WO2022036506A1 - Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途 - Google Patents

Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途 Download PDF

Info

Publication number
WO2022036506A1
WO2022036506A1 PCT/CN2020/109533 CN2020109533W WO2022036506A1 WO 2022036506 A1 WO2022036506 A1 WO 2022036506A1 CN 2020109533 W CN2020109533 W CN 2020109533W WO 2022036506 A1 WO2022036506 A1 WO 2022036506A1
Authority
WO
WIPO (PCT)
Prior art keywords
sglt
composition
inhibitor
angiotensin
medicine
Prior art date
Application number
PCT/CN2020/109533
Other languages
English (en)
French (fr)
Inventor
贾慧娟
石洪卫
张加晏
任晓慧
Original Assignee
天津睿创康泰生物技术有限公司
北京睿创康泰医药研究院有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 天津睿创康泰生物技术有限公司, 北京睿创康泰医药研究院有限公司 filed Critical 天津睿创康泰生物技术有限公司
Priority to CN202080105705.3A priority Critical patent/CN116490178A/zh
Priority to US18/025,751 priority patent/US20230346817A1/en
Priority to PCT/CN2020/109533 priority patent/WO2022036506A1/zh
Priority to EP20949719.7A priority patent/EP4197543A4/en
Priority to KR1020237009242A priority patent/KR20230057388A/ko
Publication of WO2022036506A1 publication Critical patent/WO2022036506A1/zh

Links

Images

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to the field of medicine, in particular to the composition and use of an SGLT-2 inhibitor and an angiotensin receptor blocker.
  • Hypertension is a major risk factor for cardiovascular disease, especially for patients with diabetes, the sum of the two has a synergistic effect on cardiovascular harm.
  • the abnormally elevated blood sugar and insulin resistance in patients with type 2 diabetes are independent risk factors for a variety of cardiovascular diseases, including hypertension.
  • controlling blood pressure in patients with type 2 diabetes and avoiding excessive blood pressure fluctuations
  • the benefits are significant.
  • the prevalence of hypertension and diabetes in China has been increasing year by year. 32.9% of hypertensive patients treated in cardiology department also have diabetes, while those treated in endocrinology department have diabetes. Among them, 58.9% had hypertension.
  • diabetes In the general population, 45.3% of patients had co-morbidities. The prevalence of hypertension in diabetic patients was significantly higher, about twice that of non-diabetic patients. In the United States, diabetes has the highest prevalence among American adults, and about half of diabetic patients suffer from high blood pressure, which undoubtedly increases the cardiovascular burden of diabetic patients. Diabetes combined with hypertension further increases the risk of left ventricular wall hypertrophy, proteinuria, and renal function damage in patients with type 2 diabetes, increases the incidence of adverse cardiovascular events in patients with cardiovascular disease, and increases the economic burden of such patients.
  • Hypertension combined with type 2 diabetes seriously damages the heart, brain, kidney and other important target organs and the body's vascular system, resulting in coronary atherosclerotic heart disease, cardiac insufficiency, central nervous system ischemia or hemorrhagic stroke As well as complications such as renal insufficiency and even uremia, it seriously affects the health and quality of life of these patients. Therefore, when hypertension and diabetes co-occur, controlling blood sugar and blood pressure at the same time can more effectively reduce the occurrence of complications and reduce the risk of death.
  • Irbesartan active ingredient A
  • Irbesartan active ingredient A
  • Irbesartan can protect the kidney by inhibiting the proliferation of cells in the mesangium, reducing the content of basal protein in the body, and increasing the excretion rate of urinary albumin. Irbesartan is used for the treatment of essential hypertension and type 2 diabetic nephropathy associated with hypertension. Clinical studies have shown that irbesartan benefits the kidneys of hypertensive patients with type 2 diabetes.
  • Dapagliflozin active ingredient B is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor with extremely high selectivity and specificity. Glucose absorption, increase body excretion, reduce glycosylated hemoglobin level, and achieve the purpose of controlling blood sugar. What is even more exciting is that SGLT-2 inhibitors have also shown good prospects in reducing blood pressure, which is a good source of diabetes and hypertension. Therapy offers new and unique ideas.
  • SGLT-2 sodium-glucose co-transporter 2
  • co-administration of SGLT-2 inhibitors and angiotensin receptor antagonists can achieve the effect of reducing blood pressure and blood sugar at the same time, and can benefit the kidneys and cardiovascular, prevent or delay chronic kidney disease (CKD) ) in patients with worsening renal failure and prevention of cardiovascular (CV) and renal death.
  • CKD chronic kidney disease
  • CV cardiovascular
  • the unilateral preparations of the two are clinically administered to patients at the same time, which is inconvenient to carry or take, and has poor compliance.
  • Irbe The compound preparation of sartan and dapagliflozin is on the market, and there is no related compound preparation patent.
  • the present invention provides compositions and uses of SGLT-2 inhibitors and angiotensin receptor blockers.
  • the composition is used for the treatment of diabetes mellitus with hypertension, while benefiting the kidneys or cardiovascular of the patients, and reducing the risk of cardiovascular and renal complications in patients with type 2 diabetes.
  • the composition of the invention is convenient to carry or take, the cost of medication is relatively reduced, the risk of multiple doses and missed doses is avoided, and the compliance of patients taking medication is improved.
  • compositions comprising SGLT2 inhibitors and angiotensin-II receptor antagonists.
  • the SGLT-2 inhibitors include, but are not limited to, Dapagliflozin, Canagliflozin, Empagliflozin, Epagliflozin ( Ipragliflozin, Luseogliflozin, Tofogliflozin, Ertugliflozin, Janagliflozin, Bexagliflozin, Sotagliflozin , Henagliflozin, Tianagliflozin, Remogliflozin, Alligliflozin, Remogliflozin etabonate, Ringagliflozin ((1R) ,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxy ethyl)-6,8-dioxabicyclo[3.2.1] one or a combination of two or more of o
  • the angiotensin-II receptor antagonists include, but are not limited to, irbesartan, candesartan, valsartan, tilimibe One or a combination of two or more of Telmisartan, Losartan, Iprasartan, Olmesartan, and Azilsartan.
  • the SGLT-2 inhibitor comprises one or a combination of two or more of dapagliflozin or a pharmaceutically acceptable salt, ester, co-crystal, complex or solvate thereof ;
  • the angiotensin-II receptor antagonist includes one or more combinations of irbesartan, its pharmaceutically acceptable salts or solvates.
  • the weight ratio of the SGLT-2 inhibitor and the angiotensin-II receptor antagonist is 1:960-300:1, preferably 1:240-75:1, More preferably 1:120-1:7.5, more preferably (8-300):(2-300), most preferably 8:300, 20:12.3, 40:12.3, 50:4.1, 50:2, 44.8:3.7, 32.5:2.7, 150:12.3, 150:6.15, 75:12.3, 300:6.15, or 300:12.3.
  • the composition is used in the preparation of treatment for essential hypertension, type 2 diabetic nephropathy with hypertension, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acid or glycerol.
  • the present invention also provides a medicine, including the composition and pharmaceutically acceptable excipients.
  • the adjuvants include but are not limited to: fillers, binders, disintegrants, anti-sticking agents, adsorbents, glidants, lubricants, surfactants, chelating agents, One or a combination of colorants and taste-masking agents.
  • the dosage form of the drug includes one or more of tablets, capsules, granules, suspensions, and films, preferably tablets, dry suspensions, and capsules , Granules.
  • the medicament is a tablet, granule or capsule comprising:
  • glidants or lubricants optionally one or more glidants or lubricants
  • SGLT-2 inhibitors include but are not limited to Dapagliflozin, Canagliflozin, Empagliflozin, Ipragliflozin, Luseogliflozin, Tofogliflozin, Ertugliflozin, Janagliflozin, Bexagliflozin, Sotagliflozin, Henagliflozin, Tigermed Tianagliflozin, Remogliflozin, Alligliflozin, Remogliflozin etabonate, Ringagliflozin ((1R,2S,3S,4R,5S)-5 -(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxy ethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol) one or more of.
  • it is dapagliflozin. It is
  • Angiotensin-II receptor antagonists include, but are not limited to, Irbesartan, Candesartan, Valsartan, Telmisartan, Losartan , Iprasartan (Iprasartan), Olmesartan (Olmesartan), Azilsartan (Azilsartan). It is preferably selected from irbesartan, its pharmaceutically acceptable salts, co-crystals, complexes or solvates.
  • the diluent in the compositions of the present invention can be one or more compounds which provide for obtaining the desired tablet volume.
  • Desirable diluents include, but are not limited to, microcrystalline cellulose, lactose, mannitol, erythritol, maltitol, sorbitol, trehalose, sucrose, white sugar, glucose, fructose, corn starch, wheat starch, dextrin, licorice Powder, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, calcium citrate, calcium lactate, magnesium oxide, magnesium hydroxide, calcium oxide, magnesium carbonate, potassium carbonate, zinc carbonate, titanium oxide, silicic anhydride, magnesium silicate, silicic acid Calcium, sodium bicarbonate, magnesium sulfate, calcium sulfate, silica.
  • the binder in the compositions of the present invention can be one or more compounds that enable the main drug and adjuvant to form the desired free-flowing particles.
  • Desirable binders include, but are not limited to, hydroxypropylcellulose, hypromellose, sugar, gelatin, starch, acacia, tragacanth, carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, partial alpha starch, alpha starch, polyvinyl alcohol, sodium alginate, pullulan, glycerin.
  • Disintegrants in the compositions of the present invention may be one or more compounds that promote disintegration of the composition upon contact with an aqueous medium.
  • Preferred disintegrants include, but are not limited to, corn starch, partially alpha-starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low substituted Hydroxypropyl cellulose, croscarmellose sodium, crospovidone.
  • An anti-adherent or adsorbent in the composition of the present invention refers to one or more compounds that reduce the viscosity of the formulation or adsorb liquid components in the formulation, preventing them from sticking to metal surfaces.
  • Anti-sticking agents or adsorbents include, but are not limited to, silica, magnesium silicate, talc, dibasic calcium phosphate, and the like.
  • the glidant in the composition of the present invention can be one or more compounds that can reduce the friction between particles, improve the fluidity of the powder, and help reduce the weight difference.
  • the glidant includes but is not limited to talc, Silica.
  • the lubricant in the composition of the present invention is one or more compounds that can reduce the friction force between the material and the mold wall, and ensure the smooth progress of tablet pressing, capsule filling or granule dispensing.
  • Lubricants include, but are not limited to, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, hydrogenated vegetable oils, polyethylene glycol, sodium lauryl sulfate.
  • Surfactant in the compositions of the present invention refers to one or more compounds that can improve the wetting properties of the formulation and/or facilitate dissolution.
  • Surfactants include, but are not limited to, poloxamers, sodium lauryl sulfate, Tween, Span.
  • Colorants in the compositions of the present invention refer to one or more compounds capable of imparting the desired color to the formulation prepared from the composition.
  • Colorants include but are not limited to amaranth, carmine, erythrosine, new red, lemon yellow, sunset yellow, quinoline yellow, indigo, brilliant blue, beet red, shellac red, bilberry red, capsicum red, red rice Red etc.
  • Flavoring agents in the compositions of the present invention refer to one or more compounds used to improve or mask the unpleasant odor and taste of a drug. Flavoring agents include, but are not limited to, sucrose, mannitol, sorbitol, sodium citrate, aspartame, peppermint oil, essence, sodium alginate, acacia.
  • the mixed mode of described SGLT-2 inhibitor and described angiotensin-II receptor antagonist comprises:
  • the angiotensin-II receptor antagonist is used as an added component, and the SGLT-2 inhibitor is used as an additional component.
  • the present invention also provides the preparation method of the medicine, in which the raw and auxiliary materials are directly mixed.
  • the present invention also provides the preparation method of the medicine, which includes the steps of mixing, granulating, granulating and mixing.
  • the present invention also provides the preparation method of the medicine, which includes the steps of mixing, granulating, drying, granulating and mixing.
  • the mixing mode of the SGLT-2 inhibitor and the angiotensin-II receptor antagonist includes:
  • the angiotensin-II receptor antagonist is used as an internal component, and the SGLT-2 inhibitor is used as an external component.
  • the present invention also provides that the medicine or the medicine prepared by the preparation method is used in the preparation and treatment of essential hypertension, type 2 diabetic nephropathy with hypertension, diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol for elevated blood levels, hyperlipidemia, dyslipidemia, obesity, or the use of a drug for complications of diabetes.
  • the present invention provides a fixed-dose combination of SGLT-2 inhibitor and angiotensin-II receptor antagonist.
  • the composition is used for the treatment of diabetes mellitus with hypertension, while benefiting the kidneys, preventing or delaying the worsening of renal failure in patients with chronic kidney disease (CKD) and preventing cardiovascular (CV) and renal death.
  • CKD chronic kidney disease
  • CV cardiovascular
  • the fixed-dose compound composition of the present invention has good synergy, good stability, is convenient to carry or take, significantly reduces the cost of medication, avoids the risk of multiple doses or missed doses, and improves the compliance of patients taking medication .
  • Figure 1 shows the cumulative dissolution rate (%) of active ingredient A in pH 1.0 hydrochloric acid solution
  • Figure 2 shows the cumulative dissolution rate (%) of active ingredient B in a pH 1.0 hydrochloric acid solution.
  • the invention discloses a compound composition and application of a fixed dose of sodium-glucose co-transporter 2 (SGLT-2) inhibitor and angiotensin receptor blockers (ARBs), and those skilled in the art can learn from the content , appropriate improvement of process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • the compound composition of the fixed-dose sodium-glucose co-transporter 2 (SGLT-2) inhibitor and angiotensin receptor blocker (ARBs) provided by the present invention and the raw and auxiliary materials used in the application can be purchased from the market.
  • SGLT-2 fixed-dose sodium-glucose co-transporter 2
  • ARBs angiotensin receptor blocker
  • Lactose (FOREMOST), Mannitol (ROQUETTE), Sucrose (Sichuan Boliheng), Calcium Carbonate (Shanghai Nuocheng), Magnesium Oxide (Hebei Burst), Crospovidone (BASF), Croscarmellose Sodium (Asahi Kasei), Hypromellose (Dow Chemical), Microcrystalline Cellulose (JRS), Silica (Huzhou Prospect), Magnesium Stearate (Huzhou Prospect), Low-Substituted Hypromellose (Shin-Etsu Chemical) ), hypromellose (Caoda Chemical), pregelatinized starch (ASAHI KASEI), talc (Guangxi Longsheng Huamei), sodium stearyl fumarate (Shanghai Changwei), gelatin hollow capsules (Suzhou Capsule Co., Ltd. ), hypromellose hollow capsules (Suzhou Capsule Co., Ltd.).
  • Example 13 Weigh 100 capsules of recipe quantity and mix for 15 minutes; then add purified water to make soft material, granulate with a 40-mesh sieve, or dry at 50°C, granulate with a 40-mesh sieve, and control the moisture to 2% or below; after conversion, weigh and mix in a bag of raw and auxiliary materials for 10 minutes, then put into a gelatin capsule.
  • Example 14 Weigh 50 pieces of recipe quantity and mix evenly with the added raw and auxiliary materials, use purified water to make soft material, granulate with an 80-mesh sieve, dry at 40°C, granulate with an 80-mesh sieve, and control the moisture to be 2% or less. Weigh the additional raw and auxiliary materials through an 80-mesh sieve and mix for 8 times, then add the corresponding dry granules, mix well, and press into tablets.
  • Example 15 Weigh 50 capsules of the recipe quantity and mix evenly; then use purified water to make soft material, granulate with a 40-mesh sieve, dry at 50°C, and granulate with a 40-mesh sieve; Dry granulation with a 30-mesh sieve; mix the internal and external granules with raw and auxiliary materials in proportion, and pack into hypromellose capsules.
  • Avapro is the commercial product of the active ingredient A single tablet reference preparation, batch number: DT04448.
  • the comparative example has an impurity at RRT 0.85 that grows after being placed at a high temperature, while the examples 1 to 15 have no obvious increase in impurities after being placed at a high temperature, and the total impurity is also small.
  • Example 19 uses 10% hypromellose aqueous solution to make soft material, granules with a 65 mesh sieve, dried at 40 ° C, granulated with a 65 mesh sieve, and converted into Add adjuvant and mix well;
  • Example 20 dry granulation, add adjuvant and mix well.
  • the dissolution in 15 minutes of pH 1.0 hydrochloric acid medium was determined. Measurement method: paddle method, medium volume: 1000ml, temperature: 37°C, rotation speed: 50rpm. Unless otherwise specified, the dissolution of the following examples was determined by this method.
  • Example 16 94.2 93.5
  • Example 17 93.7 87.0
  • Example 18 93.8 94.7
  • Example 19 95.5 92.8
  • Example 20 95.6 93.0
  • Example 21 99.0 94.6
  • Example 22 89.8 86.2
  • Example 23 97.7 90.0
  • Example 24 91.0 88.8 Comparative example/Avapro (8A430) 92.6 / Comparative example/FORXIGA (KJ3245) / 97.4
  • Example 31 Weigh 100 tablets of the recipe quantity of the internal added raw materials and mix well; mixed powder is made of soft material with purified water, granulated with a 40-mesh sieve, dried at 50°C, and granulated with a 40-mesh sieve; evenly; tableting.
  • Example 32 Weigh 25 pieces of the recipe quantity and mix them evenly, then use purified water to make soft material, granulate with a 40-mesh sieve, dry at 60°C, and granulate with a 40-mesh sieve; the obtained dry granules are converted into additional raw and auxiliary materials. Mix well; tablet.
  • Example 33 Weigh 25 pieces of the recipe quantity and mix evenly; then add purified water to make soft material, granulate with a 40-mesh sieve, dry at 40°C, and granulate with a 40-mesh sieve; , tablet.
  • Embodiment 34,37 a) take 100 pieces of recipe quantity first layer except sodium hydroxide and magnesium stearate and mix the raw and auxiliary materials; mix powder with sodium hydroxide aqueous solution to make soft material, 40 mesh sieve granulation , dried at 40°C, sieved with a 40-mesh sieve; converted into magnesium stearate and mixed; b) weighed the raw and auxiliary materials of the second layer and mixed; c) pressed the first layer of total mixed particles and the second layer of mixed powder Double layer.
  • Embodiments 35 and 36 a) Weigh 100 pieces of the first layer of raw and auxiliary materials and mix them evenly; b) Weigh the second layer of raw and auxiliary materials and mix them evenly; c) Mix the mixed powder of the first layer and the second layer of Mixed powder pressed double-layer tablet.
  • Example 38 to Example 40 a) Weigh 100 tablets of the first layer of magnesium stearate and all other raw and auxiliary materials and mix them uniformly, dry granulate, and then add the remaining magnesium stearate and mix well; b) Weigh part of the silicon dioxide, magnesium stearate and all other raw and auxiliary materials in the second layer and mix, dry granulate, then add the remaining silicon dioxide and magnesium stearate and mix well; c) mix the first layer of the total The granules and the blended granules of the second layer are laminated to a bilayer tablet.
  • compositions and uses of the SGLT-2 inhibitor and angiotensin receptor blocker provided by the present invention are described above in detail.
  • the principles and implementations of the present invention are described herein by using specific examples, and the descriptions of the above embodiments are only used to help understand the method and the core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can also be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

涉及药物领域，特别涉及SGLT-2抑制剂与血管紧张素受体阻滞剂的组合物及用途，具体涉及一种固定剂量的钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂与血管紧张素受体阻滞剂（ARBs）的复方组合物及用途。该固定剂量复方组合物用于糖尿病伴高血压患者的治疗，同时使慢性肾病患者获益，预防或延缓慢性肾脏病（CKD）患者肾功能衰竭恶化、预防心血管（CV）死亡或肾病死亡。另外，所涉及的固定剂量复方组合物具有良好的协同性、稳定性好、携带或服用方便，用药成本显著降低，同时避免了多服、漏服的风险，改善了患者服药的顺应性。

Description

SGLT-2抑制剂与血管紧张素受体阻滞剂的组合物及用途 技术领域
本发明涉及药物领域，特别涉及SGLT-2抑制剂与血管紧张素受体阻滞剂的组合物及用途。
背景技术
高血压是心血管疾病的主要危险因素，尤其是对于合并糖尿病的患者，两者相加对心血管的危害有协同效应。而2型糖尿病患者异常升高的血糖及胰岛素抵抗是包括高血压病在内的多种心血管疾病发病的独立危险因素，与此同时，控制2型糖尿病患者的血压以及避免血压过度波动，在预防或控制糖尿病患者的远期心血管并发症方面具有显著的功效，当这些危险因素得到有效控制时，获益非常明显。据相关流行病学调查研究显示，近年来，中国的高血压与糖尿病的患病率均呈逐年上升趋势，在心内科就诊的高血压患者有32.9％同时合并糖尿病，而在内分泌科就诊的糖尿病患者中则有58.9％合并高血压。在总体人群中，有45.3％的患者二病共患。糖尿病病人中高血压的患病率明显增高,约为非糖尿病人群的2倍。在美国，糖尿病是美国成人中患病率最高的，并且大约一半的糖尿病患者均同时患有高血压，这无疑加大了糖尿病人的心血管负担。糖尿病合并高血压进一步增加了2型糖尿病患者的左心室壁肥厚、蛋白尿和肾功能损伤等风险，增加了心血管疾病患者的不良心血管事件的发生，增加了这类患者的经济负担。高血压病合并2型糖尿病严重损害患者的心、脑、肾等身体重要靶器官和机体血管系统，进而出现冠状动脉粥样硬化性心脏病、心功能不全、神经中枢血管缺血或出血性卒中以及肾功能不全甚至尿毒症等并发症，严重影响到这类患者的机体健康及生存质量。因此，高血压和糖尿病合并发生时，同时控制血糖和血压，才能更加有效地减少并发症的发生，降低死亡风险。
高血压以及糖尿病发病率以及死亡率均较高，确诊后需及时进行相关治疗，但对于糖尿病伴高血压病患而言，由于其同时患有两种疾病，为临 床治疗带来一定挑战。临床治疗糖尿病伴高血压方法较多，其中药物治疗最为常见。但糖尿病伴高血压病患大多为老年人，且均为终生服药，针对该类病患治疗一方面需尽可能提升治疗效果，另一方面尽量减少不良反应的出现，增加病患治疗依从性，从而获得满意的治疗效果。厄贝沙坦(活性成分A)为血管紧张素受体阻滞剂，具有较高的选择性，在竞争拮抗的同时不会产生激动作用，通过抑制肾上腺素释放醛固酮以及扩张血管来达到降血压的目的。厄贝沙坦通过抑制系膜内细胞数量的增殖，减少体内基底蛋白含量，提升机体尿白蛋白排泄率，达到保护肾脏的目的。厄贝沙坦用于治疗原发性高血压以及合并高血压的2型糖尿病肾病的治疗。临床研究证明，厄贝沙坦使高血压伴2型糖尿病患者的肾脏受益。
达格列净(活性成分B)是一种钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂，具有极高的选择性和特异性，该药物进入体内后通过阻断曲小管对机体内葡萄糖的吸收，增加机体排泄量，降低糖化血红蛋白水平，达到控制血糖的目的，更让人兴奋的是SGLT-2抑制剂在降低血压方面也显示出了良好的前景，这为糖尿病及高血压的治疗提供了新的、独特的思路。近期SGLT-2抑制剂临床试验显示，糖尿病患者的收缩压降低4mmHg时，其舒张压仅降低1.6mmHg，而通常的降压药单药治疗当收缩压降低9.1mmHg时，舒张压要降低5.5mmHg，舒张压降得过低，会导致心脏缺血风险。2019年，达格列净被美国食品和药物管理局(FDA)授予快速通道资格，以延缓慢性肾脏病(CKD)患者肾功能衰竭恶化以及预防心血管(CV)和肾脏死亡，包括患有或不患有2型糖尿病(T2D)的CKD患者。
Figure PCTCN2020109533-appb-000001
对于糖尿病伴高血压的患者，SGLT-2抑制剂和血管紧张素受体拮抗 剂同服可达到同时降低血压和血糖的效果，且可使肾脏和心血管受益，预防或延缓慢性肾脏病(CKD)患者肾功能衰竭恶化以及预防心血管(CV)和肾脏死亡。目前临床上将两者的单方制剂同时给患者服用，存在携带或服用不便，顺应性差，某一药物存在多服或漏服的风险、潜在的安全隐患及用药成本较高，目前还没有厄贝沙坦和达格列净的复方制剂上市，也没有相关复方制剂专利。
发明内容
有鉴于此，本发明提供了SGLT-2抑制剂与血管紧张素受体阻滞剂的组合物及用途。该组合物用于糖尿病伴高血压治疗，同时使患者肾脏或心血管受益，降低2型糖尿病患者心血管和肾脏并发症的发生风险。本发明组合物携带或服用方便，用药成本相对降低，避免了多服漏服的风险，改善了患者服药的顺应性。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了组合物，包括SGLT2抑制剂和血管紧张素-II受体拮抗剂。
在本发明的一些具体实施方案中，所述SGLT-2抑制剂包括但不限于达格列净(Dapagliflozin)、坎格列净(Canagliflozin)、恩格列净(Empagliflozin)、依格列净(Ipragliflozin)、鲁格列净(Luseogliflozin)、托格列净(Tofogliflozin)、埃格列净(Ertugliflozin)、加格列净(Janagliflozin)、贝格列净(Bexagliflozin)、索格列净(Sotagliflozin)、恒格列净(Henagliflozin)、泰格列净(Tianagliflozin)、瑞格列净(Remogliflozin)、艾格列净(Alligliflozin)、依碳酸瑞格列净(Remogliflozin etabonate)、荣格列净((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxy ethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol)中的一种或两者以上的组合。
在本发明的一些具体实施方案中，所述血管紧张素-II受体拮抗剂包括但不限于厄贝沙坦(Irbesartan)、坎地沙坦(Candesartan)、缬沙坦 (Valsartan)、替米沙坦(Telmisartan)、洛沙坦(Losartan)、依普沙坦(Iprasartan)、奥美沙坦(Olmesartan)、阿齐沙坦(Azilsartan)中的一种或两者以上的组合。
在本发明的一些具体实施方案中，所述SGLT-2抑制剂包括达格列净或其药用盐、酯、共晶、络合物或溶剂合物中的一种或两者以上的组合；所述血管紧张素-II受体拮抗剂包括厄贝沙坦、其可药用盐或溶剂合物中的一种或两者以上的组合。
在本发明的一些具体实施方案中，所述SGLT-2抑制剂和所述血管紧张素-II受体拮抗剂的重量比为1:960～300:1，优选1:240～75:1，更优选1:120～1:7.5，更优选(8～300)：(2～300)，最优选8:300、20:12.3、40:12.3、50:4.1、50:2、44.8:3.7、32.5:2.7、150:12.3、150:6.15、75:12.3、300:6.15或300:12.3。
在上述研究的基础上，所述的组合物在制备治疗原发性高血压、合并高血压的2型糖尿病肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症的药物中的应用。
本发明还提供了药物，包括所述的组合物及药学上可接受的辅料。
在本发明的一些具体实施方案中，所述辅料包括但不限于：填充剂，粘合剂，崩解剂，抗粘剂，吸附剂，助流剂，润滑剂，表面活性剂，螯合剂，着色剂，掩味剂中的一种或两者以上的组合。
在本发明的一些具体实施方案中，所述药物的剂型包括片剂、胶囊剂、颗粒剂、混悬剂、膜剂中的一种多种，优选为片剂、干混悬剂、胶囊剂、颗粒剂。
在本发明的一些实施方案中，所述药物为片剂、颗粒剂或胶囊剂，其包含：
a)SGLT-2抑制剂和血管紧张素-II受体阻滞剂；
b)任选的一种或多种填充剂；
c)任选的一种或多种粘合剂；
d)任选的一种或多种崩解剂；
e)任选的一种或多种抗粘剂或吸附剂；
f)任选的一种或多种助流剂或润滑剂；
g)任选的一种或多种表面活性剂；
h)任选的一种或多种着色剂；
i)任选的一种或多种矫味剂。
其中SGLT-2抑制剂包括但不限于达格列净(Dapagliflozin)、坎格列净(Canagliflozin)、恩格列净(Empagliflozin)、依格列净(Ipragliflozin)、鲁格列净(Luseogliflozin)、托格列净(Tofogliflozin)、埃格列净(Ertugliflozin)、加格列净(Janagliflozin)、贝格列净(Bexagliflozin)、索格列净(Sotagliflozin)、恒格列净(Henagliflozin)、泰格列净(Tianagliflozin)、瑞格列净(Remogliflozin)、艾格列净(Alligliflozin)、依碳酸瑞格列净(Remogliflozin etabonate)、荣格列净((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxy ethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol)中的一种或多种。优选自达格列净。优选自达格列净或其药用盐、酯、共晶、络合物或溶剂合物。
血管紧张素-II受体拮抗剂包括但不限于厄贝沙坦(Irbesartan)、坎地沙坦(Candesartan)、缬沙坦(Valsartan)、替米沙坦(Telmisartan)、洛沙坦(Losartan)、依普沙坦(Iprasartan)、奥美沙坦(Olmesartan)、阿齐沙坦(Azilsartan)。优选自厄贝沙坦、其可药用盐、共晶、络合物或溶剂合物。
本发明组合物中的稀释剂可以是一种或多种能提供获得期望的片剂体积的化合物。理想的稀释剂包含但不限于微晶纤维素、乳糖、甘露醇、赤藓醇、麦芽糖醇、山梨糖醇、海藻糖、蔗糖、白糖、葡萄糖、果糖、玉米淀粉、小麦淀粉、糊精、甘草粉末、磷酸钙、磷酸氢钙、碳酸钙、柠檬酸钙、乳酸钙、氧化镁、氢氧化镁、氧化钙、碳酸镁、碳酸钾、碳酸锌、氧化钛、硅酸酐、硅酸镁、硅酸钙、碳酸氢钠、硫酸镁、硫酸钙、二氧化硅。
本发明组合物中的粘合剂可以是使得主药和辅料能成为期望的自由流动的颗粒的一种或多种化合物。理想的粘合剂包括但不限于羟丙基纤维素、羟丙甲纤维素、白糖、明胶、淀粉、阿拉伯胶、黄芪胶、羧甲基纤维 素、聚乙烯吡咯烷酮、甲基纤维素、部分α化淀粉、α化淀粉、聚乙烯醇、海藻酸钠、普鲁兰多糖、甘油。
本发明组合物中的崩解剂可以是能促进组合物与水介质接触时崩解的一种或多种化合物。优选的崩解剂包括但不限于玉米淀粉、部分α化淀粉、羟丙基淀粉、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交聚维酮。
本发明组合物中的抗粘剂或吸附剂指的是能降低制剂的粘度或吸附制剂中的液体成分，防止其黏着于金属表面的一种或多种化合物。抗粘剂或吸附剂包括但不限于二氧化硅、硅酸镁、滑石、磷酸氢钙等。
本发明组合物中的助流剂可以是能降低颗粒之间的摩擦力，改善粉体流动性，有助于减少重量差异的一种或多种化合物，助流剂包括但不限于滑石粉、二氧化硅。
本发明组合物中的润滑剂是可以降低物料与模壁之间的摩擦力，保证压片推片、胶囊灌装或颗粒分装顺利进行的一种或多种化合物。润滑剂包括但不限于硬脂酸镁、硬脂酸、硬脂酸钙、硬脂富马酸钠、聚乙二醇、氢化植物油、聚乙二醇、十二烷基硫酸钠。
本发明组合物中的表面活性剂指的是可改善制剂润湿性和/或促进溶解的一种或多种化合物。表面活性剂包括但不限于泊洛沙姆、十二烷基硫酸钠、吐温、司盘。
本发明组合物中的着色剂指能给予组合物制备的制剂期望的颜色的一种或多种化合物。着色剂包括但不限于苋菜红、胭脂红、赤藓红、新红、柠檬黄、日落黄、喹啉黄、靛蓝、亮蓝、甜菜红、紫胶红、越桔红、辣椒红、红米红等。
本发明组合物中的矫味剂指用以改善或屏蔽药物不良气味和味道的一种或多种化合物。矫味剂包括但不限于蔗糖、甘露醇、山梨醇、枸橼酸钠、阿斯巴甜、薄荷油、香精、海藻酸钠、阿拉伯胶。
在本发明的一些具体实施方案中，所述SGLT-2抑制剂和所述血管紧张素-II受体拮抗剂的混合方式包括：
(1)直接混合；或
(2)分别作为内加组分或外加组分；或
(3)同时作为内加组分。
在本发明的一些具体实施方案中，所述血管紧张素-II受体拮抗剂作为内加组分，所述SGLT-2抑制剂作为外加组分。
本发明还提供了所述的药物的制备方法，将原辅料直接混合。
本发明还提供了所述的药物的制备方法，包括混合、制粒、整粒、总混的步骤。
本发明还提供了所述的药物的制备方法，包括混合、制粒、干燥、整粒、总混的步骤。
此外，本发明提供的药物制备方法中，所述SGLT-2抑制剂和所述血管紧张素-II受体拮抗剂的混合方式包括：
(1)直接混合；或
(2)分别作为内加组分或外加组分；或
(3)同时作为内加组分。
在本发明的一些具体实施方案中，本发明提供的药物制备方法中所述血管紧张素-II受体拮抗剂作为内加组分，所述SGLT-2抑制剂作为外加组分。
本发明还提供了所述的药物或所述制备方法制得的药物在制备治疗原发性高血压、合并高血压的2型糖尿病肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症的药物中的应用。
本发明提供一种固定剂量的SGLT-2抑制剂和血管紧张素-II受体拮抗剂的组合物。该组合物用于糖尿病伴高血压治疗，同时可使肾脏受益，预防或延缓慢性肾脏病(CKD)患者肾功能衰竭恶化以及预防心血管(CV)和肾脏死亡。另外，本发明所涉及的固定剂量复方组合物具有良好的协同性、稳定性好、携带或服用方便，用药成本显著降低，同时避免了多服、漏服的风险，改善了患者服药的顺应性。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示活性成分A在pH1.0盐酸溶液中的累积溶出度(％)；
图2示活性成分B在pH1.0盐酸溶液中的累积溶出度(％)。
具体实施方式
本发明公开了一种固定剂量的钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂与血管紧张素受体阻滞剂(ARBs)的复方组合物及用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明提供的固定剂量的钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂与血管紧张素受体阻滞剂(ARBs)的复方组合物及用途中所用原辅料均可由市场购得。
乳糖(FOREMOST)、甘露醇(ROQUETTE)、蔗糖(四川博利恒)、碳酸钙(上海诺诚)、氧化镁(河北伯斯特)、交聚维酮(BASF)、交联羧甲基纤维素钠(旭化成)、羟丙甲纤维素(陶氏化学)、微晶纤维素(JRS)、二氧化硅(湖州展望)、硬脂酸镁(湖州展望)、低取代羟丙纤维素(信越化学)、羟丙纤维素(曹达化学)、预胶化淀粉(ASAHI KASEI)、滑石粉(广西龙胜华美)、硬脂富马酸钠(上海昌为)、明胶空心胶囊(苏州胶囊有限公司)、羟丙甲纤维素空心胶囊(苏州胶囊有限公司)。
下面结合实施例，进一步阐述本发明：
实施例1～实施例15
表1以重量百分比计的处方组成(％)
Figure PCTCN2020109533-appb-000002
Figure PCTCN2020109533-appb-000003
表2以重量百分比计的处方组成(％)
Figure PCTCN2020109533-appb-000004
Figure PCTCN2020109533-appb-000005
制备工艺：
称取处方量的原辅料混匀。将各实施例混粉分别用干净的称量纸包好后放入铝箔袋中封好，于50℃放置10天取样测定有关物质，与对比例比较。因活性成分B较稳定，影响因素放置后无增长杂质所以本发明只列出活性成分A的有关物质。
表3以重量百分比计的处方组成(％)
Figure PCTCN2020109533-appb-000006
Figure PCTCN2020109533-appb-000007
制备工艺：
实施例13：称取100粒处方量的内加原辅料袋混15分钟；然后加入纯化水制软材，40目筛制粒，或50℃干燥，40目筛整粒，水分控制在2％或以下；折算称取外加原辅料袋混10分钟，装入明胶胶囊。
实施例14：按50片处方量称取内加原辅料混合均匀，使用纯化水制软材，80目筛制粒，40℃干燥，80目筛整粒，水分控制在2％或以下，折算称取外加原辅料过80目筛混8次，然后加入对应的干颗粒混匀，压片。
实施例15：称取50粒处方量的内加原辅料混匀；然后用纯化水制软材，40目筛制粒，50℃干燥，40目筛整粒；称取外加原辅料混匀，干法30目筛制粒；将内外加原辅料颗粒按比例混匀，装羟丙甲纤维素胶囊。
表4活性成分A有关物质测定结果(％)
Figure PCTCN2020109533-appb-000008
Figure PCTCN2020109533-appb-000009
注1：Avapro为活性成分A单方片剂参比制剂的商品，批号：DT04448。
结论：由活性成分A的有关物质结果知，对比例在RRT 0.85处有一杂质高温放置后增长，而实施例1～实施例15高温放置后无明显增长的杂质，总杂也较小。
实施例16～实施例18
表5单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000010
Figure PCTCN2020109533-appb-000011
制备工艺：
按50片处方量称取活性成分B、无水乳糖、交联羧甲基纤维素钠、泊洛沙姆188和二氧化硅过65目筛混合6次，再加入活性成分A和预胶化淀粉过65目筛混合8次；干法制粒；折算加入外加辅料混匀，压片。考察pH1.0盐酸介质中的15分钟的溶出度。溶出方法：pH1.0盐酸溶液，桨法，介质体积：900ml，温度：37℃，转速：50rpm。判定方法：活性成分A与活性成分B的单方参比制剂的15分钟溶出均在85％以上，实施例的溶出要求与参比制剂一致，所以目标值也为85％以上。
实施例19～实施例20
表6单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000012
Figure PCTCN2020109533-appb-000013
制备工艺：
称取50片处方量的内加原辅料过筛混匀；实施例19使用10％的羟丙甲纤维素水溶液制软材，65目筛制粒，40℃干燥，65目筛整粒，折算加入外加辅料混匀；实施例20干法制粒，折算加入外加辅料混匀。测定pH1.0盐酸介质中15分钟的溶出。测定方法：桨法，介质体积：1000ml，温度：37℃，转速：50rpm。如无特殊说明，之后实施例的溶出均以此方法测定。
实施例21～实施例24
表7单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000014
制备工艺：
按50片处方量称取内加原辅料混合均匀，向实施例21中加入纯化水制软材，40目筛制粒，50℃干燥，40目筛整粒，折算加入外加辅料袋混10分钟，压片。向实施例22的混粉中加入羟丙甲纤维素水溶液制软材，实施例23和实施例24使用纯化水制软材，80目筛制粒，40℃干燥，80目筛整粒，水分控制在2％或以下，折算称取外加原辅料过80目筛混8次，然后加入对应的干颗粒混匀，压片。测定pH1.0盐酸介质中15分钟的溶出度。
表8实施例16～实施例24的溶出度结果
溶出度(％) 活性成分A 活性成分B
实施例16 94.2 93.5
实施例17 93.7 87.0
实施例18 93.8 94.7
实施例19 95.5 92.8
实施例20 95.6 93.0
实施例21 99.0 94.6
实施例22 89.8 86.2
实施例23 97.7 90.0
实施例24 91.0 88.8
对比例/Avapro(8A430) 92.6 /
对比例/FORXIGA(KJ3245) / 97.4
结论：各实施例的活性成分A和活性成分B的15分钟的溶出均大于85％，与对应的对比例的溶出一致。
实施例25～实施例30
表9单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000015
Figure PCTCN2020109533-appb-000016
制备工艺：
称取处方量的活性成分A、交联聚维酮、一水乳糖和羟丙甲纤维素混匀；加入纯化水制软材，80目筛制粒，40℃干燥，80目筛整粒，水分控制在2％或以下；折算称取外加原辅料过80目筛混合8次，然后加入干颗粒混匀；压片。测定pH1.0盐酸介质中15分钟的溶出度。
表10实施例25～实施例30的溶出度结果
溶出度(％) 活性成分A 活性成分B
实施例25 99.0 95.8
实施例26 98.5 88.9
实施例27 98.6 96.4
实施例28 93.5 95.2
实施例29 100.6 88.0
实施例30 95.8 92.1
对比例/Avapro(ET01506，规格：75mg) 90.0 /
对比例/Avapro(DT04448，规格：150mg) 92.6 /
对比例/Avapro(DT03090A，规格：300mg) 93.2 /
对比例/FORXIGA(LB0143，规格：5mg) / 92.1
对比例/FORXIGA(KJ3245，规格：10mg) / 91.8
实施例31～实施例33
表11单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000017
制备工艺：
实施例31：称取100片处方量的内加原辅料混匀；混粉用纯化水制软材，40目筛制粒，50℃干燥，40目筛整粒；折算称取外加原辅料混匀；压片。
实施例32：称取25片处方量的内加原辅料混匀，然后用纯化水制软材，40目筛制粒，60℃干燥，40目筛整粒；所得干颗粒折算加入外加原辅料混匀；压片。
实施例33：称取25片处方量的内加原辅料混匀；然后加入纯化水制软材，40目筛制粒，40℃干燥，40目筛整粒；折算称取外加原辅料混匀，压片。
测定各实施例在pH1.0盐酸介质中15分钟的溶出度，结果如下：
表12实施例31～实施例33的溶出度结果
溶出度(％) 活性成分A 活性成分B
实施例31 97.1 94.8
实施例32 89.7 86.5
实施例33 86.7 87.9
实施例34～实施例40
表13单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000018
Figure PCTCN2020109533-appb-000019
表14单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000020
制备工艺：
实施例34、37：a)称取100片处方量的第一层除氢氧化钠和硬脂酸镁外的原辅料混匀；混粉用氢氧化钠水溶液制软材，40目筛制粒，40℃干燥，40目筛整粒；折算加入硬脂酸镁混匀；b)称取第二层的原辅料混匀；c)将第一层总混颗粒和第二层的混粉压双层片。
实施例35、36：a)称取100片处方量的第一层原辅料混匀；b)称取第二层的原辅料混匀；c)将第一层的混粉和第二层的混粉压双层片。
实施例38～实施例40：a)称取100片处方量的第一层的部分硬脂酸镁和全部其他原辅料混匀，干法制粒，然后加入剩余硬脂酸镁混匀；b)称取第二层的部分二氧化硅、硬脂酸镁和所有其他原辅料混匀，干法制粒， 然后加入剩余二氧化硅和硬脂酸镁混匀；c)将第一层的总混颗粒和第二层的总混颗粒压双层片。
测定部分实施例在pH1.0盐酸介质中15分钟的溶出度，结果如下：
表15实施例39、实施例40的溶出度结果
溶出度(％) 奥美沙坦 活性成分A 活性成分B
实施例39 85.6 / 89.8
实施例40 / 87.3 90.1
效果例
表16单位制剂处方组成(mg/片)
Figure PCTCN2020109533-appb-000021
制备工艺：
称取100片处方量的内加原辅料袋混15分钟；然后加入纯化水制软材，40目筛制粒，40℃(实施例42)或50℃(实施例41)干燥，40目筛整粒，水分控制在2％或以下；折算称取外加原辅料袋混10分钟，压片。测定实施例在pH1.0盐酸介质中的溶出曲线。
表17活性成分A在pH1.0盐酸溶液中的累计溶出度(％)
Figure PCTCN2020109533-appb-000022
表18活性成分B在pH1.0盐酸溶液中的累计溶出度(％)
Figure PCTCN2020109533-appb-000023
表19活性成分A有关物质测定结果(％)
Figure PCTCN2020109533-appb-000024
将实施例41和42的自制制剂和参比制剂进行比格犬的PK研究。使用3只比格犬(11.6–14.8kg)进行3周期3交叉研究，其中单方参比制剂A和参比制剂B同时给药。给药后分别于0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、12和24h取血，使用LC-MS进行检测。结果如下：
表20活性成分A的动物实验结果
Figure PCTCN2020109533-appb-000025
表21活性成分B的动物实验结果
Figure PCTCN2020109533-appb-000026
结论：由上述结果知，自制制剂与原研制剂在比格犬体内C max Ratio和AUC 0-24Ratio均在80％-125％范围内，说明自制制剂与原研制剂在比格犬体内生物等效。
以上对本发明所提供的SGLT-2抑制剂与血管紧张素受体阻滞剂的组合物及用途进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (15)

  1. 组合物，其特征在于，包括SGLT-2抑制剂和血管紧张素-II受体拮抗剂。
  2. 如权利要求1所述的组合物，其特征在于，所述SGLT-2抑制剂包括但不限于达格列净(Dapagliflozin)、坎格列净(Canagliflozin)、恩格列净(Empagliflozin)、依格列净(Ipragliflozin)、鲁格列净(Luseogliflozin)、托格列净(Tofogliflozin)、埃格列净(Ertugliflozin)、加格列净(Janagliflozin)、贝格列净(Bexagliflozin)、索格列净(Sotagliflozin)、恒格列净(Henagliflozin)、泰格列净(Tianagliflozin)、瑞格列净(Remogliflozin)、艾格列净(Alligliflozin)、依碳酸瑞格列净(Remogliflozin etabonate)、荣格列净((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxy ethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol)中的一种或两者以上的组合。
  3. 如权利要求1或2所述的组合物，其特征在于，所述血管紧张素-II受体拮抗剂包括但不限于厄贝沙坦(Irbesartan)、坎地沙坦(Candesartan)、缬沙坦(Valsartan)、替米沙坦(Telmisartan)、洛沙坦(Losartan)、依普沙坦(Iprasartan)、奥美沙坦(Olmesartan)、阿齐沙坦(Azilsartan)中的一种或两者以上的组合。
  4. 如权利要求1至3任一项所述的组合物，其特征在于，所述SGLT-2抑制剂包括达格列净或其药用盐、酯、共晶、络合物或溶剂合物中的一种或两者以上的组合；所述血管紧张素-II受体拮抗剂包括厄贝沙坦、其可药用盐或溶剂合物中的一种或两者以上的组合。
  5. 如权利要求1至4任一项所述的组合物，其特征在于，所述SGLT-2抑制剂和所述血管紧张素-II受体拮抗剂的重量比为1:960～300:1，优选1:240～75:1，更优选1:120～1:7.5，更优选(8～300)：(2～300)，最优选8:300、20:12.3、40:12.3、50:4.1、50:2、44.8:3.7、32.5:2.7、150:12.3、150:6.15、75:12.3、300:6.15或300:12.3。。
  6. 如权利要求1至5任一项所述的组合物在制备治疗原发性高血压、合并高血压的2型糖尿病肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症的药物中的应用。
  7. 药物，其特征在于，包括如权利要求1至5任一项所述的组合物及药学上可接受的辅料。
  8. 如权利要求7所述的药物，其特征在于，所述辅料包括但不限于：填充剂，粘合剂，崩解剂，抗粘剂，吸附剂，助流剂，润滑剂，表面活性剂，螯合剂，着色剂，掩味剂中的一种或两者以上的组合。
  9. 如权利要求7或8所述的药物，其特征在于，其剂型包括片剂、胶囊剂、颗粒剂、混悬剂、膜剂中的一种多种，优选为片剂、干混悬剂、胶囊剂、颗粒剂。
  10. 如权利要求7至9任一项所述的药物，其特征在于，所述SGLT2抑制剂和所述血管紧张素-II受体拮抗剂的混合方式包括：
    (1)直接混合；或
    (2)分别作为内加组分或外加组分；或
    (3)同时作为内加组分；或
    (4)分别压片再压制成双层片。
  11. 如权利要求10所述的药物，其特征在于，所述血管紧张素-II受体拮抗剂作为内加组分，所述SGLT-2抑制剂作为外加组分。
  12. 如权利要求7至11任一项所述的药物的制备方法，其特征在于，将原辅料直接混合。
  13. 如权利要求7至11任一项所述的药物的制备方法，其特征在于，包括混合、制粒、整粒、总混的步骤。
  14. 如权利要求7至1任一项所述的药物的制备方法，其特征在于，包括混合、制粒、干燥、整粒、总混的步骤。
  15. 如权利要求7至11任一项所述的药物或如权利要求12～14任一项所述制备方法制得的药物在制备治疗原发性高血压、合并高血压的2型糖尿病肾病、糖尿病、胰岛素抵抗、高血糖、高胰岛素血症、脂肪酸或 甘油的升高的血含量、高脂血、血脂障碍、肥胖、或糖尿病并发症的药物中的应用。
PCT/CN2020/109533 2020-08-17 2020-08-17 Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途 WO2022036506A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN202080105705.3A CN116490178A (zh) 2020-08-17 2020-08-17 Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途
US18/025,751 US20230346817A1 (en) 2020-08-17 2020-08-17 Composition and use of sglt-2 inhibitor and angiotensin receptor blockers
PCT/CN2020/109533 WO2022036506A1 (zh) 2020-08-17 2020-08-17 Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途
EP20949719.7A EP4197543A4 (en) 2020-08-17 2020-08-17 COMPOSITION AND USE OF SGLT-2 INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS
KR1020237009242A KR20230057388A (ko) 2020-08-17 2020-08-17 Sglt-2 억제제와 안지오텐신 수용체 길항제의 조성물 및 이의 용도

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/109533 WO2022036506A1 (zh) 2020-08-17 2020-08-17 Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途

Publications (1)

Publication Number Publication Date
WO2022036506A1 true WO2022036506A1 (zh) 2022-02-24

Family

ID=80323266

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/109533 WO2022036506A1 (zh) 2020-08-17 2020-08-17 Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途

Country Status (5)

Country Link
US (1) US20230346817A1 (zh)
EP (1) EP4197543A4 (zh)
KR (1) KR20230057388A (zh)
CN (1) CN116490178A (zh)
WO (1) WO2022036506A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106316975A (zh) * 2015-06-15 2017-01-11 山东轩竹医药科技有限公司 酰胺类化合物及其作为tgr5激动剂的应用
CN110520133A (zh) * 2017-09-19 2019-11-29 奥托泰利克生物公司 包含钠-葡萄糖协同转运蛋白-2抑制剂及血管紧张素受体阻滞剂的医药组合物
WO2020039394A1 (en) * 2018-08-24 2020-02-27 Novartis Ag New drug combinations
WO2020050677A1 (ko) * 2018-09-07 2020-03-12 오토텔릭바이오 주식회사 안정성이 향상된 의약 조성물

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104780942A (zh) * 2012-08-30 2015-07-15 大正制药株式会社 Sglt2抑制剂和抗高血压药的组合
CN113144204A (zh) * 2014-01-31 2021-07-23 詹森药业有限公司 用于治疗和预防肾病和脂肪肝病的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106316975A (zh) * 2015-06-15 2017-01-11 山东轩竹医药科技有限公司 酰胺类化合物及其作为tgr5激动剂的应用
CN110520133A (zh) * 2017-09-19 2019-11-29 奥托泰利克生物公司 包含钠-葡萄糖协同转运蛋白-2抑制剂及血管紧张素受体阻滞剂的医药组合物
WO2020039394A1 (en) * 2018-08-24 2020-02-27 Novartis Ag New drug combinations
WO2020050677A1 (ko) * 2018-09-07 2020-03-12 오토텔릭바이오 주식회사 안정성이 향상된 의약 조성물

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABDEL-WAHAB ALI F., GHAZI A BAMAGOUS, RANDA M AL-HARIZY, NASER A ELSAWY, NAIYER SHAHZAD, IBRAHIM A IBRAHIM, SAEED S AL GHAMDI : "Renal protective effect of SGLT2 inhibitor dapagliflozin alone and in combination with irbesartan in a rat model of diabetic nephropathy", BIOMEDICINE & PHARMACOTHERAPY, vol. 103, 7 April 2018 (2018-04-07), pages 59 - 66, XP055908647, DOI: 10.1016/j.biopha.2018.03.176 *
GONG, ZHUO: "Clinical Study of Dapagliflozin Combined with Irbesartan in the Treatment of Diabetic Nephropathy", DIABETES NEW WORLD, no. 14, 31 July 2019 (2019-07-31), pages 173 - 174, XP009535026, ISSN: 1672-4062, DOI: 10.16658/j.cnki.1672-4062.2019.14.173 *
LIU JIE, ZHANG JING, HOU MING-HUI, DU WEI-XUAN: "Clinical efficacy of linagliptin combined with irbesartan in patients with diabetic nephropathy", PAKISTAN JOURNAL OF MEDICAL SCIENCE, PROFESSIONAL MEDICAL PUBLICATIONS, KARACHI, PK, vol. 38, no. 1, 1 January 2022 (2022-01-01), PK , XP055908639, ISSN: 1682-024X, DOI: 10.12669/pjms.38.1.4417 *
See also references of EP4197543A4 *

Also Published As

Publication number Publication date
EP4197543A4 (en) 2024-05-15
EP4197543A1 (en) 2023-06-21
CN116490178A (zh) 2023-07-25
US20230346817A1 (en) 2023-11-02
KR20230057388A (ko) 2023-04-28

Similar Documents

Publication Publication Date Title
TWI764000B (zh) 含葡萄糖激酶啟動劑和雙胍類降糖藥物的藥物組合、組合物和複方製劑及其製備方法和用途
JP5284967B2 (ja) 打錠障害を生じない錠剤製剤
JP5779566B2 (ja) ジペプチジルペプチダーゼ−４インヒビターとメトホルミンとを組み合わせた医薬組成物
RU2616516C2 (ru) Фармацевтическая композиция, содержащая олмесартана медоксомил и розувастатин или его соль
JP2012530135A (ja) ジペプチジルペプチダーゼ−４阻害剤及びピオグリタゾンの併用医薬組成物
WO2011069326A1 (zh) 包含阿替洛尔和氨氯地平的双层片剂
KR20120104523A (ko) 디펩티딜 펩티다제―４ 억제제와 피오글리타존의 조합물의 제약 조성물
EP4112047A1 (en) Oral complex tablet comprising sitagliptin, dapagliflozin, and metformin
WO2021086292A1 (en) Bilayer tablet formulations comprising dapagliflozin and metformin
CN116159052A (zh) 联合用药应用以及一种药用组合物及其应用
US20120010216A1 (en) Pharmaceutical compositions containing vanoxerine
US6333361B1 (en) Pharmaceutical composition containing zafirlukast
EP3886817A1 (en) Pharmaceutical composition comprising ramipril and indapamide
WO2022036506A1 (zh) Sglt-2抑制剂与血管紧张素受体阻滞剂的组合物及用途
KR101686265B1 (ko) 타입 2 당뇨병 치료용 약학적 조성물
KR102409102B1 (ko) 제약 조성물
EP2682109B1 (en) Combined immediate release formulations of flurbiprofen and famotidine
CN114306263B (zh) 一种复方降压药物组合物及其制备方法
EP4212150A1 (en) A bilayer tablet composition comprising amorphous dapagliflozin and metformin
EP4079296A1 (en) A bilayer tablet formulation comprising amorphous dapagliflozin and metformin
JP2024524113A (ja) シタグリプチン、ダパグリフロジン及びメトホルミンを含む経口用複合錠剤
CN113226315A (zh) 一种含有肾脏钾离子外排通道抑制剂的药物组合物及其制备方法
EP4008315A1 (en) A process for formulations of dapagliflozin and metformin hydrochloride
TWI484955B (zh) 治療包括人類之哺乳動物中第２型糖尿病的醫藥組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20949719

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 20237009242

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2020949719

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020949719

Country of ref document: EP

Effective date: 20230317

WWE Wipo information: entry into national phase

Ref document number: 202080105705.3

Country of ref document: CN