Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

• This invention relates to a pharmaceutical formulation with improved physical stability being a mixture of a soluble acylated insulin analogue and a monomeric insulin or human insulin, preferably for use in an infusion system. Furthermore, this invention relates to the additional aspects mentioned in the claims below.
• the object of this invention is to overcome or ameliorate at lest some of the disadvantages of the prior art. Hence, the more specific objects mentioned below are more or less fulfilled.
• Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus.
• Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes.
• insulin formulations In the treatment of diabetes mellitus, many varieties of insulin formulations have been suggested and used, such as regular insulin, isophane insulin (designated NPH), insulin zinc suspensions (such as Semilente®, Lente®, and Ultralente®), and biphasic isophane insulin. As diabetic patients are treated with insulin for several decades, there is a major need for safe and life quality improving insulin formulations. Some of the commercial available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action.
• Stable insulin formulations are particularly required for use in delivery devices that expose these agents to elevated temperatures and/or mechanical stress.
• stable insulin formulations are required for use in continuous infusion systems and pen delivery devices.
• a fluid containing an insulin formulation is pumped from a reservoir, usually to a subcutaneous, intravenous, or intraperitoneal depot.
• the reservoir which must be exchanged or refilled periodically, is attached to the patient's body, or implanted into the patient's body. In either case, the patient's body heat and body motion, plus turbulence in the tubing and pump impart a relatively high amount of thermo-mechanical energy to the formulation.
• formulations having a relatively high concentration of insulin are highly advantageous. It is desirable to have insulin formulations which are stable for at least one month under stressful in-use conditions.
• Formulations of insulin for use in continuous infusion systems must remain soluble and substantially free of aggregation, even though subjected to the patient's body heat and motion for periods ranging from a few days to several months. Instability is promoted by the thermo-mechanical stress to which formulations are exposed in continuous infusion systems. Therefore, improvements in the physical stability of concentrated insulin formulations is urgently needed to permit them to be used successfully in continuous infusion systems.
• the catheter may clog
• Ketoacidosis may result from discontinuation of insulin delivery, for example due to fibrillation, pump failure, or the patient forgetting to reapply the pump after disconnection.
• insulin solutions may be stabilized by using a phospholipid.
• insulin formulations of superior chemical stability can be obtained in the presence of glycerol and/or mannitol and rather low halogenide concentrations.
• One object of this invention is to furnish insulin formulations especially suited for use in an infusion system.
• Another object of this invention is to furnish insulin formulations having superior long-term physical stability when exposed to high mechanical energy input.
• Another object of this invention is to furnish insulin formulations having superior long-term physical stability when exposed to high temperature.
• Another object of this invention is to furnish insulin formulations having superior long-term physical stability when exposed to high temperature and mechanical energy input.
• Another object of this invention is to furnish insulin formulations having a low tendency of fibrillation.
• Another object of this invention is to furnish insulin formulations having a convenient profile of action.
• Another object of this invention is to furnish insulin formulations having both a fast on-set of action and also a retarded action.
• Another object of this invention is to furnish insulin formulations having no or only a minor amount of non-dissolved material.
• amino acid refers to amino acids which can be coded for by nucleotide sequences. Analogously, this applies to the term amino acid residue which is an amino acid from which hydroxy has been removed from a carboxyl group and/or hydrogen has been removed from an amino group. Similarly, a peptide and a peptide residue consists of amino acid residues.
• human insulin analogue refers to human insulin wherein one or more of the amino acid residues have been exchanged with another amino acid residue and/or from which one or more amino acid residue has been deleted and/or from which one or more amino acid residue has been added. These human insulin analogues have an anti-diabetic activity sufficiently high to be used to treat diabetic patients.
• acylated insulin analogue refers to human insulin or a human insulin analogue having one or more lipophilic substituents.
• the preferred lipophilic substituents are acyl groups. Examples of acylated insulin analogues are described in WO 95/07931 and WO 96/29344, more precisely in claim 1 thereof. These publications are hereby incorporated by reference.
• An example of a specific acylated insulin analogue is insulin detemir (i.e., LYS B29 (N ⁇ -tetradecanoyl) des(B30) human insulin).
• monomeric insulin refers to human insulin analogs that are less prone to self-association (into dimers and hexamers) than human insulin.
• monomeric insulins are human insulin wherein Pro at position B28 is replaced by Asp, Lys, Leu, Val, or Ala; Lys at position B29 optionally is replaced by Pro; the amino acids at positions B28-B30 are deleted; or the amino acid at position B27 is deleted.
• Insulin means human insulin, human insulin analogs, monomeric insulin plus acylated insulin analogues.
• the term “infusion system”, when used herein, refers to a device for continuously administering a fluid to a patient parenterally for an extended period of time or for intermittently administering a fluid to a patient parenterally over an extended period of time without having to establish a new site of administration each time the fluid is administered.
• the fluid contains a compound having insulin activity.
• the device comprises a reservoir for storing the fluid before it is infused, a pump, a catheter, or other tubing for connecting the reservoir to the administration site via the pump, and control elements to regulate the pump.
• the device may be constructed for implantation, usually into the peritoneum. In such a case, the insulin reservoir will usually be adapted for percutaneous refilling. Obviously, when the device is implanted, the contents of the reservoir will be at body temperature, and subject to the patient's body motion.
• fibrillation refers to a physical process by which partially unfolded insulin molecules interact with each other to form insoluble linear aggregates. Under the influence of heat and exposure to hydrophobic surfaces, insulin undergoes conformational changes, resulting in successive, linear aggregation and formation of a viscous gel or insoluble precipitates. The degree of fibrillation can be determined as described in the stress test, below. A more detailed explanation is given in J. Pharm. Science. 86 (1997), 517-525, which is incorporated by reference.
• U refers to insulin units. Most of the currently used (marketed) insulins (bovine, porcine, human, lispro, aspart, and glargine) have a potency of one unit which equals 6 nmol. Long-acting acylated insulins have reduced potency compared to human insulin. Thus, for insulin detemir one unit corresponds to 24 nmol. For other insulins, the relation between U and nmol can be determined, if not known already, for example, by determining the amount giving a similar pharmacological (blood glucose lowering) effect as that of human insulin.
• blood glucose lowering blood glucose lowering
• the content of zinc is expressed per hexamer insulin as a theoretical value, i.e., as the number of zinc atoms per 6 molecules of monomer insulin, independent on whether all hexamer insulin actually is present as hexamer insulin or not.
• Stabilization of a formulation as used herein refers to a reduction in the formation of fibrils or other aggregates or maintenance of overall solubility and/or chemical integrity and corresponding maintenance of pharmacological efficacy.
• a stable formulation according to the invention is one that can be stored at 4° C. without forming fibrils after at least about 10 days, preferably at least about 20 days, more preferably at least about 50 days, and, most preferably, at least about 100 days; or that can be stored at 25° C. without forming fibrils after at least about 2 days, preferably at least about 5 days, more preferably at least about 10 days, most preferably at least about 25 days.
• This invention relates to mixtures of a soluble acylated insulin analog and a monomeric insulin or human insulin. It has, surprisingly, been found that such formulations have a substantially improved stability, for example, when exposed to physical stress. For example, the formulations of this invention have a low tendency to fibrillation.
• the formulations of this invention contain no or only a minor amount of non-dissolved material. Furthermore, said formulations give both a fast onset of action and also a retarded action. In addition to this, said formulations have convenient profiles of action.
• this invention relates to a pharmaceutical soluble formulation comprising a soluble acylated insulin analogue and a monomeric insulin or human insulin wherein the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 7:93, preferably 11:89, more preferred 14:86, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 57:43, preferably 41:59, more preferred 31:69, preferably 24:76 and even more preferred 20:80.
• the pharmaceutical soluble formulation according to this invention comprises a soluble acylated insulin analogue and a monomeric insulin or human insulin wherein the ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is in the range from about 7:93 to about 57:43 on a mole to mole basis (corresponding to a content of 7-57% on a mole to mole basis). Since the skilled art worker, especially physicians, are more familiar with U (units) than moles, it can be added that if the soluble acylated insulin analogue and the monomeric insulin or human insulin have the same strength, the content of the soluble acylated insulin analogue will be 7-57% on a unit to unit basis.
• the pharmaceutical soluble formulation according to this invention comprises a soluble acylated insulin analogue and human insulin or a monomeric insulin wherein the ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is in the range from about 2:98 to about 25:75, on a unit to unit basis, preferably in the range from about 3:97 to about 15:85, on a unit to unit basis, more preferred in the range from about 4:96 to about 10:90, on a unit to unit basis.
• the present invention does not cover a pharmaceutical soluble formulation comprising insulin aspart and insulin detemir wherein the ratio between insulin aspart and insulin detemir is in the range from 15:85 to 85:15, on a unit to unit basis, corresponding to the ratio between detemir and aspart being not more than about 41:59 on a mole to mole basis, vide our Danish patent application No. PA 2002 00684 the content of which is hereby incorporated by reference.
• the present invention relates to a pharmaceutical soluble formulation comprising a soluble acylated insulin analogue and a monomeric insulin or human insulin wherein the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is in the range from about 11:89 to about 41:59, preferably in the range from about 14:86 to about 31:69.
• the formulations of the present invention exhibit a stability that is enhanced relatively to formulations of monomeric insulin or human insulin alone, i.e, without the soluble acylated insulin component.
• the stability may be enhanced 2-fold, preferably 3-fold, more preferably 5-fold, even more preferably 10-fold or most preferably more than 10-fold.
• fibril formation can be measured visually, by conventional spectroscopic means, or by, e.g.thioflavin T fluorescence spectroscopy (Nielsen et al.: Biochemistry 40 (2001) p. 8397-8409).
• a formulation according to the invention that exhibits a 2-fold enhanced stability relative to a reference formulation is a formulation that, e.g., must be stored twice as long as the reference formulation before fibril formation can be detected.
• the formulation is suitable for use in a continuous infusion pump.
• the present invention relates to a reservoir in a continuous infusion system comprising a soluble acylated insulin analogue as mentioned herein.
• this invention relates to a reservoir containing a pharmaceutical soluble formulation comprising a soluble acylated insulin analogue and a monomeric insulin or human insulin wherein the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 7:93, preferably 11:89, more preferred 14:86, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 57:43, preferably 41:59, more preferred 31:69, preferably 24:76 and even more preferred 20:80.
• the pharmaceutical formulation of this invention may be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the pertinent ingredients as appropriate to give the desired end product.
• a soluble acylated insulin analogue in an amount from about 1% to about 15% of the total activity of the insulin calculated in insulin units, it is possible to prepare a medicament having improved physical stability in an aqueous solution containing a monomeric insulin or human insulin.
• a soluble acylated insulin analogue and, on the other hand, a monomeric insulin or human insulin is dissolved in an amount of water, the total volume of which is somewhat less than the final volume of the formulation to be prepared.
• An isotonic agent, a preservative and a buffer is added as required and the pH value of the solution is adjusted—if necessary—using an acid, for example, hydrochloric acid, or a base, for example, aqueous sodium hydroxide as needed.
• the volume of the solution is adjusted with water to give the desired concentration of the ingredients.
• the soluble acylated insulin analogue is insulin detemir (Lys B29 (N ⁇ -tetradecanoyl) des( B30) human insulin).
• the acylated insulin is Lys B29 (N ⁇ -hexadecanoyl) des(B30) human insulin; Lys B29 (N ⁇ -tetradecanoyl) human insulin; Lys B29 (N ⁇ -hexadecanoyl) human insulin; Lys B28 (N ⁇ -tetradecanoyl) Lys B28 Pro B29 human insulin; Lys B28 (N ⁇ -hexadecanoyl) Lys B28 Pro B29 human insulin; Lys B30 (N ⁇ -tetradecanoyl) Thr B29 Lys B30 human insulin; Lys B30 (N ⁇ -hexadecanoyl) Thr B29 Lys B30 human insulin; Lys B30 (N ⁇ -hexade
• human insulin is used.
• the monomeric insulin is insulin aspart.
• the monomeric insulin is insulin lispro.
• the monomeric insulin is Lys B3 , Glu B29 human insulin.
• the release of insulin activity from the formulation of this invention, after parenteral administration thereof to a human being within the first 4 hours, is at least about 50%.
• the formulation contains an agent rendering the solution isotonic, an antimicrobial preservative, a pH-buffering agent, and a suitable zinc salt.
• the formulation has a pH value in the range from about 7 to about 8.
• the formulation has a total amount of the insulin in the range with the lower limit being 10 U/ml, preferably 40 U/ml, more preferred 100 U/ml, and even more preferred 150 U/ml, and the upper limit being 1500 U/ml, preferably 1000 U/ml, more preferred 500 U/ml.
• the formulation has a total amount of the insulin in the range from about 10 U/ml to about 1500 U/ml, preferably in the range from about 40 U/ml to about 1000 U/ml, more preferred in the range from about 100 U/ml to about 500 U/ml, for example, 100, 200, 400, or 500 U/ml.
• the preservative is phenol, m-cresol or a mixture of phenol and m-cresol.
• the total concentration of phenol and/or m-cresol is in the range from about 20 mM to about 50 mM, preferably in the range from about 30 mM to about 45 mM.
• the concentration of phenol and/or m-cresol is, inter alia, depending on the concentration of insulin.
• the formulation has a content of zinc ions at the disposal of insulin in proportions in the range from about 2.3 to about 4.5 Zn 2+ per hexamer insulin (corresponding to from about 0.38 to about 0.75 Zn 2+ /monomer insulin).
• the zinc salt used for preparing the formulations of this invention may, for example, be zinc chloride, zinc oxide or zinc acetate.
• the isotonic agent is glycerol, mannitol, sorbitol or a mixture thereof at a concentration in the range from about 100 to 250 mM.
• the formulation contains halogenide ions, preferably as sodium chloride, in an amount corresponding to from about 1 mM to about 100 mM, preferably from about 5 mM to about 40 mM.
• the pH buffer is sodium phosphate, TRIS (trometamol), N-glycylglycine or L-arginine.
• the pH buffer is a physiologically acceptable buffer in a concentration in the range from about 3 mM to about 20 mM, preferably from about 5 mM to about 15 mM.
• the formulations of this invention have a pH value is in the range from about 7.0 to about 8.0.
• the formulation is a neutral, aqueous soluble formulation containing a combination of insulin aspart and insulin detemir in a concentration suitable for infusion systems and, furthermore, essentially consisting of phenolic preservatives (in a total concentration in the range from about 30 mM to about 40 mM), glycerol as isotonicity agent (in a concentration of about 0.17 M), dibasic sodium phosphate (in a concentration in the range from about 5 mM to about 7 mM), zinc ions corresponding to from about 2.5 to about 3.5 Zn 2+ /hexamer insulin or from about 0.4 to about 0.6 Zn 2+ /monomer insulin.
• phenolic preservatives in a total concentration in the range from about 30 mM to about 40 mM
• glycerol as isotonicity agent in a concentration of about 0.17 M
• dibasic sodium phosphate in a concentration in the range from about 5 mM to about 7 mM
• the formulation of this invention has a content of non-dissolved material below about 0.1%, preferably below 0.01% (weight per weight).
• the stability factor, when determined by the test described in example 1 above, of the formulation of this invention is above about 2.5, preferably above about 4.
• a soluble acylated insulin analogue is used in an amount in the range with the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin being 7%, preferably 11%, more preferred 14%, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin being 57%, preferably 41%, more preferred 31%, preferably 24% and even more preferred 20%, of the total amount of insulin to improve the physical stability in an aqueous solution containing a monomeric insulin or human insulin.
• Administration of the formulations of this invention may be via any route known to be effective by the physician of ordinary skill. Parenteral and preferably subcutaneous and intraperitoneal administration is preferred.
• the amount of the formulation of this invention that is administered to treat diabetes depends on a number of factors, among which are included the patient's sex, weight, physical activity, and age, diet of the patient, the underlying causes of the condition or disease to be treated, the route of administration and bioavailability, the persistence of the administered insulin or insulin analogues in the body, the specific formulation used, the potency of the insulin or insulin analogue used, a possible combination with other drugs, the severity of the case of diabetes, and the interval between dosages, if any interval. It is within the skill of the ordinary physician to titrate the dose and infusion rate and frequency of administration of the formulation of this invention to achieve the desired result. It is recommended that the daily dosage of the insulin components used in the formulations of this invention be determined for each individual patient by those skilled in the art in a similar way as for known insulin compositions.
• the cartridges were fixed to a rotator placed in an incubator kept at a constant temperature of 37° C. ⁇ 2° C. and rotated 360° at a frequency of 30 rpm (rotations per minute) for four hours per day.
• the cartridges were stored at a constant temperature of 37° C. ⁇ 2° C. between the rotation periods.
• the opalescence of the cartridges was evaluated by visual inspection at regular time intervals—once daily in the first week and thereafter three times a week for up to 31 days. When opalescence or precipitates occurs and is visible with the naked eye, the sample is considered fibrillated. The number of days without fibrillation is defined as the Fibrillation time.
• the Stability Factor of a sample is calculated by dividing the Fibrillation time of said sample with the Fibrillation time of a specified reference sample tested in the same experiment.
• the specified reference sample was insulin aspart 200 U/ml which was prepared as follows:
• a solution with the following composition was prepared: Insulin aspart 200 U/ml (1200 nmol/ml), phenol 1.80 mg/ml (19 mM), m-cresol 2.06 mg/ml (19 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 1.25 mg/ml (7 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride up to a total concentration of 39.2 ⁇ g Zn 2+ /ml (3.0 Zn 2+ per hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 1.5 ml using aseptic technique.
• Example 1 14 ⁇ 12 3 aspart/detemir 98/2
• Example 2 >31 >6 aspart/detemir 95/5
• Example 3 >31 >6 aspart/detemir 90/10
• Example 4 >31 >6 aspart/detemir 75/25 Reference 5 ⁇ 3 1 aspart 100%
• a solution with the following composition was prepared: Insulin aspart 196 U/ml (1176 nmol/ml), Insulin detemir 4 U/ml (96 nmol)ml, phenol 1.80 mg/ml (19 mM), m-cresol 2.06 mg/ml (19 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 1.25 mg/ml (7 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride and zinc acetate up to a total concentration of 41.5 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 1.5 ml using aseptic technique.
• a solution with the following composition was prepared: Insulin aspart 190 U/ml (1140 nmol/ml), Insulin detemir 10 U/ml (240 nmol/ml), phenol 1.80 mg/ml (19 mM), m-cresol 2.06 mg/ml (19 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 1.25 mg/ml (7 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride and zinc acetate up to a total concentration of 45.1 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 1.5 ml using aseptic technique.
• a solution with the following composition was prepared: Insulin aspart 180 U/ml (1080 nmol/ml), Insulin detemir 20 U/ml (480 nmol)ml, phenol 1.80 mg/ml (19 mM), m-cresol 2.06 mg/ml (19 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 1.25 mg/ml (7 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride and zinc acetate up to a total concentration of 51.0 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 1.5 ml using aseptic technique.
• a solution with the following composition was prepared: Insulin aspart 150 U/ml (900 nmol/ml), Insulin detemir 50 U/ml (1200 nmol)ml, phenol 1.80 mg/ml (19 mM), m-cresol 2.06 mg/ml (19 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 1.25 mg/ml (7 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride and zinc acetate up to a total concentration of 68.6 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 1.5 ml using aseptic technique.
• a solution with the following composition was prepared: Insulin aspart 95 U/ml (570 nmol/ml), Insulin detemir 5 U/ml (120 nmol/ml), phenol 1.5 mg/ml (16 mM), m-cresol 1.7 mg/ml (16 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 0.9 mg/ml (5 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride and zinc acetate up to a total concentration of 22.6 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 3 ml using aseptic technique.
• a solution with the following composition was prepared: Insulin aspart 90 U/ml (540 nmol/ml), Insulin detemir 10 U/ml (240 nmol/ml), phenol 1.5 mg/ml (16 mM), m-cresol 1.7 mg/ml (16 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 0.9 mg/ml (5 mM), sodium chloride 0.58 mg/ml (10 mM), zinc chloride and zinc acetate up to a total concentration of 25.5 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 3 ml using aseptic technique.
• a solution with the following composition was prepared: Insulin aspart 380 U/ml (2280 nmol/ml), Insulin detemir 20 U/ml (480 nmol/ml), phenol 1.8 mg/ml (19 mM), m-cresol 2.1 mg/ml (19 mM), glycerol 16 mg/ml (174 mM), dibasic sodium phosphate dihydrate 0.9 mg/ml (5 mM), sodium chloride 1.2 mg/ml (20 mM), zinc chloride and zinc acetate up to a total concentration of 90 ⁇ g Zn 2+ /ml (3.0 Zn 2+ /hexamer). Hydrochloric acid and sodium hydroxide were used for dissolution of the insulin and adjustment of the pH value to 7.40. Finally, the solution was sterilized by filtration and filled into sterile Penfill® cartridges 1.5 ml using aseptic technique.

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