WO2010149772A1 - Preparation comprising insulin, nicotinamide and an amino acid - Google Patents
Preparation comprising insulin, nicotinamide and an amino acid Download PDFInfo
- Publication number
- WO2010149772A1 WO2010149772A1 PCT/EP2010/059069 EP2010059069W WO2010149772A1 WO 2010149772 A1 WO2010149772 A1 WO 2010149772A1 EP 2010059069 W EP2010059069 W EP 2010059069W WO 2010149772 A1 WO2010149772 A1 WO 2010149772A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- insulin
- preparation according
- compound
- insulin preparation
- arginine
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 630
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- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 title claims description 36
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- 230000004845 protein aggregation Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
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- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000930 thermomechanical effect Effects 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K2121/00—Preparations for use in therapy
Definitions
- the present invention relates to pharmaceutical preparations comprising an insulin com- pound, a nicotinic compound and an amino acid.
- 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 and the disorder approaches epidemic proportions. Since the introduction of insulin in the 1920's, continuous improvements have been made in the treatment of diabetes. To help avoid high glycaemia levels, diabetic patients often practice multiple injection therapy, whereby insulin is administered with each meal. As diabetic patients have been treated with insulin for several decades, there is a major need for safe and life-quality improving insulin preparations. Among the commercially available insulin preparations, rapid-acting, intermediate-acting and prolonged-acting preparations can be mentioned.
- Some of the commercially available insulin preparations comprising such rapid acting insulin analogues include NovoRapid® (preparation of B28Asp human insulin), Humalog® (preparation of B28LysB29Pro human insulin) and Apidra® (preparation of B3LysB29Glu human insulin).
- insulin preparations of insulins are administered by subcutaneous injection.
- the action profile of the insulin meaning the action of insulin on glucose metabolism as a function of time from injection.
- the time of the onset the maximum value and the total duration of action are important.
- bolus insulins a variety of insulin preparations with different action profiles are desired and requested by the patients.
- One patient may, on the same day, use insulin prepa- rations with very different action profiles.
- the action profile desired for example depends on the time of the day and the amount and composition of the meal eaten by the patient.
- the chemical stability of the insulin preparations for example, due to the abundant use of pen-like injection devices such as devices which contain Penfill ® cartridges, in which an insulin preparation is stored until the entire cartridge is empty which may be at least 1 to 2 weeks for devices containing 1.5-3.OmI cartridges.
- pen-like injection devices such as devices which contain Penfill ® cartridges
- an insulin preparation is stored until the entire cartridge is empty which may be at least 1 to 2 weeks for devices containing 1.5-3.OmI cartridges.
- covalent chemical changes in the insulin structure occur. This may lead to formation of molecules which may be less active and/or potentially immunogenic such as deamidation products and higher molecular weight transformation products (dimers, polymers).
- dimers, polymers molecular weight transformation products
- the physical stability of the insulin preparations since long term storage may eventually lead to formation of insoluble fibrils, which are biologically inactive and potentially immunogenic.
- the invention relates to insulin preparations with favourable absorption rate and favourable chemical and physical stability.
- the present invention relates to insulin preparations comprising human insulin and/or analogues thereof, nicotinamide or nicotinic acid and/or salts thereof and arginine.
- the present invention relates to an insulin preparation comprising:
- the insulin preparation may further comprise glutamic acid.
- the present invention also contemplates a method for the treatment of diabetes mellitus in a subject or for reducing the blood glucose level in a subject comprising administering to a subject or mammal an insulin preparation according to the invention.
- Figure 1 shows the development in percentage of total insulin content of degradation products during 2 weeks of storage at 37 ° C of preparations according to the present invention.
- the letter A refers to a NovoRapid ® reference and remaining letters correspond to insulin as- part preparations as described in Table 1 of Example 1.
- addition of nicotinamide leads to an increased formation of degradation products
- the combined addition of nicotinamide, glutamic acid and arginine has a mostly similar degradation pattern, with lower formation of HMWP.
- Figure 2 shows the development in percentage of total insulin content of degradation products during 2 weeks of storage at 37 ° C of preparations according to this invention.
- the letter A refers to a NovoRapid ® reference and remaining letters correspond to insulin aspart prepa- rations as described in Table 1 of Example 1.
- the letter A refers to a NovoRapid ® reference and remaining letters correspond to insulin aspart preparations as described in Table 1 of Example 1.
- the initial rate of plasma glucose lowering is faster for the prepa- ration with addition of nicotinamide (preparation N) and even faster for a combination of nicotinamide and arginine (preparation M).
- the letter A refers to a NovoRapid ® reference and remaining letters correspond to insulin aspart preparations as described in Table 1 of Example 1.
- the initial rate of plasma glucose lowering is faster for a preparation with a combination of nicotinamide, arginine and glutamic acid (preparation L) and for a preparation with a combination of nicotinamide and arginine (preparation K).
- the letter A refers to a NovoRapid ® reference and remaining letters correspond to insulin aspart preparations as described in Table 1 of Example 1.
- the initial absorption rate of the insulin component of the preparations with nicotinamide preparation J
- the combination of nicotinamide and ar- ginine preparation K
- the combination of nicotinamide, arginine and glutamic acid preparation L
- the absorption after subcutaneous injection of the insulin compound in the insulin preparations of the present invention was surprisingly found to be faster than that of the reference insulin preparations.
- This property is useful for rapid-acting insulins, in particular in connection with a multiple injection regimen where insulin is given before each meal. With faster on- set of action, the insulin can conveniently be taken closer to the meal than with conventional rapid acting insulin solutions. Furthermore, a faster disappearance of insulin probably diminishes the risk of post-meal hypoglycaemia.
- the insulin preparations of the present invention are rapid-acting insulin preparations comprising an insulin compound such as insulin aspart, a nicotinic compound, such as nicotinamide and the amino acid arginine.
- the insulin preparations of the present invention may comprise further amino acids such as glutamic acid.
- These insulin preparations have a rapid absorption profile that mimics normal physiology more closely than existing therapies.
- the insulin preparations of the present invention have chemical and physical stability suitable for commercial pharmaceutical preparations.
- the insulin preparations of the present invention provide an even faster onset of action compared with existing insulin therapies. Such ultra-fast insulin preparations have the advantage of restoring first phase insulin release, injection convenience and shutting down hepatic glucose production.
- the insulin preparations of the present invention have a favourable absorption rate from subcutis into plasma with an increase in initial absorption rate rang- ing from 1.5 to 5 times, when compared to conventional preparations such as NovoRapid ® , as suggested by several PK/PD experiments in pigs.
- This faster absorption rate may improve glycaemic control and convenience and may allow for a shift from pre-meal to post-meal dosing.
- the present invention is based in part, on the surprising discovery that although, the addition of nicotinamide allows the increase in absorption rate, it also has a negative effect on chemical stability by significantly increasing the amount of HMWP.
- the insulin preparations of the present invention have an improved chemical stability by addition of arginine, which is reflected in e.g. a reduction in the formation of dinners and polymers and desamido insulins after storage.
- the insulin preparations of the present invention may furthermore also have improved physical stability, which may be useful for use in pumps.
- the present invention provides an insulin preparation comprising an insulin compound according to the present invention which is present in a concentration from about 0.1 mM to about 10.OmM, and wherein said preparation has a pH from 3 to 8.5.
- the preparation also comprises a nicotinic compound and arginine.
- the preparation may further comprise protease inhibitor(s), metal ions, a buffer system, preservative(s), tonicity agent(s), chelating agent(s), stabilizers and surfactants.
- the insulin preparations comprise a human insulin, an analogue or combinations thereof, nicotinamide and/or nicotinic acid and/or salts thereof and arginine and/or salts thereof.
- the insulin preparations according to the present invention comprise an aqueous solution of B28Asp human insulin, nicotinamide and arginine.
- the content of B28Asp human insulin in the solutions of this invention may be in the range of 15 to 500 international units (IU)/ml, preferably in the range of 50 to 333 Ill/ml, in preparations for injection.
- IU international units
- the con- tent of insulin compound may be higher.
- an insulin preparation comprising an insulin compound, a nicotinic compound and glutamic acid.
- unit "IU" corresponds to 6 nmol.
- insulin aspart refers to the human insulin analogue B28Asp human insu- Nn.
- onset refers to the time from injection until the PK curve shifts to an increase.
- absorption rate refers to the slope of the PK curve.
- An "insulin compound” according to the invention is herein to be understood as hu- man insulin, an insulin analogue and/or any combination thereof.
- human insulin as used herein means the human hormone whose structure and properties are well-known. Human insulin has two polypeptide chains that are connected by disulphide bridges between cysteine residues, namely the A-chain and the B- chain.
- the A-chain is a 21 amino acid peptide and the B-chain is a 30 amino acid peptide, the two chains being connected by three disulphide bridges: one between the cysteines in position 6 and 1 1 of the A-chain, the second between the cysteine in position 7 of the A- chain and the cysteine in position 7 of the B-chain, and the third between the cysteine in position 20 of the A-chain and the cysteine in position 19 of the B-chain.
- the hormone is synthesized as a single-chain precursor proinsulin (preproinsulin) consisting of a prepeptide of 24 amino acids followed by proinsulin containing 86 amino acids in the configuration: prepeptide-B-Arg Arg-C-Lys Arg-A, in which C is a connecting peptide of
- Arg-Arg and Lys-Arg are cleavage sites for cleavage of the connecting peptide from the A and B chains.
- insulin analogue as used herein is meant a polypeptide derived from the pri- mary structure of a naturally occurring insulin, for example that of human insulin, by mutation.
- One or more mutations are made by deleting and/or substituting at least one amino acid residue occurring in the naturally occurring insulin and/or by adding at least one amino acid residue.
- the added and/or substituted amino acid residues can either be codable amino acid residues or other naturally occurring amino acid residues.
- an insulin analogue comprises less than 8 modifications (substitutions, deletions, additions and any combination thereof) relative to the parent insulin, alternatively less than 7 modifications relative to the parent insulin, alternatively less than 6 modifications relative to the parent insulin, alternatively less than 5 modifications relative to the parent insulin, alternatively less than 4 modifications relative to the parent insulin, alterna- tively less than 3 modifications relative to the parent insulin, alternatively less than 2 modifications relative to the parent insulin.
- mutants in the insulin molecule are denoted stating the chain (A or B), the position, and the three letter code for the amino acid substituting the native amino acid.
- desB30 or “B(1-29)” is meant a natural insulin B chain or analogue thereof lacking the B30 amino acid residue, and by B28Asp human insulin is meant human insulin wherein the amino acid residue in position 28 of the B chain has been substituted with Asp.
- insulin analogues are such wherein Pro in position 28 of the B chain is mutated with Asp, Lys, Leu, VaI, or Ala and/or Lys at position B29 is mutated with Pro, GIu or Asp. Furthermore, Asn at position B3 may be mutated with Thr, Lys, GIn, GIu or Asp. The amino acid residue in position A21 may be mutated with GIy. The amino acid in position B1 may be mutated with GIu. The amino acid in position B16 may be mutated with GIu or His. Further examples of insulin analogues are the deletion analogues e.g.
- insulin analogues where the B30 amino acid in human insulin has been deleted (des(B30) human insulin), insulin analogues wherein the B1 amino acid in human insulin has been deleted (des(B1) human insu- Nn), des(B28-B30) human insulin and des(B27) human insulin.
- Insulin analogues wherein the A-chain and/or the B-chain have an N-terminal extension and insulin analogues wherein the A-chain and/or the B-chain have a C-terminal extension such as with two arginine residues added to the C-terminal of the B-chain are also examples of insulin analogues. Further examples are insulin analogues comprising combinations of the mentioned mutations.
- Insulin analogues wherein the amino acid in position A14 is Asn, GIn, GIu, Arg, Asp, GIy or His, the amino acid in position B25 is His and which optionally further comprises one or more additional mutations are further examples of insulin analogues.
- Insulin analogues of human insulin wherein the amino acid residue in position A21 is GIy and wherein the insulin analogue is further extended in the C-terminal with two arginine residues are also examples of insulin analogues.
- insulin analogues include, but are not limited to: DesB30 human insulin; AspB28 human insulin; AspB28,desB30 human insulin; LysB3,GluB29 human insulin; LysB28,ProB29 human insulin; GlyA21 ,ArgB31 ,ArgB32 human insulin; GluA14,HisB25 human insulin; HisA14,HisB25 human insulin; GluA14,HisB25,desB30 human insulin; HisA14, HisB25,desB30 human insulin; GluA14,HisB25,desB27,desB28,desB29,desB30 human insulin; GluA14,HisB25,GluB27,desB30 human insulin; GluA14,HisB16,HisB25,desB30 human insulin; HisA14,HisB16,HisB25,desB30 human insulin; HisA14,HisB16,HisB25,desB30 human insulin; HisA8,GluA14,HisB25,GluB27,des
- nicotinic compound includes nicotinamide, nicotinic acid, niacin, niacin amide and vitamin B3 and/or salts thereof and/or any combination thereof.
- the concentration of the nicotinic compound and/or salts thereof is in the range from about 1 mM to about 30OmM or from about 5mM to about 20OmM.
- the term "arginine" or "Arg” includes the amino acid arginine and/or a salt thereof.
- the insulin preparation comprises 1 to 10OmM of arginine. In one embodiment, the insulin preparation comprises 1 to 2OmM of arginine. In one embodiment, the insulin preparation comprises 20 to 9OmM of arginine. In one embodiment, the insulin preparation comprises 30 to 85mM of arginine.
- glutamic acid or "GIu” includes the aminoacid glutamic acid and/or a salt thereof.
- the insulin preparation comprises 1 to 10OmM of glutamic acid. In one embodiment, the insulin preparation comprises 20 to 9OmM of glutamic acid.
- the insulin preparation comprises 30 to 85mM of glutamic acid.
- pharmaceutical preparation or "insulin preparation” as used herein means a product comprising an insulin compound, i.e., a human insulin, an analogue thereof and/or combinations thereof and a nicotinic compound and an aminoacid, optionally together with other excipients such as preservatives, chelating agents, tonicity modifiers, bulking agents, stabilizers, antioxidants, polymers and surfactants, metal ions, oleaginous vehicles and proteins (e.g., human serum albumin, gelatine or proteins), said insulin preparation being useful for treating, preventing or reducing the severity of a disease or disorder by administration of said insulin preparation to a person.
- an insulin preparation is also known in the art as a pharmaceutical preparation or pharmaceutical composition.
- the buffer may be selected from the group consisting of, but not limited to, sodium acetate, sodium carbonate, citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethan, bicine, tricine, malic acid, succinate, maleic acid, fumaric acid, tartaric acid, aspartic acid or mixtures thereof. Each one of these specific buffers constitutes an alternative embodiment of the invention.
- the insulin preparation of the present invention may further comprise other ingredients common to insulin preparations, for example zinc complexing agents such as citrate, and phosphate buffers.
- zinc complexing agents such as citrate, and phosphate buffers.
- Glycerol and/or mannitol and/or sodium chloride may be present in an amount cor- responding to a concentration of 0 to 25OmM, 0 to 20OmM or 0 to 10OmM.
- Stabilizers, surfactants and preservatives may also be present in the insulin preparations of this invention.
- the insulin preparations of the present invention may further comprise a pharmaceutically acceptable preservative.
- the preservative may be present in an amount sufficient to obtain a preserving effect.
- the amount of preservative in an insulin preparation may be determined from e.g. literature in the field and/or the known amount(s) of preservative in e.g. commercial products. Each one of these specific preservatives constitutes an alternative embodiment of the invention.
- the use of a preservative in pharmaceutical preparations is described, for example in Remington: The Science and Practice of Pharmacy, 19 th edition, 1995.
- the preservative present in the insulin preparation of this invention may be as in the heretofore conventional insulin preparations, for example phenol, m-cresol and methylpara- ben.
- the insulin preparation of the present invention may further comprise a chelating agent.
- a chelating agent in pharmaceutical preparations is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19 th edition, 1995.
- the insulin preparation of the present invention may further comprise a stabilizer.
- stabilizer refers to chemicals added to polypeptide containing pharmaceutical preparations in order to stabilize the peptide, i.e. to increase the shelf life and/or in-use time of such preparations.
- Remington For convenience reference is made to Remington:
- the insulin preparation of the present invention may further comprise a surfactant.
- surfactant refers to any molecules or ions that are comprised of a water-soluble (hydrophilic) part, the head, and a fat-soluble (lipophilic) segment. Surfactants accumulate preferably at interfaces, which the hydrophilic part is orientated towards the water (hydrophilic phase) and the lipophilic part towards the oil- or hydrophobic phase (i.e. glass, air, oil etc.). The concentration at which surfactants begin to form micelles is known as the critical micelle concentration or CMC. Furthermore, surfactants lower the surface tension of a liquid. Surfactants are also known as amphipathic compounds.
- detergent is a synonym used for surfactants in general. The use of a surfactant in pharmaceutical preparations is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19 th edition, 1995.
- the invention relates to an insulin preparation
- an insulin preparation comprising an aqueous solution of an insulin compound of the present invention, and a buffer, wherein said insulin compound is present in a concentration from 0.1 mM or above, and wherein said preparation has a pH from about 3.0 to about 8.5 at room temperature ( ⁇ 25°C).
- the present invention also relates to methods for producing the insulin preparations of the invention.
- the method for making insulin preparations of the invention comprises: a) preparing a solution by dissolving the insulin compound or a mixture of insulin compounds in water or buffer; b) preparing a solution by dissolving a divalent metal ion in water or buffer; c) preparing a solution by dissolving a preservative in water or buffer; d) preparing a solution by dissolving an isotonicity agent in water or buffer ; e) preparing a solution by dissolving a surfactant and/or a stabilizer in water or buffer; f) mixing solution a) and one or more of solutions b), c), d), and e); Finally adjusting the pH of the mixture in f) to the desired pH followed by a sterile filtration.
- the insulin preparations of the present invention can be used in the treatment of diabetes by parenteral administration. It is recommended that the dosage of the insulin preparations of this invention which is to be administered to the patient be selected by a phy- sician. Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal or intravenous injection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump. As a further option, the insulin preparations containing the insulin compound of the invention can also be adapted to transdermal administration, e.g. by needle-free injection or from a patch, optionally an iontophoretic patch, or transmucosal, e.g. buccal, administration.
- transdermal administration e.g. by needle-free injection or from a patch, optionally an iontophoretic patch, or transmucosal, e.g. buccal, administration.
- Insulin preparations according to the present invention may be administered to a patient in need of such treatment at several sites, for example, at topical sites, for example, skin and mucosal sites, at sites which bypass absorption, for example, administration in an artery, in a vein, in the heart, and at sites which involve absorption, for example, administration in the skin, under the skin, in a muscle or in the abdomen.
- topical sites for example, skin and mucosal sites
- sites which bypass absorption for example, administration in an artery, in a vein, in the heart
- absorption for example, administration in the skin, under the skin, in a muscle or in the abdomen.
- the insulin preparation is an aqueous preparation, i.e. preparation comprising water. Such preparation is typically a solution or a suspension. In a further embodiment of the invention the insulin preparation is an aqueous solution.
- aqueous preparation is defined as a preparation comprising at least 50
- aqueous solution is defined as a solution comprising at least 50 %w/w water
- aqueous suspension is defined as a suspension comprising at least 50 %w/w water.
- Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
- the insulin preparations of this invention are well-suited for application in pen-like devices used for insulin therapy by injection.
- the insulin preparations of the present invention can be used in pumps for insulin administration.
- physical stability of the insulin preparation as used herein refers to the tendency of the protein to form biologically inactive and/or insoluble aggregates of the protein as a result of exposure of the protein to thermo-mechanical stresses and/or interaction with interfaces and surfaces that are destabilizing, such as hydrophobic surfaces and interfaces.
- Physical stability of the aqueous protein preparations is evaluated by means of visual inspec- tion and/or turbidity measurements after exposing the preparation filled in suitable containers (e.g. cartridges or vials) to mechanical/physical stress (e.g. agitation) at different temperatures for various time periods. Visual inspection of the preparations is performed in a sharp focused light with a dark background.
- the turbidity of the preparation is characterized by a visual score ranking the degree of turbidity for instance on a scale from 0 to 3 (a preparation showing no turbidity corresponds to a visual score 0, and a preparation showing visual tur- bidity in daylight corresponds to visual score 3).
- a preparation is classified physically unstable with respect to protein aggregation, when it shows visual turbidity in daylight.
- the turbidity of the preparation can be evaluated by simple turbidity measurements well-known to the skilled person. Physical stability of the aqueous protein preparations can also be evaluated by using a spectroscopic agent or probe of the conformational status of the protein.
- the probe is preferably a small molecule that preferentially binds to a non-native conformer of the protein.
- a small molecular spectroscopic probe of protein structure is Thioflavin T.
- Thioflavin T is a fluorescent dye that has been widely used for the detection of amyloid fibrils. In the presence of fibrils, and perhaps other protein configurations as well, Thioflavin T gives rise to a new excitation maximum at about 450 nm and enhanced emission at about 482 nm when bound to a fibril protein form. Unbound Thioflavin T is essentially non-fluorescent at the wavelengths.
- chemical stability of the protein preparation refers to changes in the covalent protein structure leading to formation of chemical degradation prod- ucts with potential less biological potency and/or potential increased immunogenic properties compared to the native protein structure.
- chemical degradation products can be formed depending on the type and nature of the native protein and the environment to which the protein is exposed. Increasing amounts of chemical degradation products is often seen during storage and use of the protein preparation.
- Most proteins are prone to deamidation, a process in which the side chain amide group in glutaminyl or asparaginyl residues is hydro- lysed to form a free carboxylic acid or asparaginyl residues to form an IsoAsp derivative.
- the amount of each individual degradation product is often determined by separation of the degradation products depending on molecule size and/or charge using various chromatography techniques (e.g. SEC-HPLC and/or RP-HPLC). Since HMWP products are potentially immunogenic and not biologically active, low levels of HMWP are advantageous.
- stabilized preparation refers to a preparation with increased physical stability, increased chemical stability or increased physical and chemical stability. In general, a preparation must be stable during use and storage (in compliance with recommended use and storage conditions) until the expiration date is reached.
- diabetes or “diabetes mellitus” includes type 1 diabetes, type 2 diabetes, gestational diabetes (during pregnancy) and other states that cause hyperglycaemia.
- Type 1 diabetes also called insulin-dependent diabetes mellitus (IDDM) and juvenile- onset diabetes, is caused by B-cell destruction, usually leading to absolute insulin deficiency.
- IDDM insulin-dependent diabetes mellitus
- juvenile- onset diabetes is caused by B-cell destruction, usually leading to absolute insulin deficiency.
- Type 2 diabetes also known as non-insulin-dependent diabetes mellitus (NIDDM) and adult-onset diabetes, is associated with predominant insulin resistance and thus relative insulin deficiency and/or a predominantly insulin secretory defect with insulin resistance.
- NIDDM non-insulin-dependent diabetes mellitus
- pharmaceutically acceptable means suited for normal pharmaceutical applications, i.e., not giving rise to any serious adverse events in patients.
- treatment of a disease means the management and care of a patient having developed the disease, condition or disorder and includes treatment, prevention or alleviation of the disease.
- the purpose of treatment is to combat the disease, con- dition or disorder.
- Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder, and prevention of the disease, condition or disorder.
- an insulin analogue according to the invention is used as a medicament for delaying or preventing disease progression in type 2 diabetes.
- the insulin preparation according to the invention is for use as a medicament for the treatment or prevention of hyperglycemia including stress induced hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, and burns, operation wounds and other diseases or injuries where an anabolic effect is needed in the treatment, myocardial infarction, stroke, coronary heart disease and other cardiovascular disorders is provided.
- hyperglycemia including stress induced hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, and burns, operation wounds and other diseases or injuries where an anabolic effect is needed in the treatment, myocardial infarction, stroke, coronary heart disease and other cardiovascular disorders is provided.
- a method for the treatment or prevention of hyperglycemia including stress induced hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, and burns, operation wounds and other diseases or inju- ries where an anabolic effect is needed in the treatment, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, the method comprising administering to a patient in need of such treatment an effective amount for such treatment of an insulin preparation according to the invention, is provided.
- the treatment with an insulin preparation according to the present invention may also be combined with a second or more pharmacologically active substances, e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
- a second or more pharmacologically active substances e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
- the treatment with an insulin preparation according to the present invention may also be combined with bariatric surgery - a surgery that influences the glucose levels and/or lipid homeostasis such as gastric banding or gastric bypass.
- polypeptides e.g., insulins
- An insulin analogue according to the invention may for instance be produced by classical peptide syn- thesis, e.g. solid phase peptide synthesis using t-Boc or Fmoc chemistry or other well established techniques, see e.g. Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999.
- the insulin analogue may also be produced by a method which comprises culturing a host cell containing a DNA sequence encoding the analogue and capable of expressing the insulin analogue in a suitable nutrient medium under conditions per- mitting the expression of the insulin analogue.
- the recombinant cell should be modified such that the non-natural amino acids are incorporated into the analogue, for instance by use of tRNA mutants.
- the insulin analogues according to the invention are prepared analogously to the preparation of known insulin analogues.
- Several methods may be used for the production of human insulin and human insulin analogues. For example three major methods which are used in the production of insulin in microorganisms are disclosed in WO2008034881. Two of these involve Escherichia coli, with either the expression of a large fusion protein in the cytoplasm (Frank et al.
- the insulin analogues are produced by expressing a DNA sequence encoding the insulin analogue in question in a suitable host cell by well known technique as disclosed in e.g. US 6500645.
- the insulin analogue is either expressed directly or as a precursor molecule which has an N-terminal extension on the B-chain or a C-terminal extension on the B- chain.
- the N-terminal extension may have the function of increasing the yield of the directly expressed product and may be of up to 15 amino acid residues long.
- the N-terminal extension is to be cleaved of in vitro after isolation from the culture broth and will therefore have a cleavage site next to B1.
- N-terminal extensions of the type suitable in the present invention are disclosed in US 5,395,922, and EP 765,395.
- the C-terminal extension may have the function of protecting the mature insulin or insulin analogue molecule against intracellular proteolytic processing by host cell exoproteases.
- the C-terminal extension is to be cleaved of either extra-cellularly in the culture broth by secreted, active carboxypeptidase or in vitro after isolation from the culture broth.
- a method for producing mature insulin and insulin analogs with C-terminal extensions on the B-chain that are removed by carboxypetidase are dis- closed in WO 08037735.
- the target insulin product of the process may either be a two-chain human insulin or a two-chain human insulin analogue which may or may not have a short C- terminal extension of the B-chain. If the target insulin product will have no C-terminal extension of the B-chain, then said C-terminal extension should be capable of subsequently being cleaved off from the B-chain before further purification steps.
- the present invention also contemplates the following non-limiting list of embodiments, which are further described elsewhere herein:
- An insulin preparation comprising:
- insulin preparation according to any of the preceding embodiments, wherein the insulin compound is B3LysB29Glu human insulin. 6. The insulin preparation according to any of the preceding embodiments, wherein the in- sulin compound is present in a range selected from the following: 0.1-10.OmM; 0.1 -
- the insulin preparation according to any of the preceding embodiments wherein the insulin compound is present in the amount from about 0.1 mM to about 2.5mM. 10. The insulin preparation according to any of the preceding embodiments, wherein the insulin compound is present in the amount from about 0.1 mM to about 2.OmM.
- nicotinic compound is selected from the group consisting of nicotinamide, nicotinic acid, niacin, niacin amide and vitamin B3 and/or salts thereof and/or any combination thereof.
- the nicotinic compound is selected from nicotinamide and nicotinic acid and/or salts thereof and/or any combination thereof.
- the insulin preparation according to any of the preceding embodiments comprising from about 1 mM to about 30OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 8mM to about 26OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 5mM to about 20OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 1mM to about 15OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 5mM to about 2OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 2OmM to about 12OmM of the nicotinic compound.
- 35 The insulin preparation according to any of the preceding embodiments, comprising from about 4OmM to about 12OmM of the nicotinic compound.
- 36 The insulin preparation according to any of the preceding embodiments, comprising from about 2OmM to about 4OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 6OmM to about 8OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 7OmM to about 14OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising from about 8OmM to about 13OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising about 8mM, 3OmM, 10OmM or 13OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising about 3OmM, 10OmM or 13OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising about 3OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising about 10OmM of the nicotinic compound.
- the insulin preparation according to any of the preceding embodiments comprising about 13OmM of the nicotinic compound. 46. The insulin preparation according to any of the preceding embodiments, comprising about 15OmM of the nicotinic compound. 47. The insulin preparation according to any of the preceding embodiments, comprising the following ranges of arginine compound: 1-10OmM, 5-12OmM, 8-85mM, 20-9OmM, 30-
- the insulin preparation according to any of the preceding embodiments comprising the following ranges of arginine compound: 1 -12OmM, 8-85mM or 1 -4OmM.
- the insulin preparation according to any of the preceding embodiments comprising from about 1mM to about 12OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 1 mM to about 10OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 5mM to about 12OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 2OmM to about 9OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 8mM to about 85mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 3OmM to about 6OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 1OmM to about 4OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising from about 1 mM to about 4OmM of arginine.
- arginine is present in a range selected from the following: 1 mM, 2mM, 3mM, 4mM, 5mM, 6mM, 7mM, 8mM, 9mM, 1OmM, 15mM, 2OmM, 25mM, 3OmM, 35mM or 4OmM, 45mM, 5OmM, 55mM or 6OmM.
- the insulin preparation according to any of the preceding embodiments comprising about 1 mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 2mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 3mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 4mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 5mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 6mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 7mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 8mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 9mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 1OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 15mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 2OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 25mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 35mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 4OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 45mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 5OmM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 55mM of arginine.
- the insulin preparation according to any of the preceding embodiments comprising about 6OmM of arginine.
- the insulin preparation according to embodiment 79 comprising from about 1 mM to about 10OmM of glutamic acid.
- the insulin preparation according to embodiment 79 comprising from about 2OmM to about 9OmM of glutamic acid.
- the insulin preparation according to embodiment 79 comprising from about 3OmM to about 85mM of glutamic acid.
- the insulin preparation according to embodiment 79 comprising from about 3OmM to about 5OmM of glutamic acid.
- the insulin preparation according to embodiment 79 comprising about 3OmM or 5OmM of glutamic acid.
- the insulin preparation according to embodiment 79 comprising about 3OmM of glutamic acid.
- the insulin preparation according to embodiment 79 comprising about 5OmM of glutamic acid.
- the insulin preparation according to any of the preceding embodiments which further comprises a metal ion, preservative agent(s), isotonicity agent(s) and stabilizer(s), deter- gent(s) and buffer(s).
- a metal ion preservative agent(s), isotonicity agent(s) and stabilizer(s), deter- gent(s) and buffer(s).
- said buffer is Tris.
- the insulin preparation according to embodiment 89 comprising from about 2mM to about 5OmM of Tris.
- the insulin preparation according to embodiment 89 comprising from about 1 OmM to about 4OmM of Tris.
- the insulin preparation according to embodiment 89 comprising from about 2OmM to about 3OmM of Tris.
- the insulin preparation according to embodiment 89 comprising about 1OmM, 2OmM, 3OmM or 4OmM of Tris.
- the insulin preparation according to embodiment 89 comprising about 1 OmM of Tris.
- the insulin preparation according to embodiment 89 comprising about 2OmM of Tris.
- the insulin preparation according to embodiment 89 comprising about 3OmM of Tris.
- the insulin preparation according to embodiment 89 comprising about 4OmM of Tris.
- the insulin preparation according to any of embodiments 112-115 comprising from about 5 to 100ppm, from about 10 to about 50ppm or from about 10 to about 20ppm of polysorbate.
- the insulin preparation according to embodiment 88 further comprising a phenolic compound.
- a method for the treatment of diabetes mellitus in a subject comprising administer- ing to a subject an insulin preparation according to any of the preceding embodiments.
- the pharmaceutical preparations of the present invention may be formulated as an aqueous solution.
- the aqueous medium is made isotonic, for example, with sodium chloride or glycerol.
- the aqueous medium may contain zinc ions, for example added as zinc acetate or zinc chloride, buffers and preservatives.
- Arginine may be added as Arg, HCI.
- the pH value of the preparation is adjusted to the desired value and may be between about 3 to about 8.5, between about 3 and about 5 or about 6.5 and about 7.5 depending on the isoelectric point, pi, of the insulin in question.
- HMWP high molecular weight protein
- monomer insulin aspart was performed on Waters insulin (300 x 7.8mm, part nr wat 201549) with an eluent containing 2.5M acetic acid, 4mM L-arginine and 20 %(V/V) acetonitrile at a flow rate of 1 ml/min. and 40 0 C.
- Detection was performed with a tuneable absorbance detector (Waters 486) at 276nm. Injection volume was 40 ⁇ l and a 600 ⁇ M human insulin standard. HMWP and concentration of the preparations were measured at each sampling point.
- Reverse phase chromatography Determination of the insulin aspart related impurities were performed on a UPLC system using a BEH RP C8 2.1 x 100mm column, particle size of 1 ,7 ⁇ m. Waters part no 186002878. with a flow rate of 0,5ml/min., at 40° C detection at 220nm. Elution was performed with a mobile phase consisting of the following:
- the amount of B28iso-aspartate, desamido and other related impurities were determined as absorbance area measured in percent of total absorbance area determined after elution of the preservatives.
- the RP-UPLC method is equivalent to the analytical method used for quality control of Novo Nordisk marketed insulin aspart pharmaceuticals.
- the PK/PD studies were performed on domestic female pigs, LYD cross-breed, weighing between 55 and 1 10kg.
- the pigs were catheterised into the jugular vein through an ear vein at least 2 days before start of the study.
- the last meal before the start of the study was served to the animals approx. 18 hours prior to the injection of the test preparation, and the animals had free access to water at all time during the fasting period and the test period.
- the test preparation was given subcutaneous on the lateral side of the neck.
- a blood sample was drawn prior dosing and at regular time intervals after dosing samples were drawn from the catheter and sampled into 1.5ml glass tubes pre-coated with heparin.
- the blood samples were kept in ice water until separation of plasma by centrifugation for 10min. 3000rpm at 4 0 C, which was done within the first 30 minutes.
- Plasma samples were stored at 4°C for short time (2-3 hours) or at -18°C for long term storage and were analysed for glucose on YSI or Konelab 3Oi and for insulin Aspart concentration by LOCI.
- LOCI Luminescent Oxygen Channeling Immunoassay
- the insulin Aspart LOCI is a monoclonal antibody-based sandwich immunoassay and applies the proximity of two beads, the europium-coated acceptor beads and the streptavidin coated donor-beads.
- the acceptor beads were coated with a specific antibody against human insulin and recognize insulin Aspart in plasma samples.
- a second biotinylated antibody bind specific to insulin Aspart and together with the streptavidin coated beads, they make up the sandwich. Illumination of the beads-aggregate-immunocomplex releases singlet oxygen from the donor beads which channels into the acceptor beads and triggers chemilumines- cence. The chemiluminescence was measured and the amount of light generated is proportional to the concentration of insulin Aspart.
- Thioflavin T is such a probe and has a distinct fluorescence signature when binding to fibrils [Naiki et al. (1989) Anal. Biochem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284].
- the time course for fibril formation can be described by a sigmoidal curve with the following expression [Nielsen et al. (2001) Biochemistry 40, 6036-6046]:
- F is the ThT fluorescence at the time t.
- t 0 is the time needed to reach 50% of maximum fluorescence.
- Lag-time t Q - 2 ⁇ Formation of a partially folded intermediate of the peptide is suggested as a general initiating mechanism for fibrillation. Few of those intermediates nucleate to form a template onto which further intermediates may assembly and the fibrillation proceeds.
- the lag-time corresponds to the interval in which the critical mass of nucleus is built up and the apparent rate constant is the rate with which the fibril itself is formed.
- Sample aliquots of 200 ⁇ l were placed in a 96 well microtiter plate (Packard Opti- PlateTM-96, white polystyrene). Usually, four or eight replica of each sample (corresponding to one test condition) were placed in one column of wells. The plate was sealed with Scotch Pad (Qiagen).
- the measurement points were saved in Microsoft Excel format for further processing and curve drawing and fitting was performed using GraphPad Prism.
- the background emission from ThT in the absence of fibrils was negligible.
- the data points are typically a mean of four or eight samples and shown with standard deviation error bars. Only data obtained in the same experiment (i.e. samples on the same plate) are presented in the same graph ensuring a relative measure of fibrillation between experiments.
- the data set may be fitted to Eq. (1). However, since full sigmodial curves are not always achieved during the measurement time, lag times were here visually determined from the ThT fluorescence curve as the time point at which the ThT fluorescence is different than the background level.
- the peptide concentration in each of the tested formulations were measured both before application in the ThT fibrillation assay ("Initial") and after completion of the ThT fibrillation ("After ThT assay”). Concentrations were determined by reverse HPLC methods using a pramlin- tide standard as a reference. Before measurement after completion 150 ⁇ l was collected from each of the replica and transferred to an Eppendorf tube. These were centrifuged at 30000 G for 40mins. The supernatants were filtered through a 0.22 ⁇ m filter before application on the HPLC system.
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Abstract
Description
Claims
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
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CA2764423A CA2764423A1 (en) | 2009-06-26 | 2010-06-25 | Preparation comprising insulin, nicotinamide and an amino acid |
JP2012516763A JP5669834B2 (en) | 2009-06-26 | 2010-06-25 | Formulation containing insulin, nicotinamide and amino acid |
MX2011012764A MX2011012764A (en) | 2009-06-26 | 2010-06-25 | Preparation comprising insulin, nicotinamide and an amino acid. |
DK10730134.3T DK2340033T3 (en) | 2009-06-26 | 2010-06-25 | Composition comprising insulin, nicotinamide and arginine |
CN201080029548.9A CN102470165B (en) | 2009-06-26 | 2010-06-25 | Preparation comprising insulin, nicotinamide and an amino acid |
RU2012100397A RU2533217C3 (en) | 2009-06-26 | 2010-06-25 | PREPARATION CONTAINING INSULIN, NICOTINAMIDE AND AMINO ACID |
PL10730134T PL2340033T3 (en) | 2009-06-26 | 2010-06-25 | PREPARATION COMPRISING INSULIN, NICOTINAMIDE AND Arginine |
AU2010264636A AU2010264636B2 (en) | 2009-06-26 | 2010-06-25 | Preparation comprising insulin, nicotinamide and an amino acid |
EP10730134.3A EP2340033B1 (en) | 2009-06-26 | 2010-06-25 | PREPARATION COMPRISING INSULIN, NICOTINAMIDE AND Arginine |
BRPI1014760A BRPI1014760B8 (en) | 2009-06-26 | 2010-06-25 | preparation comprising insulin, nicotinamide and arginine |
KR1020127000115A KR101775000B1 (en) | 2009-06-26 | 2010-06-25 | Preparation comprising insulin, nicotinamide and an amino acid |
ES10730134.3T ES2440289T3 (en) | 2009-06-26 | 2010-06-25 | Preparation comprising insulin, nicotinamide and arginine |
IL216520A IL216520A (en) | 2009-06-26 | 2011-11-22 | Preparation comprising insulin, nicotinamide and an amino acid |
US13/309,134 US8324157B2 (en) | 2009-06-26 | 2011-12-01 | Preparation comprising insulin, nicotinamide and an amino acid |
ZA2011/08942A ZA201108942B (en) | 2009-06-26 | 2011-12-06 | Preparation comprising insulin, nicotinamide and an amino acid |
US14/223,408 US20140206610A1 (en) | 2009-06-26 | 2014-03-24 | Preparation Comprising Insulin, Nicotinamide and an Amino Acid |
US14/658,358 US20150182595A1 (en) | 2009-06-26 | 2015-03-16 | Preparation Comprising Insulin, Nicotinamide and an Amino Acid |
NO2017031C NO2017031I1 (en) | 2009-06-26 | 2017-07-06 | insulin aspart |
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EP09163940 | 2009-06-26 | ||
EP09163940.1 | 2009-06-26 | ||
US22216809P | 2009-07-01 | 2009-07-01 | |
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US13/309,134 Continuation US8324157B2 (en) | 2009-06-26 | 2011-12-01 | Preparation comprising insulin, nicotinamide and an amino acid |
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WO2010149772A1 true WO2010149772A1 (en) | 2010-12-29 |
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US (4) | US8324157B2 (en) |
EP (2) | EP2612677B1 (en) |
JP (2) | JP5669834B2 (en) |
KR (1) | KR101775000B1 (en) |
CN (2) | CN104667264B (en) |
AU (1) | AU2010264636B2 (en) |
BR (1) | BRPI1014760B8 (en) |
CA (1) | CA2764423A1 (en) |
DK (2) | DK2612677T3 (en) |
ES (2) | ES2440289T3 (en) |
HU (2) | HUE027239T2 (en) |
IL (1) | IL216520A (en) |
MX (1) | MX2011012764A (en) |
NO (1) | NO2017031I1 (en) |
PL (2) | PL2612677T3 (en) |
PT (2) | PT2612677E (en) |
RU (1) | RU2533217C3 (en) |
TW (1) | TWI459962B (en) |
WO (1) | WO2010149772A1 (en) |
ZA (1) | ZA201108942B (en) |
Cited By (35)
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Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0055945A2 (en) | 1981-01-02 | 1982-07-14 | Genentech, Inc. | Human proinsulin and analogs thereof and method of preparation by microbial polypeptide expression and conversion thereof to human insulin |
EP0163529A1 (en) | 1984-05-30 | 1985-12-04 | Novo Nordisk A/S | Insulin precursors, process for their preparation and process for preparing human insulin from such insulin precursors |
EP0347845A2 (en) | 1988-06-20 | 1989-12-27 | Novo Nordisk A/S | Insulin precursors, their preparation, and DNA sequences, expression vehicles and primers and a process for producing human insulin and analogues |
WO1991009617A1 (en) | 1989-12-21 | 1991-07-11 | Novo Nordisk A/S | Insulin preparations containing nicotinic acid or nicotinamide |
US5395922A (en) | 1989-03-03 | 1995-03-07 | Novo Nordisk A/S | Yeast processing system |
WO1995016708A1 (en) | 1993-12-17 | 1995-06-22 | Novo Nordisk A/S | Proinsulin-like compounds |
WO1996010417A1 (en) | 1994-10-04 | 1996-04-11 | Novo Nordisk A/S | PREPARATIONS CONTAINING AspB28 HUMAN INSULIN AND NICOTINAMIDE |
EP0741188A2 (en) | 1995-05-05 | 1996-11-06 | Eli Lilly And Company | Single chain insulin with high bioactivity |
EP0765395A1 (en) | 1994-06-17 | 1997-04-02 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
US5962267A (en) | 1995-02-15 | 1999-10-05 | Hanil Synthetic Fiber Co., Ltd. | Proinsulin derivative and process for producing human insulin |
US6500645B1 (en) | 1994-06-17 | 2002-12-31 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
EP1283051A1 (en) * | 1997-06-13 | 2003-02-12 | Eli Lilly And Company | Stable insulin formulations |
WO2008034881A1 (en) | 2006-09-22 | 2008-03-27 | Novo Nordisk A/S | Protease resistant insulin analogues |
WO2008037735A1 (en) | 2006-09-27 | 2008-04-03 | Novo Nordisk A/S | Method for making maturated insulin polypeptides |
WO2009021955A1 (en) * | 2007-08-13 | 2009-02-19 | Novo Nordisk A/S | Rapid acting insulin analogues |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4205126A (en) * | 1978-01-01 | 1980-05-27 | Cartaya Oscar A | Serum-free cell culture media |
JPS5885815A (en) * | 1981-10-30 | 1983-05-23 | ノボ・インダストリ・アクテイ−ゼルスカブ | Stabilized insulin medicine |
DE3313386A1 (en) * | 1983-04-13 | 1984-10-18 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V., 8000 München | METHOD FOR PRODUCING INFLAMMABLE, THERMALLY INSULATING SHAPED BODIES FROM FLOWED PERLITE |
RU2175556C2 (en) * | 1994-03-07 | 2001-11-10 | Инхейл Терапьютик Системз | Methods and compositions for light delivery of insulin |
US6043092A (en) * | 1996-03-18 | 2000-03-28 | University Of Pittsburgh | Cell culture media for mammalian cells |
US5866538A (en) | 1996-06-20 | 1999-02-02 | Novo Nordisk A/S | Insulin preparations containing NaCl |
CO4750643A1 (en) * | 1997-06-13 | 1999-03-31 | Lilly Co Eli | STABLE FORMULATION OF INSULIN CONTAINING L-ARGININ AND PROTAMINE |
WO2001052937A1 (en) * | 2000-01-24 | 2001-07-26 | Medtronic Minimed, Inc. | Mixed buffer system for stabilizing polypeptide formulations |
US6573237B2 (en) | 2001-03-16 | 2003-06-03 | Eli Lilly And Company | Protein formulations |
DE10114178A1 (en) * | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinc-free and low-zinc insulin preparations with improved stability |
JP2005508895A (en) * | 2001-08-28 | 2005-04-07 | イーライ・リリー・アンド・カンパニー | Premix of GLP-1 and basal insulin |
US7115563B2 (en) | 2002-05-29 | 2006-10-03 | Insignion Holding Limited | Composition and its therapeutic use |
US20050232974A1 (en) | 2004-04-19 | 2005-10-20 | Gore Makarand P | System and a method for pharmaceutical dosage preparation using jettable microemulsions |
AU2007238114B2 (en) | 2006-04-12 | 2010-10-14 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
EA016926B1 (en) | 2006-12-15 | 2012-08-30 | Тима Фаундейшн | Compositions for prophylaxis anf treatment of hyperglycemia |
ES2440289T3 (en) * | 2009-06-26 | 2014-01-28 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and arginine |
-
2010
- 2010-06-25 ES ES10730134.3T patent/ES2440289T3/en active Active
- 2010-06-25 MX MX2011012764A patent/MX2011012764A/en active IP Right Grant
- 2010-06-25 RU RU2012100397A patent/RU2533217C3/en active Protection Beyond IP Right Term
- 2010-06-25 WO PCT/EP2010/059069 patent/WO2010149772A1/en active Application Filing
- 2010-06-25 PT PT131589608T patent/PT2612677E/en unknown
- 2010-06-25 JP JP2012516763A patent/JP5669834B2/en active Active
- 2010-06-25 CN CN201410659076.5A patent/CN104667264B/en active Active
- 2010-06-25 CN CN201080029548.9A patent/CN102470165B/en active Active
- 2010-06-25 PT PT107301343T patent/PT2340033E/en unknown
- 2010-06-25 EP EP20130158960 patent/EP2612677B1/en active Active
- 2010-06-25 AU AU2010264636A patent/AU2010264636B2/en active Active
- 2010-06-25 PL PL13158960T patent/PL2612677T3/en unknown
- 2010-06-25 HU HUE13158960A patent/HUE027239T2/en unknown
- 2010-06-25 PL PL10730134T patent/PL2340033T3/en unknown
- 2010-06-25 BR BRPI1014760A patent/BRPI1014760B8/en active IP Right Grant
- 2010-06-25 ES ES13158960.8T patent/ES2543705T3/en active Active
- 2010-06-25 EP EP10730134.3A patent/EP2340033B1/en active Active
- 2010-06-25 DK DK13158960.8T patent/DK2612677T3/en active
- 2010-06-25 KR KR1020127000115A patent/KR101775000B1/en active Protection Beyond IP Right Term
- 2010-06-25 DK DK10730134.3T patent/DK2340033T3/en active
- 2010-06-25 CA CA2764423A patent/CA2764423A1/en not_active Withdrawn
- 2010-06-28 TW TW099121012A patent/TWI459962B/en active
-
2011
- 2011-11-22 IL IL216520A patent/IL216520A/en active IP Right Grant
- 2011-12-01 US US13/309,134 patent/US8324157B2/en active Active
- 2011-12-06 ZA ZA2011/08942A patent/ZA201108942B/en unknown
-
2012
- 2012-11-07 US US13/671,034 patent/US20130281364A1/en not_active Abandoned
-
2014
- 2014-03-24 US US14/223,408 patent/US20140206610A1/en not_active Abandoned
- 2014-11-04 JP JP2014223915A patent/JP6026485B2/en active Active
-
2015
- 2015-03-16 US US14/658,358 patent/US20150182595A1/en not_active Abandoned
-
2017
- 2017-06-06 HU HUS1700027C patent/HUS1700027I1/en unknown
- 2017-07-06 NO NO2017031C patent/NO2017031I1/en unknown
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0055945A2 (en) | 1981-01-02 | 1982-07-14 | Genentech, Inc. | Human proinsulin and analogs thereof and method of preparation by microbial polypeptide expression and conversion thereof to human insulin |
EP0163529A1 (en) | 1984-05-30 | 1985-12-04 | Novo Nordisk A/S | Insulin precursors, process for their preparation and process for preparing human insulin from such insulin precursors |
EP0347845A2 (en) | 1988-06-20 | 1989-12-27 | Novo Nordisk A/S | Insulin precursors, their preparation, and DNA sequences, expression vehicles and primers and a process for producing human insulin and analogues |
US5395922A (en) | 1989-03-03 | 1995-03-07 | Novo Nordisk A/S | Yeast processing system |
WO1991009617A1 (en) | 1989-12-21 | 1991-07-11 | Novo Nordisk A/S | Insulin preparations containing nicotinic acid or nicotinamide |
WO1995016708A1 (en) | 1993-12-17 | 1995-06-22 | Novo Nordisk A/S | Proinsulin-like compounds |
EP0765395A1 (en) | 1994-06-17 | 1997-04-02 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
US6500645B1 (en) | 1994-06-17 | 2002-12-31 | Novo Nordisk A/S | N-terminally extended proteins expressed in yeast |
WO1996010417A1 (en) | 1994-10-04 | 1996-04-11 | Novo Nordisk A/S | PREPARATIONS CONTAINING AspB28 HUMAN INSULIN AND NICOTINAMIDE |
US5962267A (en) | 1995-02-15 | 1999-10-05 | Hanil Synthetic Fiber Co., Ltd. | Proinsulin derivative and process for producing human insulin |
EP0741188A2 (en) | 1995-05-05 | 1996-11-06 | Eli Lilly And Company | Single chain insulin with high bioactivity |
EP1283051A1 (en) * | 1997-06-13 | 2003-02-12 | Eli Lilly And Company | Stable insulin formulations |
WO2008034881A1 (en) | 2006-09-22 | 2008-03-27 | Novo Nordisk A/S | Protease resistant insulin analogues |
WO2008037735A1 (en) | 2006-09-27 | 2008-04-03 | Novo Nordisk A/S | Method for making maturated insulin polypeptides |
WO2009021955A1 (en) * | 2007-08-13 | 2009-02-19 | Novo Nordisk A/S | Rapid acting insulin analogues |
Non-Patent Citations (5)
Title |
---|
CHAN ET AL., PNAS, vol. 78, 1981, pages 5401 - 5404 |
LEVINE, METHODS. ENZYMOL., vol. 309, 1999, pages 274 - 284 |
NAIKI ET AL., ANAL. BIOCHEM., vol. 177, 1989, pages 244 - 249 |
NIELSEN ET AL., BIOCHEMISTRY, vol. 40, 2001, pages 6036 - 6046 |
THIM ET AL., PNAS, vol. 83, 1986, pages 6766 - 6770 |
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