WO2020173476A1 - Composition pharmaceutique contenant un inhibiteur du canal potassique médullaire externe rénal et son procédé de préparation - Google Patents

Composition pharmaceutique contenant un inhibiteur du canal potassique médullaire externe rénal et son procédé de préparation Download PDF

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Publication number
WO2020173476A1
WO2020173476A1 PCT/CN2020/076925 CN2020076925W WO2020173476A1 WO 2020173476 A1 WO2020173476 A1 WO 2020173476A1 CN 2020076925 W CN2020076925 W CN 2020076925W WO 2020173476 A1 WO2020173476 A1 WO 2020173476A1
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pharmaceutical composition
content
total weight
composition according
ethyl
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English (en)
Chinese (zh)
Inventor
奚宏磊
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to CN202080007525.1A priority Critical patent/CN113226315B/zh
Publication of WO2020173476A1 publication Critical patent/WO2020173476A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This application belongs to the field of medical technology, and relates to a pharmaceutical composition containing a renal potassium efflux channel (ROMK) inhibitor.
  • ROMK renal potassium efflux channel
  • Diuretics are generally recommended as first-line antihypertensive drugs in the latest national hypertension guidelines, and are suitable for mild to moderate hypertension, especially in elderly hypertension or complicated by heart failure. According to statistics, there were nearly 263 million hypertensive patients in China in 2010, and the diuretic use rate of hypertensive population was 10%, and there is a lot of room for growth.
  • ROMK new rake point antihypertensive diuretic development ROMK for the inward rectifier K + channels (inwardly rectifying K channels, Kir) a family, belong Kiri type, the maintenance of renal potassium ions play a crucial balance effect.
  • ROMK1 is mostly distributed in the ascending limb of Henle (TALH); ROMK1 and ROMK3 are mainly expressed in the cortical collecting duct (CCD).
  • ROMK expressed in TALH and Na + /K72Cl_ transporter regulate the secretion and reabsorption of sodium and potassium ions
  • ROMK expressed in CCD and Na + /K + transporter regulate the secretion of potassium ions together. Therefore, blocking the ROMK site can not only diuresis and lower blood pressure by inhibiting the reabsorption of Na + , but also does not cause hypokalemia due to excessive reduction of serum potassium, which is a good diuretic research direction.
  • WO2016091042A1 discloses a class of extrarenal medullary secretory potassium channel (ROMK) inhibitors, chemically named (8) -5-cyano-AK1_(2-hydroxy-2-(4-methyl) -1-carbonyl-1,3-dihydro Isobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide.
  • ROMK extrarenal medullary secretory potassium channel
  • the active compound must be provided to the patient in the form of a composition in order to use its activity to effectively treat various diseases, and the appropriate components can overcome the stability and dissolution problems.
  • This application provides a pharmaceutical composition containing the active substance (8) -5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzo Furan-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt and at least one pharmaceutical excipient, the content of impurity A in the pharmaceutical composition is less than 0.5% of the total weight of the active material, preferably less than 0.1% of the total weight of the active material, the content of impurity B is less than 1.0% of the total weight of the active material, preferably less than 0.5% of the total weight of the active material, where impurities A and B refer to
  • the detection method detects impurities with a relative retention time of 0.44 (impurity A) and a relative retention time of 0.62 (impurity B)
  • the detection method is as follows: Chromatographic column: Phenomenex Luna, 4.6 mmx200 mm, 5 (
  • This application provides a pharmaceutical composition containing the active substance CR>5-cyano-N-(1-(2-hydroxyl-2-(4-methyl-1-carbonyl-1,3-di Hydroisobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient, the pharmaceutical composition does not Contains polyethylene glycol and/or polyvinyl alcohol.
  • the pharmaceutical excipient can be selected from at least one pharmaceutical excipient selected from fillers, disintegrants, glidants, and lubricants.
  • the filler can be selected from glucose, sucrose, mannitol, sorbitol, lactose, pregelatinized starch, dextrin, silicified microcrystalline cellulose, microcrystalline cellulose, and cellulose -One or more of lactose, preferably one or more of lactose, microcrystalline cellulose, and cellulose-lactose.
  • the content of the filler may be 20%-99% of the total weight of the pharmaceutical composition, preferably 50%-95%.
  • Disintegrants are substances that can quickly break the tablets into fine particles in the gastrointestinal juice, so that the functional ingredients can be quickly dissolved and absorbed, and play a role. Most of them have good water absorption and swelling properties, so as to realize the disintegration of oral preparations. solution.
  • the disintegrant can be selected from one of crospovidone, croscarmellose sodium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose Or more, preferably low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, most preferably low-substituted hydroxypropyl cellulose.
  • the content of the disintegrant in the pharmaceutical composition provided in the present application can be 0.5%-20% of the total weight of the composition, preferably 1%-10%, specifically 0.5%, 0.6%, 0.7%, 0.8%, 0.9% , 1.0%, 1.2%,
  • the pharmaceutical composition provided in the present application optionally contains a binder, and the binder may be selected from the group consisting of hydroxypropyl methylcellulose, starch slurry, mucilage, povidone, methylcellulose, One or more of ethyl cellulose and sodium carboxymethyl cellulose.
  • the content of the binder may account for 0.1%-20% of the total weight of the pharmaceutical composition, preferably 1%-10%, most preferably 2%-5%.
  • Lubricants are generally used to facilitate processing, prevent the formulation material from adhering to the production equipment, reduce friction between particles, improve the flow rate of the formulation, and help the formulation to be discharged from the production equipment.
  • the lubricant can be selected from magnesium stearate, stearic acid, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, palmitic acid, and stearin
  • One or more of calcium acid, talc, silicon dioxide, carnauba wax, sodium stearyl fumarate, preferably magnesium stearate, and the content of the lubricant may be 0.1% of the total weight of the pharmaceutical composition 5%, preferably 0.1%-3%, most preferably 0.1%-1.5%, specifically 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1% , 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%.
  • the glidant may be selected from one or more of silicon dioxide, corn starch, micronized silica gel, and talc, preferably silicon dioxide, and the content of the glidant It can be 0.1%-8% of the total weight of the composition, preferably 0.5%-5%, most preferably 1.0%-3.0%.
  • the content of the active substance may be 0.1%-25% of the total weight of the pharmaceutical composition, preferably 0.5%-20%.
  • the pharmaceutical composition contains an active substance (R>5-cyano-N-(1-(2-hydroxyl-2-(4-methyl-1-carbonyl-1,3-di Hydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient, in the pharmaceutical composition
  • the content of impurity A is less than 0.5% of the total weight of the active material, and the content of impurity B is less than 1.0% of the total weight of the active material.
  • the filler is selected from lactose, microcrystalline cellulose, cellulose-lactose, preferably cellulose-lactose, and the content is 20%-99% of the total weight of the composition, preferably 50%-95% ;
  • the disintegrant is selected from low-substituted hydroxypropyl cellulose and/or croscarmellose sodium, preferably low-substituted hydroxypropyl cellulose ,
  • the content is the drug group 0.5%-20% of the total weight of the compound, preferably 1%-10% ;
  • the lubricant is magnesium stearate, and the content is 0.1%-3% of the total weight of the pharmaceutical composition, most preferably 0.1%-1.5% ;
  • the agent is silicon dioxide, and the content is 0.5%-5% of the total weight of the pharmaceutical composition, most preferably 1.0%-3.0%.
  • (R)-5 -cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroiso) The content of benzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt can be 0.5 mg-100 mg, preferably 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg , 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, most preferably 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg.
  • the pharmaceutical composition provided in this application may be a tablet, granule, powder (including fine granules) or a capsule, preferably a tablet.
  • the tablet or granule may also contain at least one coating material, and the coating material may be selected from hypromellose, ethylcellulose, methylcellulose, Hydroxypropyl cellulose, povidone, polyvinyl acetate resin polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion One or more of body, Opadry.
  • the coating material may be selected from hypromellose, ethylcellulose, methylcellulose, Hydroxypropyl cellulose, povidone, polyvinyl acetate resin polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer dispersion One or more of body, Opadry.
  • the active substance in the preferred pharmaceutical combination of this application (8) -5 -cyano-N- (1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran- 5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or its pharmaceutically acceptable salt.
  • the particle size d0.9 is less than 80 fim, preferably d0.9 is less than 60 fim, most preferably d0 .9 is less than 40 fim.
  • the pharmaceutically acceptable salt of benzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate Salt, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, right Tosylate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilla Acid salt, mandelate, succinate, gluconate, citrate, benzene sulfonate, hydrobromide, fumarate, hydrobromid
  • Another aspect of the present application provides a method for preparing the above-mentioned pharmaceutical composition, comprising: 1) (R)-5 -cyano-N-(1-(2-hydroxy-2-(4-methyl-1-carbonyl) -1,3-dihydroisobenzofuran-5-yl) ethyl) piperidin-4-yl)-4-methoxypyridinecarboxamide or a pharmaceutically acceptable salt thereof and selected from fillers and optionally selected from The step of mixing at least one pharmaceutical excipient among disintegrant, glidant and lubricant; 2) the step of wet granulation, dry granulation, direct compression or capsule filling of the mixture obtained from step 1) , The step 2) is preferably dry granulation or direct compression.
  • the preparation method of the pharmaceutical composition provided in the present application further includes a coating step after the tableting step, and the coating agent used can be selected from Opadry, hypromellose, and ethyl cellulose One or more, preferably Opadry, which does not contain polyvinyl alcohol and/or polyethylene glycol.
  • the pharmaceutical composition described in the present application is a tablet
  • it can be prepared by compressing the granules obtained as described above, and the shape of the tablet is not particularly limited, preferably lentil, disc, round, oval (such as capsule). Tablets:), teardrop-shaped or polygonal (such as triangles or diamonds)>
  • the prepared tablets can be coated by spraying a suspension/solution of the coating agent with a pan coater (pan coater:).
  • the granules obtained as described above can be used directly or can be granulated into a desired granular shape by appropriate techniques.
  • the granules thus prepared can be coated with a coating agent by spraying a suspension/solution of the coating agent.
  • the diseases may be selected from liver cirrhosis, acute and chronic renal insufficiency, nephrotic syndrome, pulmonary hypertension , Cardiovascular disease, myocardial infarction, stroke, heart failure, pulmonary hypertonia, atherosclerosis and kidney stones.
  • the pharmaceutical composition provided in this application is placed at 60 ° C. After 30 days, the content of impurity A in the pharmaceutical composition does not exceed 0.5%, preferably not more than 0.1%; the content of impurity B in the composition does not exceed 1.0 %, preferably not more than 0.5%. Put the pharmaceutical composition provided by this application in an aluminum foil bag and place it at 60 ° C. After 30 days, the content of impurity A in the pharmaceutical composition does not exceed 0.5%, preferably not more than 0.1%; the content of impurity B does not It exceeds 1.0%, preferably not more than 0.5%. detailed description
  • WO2017211271A discloses (R)-5-cyano-N-( 1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl (Yl) piperidin-4-yl)-4-methoxypyridine carboxamide and its L-tartrate salt preparation method.
  • the pharmaceutical excipients used in this application can all be purchased through commercial channels.
  • the active pharmaceutical ingredient (8) -5 -cyano-N- (1- (2-hydroxy-2-( 4 -methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl)piperidin-4-yl)-4 -methoxypyridinecarboxamide L (+) -tartrate is mixed with lactose, microcrystalline cellulose, croscarmellose sodium, and the binder is polyvinylpyrrolidone
  • the K30 aqueous solution is prepared by high-speed shear granulation process to prepare granules, and then the granules are dried with a water content of less than 3%, sieved, and then mixed with magnesium stearate to be uniformly compressed into tablets, and the composition 1 is obtained.
  • the active pharmaceutical ingredient (8) -5 -cyano-N- (1- (2 -hydroxy-2-(4 -methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl) (Ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide L (+) -tartrate with lactose, microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone K30, stearin Magnesium acid was mixed and uniformly compressed into tablets to obtain composition 2.
  • the active pharmaceutical ingredient (8) -5 -cyano-N- (1- (2-hydroxy-2-( 4 -methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl)piperidin-4-yl)-4-methoxypyridinecarboxamide L (+) -tartrate and cellulose-lactose, croscarmellose sodium, silicon dioxide, and magnesium stearate are mixed uniformly Compressed into tablets, the composition 3 was obtained.
  • composition 2 has better stability during the stability test. Show The water added in the wet granulation process will have a significant impact on the levels of impurities A and B, and the powder direct pressing process is better.
  • the active pharmaceutical ingredient (8) -5-cyano-N- (1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl) piperidine-4-yl) -4-methoxypyridinecarboxamide L( +) -tartrate and cellulose-lactose, croscarmellose sodium or low-substituted hydroxypropyl cellulose, dioxide
  • the silicon and magnesium stearate were mixed and uniformly compressed into tablets to obtain compositions 4 and 5.
  • compositions 6-8 On the basis of composition 5, coating was prepared to prepare compositions 6-8, the composition of which is shown in Table 6.
  • composition 6 into a thermostat at 40 ° C, 60 ° C, 25 ° C ⁇ 2 ° C/RH75% ⁇ 5% and 25 ° C ⁇ 2 ° C/RH90% ⁇ 5%, light (total)
  • the illuminance is greater than 1.2*10 6 Lux-hr) and placed without packaging. Samples were taken at 5 days, 10 days, and 30 days to detect the impurity content and dissolution. The measurement results are shown in Table 8.
  • composition 7 was packaged in a polyester/aluminum/polyethylene medicinal composite bag, and placed at 40 ° C ⁇ 2 ° C/RH75% ⁇ 5% for 6 months and 25 ° 0 ⁇ 2 ° 0/111160% ⁇
  • the stability of the impurity content and dissolution rate of composition 7 was investigated under the condition of 5% for 12 months. The measurement results are shown in Table 9 and Table 10.
  • the active pharmaceutical ingredient (8) -5-cyano-N- (1-(2-hydroxy-2-(4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl) ethyl Yl) piperidine-4-yl) -4-methoxypyridinecarboxamide L( +) -tartrate and cellulose-lactose, croscarmellose sodium or low-substituted hydroxypropyl cellulose, dioxide Silicon and magnesium stearate are uniformly mixed and compressed into tablets, and then coated with a film coating premix to obtain composition 9.
  • composition 9 in a polyester/aluminum/polyethylene medicinal composite bag, and place it at 40 ° C ⁇ 2 ° C/RH75% ⁇ 5% for 6 months and 25 ° C ⁇ 2 ° C/RH60% ⁇
  • the stability of the impurity content and dissolution rate of Composition 9 was examined for 12 months under the condition of 5%.
  • the measurement results are shown in Table 12 and Table 13.

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  • Bioinformatics & Cheminformatics (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique contenant un inhibiteur du canal potassique médullaire externe rénal et son procédé de préparation. La composition pharmaceutique contient du (R)-5-cyano-N-(1-(2-hydroxy-2-(4-méthyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl)éthyl)pipéridin-4-yl)-4-méthoxy pyridine carboxamide ou un sel pharmaceutiquement acceptable de celui-ci. La composition pharmaceutique présente un bon taux de dissolution et une excellente stabilité.
PCT/CN2020/076925 2019-02-28 2020-02-27 Composition pharmaceutique contenant un inhibiteur du canal potassique médullaire externe rénal et son procédé de préparation Ceased WO2020173476A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080007525.1A CN113226315B (zh) 2019-02-28 2020-02-27 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

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910152541 2019-02-28
CN201910152541.9 2019-02-28

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WO2020173476A1 true WO2020173476A1 (fr) 2020-09-03

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PCT/CN2020/076925 Ceased WO2020173476A1 (fr) 2019-02-28 2020-02-27 Composition pharmaceutique contenant un inhibiteur du canal potassique médullaire externe rénal et son procédé de préparation

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CN (1) CN113226315B (fr)
TW (1) TW202045170A (fr)
WO (1) WO2020173476A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016091042A1 (fr) * 2014-12-08 2016-06-16 江苏恒瑞医药股份有限公司 Dérivés du pyridinecarboxamide, méthode de préparation de ces derniers, et utilisations pharmaceutiques de ce derniers
CN108113988A (zh) * 2016-11-29 2018-06-05 江苏恒瑞医药股份有限公司 一种romk抑制剂与arb联合在制备治疗和/或预防高血压或心力衰竭的药物中的用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2018014759A (es) * 2016-06-07 2019-03-11 Jiangsu Hengrui Medicine Co Sal farmaceuticamente aceptable como inhibidor del canal de potasio medular externo renal.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016091042A1 (fr) * 2014-12-08 2016-06-16 江苏恒瑞医药股份有限公司 Dérivés du pyridinecarboxamide, méthode de préparation de ces derniers, et utilisations pharmaceutiques de ce derniers
CN108113988A (zh) * 2016-11-29 2018-06-05 江苏恒瑞医药股份有限公司 一种romk抑制剂与arb联合在制备治疗和/或预防高血压或心力衰竭的药物中的用途

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