Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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]
• • 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
  • A61K38/26—Glucagons
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

• the present invention relates to an aqueous pharmaceutical formulation comprising 200 - 1000 U/mL of insulin glulisine with improved stability, and its use in the treatment of type 1 diabetes mellitus or type 2 diabetes mellitus.
• type 1 diabetes the substitution of the lacking endocrine insulin secretion is the only currently possible therapy.
• the affected persons are dependent lifelong on insulin injections, as a rule a number of times daily.
• treatment with insulin optionally in combination with an oral antidiabetic, is regarded as the most favorable form of therapy.
• diabetic late complications such as microvascular and macrovascular damage which is manifested, under certain circumstances, as retinopathy, nephropathy or neuropathy and leads to loss of sight, kidney failure and the loss of extremities.
• diabetes is accompanied by an increased risk of cardiovascular diseases. It is to be derived from this that an improved therapy of diabetes is primarily to be aimed at keeping the blood glucose as closely as possible in the physiological range. According to the concept of intensified insulin therapy, this should be achieved by repeated daily injections of rapid- and slow-acting insulin preparations. Rapid-acting formulations are given at meals in order to level out the postprandial increase in the blood glucose. Slow- acting basal insulins should ensure the basic supply with insulin, in particular during the night, without leading to hypoglycemia.
• Insulin is a polypeptide of 51 amino acids, which are divided into 2 amino acid chains: the A chain having 21 amino acids and the B chain having 30 amino acids. The chains are connected to one another by means of 2 disulfide bridges. Insulin preparations have been employed for diabetes therapy for many years. Not only naturally occurring insulins are used here, but recently also insulin derivatives and analogs.
• the insulin preparations of naturally occurring insulins on the market for insulin substitution differ in the origin of the insulin (e.g. bovine, porcine, human insulin, or another mammalian or animal insulin), and also the composition, whereby the profile of action (onset of action and duration of action) can be influenced.
• the profile of action onset of action and duration of action
• very different profiles of action can be obtained and blood sugar values which are as physiological as possible can be established.
• Preparations of naturally occurring insulins, as well as preparations of insulin derivatives or insulin analogs which show modified kinetics have been on the market for some time.
• modified insulins include "monomeric insulin analogs” such as insulin lispro, insulin aspart, and HMR 1964 (Lys(B3), Glu(B29) human insulin, insulin glulisine), all of which have a rapid onset of action, as well as insulin glargin, which has a prolonged duration of action.
• monomeric insulin analogs such as insulin lispro, insulin aspart, and HMR 1964 (Lys(B3), Glu(B29) human insulin, insulin glulisine), all of which have a rapid onset of action, as well as insulin glargin, which has a prolonged duration of action.
• Stabilized insulin formulations having increased physical long-term stability are needed in particular for preparations which are exposed to particular mechanical stresses or relatively high temperatures. These include, for example, insulins in administration systems such as pens, inhalation systems, needleless injection systems or insulin pumps. Insulin pumps are either worn on or implanted in the body of the patient. In both cases, the preparation is exposed to the heat of the body and movement and to the delivery motion of the pump and thus to a very high thermomechanical stress. Since insulin pens too (disposable and reutilizable pens) are usually worn on the body, the same applies here. Previous preparations have only a limited stability under these conditions.
• Insulin is generally present in neutral solution in pharmaceutical concentration in the form of stabilized zinc-containing hexamers, which are composed of 3 identical dimer units (Brange et al., Diabetes Care 13:923-954 (1990)).
• the profile of action of an insulin preparation may be improved by reducing the oligomeric state of the insulin it contains.
• the self-association of insulin can be decreased.
• the insulin analog lispro for example, mainly exists as a monomer and is thereby absorbed more rapidly and shows a shorter duration of action (HPT Ammon and C. Werning; Antidiabetika [Antidiabetics]; 2. Ed.; Wiss. Verl.-Ges. Stuttgart; 2000; p. 94.f).
• the rapid-acting insulin analogs which often exist in the monomeric or dimeric form are less stable and more prone to aggregate under thermal and mechanical stress than hexameric insulin. This makes itself noticeable in
• 5,948,751 describes insulin preparations having increased physical stability, which is achieved by addition of mannitol or similar sugars.
• the addition of excess zinc to a zinc- containing insulin solution can likewise increase the stability (J. Brange et al., Diabetic Medicine, 3: 532-536, 1986).
• the influence of the pH and various excipients on the stability of insulin preparations has also been described in detail (J. Brange & L.
• Zinc-free formulations of insulin glulisine can be stabilized by surfactants.
• 02/076495 discloses an U100 insulin glulisine (100 lU/ml) formulation containing polysorbate 20, polysorbate 80 or poloxamer 171 .
• the problem of the present invention can be seen in the provision of a pharmaceutical formulation of insulin glulisine overcoming at least partially the above-described stability issues, wherein potentially disadvantageous components should be avoided.
• the problem of the present invention can be seen in the provision of a pharmaceutical formulation of insulin glulisine having an improved stability at elevated temperature (such as the body temperature).
• the physical long-term stability of a formulation containing 200 - 1000 U/mL insulin glulisine is increased, in particular at elevated temperatures.
• the formulations as described herein are suitable for administration by devices implanted into the patient or otherwise exposed to the body temperature.
• the formulation of the present invention is suitable for use in insulin pumps implanted in the patient's body or in patch pumps worn close to the body.
• the formulation is suitable for use in injection devices, such as pens, syringes, injectors, or for any use in which increased physical stability at elevated temperature is necessary, for example if these devices are worn close to the body.
• the reduced volume together with the improved stability, improves administration by an insulin pump or a patch pump, as the pump can be used for a longer time without replacement of the reservoir, or/and the size of the pump can be reduced.
• insulin glulisine is Lys(B3), Glu(B29) human insulin.
• Insulin glulisine has a molecular weight of 5823 Dalton.
• a 0.6 mM solution of insulin glulisine contains 3,4938 mg/mL insulin glulisine (100 units/mL, U100).
• An U300 insulin glulisine formulations contains 300 U/mL insulin glulisine (10.4814 mg/mL or 10.48 mg/mL).
• the term "stability" refers to the chemical and/or physical stability of active pharmaceutical ingredients, in particular of insulin analogues and/or derivatives.
• stability testing is to provide evidence on how the quality of an active pharmaceutical ingredient or dosage form varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a shelf life for the active pharmaceutical ingredient or dosage form and recommended storage conditions.
• Stability studies should include testing of those attributes of the active pharmaceutical ingredient that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.
• the testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functionality tests (e.g. for a dose delivery system).
• Analytical procedures should be fully validated and stability indicating. In general, significant changes for an active pharmaceutical ingredient and/or dosage form with regard to stability are defined as:
• the significant changes may also be evaluated against established acceptance criteria prior to starting the evaluation of the stability.
• Acceptance criteria should be derived from the monographs (e.g. monographs for the European Pharmacopeia, of the United States Pharmacopeia, of the British
• the acceptance criteria and / or test items shown above are based on monographed acceptance limits and/or are derived from extensive experience in the development of insulin formulations.
• treatment refers to any treatment of a mammalian, for example human condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease.
• the unit of measurement grillU" and/or ..international units refers to the blood glucose lowering activity of insulin and is defined (according to the World Health Organization, WHO) as follows: 1 U corresponds to the amount of highly purified insulin (as defined by the WHO) which is sufficient to lower the blood glucose level of a rabbit (having a body weight of 2 - 2.5 kg) to 50 mg / 100 ml_ within 1 hour and to 40 mg / 100 ml_ within 2 hours.
• 1 U corresponds to approximately 35 g (Lill, Pharmazie in 102 Zeit, No. 1 , pp. 56-61 , 2001 ).
• For insulin glulisine 100 U correspond to 3.49 mg (product information Apidra ® cartridges).
• An embodiment of the invention is an aqueous pharmaceutical formulation comprising 200 - 1000 U/mL of insulin glulisine, more specifically such formulations comprising insulin glulisine in a concentration of 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 U/ml.
• a further embodiment of the invention is an aqueous pharmaceutical formulation comprising 200 - 500 U/mL of insulin glulisine, more specifically 270 - 330 U/mL of insulin glulisine, further preferred 300 U/mL of insulin glulisine.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above which is essentially free of zinc or contains 20 pg/nriL of zinc or less.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above comprising at least one substance selected from buffer substances,
• preservatives and tonicity agents, preferably wherein the buffer substance is trometamol.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above comprising 3 to 10 mg/mL of trometamol.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, wherein the preservative is phenol and / or m-cresol.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above comprising 1 .5 to 3.5 mg/mL of m-cresol and / or 0.5 to 3.0 mg/ml of phenol..
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, wherein the tonicity agent is glycerol.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, comprising 5 to 26 mg/mL of glycerol.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above claims which is essentially free of phosphate.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above comprising an amino acid selected from a group comprising arginine and methionine, in particular in a concentration from 1 to 30 mg/ml.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above comprising a non-ionic surfactant, wherein the non-ionic surfactant is preferably selected from a group comprising polysorbate 20, polysorbate 80 and poloxamer 171 .
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, wherein the non-ionic surfactant is present in a concentration of 1 to 200 pg/ml, preferably 10 to 20 pg/ml, and more preferred 10 g/ml.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, wherein the pH is between 3.5 and 9.5, preferably between 6 and 8.5 and more preferred between 7 and 7.8.
• a further embodiment of the invention is a medical device comprising the formulation as described above. Such medical device can be an insulin pump or a pen for injection.
• aqueous pharmaceutical formulation of any of the foregoing claims which is essentially free of chloride.
• An essentially free of chloride formulation of the invention can, however, a low amount from chloride that is added to the formulation solely for the purpose of pH adjustment.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, for injection.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, for administration by an insulin pump.
• An embodiment of the invention is an aqueous pharmaceutical formulation as described above, for use in the treatment of type 1 diabetes mellitus or type 2 diabetes mellitus.
• An embodiment of the invention is a method of treatment of type 1 diabetes mellitus or type 2 diabetes mellitus, comprising administration of the formulation as described above to a patient suffering from type 1 diabetes mellitus or type 2 diabetes mellitus, preferably wherein the formulation is administered by injection or by an insulin pump.
• An embodiment of the invention is the use of a formulation as described above for the manufacture of a medicament for the treatment of type 1 diabetes mellitus or 2 diabetes mellitus.
• the aqueous pharmaceutical formulation of the present invention can contain a surfactant.
• Suitable pharmaceutically acceptable surfactants are disclosed in WO 02/076495, the disclosure of which is included herein by reference.
• the surfactant is selected from polysorbate 20, polysorbate 80 and poloxamer 171 .
• the surfactant, in particular polysorbate 20, can be present in an amount of 1 to 200 Mg/mL, preferably 10 to 20 Mg/mL, and more preferred 10 g/mL.
• the buffer substance can be selected from pharmaceutically acceptable buffer substances, such as phosphate or trometamol. Phosphate dihydrate can be present in an amount of 1 to 5 mg/mL.
• a preferred buffer substance is trometamol (Tris,
• tris(hydroxymethyl)-aminomethan which can be present in the formulation in a concentration of 3 to 10 mg/mL, preferably 6 mg/mL.
• the formulation of the present invention is suitable for parenteral administration.
• the formulation can be injected or administered by an insulin pump or a pen.
• the insulin pump can be a patch pump.
• suitable devices The aqueous pharmaceutical formulation of the present invention is for use in the treatment of a patient suffering from type 1 diabetes mellitus or type 2 diabetes mellitus.
• the patient is in particular a human.
• Another aspect of the present invention is a method of treatment of type 1 diabetes mellitus or type 2 diabetes mellitus, comprising administration of an aqueous
• a pharmaceutical formulation of the present invention to a patient suffering from type 1 diabetes mellitus or type 2 diabetes mellitus.
• the formulation is preferably administered by injection, an insulin pump or a pen.
• the patient is in particular a human.
• Yet another aspect of the present invention is the use of an aqueous pharmaceutical formulation of the present invention for the manufacture of a medicament for the treatment of type 1 diabetes mellitus or 2 diabetes mellitus. The invention is further described by the following figures and examples.
• Figure 2 High molecular weight proteins for U300 formulations according to the invention (_1 14, _172, _173, _174).
• HMWPs high molecular weight proteins
• An U300 insulin glulisine formulation contains 300 U/mL insulin glulisine (10.48 mg/nnL).
• HMPWs The content of HMPWs describes the degree of aggregation of insulin molecules.
• Dimers, trimers and polymers of insulin can be observed.
• An increase of HMPWs indicates a larger proportion of insulin molecules being aggregated.
• the formulations were stored at 37°C for 30 days and physical and chemical stability was assessed.
• Tests are carried out using compendial analytical test methods, where applicable.
• the quality control concept has been established taking into account the cGMP
• the identity of the active ingredient is ensured by comparing the retention time of the drug formulation sample with the retention time of the reference standard using a reversed phase HPLC method.
• the method is also used for the determination of assay of the active ingredient, for the determination of the related compounds and impurities, and for quantifying the preservatives m-cresol and phenol.
• HPLC Assay
• the test is carried out by reverse phase liquid chromatography (HPLC).
• the method is also used for the identification, the determination of assay of the active ingredient, for the determination of the related compounds and impurities, and for quantifying the preservatives m-cresol and phenol.
• Autosampler Thermostated at ⁇ +10 °C.
• Mobile phase A Buffer solution pH 2.2 / acetonitrile / water (55:20:25 v/v).
• Mobile phase B Buffer solution pH 2.2 / acetonitrile (55:45 v/v). Gradient is shown in Table 1 .
• High molecular weight proteins HMWPs
• the high molecular weight proteins are determined using high pressure size exclusion chromatography (HPSEC).
• HPSEC high pressure size exclusion chromatography
• HMWPs are calculated using the peak area percent method.
• Tests and acceptance criteria were selected based on ICH Q6B and on published monographs, analytical results obtained, precision of procedures used, Pharmacopoeial and/or regulatory guidelines, and are in agreement with the standard limits at this stage of development.
• Formulations from 100 to 900 Units/mL were included to investigate the feasibility of insulin glulisine concentrated solutions.
• the maximum solubility in water at the intended pH of 7.3 was determined to be around 1 100 Units/mL.
• the chemical and physical stability of formulations from 100 to 900 Units/mL can be confirmed.
• Tables 3 and 4 show the long term, accelerated and stress stability results, wherein batch nos. "_1 14", “_172”, “_173” and “_174" are referring to a formulation according to the present invention.
• FormuStorage Storage Content Content Content Sum of HMWPs lation condition duration Insulin m-Cresol Phenol related [%] glulisine [mg/mL] [mg/mL] proteins ⁇ f [mg/mL]
• diabetes mellitus was induced by treatment with alloxan about three week before the experiment.
• the alloxan-treated minipig is a model for type 1 diabetes mellitus in humans.
• a first group of alloxan-treated minipigs received 0.3 U/kg insulin glulisine U100 (100 U/mL) subcutaneously.
• the U100 composition corresponded to the commercial "Apidra" formulation.
• a second group received 0.3 U/kg insulin glulisine U300 (300 U/mL) subcutaneously.
• the plasma concentration of insulin glulisine was determined by a specific LC-MS/MS assay (detection level of 0.1 ng/mL). No difference was detected in the plasma concentration of insulin glulisine in U100 and U300 treated minipigs. Upon treatment with U100 or U300 insulin glulisine, the glucose concentration in the plasma rapily decreased. No difference in the effect upon the plasma glucose was detected between the U100 and U300 group. In all animals of both treatment groups, the plasma glucose concentration was below the detection threshold within 3 hours after treatment.

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