WO2015052088A1 - Novel derivative of an insulin analogue - Google Patents
Novel derivative of an insulin analogue Download PDFInfo
- Publication number
- WO2015052088A1 WO2015052088A1 PCT/EP2014/071236 EP2014071236W WO2015052088A1 WO 2015052088 A1 WO2015052088 A1 WO 2015052088A1 EP 2014071236 W EP2014071236 W EP 2014071236W WO 2015052088 A1 WO2015052088 A1 WO 2015052088A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- insulin
- hexamer
- frequently
- diabetes
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class 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 description 226
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Inorganic materials [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000012906 subvisible particle Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention provides a novel derivative of an analogue of human insulin, useful for the treatment of diabetes.
- Insulin is a polypeptide hormone secreted by ⁇ -cells of the pancreas.
- Insulin consists of two polypeptide chains designated the A and B chains which are linked together by two inter-chain disulphide bridges.
- the A and B chains contains 21 and 30 amino acid residues, respectively.
- the widespread use of genetic engineering has made it possible to prepare analogues of natural occurring insulins by exchanging, deleting and adding one or more of the amino acid residues.
- Insulin is used for the treatment of diabetes and diseases connected therewith or resulting from it.
- 2009/1 15469 relates to certain acylated protease stabilised insulins wherein at least one hydrophobic amino acid has been substituted with hydrophilic amino acids.
- the object of this invention is to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
- Another aspect of this invention relates to the furnishing of insulin derivatives with long pharmacokinetic (hereinafter PK) profiles, e.g. so that a subcutaneous treatment once a week or more seldom will be a satisfactory treatment of the diabetic patient's need for basal insulin treatment.
- PK pharmacokinetic
- Another aspect of this invention relates to the furnishing of insulin derivatives with long PK profiles, e.g. PK profiles being longer than the PK profile of human insulin, after subcutaneous administration.
- the PK profile can be determined as explained in Examples 5 and 6 herein.
- Another aspect of this invention relates to the furnishing of insulin derivatives having a high solubility in an aqueous medium optionally containing zinc, e.g. a solubility which is higher than the solubility of human insulin.
- the solubility can be determined as explained in Example 7 herein.
- Another aspect of this invention relates to the furnishing of insulin derivatives which are soluble in an aqueous medium containing zinc, such as at least 5 zinc ions per insulin hexamer, when measured after storage at least 4 weeks at 37°C or below after preparation.
- the solubility may e.g. be determined as explained in Example 7 herein.
- Another aspect of this invention relates to the furnishing of insulin derivatives which are soluble in an aqueous medium containing zinc, such as at least 5 zinc ions per insulin hexamer, when measured within 24-48 hours after preparation.
- the solubility may be determined as explained in Example 7 herein.
- Another aspect of this invention relates to the furnishing of insulin derivatives having good stability against enzymes, e.g. proteolytic enzymes, e.g. proteolytic enzymes present in the human stomach, e.g. pepsin, chymotrypsin and carboxypeptidase A.
- enzymes e.g. proteolytic enzymes, e.g. proteolytic enzymes present in the human stomach, e.g. pepsin, chymotrypsin and carboxypeptidase A.
- the stability against enzymes can be determined as explained in Example 1 of WO 2008/034881 .
- Another aspect of this invention relates to the furnishing of insulin derivatives having good stability, especially chemical stability and physical stability, at storage, e.g. storage at 5°C and at 30°C, for e.g. 2 years and for 2 weeks, respectively.
- the chemical stability can be determined as explained in Examples 9 and 10 herein and the physical stability can be determined as explained in Examples 9 and 10 herein.
- Another aspect of this invention relates to the furnishing of insulin derivatives which can efficiently be administered orally, e.g. once daily, to diabetic patients. Also, or alternatively, this invention relates to the furnishing of insulin derivatives which have a high oral bioavailability.
- Another aspect of this invention relates to the furnishing of insulin derivatives having reduced daily fluctuations, e.g. variations between plasma concentrations (C ma x and Cmin) following, e.g. once weekly subcutaneously administration.
- Another aspect of this invention relates to the furnishing of insulin derivatives having reduced influence on the day-to-day variation in bioavailability following oral administration.
- Another aspect of this invention relates to the furnishing of insulin derivatives having high potency, i.e. evoke a large response at low drug concentration, (drug activity expressed in terms of the amount required to produce an effect of given intensity).
- Another aspect of this invention relates to the furnishing of insulin derivatives that bind very well to the insulin receptor.
- the insulin receptor affinity can be determined as explained in Example 2 herein.
- Another aspect of this invention relates to the furnishing of insulin derivatives having a low insulin receptor affinity.
- the insulin receptor affinity can be determined as explained in Example 2 herein.
- diabetes or "diabetes mellitus” includes type 1 diabetes, type 2 diabetes, gestational diabetes (during pregnancy) and other states that cause
- hyperglycaemia hyperglycaemia.
- the term is used for a metabolic disorder in which the pancreas produces insufficient amounts of insulin, or in which the cells of the body fail to respond appropriately to insulin thus preventing cells from absorbing glucose. As a result, glucose builds up in the blood.
- Type 1 diabetes also called insulin-dependent diabetes mellitus (IDDM) and juvenile-onset diabetes
- IDDM insulin-dependent diabetes mellitus
- 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
- the naming of the insulins is done according to the following principles: The names are given as mutations and modifications (acylations) relative to human insulin. For the naming of the acyl moiety, the naming is done according to lUPAC nomenclature and in other cases as peptide nomenclature. For example, naming the acyl moiety:
- eicosanedioyl-yGlu-OEG-OEG can for example be named "eicosanedioyl-yGlu-OEG-OEG", “eicosanedioyl-yGlu-2xOEG” or, “eicosanedioyl-gGlu-2xOEG” or "19-carboxynonadecanoyl-yGlu-OEG-OEG", wherein OEG is short hand notation for the amino acid N ⁇ C ⁇ OtC ⁇ OC ⁇ CO ⁇ H, [2-(2- aminoethoxy)ethoxy]acetic acid and yGlu (and gGlu) is short hand notation for the amino acid gamma glutamic acid in the L-configuration.
- the acyl moiety may be named according to lUPAC nomenclature (OpenEye, lUPAC style). According to this nomenclature, the above acyl moiety of the invention is assigned the following name: [2-[2- [2-[[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]ethoxy]- ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl].
- the insulin of Example 1 (with the sequence/structure given below) is named "A14E, B16E, B25H, B29K(/ ⁇ fEicosanedioyl-gGlu-2xOEG), desB30 human insulin” to indicate that the amino acid in position A14, Y in human insulin, has been mutated to E, the amino acid in position B16, Y in human insulin, has been mutated to E, the amino acid in position B25, F in human insulin, has been mutated to H, the amino acid in position B29, K as in human insulin, has been modified by acylation on the epsilon nitrogen in the lysine residue of B29, denoted ⁇ , by the residue eicosanedioyl-gGlu-2xOEG, and the amino acid in position B30, T in human insulin, has been deleted.
- the insulins of the invention may be named according to lUPAC nomenclature (OpenEye, lUPAC style).
- the insulin of Example 1 i.e. Compound 1
- the insulin of Example 1 is assigned the following name: N ⁇ Epsilon-B29 ⁇ -[2-[2-[[2-[[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoyl amino)butanoyl]amino]ethoxy]- ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[GluA14,GluB16,HisB25],des-ThrB30- Insulin(human).
- This invention relates to a derivative of an insulin analogue, i.e. A14E, B16E, B25H, B29K(N(eps)eicosanedioyl-gGlu-2xOEG), desB30 human insulin (Compound 1 ).
- B29K(N(eps)eicosanedioyl-gGlu-2xOEG), desB30 human insulin fulfils the above objects to a sufficient degree.
- Compound 1 has a high solubility in an aqueous medium optionally containing zinc.
- Compound 1 has a solubility which is higher than the solubility of human insulin.
- Compound 1 is soluble in an aqueous medium containing zinc such as at least 5 zinc ions per insulin hexamer, at least 6 zinc ions per insulin hexamer, at least 7 zinc ions per insulin hexamer, at least 8 zinc ions per insulin hexamer or at least 9 zinc ions per insulin hexamer, wherein the solubility is measured after storage at least 4 weeks at 37°C or below after preparation.
- zinc such as at least 5 zinc ions per insulin hexamer, at least 6 zinc ions per insulin hexamer, at least 7 zinc ions per insulin hexamer, at least 8 zinc ions per insulin hexamer or at least 9 zinc ions per insulin hexamer, wherein the solubility is measured after storage at least 4 weeks at 37°C or below after preparation.
- Compound 1 is soluble in an aqueous medium containing zinc such as at least 5 zinc ions per insulin hexamer, at least 6 zinc ions per insulin hexamer, at least 7 zinc ions per insulin hexamer, at least 8 zinc ions per insulin hexamer, at least 9 zinc ions per insulin hexamer, at least 10 zinc ions per insulin hexamer, at least 1 1 zinc ions per insulin hexamer or at least 12 zinc ions per insulin hexamer, wherein the solubility is measured within 24-48 hours after preparation.
- zinc such as at least 5 zinc ions per insulin hexamer, at least 6 zinc ions per insulin hexamer, at least 7 zinc ions per insulin hexamer, at least 8 zinc ions per insulin hexamer, at least 9 zinc ions per insulin hexamer, at least 10 zinc ions per insulin hexamer, at least 1 1 zinc ions per insulin hexamer or at least 12 zinc
- the solubility is determined as explained in Example 7 herein.
- compositions containing Compound 1 can be prepared in a manner known per se, i.e., by using the excipients usually used in similar insulin compositions.
- Injectable pharmaceutical compositions containing Compound 1 can be prepared using conventional techniques of the pharmaceutical industry which involve dissolving and mixing the ingredients as appropriate to give the desired end product.
- Compound 1 is dissolved in an amount of water which is somewhat less than the final volume of the pharmaceutical composition 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.
- an insulin preparation of this invention may be prepared by dissolving Compound 1 in an aqueous medium at slightly acidic conditions.
- the aqueous medium is e.g. made isotonic by addition of a tonicity regulating agent.
- the aqueous medium may contain e.g. buffers, preservatives and zinc ions.
- the pH value of the solution is adjusted towards neutrality without getting too close to the isoelectric point of the compound of this invention in order to avoid potential precipitation.
- the pH value of the final insulin preparation depends upon the concentration of zinc ions, and the concentration of the compound of this invention.
- the insulin preparation is made sterile, for example, by sterile filtration.
- a pharmaceutical composition may contain one or more excipients.
- excipient broadly refers to any component other than the active therapeutic ingredient(s).
- the excipient may be an inert substance, an inactive substance, and/or a not medicinally active substance.
- the excipient may serve various purposes depending on the pharmaceutical composition, e.g. as a carrier, vehicle, diluent, tablet aid, and/or to improve administration, and/or absorption of the active substance.
- excipients include, but is not limited to, diluents, buffers, preservatives, tonicity regulating agents (also known as tonicity agents or isotonic agents), chelating agents, surfactants, protease inhibitors, wetting agents, emulsifiers, antioxidants, bulking agents, metal ions, oily vehicles, proteins and/or a zwitterion and stabilisers.
- compositions of pharmaceutically active ingredients with various excipients is known in the art, see e.g. Remington: The Science and Practice of Pharmacy (e.g. 19 th edition (1995), and any later editions).
- the insulin compositions are administered to the patients in a manner known per se, e.g. according to the general knowledge of the patient combined with the general knowledge of the physician.
- This invention is best used at the convenience of the patient. Therefore, specific administration intervals will be explored for each patient where dosages are administered less than daily.
- the final mode of use thus depends both on the product's capabilities and on the disposition and preference of the patient. This is due to the fact that the effect of any insulin product depends on the insulin need of the individual patient and the sensitivity to the pharmacodynamic actions of said insulin and lastly also to the preferences of the patient in a given situation. These conditions may change over time, both in terms of longer periods (years) and from day to day.
- the optimal dose level for any patient will depend on a variety of factors including the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the state to be treated. It is recommended that the dosage regimen be determined for each individual patient by those skilled in the art in a similar way as for known insulin compositions, however taking into consideration the present teachings concerning dosage intervals.
- the time interval (time lag) from the administration of Compound 1 to the next administration of Compound 1 has the same length, or approximately the same length, counted in number of days. It can even be expected that the patients will prefer that the administration of Compound 1 takes place once weekly, i.e., on the same day in the week, e.g. every Sunday. This will be an administration of Compound 1 every 7 th day and not more frequently on an average calculated for a period of time of 1 month, 6 months or 1 year. For some patients, it may be desirable to administer Compound 1 every 6 th day or approximately every 6 th day and not more frequently on an average calculated for a period of time of 1 month, 6 months or 1 year. For other patients, it may be desirable to administer Compound 1 every 5 th day or
- Compound 1 For other patients, it may be desirable to administer Compound 1 every 2 nd day or approximately every 2 nd day and not more frequently on an average calculated for a period of time of 1 month, 6 months or 1 year. For some patients, it may be desirable to administer Compound 1 every 8 th day or approximately every 8 th day and not more frequently on an average calculated for a period of time of 1 month, 6 months or 1 year. Even other patients may not administer Compound 1 with a time interval of precisely the same length (counted in days), week after week, month after month or year after year. Some patients may administer Compound 1 sometime in the time interval from every 6 th to every 8 day on an average calculated for a period of time of 1 month, 6 months or 1 year and not more frequently.
- Other patients may administer Compound 1 sometime in the time interval from every 5 th to every 7 th day on an average calculated for a period of time of 1 month, 6 months or 1 year and not more frequently. Even other patients may administer Compound 1 sometime in the time interval from every 4 th to every 8 th day on an average calculated for a period of time of 1 month, 6 months or 1 year and not more frequently.
- the time intervals mentioned here are to be understood as average time intervals within a period of time of say weeks, months or years.
- day covers 24 hours (i.e., a day and night) and, for the sake of easiness, a number of hours which is not divisible by 24 is to be rounded up to a whole number of days. Hence, e.g. 30 hours corresponds to 1 day and 40 hours corresponds to 2 days.
- the above mentioned administrations are parenterally.
- the patients may have a daily basal insulin requirement of above about 0.2 lU/kg body weight/day and below about 1 lU/kg body weight/day and, furthermore, the patients may have a total (i.e., basal plus prandial) daily insulin requirement of above about 1 lU/kg body weight/day.
- basal plus prandial daily insulin requirement
- diabetes mellitus type 1 or 2
- metabolic diseases and conditions in general where the metabolic effects of insulin has a clinical relevance or are of interest, such as pre-diabetes, impaired glucose tolerance, metabolic syndrome, obesity, cachexia, in vivo beta-cell loss/death, excessive appetite, and
- any therapeutic regimen where administration of insulin is included may be modified by implementing the current teachings, meaning that such therapies will include administration of prolonged-profile- of-action insulins according to the teachings provided herein.
- Compound 1 may be administered parenterally to patients in need of such a treatment.
- Parenteral administration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen- like syringe.
- parenteral administration can be performed by means of an infusion pump.
- Further options are to administer the insulin composition orally, nasally or pulmonary, preferably in pharmaceutical compositions, powders or liquids, specifically designed for the purpose in question.
- Compound 1 may be administered orally to patients in need of such a treatment.
- Oral administration may be performed by orally administering solid, semi-solid or liquid pharmaceutical compositions.
- Embodiments of the method of this invention include those wherein administration of Compound 1 is supplemented with more frequent administrations of a fast-acting naturally occurring insulin, insulin analogue or insulin derivative and/or administration of a non-insulin anti-diabetic drug.
- administration of Compound 1 is supplemented with administration of a non-insulin anti-diabetic drug, such as metformin.
- A14E, B16E, B25H, B29K(N(eps)eicosanedioyl-gGlu-2xOEG), desB30 human insulin (Compound 1 ).
- a pharmaceutical composition comprising Compound 1 .
- Compound 1 for use in the preparation of a pharmaceutical composition for the treatment or prevention of diabetes 4.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered to the same patient every 2 nd day or less frequently and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 3 rd day or less frequently, and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered twice a week or less frequently, and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 4 th day or less frequently, and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 5 th day or less frequently, and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes, wherein the compound is administered every 6 th day or less frequently and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered once weekly or less frequently and, on average, during a period of time of at least 1 month, 6 months or 1 year, said compound is not administered more frequently to the same patient.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 8 th day or more frequently.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 9 th day or more frequently.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 10 th day or more frequently.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 11 th day or more frequently.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 12 th day or more frequently.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 14 th day or more frequently.
- Compound 1 for use in the treatment of diabetes wherein the compound is administered every 21 st day or more frequently.
- a method of treatment or prevention of diabetes which method comprises administering to a subject in need thereof a therapeutically effective amount of Compound 1.
- An aqueous solution comprising Compound 1 and at least 5 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 6 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 7 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 8 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 9 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 10 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 1 1 zinc ions per insulin hexamer.
- An aqueous solution comprising Compound 1 and at least 12 zinc ions per insulin hexamer.
- a pharmaceutical composition comprising Compound 1 , and one more excipients.
- a pharmaceutical composition comprising Compound 1 , and one more excipients selected from the group consisting of diluents, buffers, preservatives, tonicity regulating agents, chelating agents, surfactants, protease inhibitors, wetting agents, emulsifiers, antioxidants, bulking agents, metal ions, oily vehicles, proteins and/or a zwitterion and stabilisers.
- composition according to clause 59 comprising at least 4.5 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 5 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 6 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 7 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 8 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 9 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 10 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 1 1 zinc ions per insulin hexamer.
- composition according to clause 59 comprising at least 12 zinc ions per insulin hexamer.
- pAla is beta-alanyl
- MeCN is acetonitrile
- Aoc is 8-aminooctanoic acid
- OEG is [2-(2- 10 tBu is iert-butyl; aminoethoxy)ethoxy]ethylcarbonyl;
- DCM dichloromethane
- DIC is diisopropylcarbodiimide; pyrrolidin-1-yl;
- DMSO dimethyl sulphoxide
- EtOAc is ethyl acetate
- RT room temperature
- Fmoc 9-fluorenylmethyloxy- TFA is trifluoroacetic acid
- THF is tetrahydrofuran
- yGlu is gamma L-glutamyl
- TNBS is 2,4,6-trinitrobenzene-
- DyGlu is gamma D- 40 sulfonic acid
- TRIS is tris(hydroxymethyl)-
- HCI is hydrochloric acid; aminomethane; and
- HOAc is acetic acid
- TSTU is 0-(/V-succinimidyl)-1
- HOBt is 1 -hydroxybenzotriazole
- tetramethyluronium tetrafluoroborate is 1 -hydroxybenzotriazole
- NMP is /V-methylpyrrolidone
- Insulin analogues are expressed as proinsulin-like fusion proteins, with an Ala-Ala-Lys mini C-peptide in Saccharomyces cerevisiae strain MT663.
- the single-chain precursors are enzymatically converted into two-chain desB30 analogues using A. lyticus endoprotease.
- Full conversion to the two-chain desB30 analogue is verified by MALDI-TOF MS, and its purity is measured by RP-HPLC at both acidic and neutral pH.
- the compound of the invention can be purified by employing one or more of the following procedures which are typical within the art. These procedures can - if needed - be modified with regard to gradients, pH, salts, concentrations, flow, columns and so forth. Depending on factors such as impurity profile, solubility of the insulin derivative in question etcetera, these modifications can readily be recognised and made by a person skilled in the art.
- the compounds After acidic HPLC or desalting, the compounds are isolated by lyophilisation of the pure fractions. After neutral HPLC or anion exchange chromatography, the compounds are desalted, precipitated at isoelectrical pH, or purified by acidic HPLC.
- the HPLC system is a Gilson system consisting of the following: Model 215 Liquid handler, Model 322-H2 Pump and a Model 155 UV Dector. Detection is typically at 210 nm and 280 nm.
- the Akta Purifier FPLC system (Amersham Biosciences) consists of the following: Model P-900 Pump, Model UV-900 UV detector, Model pH/C-900 pH and conductivity detector, Model Frac-950 Frction collector. UV detection is typically at 214 nm, 254 nm and 276 nm.
- Akta Explorer Air FPLC system (Amersham BioGE Health Caresciences) consists of the following: Model P-900 Pump, Model UV-900 UV detector, Model pH/C-900 pH and conductivity detector, Model Frac-950 Fraction collector. UV detection is typically at 214 nm, 254 nm and 276 nm.
- B buffer 15 mM TRIS, 500 mM Ammoniumacetat in 50% Ethanol, pH 7.5 (14 mS/cm)
- 19-((S)-1-carboxy-3- ⁇ 2-[2-( ⁇ 2-[2-(2,5-dioxopyrrolidin-1-yloxycarbonylmethoxy)- ethoxy]ethylcarbamoyl ⁇ methoxy)ethoxy]ethylcarbamoyl ⁇ propylcarbamoyl)nonadecanoic acid can be synthesised on solid support using procedures well known to skilled persons in the art of solid phase peptide synthesis.
- This procedure e.g. comprises attachment of a Fmoc protected amino acid to a polystyrene 2-chlorotritylchloride resin.
- the attachment can, e.g.
- the free N-protected amino acid in the presence of a tertiary amine, like triethyl amine or /V,/V-diisopropylethylamine (see references below).
- a tertiary amine like triethyl amine or /V,/V-diisopropylethylamine (see references below).
- the C-terminal end (which is attached to the resin) of this amino acid is at the end of the synthetic sequence being coupled to the parent insulins of the invention.
- the Fmoc group is deprotected using, e.g. secondary amines, like piperidine or diethyl amine, followed by coupling of another (or the same) Fmoc protected amino acid and deprotection.
- the synthetic sequence is terminated by coupling of a mono- ferf-butyl protected fatty (a, co) diacid, namely eicosanedioic acid mono-ferf-butyl ester.
- Cleavage of the compounds from the resin is accomplished using diluted acid like 0.5-5% TFA/DCM (trifluoroacetic acid in dichloromethane), acetic acid (e.g. 10% in DCM, or HOAc/triflouroethanol/DCM 1 :1 :8), or hecafluoroisopropanol in DCM (see e.g. "Organic Synthesis on Solid Phase", F.Z. Dorwald, Wiley-VCH, 2000. ISBN 3-527-29950-5;
- the acylation reagents 19-((S)-1 -carboxy-3- ⁇ 2-[2-( ⁇ 2-[2-(2,5-dioxo- pyrrolidin-1-yloxycarbonylmethoxy)ethoxy]ethylcarbamoyl ⁇ methoxy)ethoxy]ethylcarbamoyl ⁇ - propylcarbamoyl)nonadecanoic acid can be prepared by solution phase synthesis:
- the mono-ferf-butyl protected fatty diacid, eicosanedioic acid mono-ferf-butyl ester is activated, e.g. as OSu-ester as described below or as any other activated ester known to those skilled in the art, such as HOBt- or HOAt-ester.
- This active ester is coupled with glutamic acid oferf-butyl ester in a suitable solvent such as THF, DMF, NMP (or a solvent mixture) in the presence of a suitable base, such as DIPEA or triethylamine.
- the intermediate is isolated, e.g. by extractive procedures or by chromatographic procedures.
- the resulting intermediate is again subjected to activation (as described above) and to coupling with OEG-OEG ([2-(2- ⁇ 2-[2-(2-Amino-ethoxy)-ethoxy]-acetylamino ⁇ -ethoxy)- ethoxy]-acetic acid) as described above followed by activation with TSTU to afford the acylation reagent 19-((S)-1-carboxy-3- ⁇ 2-[2-( ⁇ 2-[2-(2,5-dioxopyrrolidin-1 -yloxycarbonyl- methoxy)ethoxy]ethylcarbamoyl ⁇ methoxy)ethoxy]ethylcarbamoyl ⁇ propylcarbamoyl)- nonadecanoic acid.
- the acylation reagent prepared by the above described methods may be ferf-butyl de-protected after activation as OSu ester. This may be done by TFA treatment of the OSu- activated ferf-butyl protected acylation reagent. After acylation of A14E,B16E,B25H,desB30 human insulin, the resulting unprotected acylated A14E,B16E,B25H,desB30 human insulin is obtained, e.g. as described in Example 1.
- acylation of A14E,B16E,B25H,desB30 human insulin affords the corresponding ferf-butyl protected acylated A14E,B16E,B25H,desB30 human insulin.
- the protected insulin is to be de-protected. This can be done by TFA treatment to afford unprotected acylated A14E,B16E,B25H,desB30 human insulin.
- the acylation reagent can be synthesised in solution using benzyl protection of the carboxylic acid groups as illustrated below.
- a Waters Micromass ZQ mass spectrometer was used to identify the mass of the sample after elution from a Waters Alliance HT HPLC system.
- Eicosanedioic acid ferf-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (6.01 g, 12.124 mmol) was dissolved in THF (150 mL) and mixed with a slurry of H-Glu-OtBu (2.71 g, 13.33 mmol) in DMF/water (1/1 , 40 mL). This resulted in a gel-like solution which was heated to give a clear solution that was stirred at RT for 3 hours. Then the solution was evaporated, 100 mL of water was added and the mixture was heated to 60°C which resulted in a solution which crystallised on cooling. The precipitate was re-crystallised from acetonitrile and the crystals were dried in vacuum. Yield 6.82 g (96%).
- acylation is preferably performed at alkaline pH (e.g. at pH 10, 10.5, or 1 1 ). This is illustrated in Example 1 herein.
- A14E, B16E, B25H, desB30 human insulin (3.0 g, 0.53 mmol) was dissolved in 150 mM aqueous Na 2 C0 3 (40 mL) and 5 mL THF was added. The pH value was adjusted to 1 1.0 with 1 M aqueous NaOH.
- the pH value was adjusted to 7.5 with 1 M HCI and 50% ethanol was added to a volume of 500 mL. The pH value was adjusted to 7.5. The conductivity was measured to 1 .6 mS/Cm.
- a buffer 15 mM TRIS, 50 mM ammonium acetate in 50% ethanol, pH 7.5 (1 .6 mS/cm)
- B buffer 15 mM TRIS, 500mM ammonium acetate in 50% ethanol, pH 7.5 (14 mS/cm)
- a buffer 15 mM TRIS, 50 mM ammonium acetate in 50% ethanol, pH 7.5 (1 .6 mS/cm)
- the product pool 300 mL, was diluted with 300 mL water and desalted on a C18 column:
- the product fraction was freeze dried to afford the TFA salt, which was dissolved in 50 mL water plus 10 mL acetonitrile and pH was adjusted to 8.0 with 0.5M aqueous NaOH and freeze dried to afford 1.25 g (36%) of the title insulin.
- the affinity of the acylated insulin analogues of this invention for the human insulin receptor is determined by a SPA assay (Scintillation Proximity Assay) microtiterplate antibody capture assay.
- SPA-PVT antibody-binding beads, anti-mouse reagent (Amersham Biosciences, Cat No. PRNQ0017) are mixed with 25 mL of binding buffer (100 mM HEPES pH 7.8; 100 mM sodium chloride, 10 mM MgS0 4 , 0.025% Tween-20). Reagent mix for a single Packard Optiplate (Packard No.
- 6005190 is composed of 2.4 ⁇ of a 1 :5000 diluted purified recombinant human insulin receptor (either with or without exon 1 1 ), an amount of a stock solution of A14Tyr[ 125 l]-human insulin corresponding to 5000 cpm per 100 ⁇ of reagent mix, 12 ⁇ of a 1 :1000 dilution of F12 antibody, 3 ml. of SPA-beads and binding buffer to a total of 12 ml_. A total of 100 ⁇ reagent mix is then added to each well in the Packard Optiplate and a dilution series of the insulin derivative is made in the Optiplate from appropriate samples. The samples are then incubated for 16 hours while gently shaken.
- the phases are the then separated by centrifugation for 1 min and the plates counted in a Topcounter.
- the binding data were fitted using the nonlinear regression algorithm in the GraphPad Prism 2.01 (GraphPad Software, San Diego, CA) and affinities are expressed relative (in percentage (%)) to the affinity of human insulin.
- binding buffer also contains 1.5%HSA in order to mimic physiological conditions.
- the hydrophobicity of an insulin derivative is found by reverse phase HPLC run under isocratic conditions.
- the elution time of the insulin derivative is compared to that of human insulin (herein designated HI) or another derivative with a known hydrophobicity under the same conditions.
- the void time of the HPLC system, t 0 is determined by injecting 5 ⁇ of 0.1 mM NaN0 3 .
- Buffer A 0.1 M natrium phosphate pH 7.3, 10 vol% CH 3 CN
- Buffer B 50 vol% CH 3 CN
- Run time Maximum 60 minutes After running an initial gradient, the isocratic level for running the derivative and reference (for example HI) is chosen, and the elution times of the derivative and reference under isocratic conditions are used in the above equation to calculate k'rel d env- Table 2
- Degradation of insulin analogues using duodenum lumen enzymes (prepared by filtration of duodenum lumen content) from SPD rats.
- the assay is performed by a robot in a 96 well plate (2ml_) with 16 wells available for insulin analogues and standards.
- Degradation half time is determined by exponential fitting of the data and normalized to half time determined for the reference insulins, A14E, B25H, desB30 human insulin or human insulin in each assay.
- the amount of enzymes added for the degradation is such that the half time for degradation of the reference insulin is between 60 minutes and 180 minutes.
- the result is given as the degradation half time for the insulin analogue in rat duodenum divided by the degradation half time of the reference insulin from the same experiment (relative degradation rate).
- Anaesthetized rats are dosed intravenously (i.v.) with insulin analogues at various doses and plasma concentrations of the test compound is measured using immunoassays or mass spectrometry at specified intervals for 4 hours or more post-dose. Pharmacokinetic parameters are subsequently calculated using WinNonLin Professional (Pharsight Inc., Mountain View, CA, USA).
- Non-fasted male Wistar rats (Taconic) weighing approximately 200 gram are used. Body weight is measured and rats are subsequently anaesthetized with Hypnorm/Dormicum (each compound is separately diluted 1 :1 in sterile water and then mixed; prepared freshly on the experimental day). Anaesthesia is initiated by 2 mL/kg Hypnorm/Doricum mixture sc followed by two maintenance doses of 1 mL/kg sc at 30 minutes intervals, and two maintenance doses of 1 mL/kg sc with 45 minutes intervals. If required in order to keep the rats lightly anaesthetised throughout a further dose(s) 1-2 mL/kg sc is supplied. Weighing and initial anaesthesia is performed in the rat holding room in order to avoid stressing the animals by moving them from one room to another.
- the objective of this protocol is to obtain pharmacokinetic (PK) data from plasma concentration-time profiles of different insulin analogues after intravenous administration to beagle dogs, and to calculate relevant pharmacokinetic parameters for the analogues.
- PK pharmacokinetic
- the animals had free access to domestic quality drinking water.
- the animals were weighed on each day of dosing.
- Each test substance was given to 3 animals. Consideration had been given to the welfare of individual animals in terms of the number and extent of procedures to be carried out on each animal.
- a full plasma concentration-time profile was obtained from each animal.
- the dogs were placed on a table and fixated by an animal technician sitting beside. This procedure was trained during the acclimatization period. Blood samples, 0.5 ml_, were collected into EDTA tubes according to the following schedule:
- Predose (-10, 0), and 5, 15, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 480, 600, 720, 960, 1440, 1920, 2880, 4320, 5760, 7200, 8640, 10080 minutes.
- the blood samples were taken from Venflon catheters in cephalic veins kept open with Heparin. saline.
- the other blood samples were taken from a jugular vein.
- Plasma concentration-time profiles were analyzed by a non-compartmental pharmacokinetics analysis using WinNonlin Professional (Pharsight Inc., Mountain View, CA, USA).
- Comparison compound in a composition without NaCI, is soluble under the tested conditions in presence of up to 12.5 zinc molecules per hexamer.
- Comparison Compound A in a composition with 20 mM NaCI, is soluble under the tested conditions in the presence of up to 10.5 molecules of zinc/hexamer.
- Compound 1 is soluble in a composition without NaCI under the tested conditions up to about 15.3 zinc hexamer insulin. Furthermore, Compound 1 is soluble with 20 mM NaCI under the tested conditions up to about 14.5 molecules of zinc per hexamer insulin.
- Example 8
- Human insulin is soluble in formulations containing up to 6 Zn/insulin hexamer when the formulation contains NaCI and up to 4 Zn/insulin hexamer when the formulation contains close to no NaCI.
- the aim of this experiment was to measure the chemical and physical stability of a formulation within the zinc/hexamer window determined by SEC experiments. Furthermore to test if the presence of sodium chloride affected the chemical and/or physical stability.
- Formulations contained: 3.6 mM of Compound 1 , 25 mM phenol, 25 mM cresol, pH 7.4. Zinc and sodium chloride as specified below. Table 8
- the formulation was prepared as follows:
- Compound 1 powder was dissolved in milli-Q water in a stock solution in about the double amount as the final concentration in the formulation. Phenol, cresol, zinc acetate, sodium chloride and glycerol was added in the mentioned order. The resulting solution had a pH about 7.8 and was adjusted to pH 7.4 using 0.2 N HCI, resulting in a final increase in chloride concentration of 1 .45 mM Chloride.
- TAT Thioflavin T
- DLS dynamic light scattering
- MFI Micro Flow Imaging
- HMWP High Molecular Weight Particles
- Lagtimes measured in hours in Thioflavin T assay Lag time to fibrillation increase as a function of zinc content in the formulation.
- Formulations containing more than 5.8 zn/ hexamer do not fibrillate and has thus a lag time higher than 45 hours.
- Diam Diameter (nm)
- the protein oligomer average size determined with DLS ranges from 3.8 nm (for a formulation with 5,8Zn/insulin hexamer, 20mM NaCI, at 37°C, after 2 weeks) to 5.95 nm (for a formulation with 10.5 Zn/insulin hexamer, 75 mM NaCI at 4°C, after 2 weeks).
- the hydrodynamic diameter decreases 1 % on average whereas it increased 1 and 4% for the samples stored at 37 and 45°C, respectively.
- all of the recorded auto-correlation functions were compatible with unimodal particle distributions, indicating rather narrow size distributions absent of any large aggregates.
- the formulations were analyzed for sub-visible particle formation in the micrometer range using Micro Flow Imaging (MFITM). Particle counts were generally low, and a large fraction of particles had a dark spherical appearance expected for silicone-oil droplets. However, large translucent flake-like particles appeared in formulations containing 10.5 Zn/hexamer and 150mM or 75mM after 2 weeks incubation at 45°C and 8 weeks at 37°C, respectively.
- MFITM Micro Flow Imaging
- Particle volume fractions (nL particles per mL sample volume) for the different formulations incubated for 2-20 weeks at 4°C, 30°C, 37°C or 45°C. Particles with
- the physical stability was measured as lag time in ThT assay as a function of zinc/hexamer increase with increasing zinc content from 5.8 to 8.1 Zn/insulin hexamer.
- Average oligomer size change as measured by DLS revealed no change in oligomer size and no aggregate formation in any of the formulations.
- Particle measurement as determined by MFI showed increase in particle formation in formulations containing 10.5 Zn/ hexamer and 75 mM NaCI.
- HMWP formation was measured using gelfiltration column in acetic acid free eluent as described in WO 2013/153000. HMWP for samples stored at 4°C was subtracted HMPW for samples stored at 30°C or 37°C.
- Formulations containing 5.8 Zn/ insulin hexamer has more HMWP development than formulations containing 8.1 Zn/ insulin hexamer or above.
- the formulations containing 5.8 Zn/insulin hexamer have the highest degradation.
- Formulations containing 8.1 Zn/insulin hexamer or more have lower degradation.
- the chemical stability is thus optimal in formulations with 8.1 .zinc/hexamer or more.
- the stability is higher in formulations containing 75 mM NaCI than in formulations containing 20 mM NaCI.
- the aim of this experiment was to investigate the oligomerisation by size exclusion chromatography as a function of NaCI content in the formulation containing comparative Compound A (i.e. N ⁇ Epsilon-B29 ⁇ -[2-[2-[2-[[2-[2-[2-[[[(4S)-4-carboxy-4-(19-carboxy- nonadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]- [GluA14, HisB16,HisB25],des-ThrB30-lnsulin(human); Alternative name: A14E, B16H, B25H, B29K(/ ⁇ / i: eicosanedioyl-gGlu-2xOEG), desB30 human insulin at 4.2 mM insulin and fixed zinc/insulin hexamer. Furthermore, the aim was to measure the physical and chemical stability.
- Compound A was dissolved in milli-Q water at a pH value of about 8. Phenol, cresol, zinc acetate (Zn) and glycerol were added in the mentioned order resulting in a final formulation containing: 4.5 Zn/ 6 insulins, 25 mM phenol, 25 mM cresol, pH 7.4 an insulin concentration of 4.2 mM and sodium chloride (NaCI), zinc acetate and glycerol as stated in the table below.
- Fibrillation tendency Measured by Thioflavin T assay. Fibrillation tendency was measured in Thioflavin T (THT) assay as lagtime to fibrillation. THT assay was measured as described on freshly prepared samples; and
- HMWP High Molecular Weight Protein
- HMWP was measured using HMWP Method 2 as described in WO 2013/153000. Formation of insulin related impurities like deamidation compounds was measured using reverse phase chromatography (UPLC).
- Amount of monomer was measured in native gel filtration using Method 2 as described in WO 2013/153000 in eluent without phenol.
- the amount of Compound A monomer decreases as a function of sodium chloride concentration with a large effect of addition of just up to 50 mM NaCI. Chemical degradation measured as HMWP formation and impurity formation is low in all formulations despite the monomeric content. THT lag times increase with zinc content and sodium chloride content.
- the hydrodynamic radius increases with increasing salt concentration.
- Zn concentration has a minor impact on size except at 7 Zn per insulin hexamer. No significant effect on oligomer size and physical stability from incubation temperature.
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KR1020167010201A KR20160065126A (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
ES14780512.1T ES2676065T3 (en) | 2013-10-07 | 2014-10-03 | New derivative of an insulin analog |
JP2016546167A JP6499184B2 (en) | 2013-10-07 | 2014-10-03 | Novel derivatives of insulin analogues |
BR112016007166A BR112016007166A2 (en) | 2013-10-07 | 2014-10-03 | derived from an insulin analog |
PL14780512T PL3055325T3 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
EP14780512.1A EP3055325B1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
SI201430644T SI3055325T1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
CA2926701A CA2926701A1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
RS20180322A RS57004B1 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
AU2014333979A AU2014333979B2 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue |
US15/023,872 US9896496B2 (en) | 2013-10-07 | 2014-10-03 | Derivative of an insulin analogue |
DK14780512.1T DK3055325T3 (en) | 2013-10-07 | 2014-10-03 | New derivative of an insulin analogue |
RU2016114098A RU2673185C2 (en) | 2013-10-07 | 2014-10-03 | Novel derivative of insulin analogue |
CN201480055375.6A CN105636979B (en) | 2013-10-07 | 2014-10-03 | Novel derivatives of insulin analogues |
MX2016004325A MX366636B (en) | 2013-10-07 | 2014-10-03 | Novel derivative of an insulin analogue. |
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SA516370893A SA516370893B1 (en) | 2013-10-07 | 2016-04-07 | Novel derivative of an insulin analogue |
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WO2018083335A1 (en) | 2016-11-07 | 2018-05-11 | Novo Nordisk A/S | Dchbs-active esters of peg compounds and their use |
WO2018109162A1 (en) * | 2016-12-16 | 2018-06-21 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
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CN111909255A (en) * | 2019-05-10 | 2020-11-10 | 宁波鲲鹏生物科技有限公司 | Insulin derivatives and process for preparing the same |
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CA2926701A1 (en) | 2015-04-16 |
SA516370893B1 (en) | 2018-08-13 |
CN105636979B (en) | 2020-01-10 |
RU2016114098A3 (en) | 2018-05-21 |
RU2673185C2 (en) | 2018-11-22 |
ES2676065T3 (en) | 2018-07-16 |
CN105636979A (en) | 2016-06-01 |
KR20160065126A (en) | 2016-06-08 |
RU2016114098A (en) | 2017-11-15 |
EP3055325A1 (en) | 2016-08-17 |
MX2016004325A (en) | 2016-07-11 |
IL244507A0 (en) | 2016-04-21 |
JP6499184B2 (en) | 2019-04-10 |
AU2014333979A1 (en) | 2016-03-24 |
DK3055325T3 (en) | 2018-04-16 |
HRP20180468T1 (en) | 2018-05-04 |
US20160215037A1 (en) | 2016-07-28 |
PT3055325T (en) | 2018-04-06 |
EP3055325B1 (en) | 2018-01-03 |
RS57004B1 (en) | 2018-05-31 |
JP2017502074A (en) | 2017-01-19 |
HUE036702T2 (en) | 2018-07-30 |
MX366636B (en) | 2019-07-17 |
SI3055325T1 (en) | 2018-05-31 |
BR112016007166A2 (en) | 2017-09-12 |
AU2014333979B2 (en) | 2018-02-15 |
US9896496B2 (en) | 2018-02-20 |
IL244507B (en) | 2018-05-31 |
PL3055325T3 (en) | 2018-06-29 |
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