially for use in peristaltic pumps.

The invention also relates to the use of the combination 30 of A) a physiologically acceptable thickener type crosslinked gelatin partial hydrolysates and / or dextran with B) a physiologically acceptable surfactant selected from 3

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B1) ethylene glycol-propylene glycol blend polymer or block polymerate, with at least half of the chain links being 1,2-propylene glycol units, B2) lecithin and 5B3) polyoxyethylene-23-lauryl ether to prepare a stabilized aqueous insulin preparation according to one or more of the claims 1-5.

The issue of stability of insulin preparations has been a difficult problem to date. Thus, it is known that dissolved proteins such as insulin are adsorbed on interfaces (including the aqueous solution / air interface), cf. C.W.N. Cumber and A.E. Alexander, Trans. Faraday Soc. 46, 235 (1950). As a result of this adsorption on interfaces, various secondary reactions are observed, which are commonly summarized under the term "denaturation".

There is a deformation of the adsorbed protein molecule (change of tertiary and / or secondary structure). In addition, adsorbed molecules can be aggregated to form soluble or insoluble polymeric forms.

20 Also, the turbulence that occurs in the passage of insulin solutions through narrow channels seems to favor insulin denaturation.

The propensity of insulin to precipitate from commercially available solutions and thereby clog mechanical parts 25 as well as supply routes has proved to be a major obstacle in the further development and clinical use of continuous-acting infusion devices. Further, there is a tendency to reduce the size of these devices so as to provide implantable systems, thereby providing a need for more concentrated, stable insulin solutions, which in turn makes the above problems even more weighty.

In particular, the issue of the physical stability of insulin solutions has been discussed since the development of automatic dosing devices. It is well known that in such devices, specially stabilized in- 4

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suliner. In the context of insufficient physical stability of insulins, not only is a reduced biological activity discussed, but more recently a process of producing amyloid A protein in serum that proceeds via stimulation 5 of macrophages and which can lead to amyloidosis in various bodies, cf. Brownlee et al., Lancet, 411-413 (1984).

In order to solve these problems, a number of proposals have already been made, but the combination of thickener and surfactant as stabilizing agent has not been described anywhere. Mainly to obtain a delayed effect, various thickening agents have already been added to insulin preparations, cf. U.S. Patent No. 2,474,729 (polyvinylpyrrolidone), U.S. Patent No. 2,574,889 (methylated or alkylated gelatin), C.A., vol. 77, 1972, ref. 56944 t (dextran). A component of the solid insulin preparation of GB Patent No. 2,101,482 is a water-soluble copolymer of N - vinylpyrrolidone, acrylamide and ethyl acrylate, using a special salicylic acid derivative as a stabilizer. An overview of various low and high molecular weight compounds suitable for stabilizing insulin can be found in an article by W.D. Lougheed et al., "Insulin Aggregation in Artificial Delivery Systems" in Diabetologia 19, 1-9 (1980).

DE Publication No. 2,917,535 discloses 25 aqueous insulin solutions containing, for protection against denaturation, a surfactant of the general formula

Ra is hydrogen, methyl or ethyl, p is a number from 2 to 80, preferably from 8 to 45, and Rb and Rc are the same or various and are hydrogen, alkyl alcohol groups having from 1 to 20 C atoms, carboxylic acid groups having from 2 to 20 C atoms, alkylphenol groups having an alkyl chain of 1 to 10 C atoms or alkylamine groups having from 1 to 20 C atoms , 5

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as a homopolymer, block polymer, or blend polymer at a concentration of 2 to 200 mg / liter.

EP Publication No. 18,609 discloses aqueous solutions of insulin and a large number of 5 other proteins which are resistant to denaturation and which are peculiar to a content of a surfactant with a chain-like basic structure whose link contains weakly hydrophobic and weakly hydrophilic areas of alternating order.

WO-A 83/00288 discloses stable aqueous 10 insulin preparations for use in insulin dosing devices having a pH of from 6.5 to 9 and containing up to 1000 ppm of a polyoxyethylene alkyl ether of formula R7-0- [ CH2-CH2-O] mH (II) wherein R7 is a saturated or unsaturated C8-C15 alkyl group and m is an integer from 2 to 25.

DE Publication No. 3,240,177 finally discloses physically stabilized insulin solutions which are unique in that they contain stabilizing amounts of a phospholipid of the formula H-CH-OR4

25 I

CH-OR5 I 0.

H-CH-O-P-OR6 (III)

OH

Wherein R4 and R5, which may be the same or different, are hydrogen, alkylcarbonyl, alkenylcarbonyl, alkanedienylcarbonyl, alkanthrienylcarbonyl or alkanetetraenylcarbonyl, with the proviso that R4 and R5 are not simultaneously hydrogen and wherein R6 is a hydrophilic group.

35 These interface active stabilizers are extremely effective in that they clearly increase the stability of insulin solutions against shaking. Undoubtedly, shaking has a significant negative effect on insulin in dosing devices.

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6

However, it has now been found that, especially in peristaltic pumps, the compression of the elastomer pump hose and / or shear effects occurring in many pumping principles further reduces insulin stability. In this way, despite the addition of the various hitherto known stabilizers, insulin precipitation can occur in pump tubes or catheters.

As used herein, "insulins" means uniform products or mixtures of multiple insulins, namely, not only human insulin and insulins of animal origin, such as insulins from mammals, for example, from bovine or swine; one also understands insulins in a broader sense, ie. modified insulins, such as des-PheB1 insulin, cf. for example, DE Patent Specification No. 2,005,658 and EP 15 Publication No. 46,979, or insulins which are basically modified at the B-chain C-terminus (such as insulin-B31-Arg-OH or insulin-B31-Arg-Arg). 0H, as proposed in DE Publication No. 3,326,472, No. 3,327,709, No. 3,333,640, and 3,334,407) and human insulin 20 or other proinsulin or proinsulin analogues, cf. for example, DE Publication No. 3,232,036, as well as the alkali metal and ammonium salts. Several of these insulins may also be present in admixture. Depending on the solubility, the insulin concentration may be up to approx. 1500 inulin units per unit but preferably it is between 5 and about

1000 units of insulin per day. ml. In depot forms, any number of one or more insulins independently of each other may be present each time in dissolved, amorphous and / or crystalline form.

As thickening agents (also called gelling agents), specially Polygeline® (i.e., gelatin partial hydrolysates, which may also be cross-linked, for example, with diisocyanates) and / or dextrans, are used as surfactants, and ethylene glycol-propylene glycol can be used as surfactants. blend polymer or block polymerisates, at least half of the chain link being 1,2-propylene glycol units, and lecithin 7

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and polyoxyethylene-23-lauryl ether.

The thickening agents cause the insulin preparation at low temperatures, for example at 4 ° C, to be readily viscous to viscous or as hydrogel. The compositions of the invention, measured at 4 ° C, preferably have a viscosity of at least 2 and, in particular, a viscosity of at least 2.5 mPa * s. The gels are partially liquid already at room temperature or at temperatures near body temperature.

The compositions of the invention, which have a high physical stability, preferably contain more than 1, especially between 2 and 20% by weight of thickener. However, hydrogels can also be formed by adding small amounts of thickeners. Upwards, the content of gelling agent, depending on its nature, may amount to 30% or more.

With a sufficiently high proportion of thickeners, it is common for all compositions of the invention that they are in solid form as a hydrogel under storage conditions. This is an advantage in terms of physical stability, as oligomer formation and denaturation, as is well known, is greatly accelerated by movement, ie. in principle, it cannot be safely excluded when handling liquid insulin preparations. Furthermore, the storage in gel form may be advantageous because this form in storage remains substantially more homogeneous than a solution or suspension.

25 It is e.g. in sedimented crystal suspensions at long shelf life, it is perfectly conceivable that relatively stable crystal associates are formed, which can then be less easily shaken to a homogeneous suspension, so that dosing errors can occur. On the other hand, if the crystal suspension is homogeneously "frozen" in a gel, the insulin molecules can only slowly diffuse to the vessel wall or liquid / air interface and such effects must be excluded. In addition, movements and turbulence within the gels during handling are significantly reduced. Thus, the compositions have a particularly good storage stability.

Prior to use, the gels, as well as 8, are brought

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are common practice with conventional insulins, up to room-to-body temperature, being fluid, but despite. all the same, viscosity is increased compared to conventional insulin solutions. Normally, in this case, suspensions 5 do not immediately settle, so that inhomogeneities and dosing errors can be less easily encountered; Of course, an inhomogeneity problem is not found in clear gel preparations. In each case, the usual injection apparatus can be used.

The increased physical stability of the gels is also 10 to Stede to some extent at body temperature, i.e. in liquid state. Thus, if such solutions are thermally-mechanically loaded in a rotational experiment at 37 °, a relative stability of from ca. 3 to approx. 5 relative to conventional insulin solutions containing no thickener, cf. the following Table I.

All compositions according to the invention can in principle be prepared from dissolved or from amorphous or crystalline insulin (clear or cloudy gels). They generally have a pH of between 2.5 and 8.5, but most preferably between 6 and 8, and preferably contain a suitable isotonic agent, a suitable preservative and optionally a suitable buffer, for example those below. mentioned. The active substance is preferably in dissolved form.

The compositions of the invention - presumably 25 due to the thickener content - exhibit some depot effect.

It is possible to enhance the depot effect by combination with conventional auxiliaries with a delaying effect, for example by adding appropriate amounts of zinc, surfactant, globin or protamine sulphate. The amount of zinc added can thus be up to 100 µg Zn2 + per day. 100 insulin units; preferably it is above 35 and mostly below 50 µg of Zn 2+ per day. 100 units of insulin. For example, the amount of protamine may be between 0.28 mg and 0.6 mg per day. 100 units (calculated on 35 protamine sulfate). In this way, it is not possible to make hitherto unavailable, particularly long-lasting preparations

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whose use is interesting because, according to recent findings from the treatment with insulin dosing devices, it proves to be therapeutically advantageous with just a basal amount of insulin.

As physiologically acceptable and with the insulin for the carrier medium, a sterile aqueous solution which is made isotonic with blood in the usual manner, e.g. by means of glycerol, sodium chloride and glucose, and additionally contains one or more of the usual preservatives such as phenol, m-cresol, benyl alcohol or p-hydroxybenzoic acid ester. The carrier medium may further contain a buffer such as sodium acetate, sodium citrate, sodium phosphate or tris (hydroxymethyl) aminomethane. To adjust the pH, dilute acids (typically 15 hydrochloric acid) or bases (typically sodium hydroxide) are used.

The insulin preparation of the invention is prepared by adding to aqueous insulin preparation a physiologically acceptable thickening agent and a physiologically acceptable surfactant of the kind mentioned. The preparations are characterized by special stability and - by subcutaneous or intramuscular administration - by a delayed recovery.

The insulin preparations of the invention are used in the treatment of Diabetes mellitus, in particular by means of continuous insulin administration apparatus, and in the prevention of adsorption or denaturation of insulin on surfaces and other phase interfaces, especially in the purification by chromatography or crystallization, in storage and in the therapeutic use.

The insulin preparations of the invention can be administered parenterally for the treatment of Diabetes mellitus, ie. intravenously, subcutaneously or intramuscularly. The depot effect of the preparations with or without surfactants is most pronounced by the subcutaneous route of administration, but is also evident by intramuscular injection. Intravasally administered (i.e., in the 35 vessels, both in arteries and in veins), the clearly dissolved compositions of the invention act as quickly as those known in the art.

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10 dissolved insulins. Thus, they are excellent for use in automatic dosing devices, such as pumps, in which the insulin administered by infusion must be immediately active, as a rapid regulation, e.g. corresponding to 5 blood glucose levels, is only possible thus.

In some dosing principles, it is necessary or at least advantageous to fill the degassed insulin solution to the reservoir. Air, in connection with contact with structural materials, as shown many times, provides the most harmful environment for insulin. This is a practical problem with conventional solutions, as solutions, possibly gassed by the manufacturer, eventually dissolve air by movement (eg transport) and diffusion. By contrast, a stiffened gel that has been degassed as liquid is much less subject to this influence; thus, it is possible to dispense with a considerable degassing (and the associated risk of non-sterility) directly prior to use in the pump.

A further practical advantage of the compositions of the invention may be that, in the case of gels stiffened at the storage temperature, direct contact with the plug is avoided. The common plugs tend to be e.g. absorption of the stabilizers, which may be problematic, given the partially low amounts.

The following examples are intended to further illustrate the invention. The compositions herein prepared at 4 ° C all have a viscosity above 1.75 mPa · s. The digits of dextran, e.g. 60, denotes, multiplied by 103, the molecular weight. The distilled water is each time p.i. (for injection) 30 with a pH of 7.3. Polygeline® is a product of Behringwerke AG, Marburg.

11

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mrfiBMPT.igR

Examples 1 and 2 - Insulin Preparations with 20% Polygeline

According to Example 1, a sterile solution of 5 a) 250 g of Polygeline®, lyophilized, in distilled water, made up to 1 liter, and b) 4,464 g of human insulin (28 units of insulin per mg) are combined each time, 21.25 g of glycerol, 7.50 g of tris- (hydroxymethyl) -aminomethane, 3.375 g of phenol, so much anhydrous zinc chloride that the total zinc content is 0.035 g, and 0.0125 g of polypropylene glycol to which at both ends are polymerized approx. 5% polyethylene glycol (average molecular weight 1800), in distilled water, filled up to 250 ml.

According to Example 2, sterile conditions are combined each time a sterile solution of a) 200 g Polygeline®, in distilled water, filled up to 800 ml, and of b) 1,429 g human insulin (28 insulin units per mg), 1 , 50 g m-cresol, 1.00 g phenol, 17.00 g glycerol, so much 20 anhydrous zinc chloride that the total zinc content is 0.028 g, 0.030 g lecithin, in distilled water, filled up to 200 ml.

The solutions prepared according to Examples 1 and 2 are generally filled into small glass bottles. At about. 15 ° C solidifies 25 as clear gels at a concentration of 100 units of insulin per day. ml.

Example 3-7 - Insulin preparations containing 8 or 16% dextran

According to Examples 3 and 4, under sterile conditions, a sterile solution of a) 180 g of dextran 60 or 160 g of dextran 60 in distilled water, made up to 800 ml, and of b) 3,571 g of human insulin (28 insulin units per unit) are combined each time. (mg), 6.00 g of tris- (hydroxymethyl) -aminomethane, 2.00 g of m-cresol, 1.00 g of phenol, 17.00 g of glycerol, and so much anhydrous zinc chloride that the total content of zinc is 0.028 g, and 0.010 g 12

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Q

polypropylene glycol (see Example 1) in distilled water, filled up to 200 ml.

These preparations are commonly filled into small glass bottles.

According to Examples 5-7, analogous to Example 3, insulin preparations are prepared, however with 10 or 20% dextran of different molecular weights (see Table I).

Example 8 - Pro Insulin Preparation with 20% Powder Line - 10 Under sterile conditions, a sterile solution of a) 20 g of Polygeline® in distilled water, made up to 80 ml, and of b) 100 mg of pigs proinsulin, are combined each time. g of NaH2 PO4 * 2H20, 15 and 0.30 g of m-cresol, so much anhydrous zinc chloride that the total zinc content is 0.0012 g, and 0.010 g of polyoxyethylene-23-lauryl ether having a molecular weight of 1200, in distilled water, filled up to 20 ml.

Physical stability of the compositions of Examples 1 and 3-7 In a standardized pump experiment with a peristaltic pump (37 ° C, movement: pump speed 12 insulin units per day), the following stability data are obtained: 13

TABLE · X

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Time until the Relative

Resolution first haze stability 5 - H-Insulin Hoechst® 3 days l

Solution b) According to. Example 1, 10 filled up with dest. water to 1.25 liters 45 days 15

Preparation according to ex 1> 80 days> 27 15 Preparation with 8% dextran (ex 3)> 60 days> 20

Preparation with 16% dextran (ex. 4)> 80 days> 27 20

Preparation with 10% dextran 32 (ex. 5)> 60 days> 20

Preparation with 10% dextran 100 25 (Ex. 6)> 60 days> 20

20% dextran 100 (Example 7)> 80 days> 27 30 H-Insulin Hoechst® is a registered trademark of a particular insulin preparation and its relative stability is an expression of stability when added to the value 1 (time to first obscurity) for H-Insulin Hoechst®.

Physical stability of the compositions according to Examples 2 and 8) The solutions prepared are tested in a standardized circulation pump experiment with a peristaltic pump (37 ° C, movement: recyclable pumping at a rate of 5 ml / hour - 500 insulin units per hour = 12000 insulin-40 units per day) for their physical stability.

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TABLE · Il

Time until the Relative

Resolution first cloud stability 5 -—---- H-Insulin Hoechst® 20 t 1

20% Polygelin® 10 Preparation (Ex. 2)> 7 days> 8

Solution b) * According to. ex 2 2 days 2.4

Preparation with 20% Polygeline® 15 (ex. 8)> 7 days> 8

Solution b) * according to Example 8 30 t 1.5 20 * each time without Polygeline®, but filled up to 1 liter (Example 2) or 100 ml (Example 8) with dest. water.

Example 9 οσ 10 - Physical Stability of Compositions Containing Only Thickener 25 According to Example 9, a preparation prepared according to Example 1 is used, but with the exception that for solution b) polypropylene glycol is not added.

According to Example 10, under sterile conditions, a sterile solution of 30 a) 1 liter of a 10% solution of Polygeline® and b) 1.786 g of pig insulin (28 units per mg) and 4.25 g of glycerol, 1.50 g are combined. tris (hydroxymethyl) aminomethane, 2.50 g phenol and so much anhydrous zinc chloride that the total zinc content is 0.014 g, in distilled water, filled up to 250 ml.

35 According to biological testing, the preparation thus prepared contains 40 units per unit. ml.

In a standardized rotational experiment at 37 ° C, 1 Hz, 5 small bottles of a preparation according to Examples 9 and 10. are tested each time for comparison, a standard insulin preparation is tested.

TABLE · III

15

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Time until the Relative

Resolution first haze stability 5 ---- H-Insulin Hoechst® 2 days 1

Solution b) According to. Ex. 10, 10 filled up with dest. water to 1.25 liters 4 days 2

Preparation according to ex 9 15 days 7.5 15 Preparation according to ex 10 22 days 11

Activity profile of insulin preparations according to Example 1 Intravenous administration to dogs and to rabbits.

Of the preparation of Example 1, 0.2 insulin units per 20 times are administered every 20 times. kg body weight in the ear vein. As comparison insulin, human insulin serves Hoechst® (II). In the drawing, FIG. 1 and 2 shows the temporal course of the blood glucose level (X ± SEM). The values are based on measurements of 5 animals each time. The composition of Example 1 (I) is equally rapid or even faster in dogs (Figure 1) and in rabbits (Figure 2) than the comparator (II).

In Figures 1 and 2, the length of the vertical dashes at the individual measurement values commonly indicates the standard deviation from the mean (SEM).

Claims (8)

1. Aqueous insulin preparation for use in automatic dosing devices and with an insulin concentration greater than one unit of insulin per day. and a content of stabilizing 5 physiologically acceptable agents, characterized in that it has a viscosity of at least 1.75 mPa * s at 4 ° C and contains as a stabilizing physiologically acceptable agent a combination of A) a physiologically acceptable thickener of 10 the type of cross-linked gelatin partial hydrolysates and / or dextran with B) a physiologically acceptable surfactant selected from B1) ethylene glycol propylene glycol blend polymer or block polymerisate, with at least half of the chain links being 1,2-propylene glycol units, B2) lecithin polyoxyethylene-23-lauryl ether. Composition according to claim 1, characterized in that it has at least one of the following characteristics: a) the concentration of insulin is up to 1500, preferably between 5 and 1000 units per day. (b) that the insulin is human insulin, a mammalian insulin, a modified insulin, or a human proinsulin; (c) it contains more than 1, preferably 2 to 20% by weight, of thickening agent; (d) it contains as a thickening agent a crosslinked gelatin partial hydrolyzate; e) that it has a pH between 2.5 and 8.5, preferably between 6 and 8, and f) at a temperature of 4 ° C as a hydrogel. Composition according to claim 1 or 2, characterized in that it contains a) a suitable isotonic agent, b) a suitable preservative, c) a suitable buffer substance and / or d) zinc in an amount of up to 100 jug of zinc ions per 100 units of insulin. Composition according to one or more of claims 1-3, 5, characterized in that it further contains an adjuvant with a delaying effect. Composition according to one or more of claims 1-4, characterized in that its viscosity is at least 2 and most preferably at least 2.5 mPa * s. Composition according to one or more of claims 1 to 5, characterized in that it is in the form of an injection solution for use in the treatment of Diabetes mellitus. Use of the combination of A) a physiologically acceptable thickener of the type crosslinked gelatin partial hydrolysates and / or dextran with B) a physiologically acceptable surfactant selected from 20 B1) ethylene glycol-propylene glycol blend polymer or block polymerate, with at least half of the chain links being 1,2-propylene glycol units, B2) lecithin and B3) polyoxyethylene-23-lauryl ether 25 to prepare a stabilized aqueous insulin preparation according to one or more of claims 1-5.