WO2009146608A1 - Compositions pharmaceutiques contenant des dérivés de l’acide imidazole-5-carboxylique et leur procédé de préparation et leur utilisation - Google Patents

Compositions pharmaceutiques contenant des dérivés de l’acide imidazole-5-carboxylique et leur procédé de préparation et leur utilisation Download PDF

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Publication number
WO2009146608A1
WO2009146608A1 PCT/CN2009/000629 CN2009000629W WO2009146608A1 WO 2009146608 A1 WO2009146608 A1 WO 2009146608A1 CN 2009000629 W CN2009000629 W CN 2009000629W WO 2009146608 A1 WO2009146608 A1 WO 2009146608A1
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Prior art keywords
pharmaceutical composition
preparation
sodium
carboxylic acid
biphenyl
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PCT/CN2009/000629
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English (en)
Chinese (zh)
Inventor
郭建辉
卢耀茹
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上海艾力斯医药科技有限公司
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Priority to CN2009801207980A priority Critical patent/CN102088972B/zh
Publication of WO2009146608A1 publication Critical patent/WO2009146608A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic 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
    • A61K31/33—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
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing an imidazole-5-carboxylic acid derivative as an active ingredient, a preparation method of the pharmaceutical composition and a preparation for reducing blood pressure of a mammal The use, especially for the preparation of antihypertensive drugs. Background technique
  • Angiotensin II is a major vasoconstrictor of the renin-angiotensin-aldosterone system (RAAS), which plays an important role in the pathophysiology of a variety of chronic diseases. It exists in a variety of tissues, and its pathway is mainly: angiotensinogen can be converted into ten-peptide angiotensin I (Angl) by renin, and Angl has only weak contractile blood vessels, which can be further Angiotensin II (Ang II), which is converted to octapeptide by angiotensin-converting enzyme. It is the ultimate physiologically active substance of RAAS. It can bind to specific angiotensin II receptor to produce vasoconstriction. Higher physiological effects.
  • RAAS renin-angiotensin-aldosterone system
  • EP0253310 discloses a series of imidazole derivatives, and the applicant of DuPont Company of the United States has developed a modern blood pressure lowering effect, and was approved for marketing in 1994, becoming the first non-peptide Ang ll.
  • the receptor antagonist namely losartan potassium, inhibits vasoconstriction by selectively blocking the action of angiotensin II of vascular smooth muscle on its type I receptor, thereby achieving the effect of relaxing blood vessels and lowering blood pressure.
  • U.S. Patent No. 5,1964,446 discloses a series of benzimidazole derivatives and processes for their preparation which have angiotensin-antagonist activity and antihypertensive activity and are useful as therapeutic high blood pressure.
  • candesartan ester was developed and marketed by Japan Takeda Company in 1997. It removes ester groups in the body, hydrolyzes into active metabolites, and exerts blood pressure lowering effect.
  • US Pat. No. 5,616,599 discloses a series of 1-linked albendazole imidazoles similar in structure to losartan. The greatest structural change is the conversion of the chlorine atom at the 4-position of the losartanazole ring to 1-hydroxy-1-methyl. Ethyl, 5 positions were modified into carboxyl, hydroxyl and prodrug structure esters or amides, which proved to have a good blood pressure lowering effect, and the Japanese Sankyo Company developed and marketed olmesartan.
  • R is selected from hydrogen, C1-C4 straight or branched alkyl, or C3-C7 cycloalkyl; wherein the alkyl or cycloalkyl is unsubstituted or is 1-3 Substituted by the following substituents: F, Cl, Br, or OH;
  • M is a metal ion or an ammonium ion.
  • 1-[(Isopropoxy)carbonyloxy]nonyl ester has significant angiotensin receptor II antagonistic activity. Compared with other Ang II receptor antagonists, 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, ⁇ -biphenyl-methyl]imidazole- 5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester has the advantage of a more economical metabolic pathway and safer use.
  • the present invention provides a pharmaceutical composition having a blood pressure lowering effect, which comprises a pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, ⁇ - a pharmaceutically acceptable salt of a biphenyl-indenyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester, and a pharmaceutically acceptable diluent or carrier material, 1%-99%, preferably 1-80% by weight of the pharmaceutical composition.
  • the pharmaceutical composition of the invention has simple preparation, low impurity content and excellent formulation performance.
  • the present invention also provides a process for the preparation of the pharmaceutical composition which is prepared by a conventional method. More specifically, the present invention preferably provides a pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-1,1 '-biphenyl- a pharmaceutically acceptable salt of imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester, and granules, tablets of pharmaceutically acceptable diluent or carrier material Or a method for preparing a capsule, wherein the pharmacologically active ingredient comprises 0.1% to 99% by weight of the pharmaceutical composition, and the preparation method comprises dry granulation, fluidized bed wet granulation, or non-aqueous use A particle preparation step of another wet granulation method in which a solvent is used as a binder, wherein a particle preparation step of dry granulation, fluidized bed wet granulation, or other conventional wet
  • Other objects of the invention include a method of treating cardiovascular disease in a mammal, particularly a primate, more particularly a human, comprising administering to a subject a pharmacologically effective amount of 2-butyl-4-chloro- 1-[2'-(1 ⁇ -tetrazol-5-yl)-1, anthracene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]indolyl
  • a pharmaceutical composition of a pharmaceutically acceptable salt of an ester is used in reducing blood pressure in mammals, especially primates, and more particularly in human patients.
  • the present invention provides the use of the pharmaceutical composition described in the manufacture of a medicament for lowering blood pressure in a mammal.
  • active ingredient or “pharmacologically active ingredient” refers to 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, fluorene-biphenyl.
  • a pharmaceutically acceptable salt of a pyridyl-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester, specifically which form of the salt, should be determined according to its context Its exact meaning; unless otherwise specified or undetermined, refers to the 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole described in the relevant part of the present invention, A pharmaceutically acceptable salt of ⁇ -biphenyl-indenyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester.
  • the term "pharmaceutically acceptable salt” refers to a relatively non-toxic salt, preferably an alkali metal or alkaline earth metal salt such as a potassium salt, a sodium salt, a lithium salt, a magnesium salt, a calcium salt, a zinc salt. Particularly preferred is a potassium salt. Unless otherwise specified, salts in the form of their different crystal forms, different isomers, hydrates, etc., are included.
  • composition is a form in which the active ingredient is co-presented with at least one carrier or diluent. It is to be understood that the term “composition” is not limited to a certain physical form or form.
  • accelerated test face is well known to those skilled in the art, for example, see Chinese Pharmacopoeia 2005 edition, Part II Appendix XI X "Stability Guideline", which refers to under extraordinary conditions, Accelerate the chemical or physical changes of the drug, study the stability of the drug, the experimental conditions are generally 40 ⁇ 2 ° C, the relative humidity of 75 soil 5%.
  • the term ""substance” experimental determination” can be found, for example, in the Chinese Pharmacopoeia 2005 edition, Part II Appendix XI XF "Guidelines for the Analysis of Pharmaceutical Impurities", including in the drug substance and in the preparation.
  • the determination of impurity content which guides the use of various modern separation and analysis methods, separates the main components from impurities and degradation products, and the detection limit should meet the requirements of limit inspection.
  • the quantitative limit of the method should meet the corresponding requirements. Requirements.
  • the measurement method is well known to those skilled in the art, and different methods can be selected as needed. For example, in the present invention, an area normalization method of high performance liquid chromatography is employed for the above quantitative measurement method.
  • multi-shield refers to impurities that are produced by the production process or raw materials in the drugs produced according to the prescribed processes and prescribed raw materials approved by the relevant drug regulatory authorities in accordance with the law. Degradation products confirmed during the storage process confirmed by sex tests. If the object to be inspected cannot be clearly identified as a single substance and only a certain type of substance, the item name may be "other carcass”, “other alkaloids”, “other amino acids”, “reducing acid”, “fatty acids”. ,, , “aromatic primary amine”, “chlorine-containing compound”, “residual solvent” or “related substances”, etc.
  • pharmacologically effective amount or "therapeutically effective amount” as used herein with respect to an active ingredient, means: providing a patient in need of treatment for hypertension or other cardiovascular-related disease in a large amount, which is desired to be administered to the pharmacologically active ingredient.
  • the dosage of the drug for a particular pharmacological response. It is emphasized that in a particular example, even if the skilled artisan is deemed to be a "therapeutically effective amount", a therapeutically effective amount of the drug administered to a particular patient is for treating the disease described herein. It is not always effective.
  • the dose of the active ingredient is determined by oral dose or by the level of the drug determined in the blood.
  • the present invention provides 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, fluorenyl-biphenyl-indenyl]imidazol-5-carboxylic acid, 1- [ A pharmaceutically acceptable salt of (isopropoxy)carbonyloxycarbonyl], preferably a pharmaceutical composition of a potassium salt, a sodium salt or a calcium salt.
  • the pharmaceutical composition of the present invention comprises 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid
  • a pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]decyl ester as an active ingredient further comprises a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable salt of 5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester is from 0.1% to 99% by weight of the pharmaceutical composition, and the rest is a pharmaceutically acceptable carrier. Or thinner.
  • a further preferred embodiment is: the pharmacologically active ingredient 2-butyl-4-chloro-1 -[2'-(1 ⁇ -tetrazol-5-yl)-1,1 '-biphenyl-fluorenyl
  • the pharmaceutically acceptable salt of imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester is from 1% to 80% by weight, more preferably 5% by weight of the pharmaceutical composition. -70°/. The remainder are pharmaceutically acceptable carriers or diluents.
  • the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazole-5-yl)-1,1 '-biphenyl-methyl] contained in the pharmaceutical composition of the present invention a pharmaceutically acceptable salt of imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester, optionally in the form of a potassium salt, or in the form of a sodium salt, or It is in the form of a calcium salt, with the potassium salt form being most preferred.
  • Optional liquid diluents such as physiologically acceptable liquid types: water, physiological saline, physiologically acceptable concentrations of ethanol solution, liquid polyethylene glycol, edible oils (e.g., corn oil, peanut oil, and sesame oil). It may also contain additional additives such as paraoxonates, sorbic acid, antioxidants such as vitamin C, vitamin E and cysteine, and flavoring agents, which may be selected from the group consisting of aspartame and stevia.
  • Glucosamine fructose, glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin, licorice and various flavors
  • the odorant is selected from aromatic oils
  • the colorant is selected from artificial Or synthetic pigments, etc.
  • the active ingredient 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, indole-biphenyl-methyl]imidazol-5-carboxylate is from 0.1% to 90%, preferably from 1% to 80%, more preferably 5%, based on the total weight of the liquid formulation. 70%.
  • the preparation is prepared in a conventional manner.
  • the present invention 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazol-5-carboxylic acid, 1 -
  • a pharmaceutical composition of a pharmaceutically acceptable salt of isopropoxy)carbonyloxy]methyl ester is: Prepared as an oral solid preparation, for example: an orally administrable tablet, capsule, powder, Granules, pills, pellets, dry suspensions.
  • a pharmaceutically acceptable carrier or diluent is included in the composition of the present invention.
  • the carrier material includes one or more of a filler, a disintegrant, a wetting agent, a binder, a lubricant, a surfactant, a flavoring agent, a flavoring agent, and a coloring agent.
  • the inventors have unexpectedly discovered in the preparation of oral solid preparations that the application of some carrier materials containing crystal water or some other carrier materials may cause the preparation to be tested in "related substances" (Chinese Pharmacopoeia 2005 edition, Part 2) , Ibid.) In the method or in the accelerated test (40 °C, RH75%) for l-3 months, the content of related impurities in the active ingredient increases more, which may lead to excessive substances.
  • the present inventors have screened the following carrier materials by a large number of experiments, including one or more of a filler, a disintegrant, a surfactant, a binder, a lubricant, a flavoring agent, a flavoring agent, or a coloring agent.
  • the above-mentioned carrier material other than the binder has a loss on drying of less than 20% by weight, more preferably the loss on drying is less than 15% by weight, more preferably less than 10% by weight, more preferably less than 5% by weight, more preferably Less than 3% by weight, more preferably less than 1% by weight.
  • the filler is selected from one or more of the group consisting of: starch, compressible starch, dextrin, sucrose, lactose, fructose, glucose, xylitol, mannitol , microcrystalline cellulose, calcium carbonate, magnesium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, magnesium oxide, aluminum hydroxide, calcium carboxymethyl cellulose, carboxymethyl cellulose Sodium, among which microcrystalline cellulose, lactose, calcium carbonate, mannitol, and anhydrous calcium hydrogen phosphate are preferred.
  • the disintegrant may be selected from one or more of the group consisting of starch, sodium carboxymethyl starch, hydroxypropyl starch, croscarmellose sodium, Crosslinked polyethylpyrrolidone, low substituted hydroxypropyl fluorenyl cellulose, and effervescent disintegrants such as a mixture of tartaric acid and sodium bicarbonate.
  • the surfactant may be selected from one or more of the group consisting of sodium lauryl sulfate, poloxamer, Tween, cetyl bromide. Trimethylammonium, sodium lauryl sulfate, sodium stearyl sulfonate, polyoxyethylene higher fatty alcohol, sucrose ester, sorbitan fatty acid ester, soybean phospholipid, alginic acid, sodium alginate, colloidal magnesium aluminum silicate.
  • the binder may be selected from one or more of the following: hydroxypropyl decyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, starch syrup, Dextrin, glucose and its syrup, sucrose and its syrup, lactose and its syrup, fructose and its syrup, sorbitol, gelatin cement, gum arabic, sassafras, microcrystalline cellulose, water, ethanol, isopropyl An alcohol, preferably one or more of polyvinylpyrrolidone, ethanol, isopropanol, water, starch slurry, microcrystalline cellulose, particularly preferably microcrystalline cellulose, a combination of polyvinylpyrrolidone and water, polyvinylpyrrolidone and A combination of ethanol, and a combination of polyvinylpyrrolidone, water, and ethanol.
  • the lubricant may be selected from one or more of the following: stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, monostearyl Glycerylglycerol, palm stearin, magnesium lauryl sulfate, polyethylene glycol, sodium stearyl fumarate, preferably magnesium stearate.
  • the other modified excipients may be selected from one or more of the following: flavoring agents, which may be selected from the group consisting of aspartame, stevioside, fructose , glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin, glycophyllin and various flavors; the odorant is selected from the group consisting of aromatic oils; the colorant is selected from artificial or synthetic pigment.
  • flavoring agents which may be selected from the group consisting of aspartame, stevioside, fructose , glucose, syrup, honey, xylitol, mannitol, lactose, sorbitol, maltitol, glycyrrhizin, glycophyllin and various flavors
  • the odorant is selected from the group consisting of aromatic oils
  • the colorant is selected from artificial or synthetic pigment.
  • the carrier is not limited to the above-described kind, and an additive which is usually used in the preparation of the solid pharmaceutical composition may be included in the oral solid composition of the present invention as long as it is suitable for the characteristics of the active ingredient and a specific formulation process.
  • the additives which are usually used in the preparation of the pharmaceutical composition may also be included in the pharmaceutical composition of the present invention, such as flavoring agents, pigments and the like, as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration desired. Tablets and pills can also be covered with casing or thin Membrane or sugar coating.
  • the oral solid pharmaceutical composition of the present invention may also be a solid preparation which is dispersed in a liquid before administration and then swallowed, or can be disintegrated into a granular state in the oral cavity to avoid swallowing a large volume of a solid preparation, such as an orally disintegrating tablet, dispersed. Tablets, effervescent tablets, which would be very beneficial for patients with dysphagia.
  • Carrier materials with excellent disintegration and/or dispersion properties should be added at this time, including but not limited to:
  • An excellent disintegrant if it is selected from the group consisting of cross-linked polyvinylpyrrolidone, croscarmellose sodium or sodium carboxymethyl starch, but is not limited thereto, and the amount thereof is 1 - 10% by weight of the total tablet, preferably 4 10%, can make tablets quickly disintegrate after encountering water.
  • the binder should be selected from substances which have good compressibility and can be used as a dry binder, and which have strong disintegration properties, such as microcrystalline cellulose, Sodium carboxymethyl cellulose, hydroxypropyl decyl cellulose, low-substituted hydroxypropyl cellulose, and the like.
  • effervescent agent a substance which can generate carbon dioxide gas in water is added to the tablet.
  • This substance is often called an effervescent agent (effervescent disintegrant) in the preparation, and the effervescent agent contained in the composition of the present invention can be used. It is selected from the group consisting of organic acids such as tartaric acid or a combination of malic acid and sodium hydrogencarbonate, or a combination of phosphates, or an organic acid anhydride such as succinic acid liver or citrate liver, which can also achieve rapid disintegration.
  • the resulting tablets are called effervescent tablets (or effervescent disintegrating tablets).
  • the effervescent disintegrant is selected from the group consisting of tartaric acid and sodium hydrogencarbonate, and the ratio of tartaric acid to sodium hydrogencarbonate is 1: 0.8-1.2.
  • Suitable effervescent agents are: Suitable organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, succinic acid, boric acid, maleic acid, alginic acid and their anhydrides and acid salts, etc., suitable hydrogencarbonate Salts such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, magnesium carbonate, sodium glycinate, L-lysine carbonate, and arginine carbonate, and the like. Effervescent tablets can be prepared according to conventional methods.
  • Suitable Surfactants The use of suitable surfactants is beneficial for promoting tablet disintegration and release of active ingredients.
  • It may be selected from one or more of the following: sodium lauryl sulfate, poloxamer, Tween, cetyltrimethylammonium bromide, sodium lauryl sulfate, stearyl sulfonic acid Sodium, polyoxyethylene higher fatty alcohol, sucrose ester, sorbitan fatty ester, soybean phospholipid, and the like.
  • the active ingredient 2-butyl-4-chloro-1 -[2'-(1 ⁇ -tetrazol-5-yl)-indole, hydrazine-biphenyl-methyl]imidazole is from 1% to 80%, more preferably from 5% to 70%, based on the total weight of the solid preparation. More preferably, it is 30% - 60%.
  • Applicants have determined the following preferred oral solid compositions by extensive extensive testing: Pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-indole, ⁇ - biphenyl-indenyl]imidazol-5-carboxylic acid, pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]nonyl ester, 30%-60% by weight of the total solid preparation, The filler accounts for 20%-67% of the total weight of the solid preparation, the disintegrant accounts for 1%-10% of the total weight of the solid preparation, and the binder accounts for 0%-10% of the total weight of the solid preparation (for some preparation methods, the direct compression method may be carried out without using a binder, and when the binder is used, the content is preferably from 1% to 10%, and the lubricant is 0.1% to 5% by weight of the total weight of the solid preparation.
  • the filler is selected from one or more of microcrystalline cellulose, lactose, calcium carbonate, mannitol, and anhydrous calcium hydrogen phosphate;
  • the disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone, cross-linked carboxy-based fiber Sodium or sodium carboxymethyl starch;
  • the binder is selected from the group consisting of a combination of polyvinylpyrrolidone and water, a combination of polyvinylpyrrolidone and ethanol, and polyvinylpyrrolidone, a combination of water and ethanol;
  • the lubricant is selected from the group consisting of magnesium stearate and talc.
  • the present invention further provides a process for the preparation of the above solid oral pharmaceutical composition.
  • the scattered The preparation method of the agent may be, for example, sufficient drying and pulverization of the active ingredient and the carrier material, preferably a dry pulverization method, wherein the pulverized material can pass through the No. 6 sieve and the fine powder content is not less than 95%, and the pulverized materials are hooked. Mix, divided dose, packaging.
  • the granules can be prepared by a conventional preparation method such as wet granulation and dry granulation.
  • a conventional preparation method such as wet granulation and dry granulation.
  • a conventional wet granulation method such as high shear granulation
  • a preparation prepared by a sieve granulation method is used.
  • the relevant substances in the "assay" method or during the accelerated test (40 °C, RH75%) for 1-3 months increase the content of related impurities of the active ingredient, which may lead to excessive substances.
  • the preparation method of the granules is preferably dry granulation, fluidized bed wet granulation, or other wet granulation method using a nonaqueous solvent as a binder, and a fluidized bed wet granulation method is particularly preferred.
  • the pharmacologically active ingredient and the carrier material are sufficiently pulverized and mixed, and the mixed powder is directly compressed into a larger tablet or sheet, and then pulverized into particles of a desired size.
  • Optional tableting method that is, the solid powder is first compacted on a heavy-duty tablet press to form a green sheet, which is then broken into particles of a desired size; or a rolling method, that is, a solid powder is charged into a rolling dry granulator. It is rolled into a sheet by a roller or a pressure roller, and then crushed to obtain particles of a desired size.
  • the filler preferably contains a carrier having good compression moldability such as microcrystalline cellulose, spray-dried lactose, and compressible starch.
  • the fluidized bed wet granulation is to fully pulverize the pharmacologically active ingredient and the carrier material, and the mixed powder is charged into a fluidized bed granulator, and the airflow of a suitable temperature is blown from the lower part of the bed through the Xueban to make the material.
  • the mixture is hooked, and the binder liquid is sprayed into the appropriate concentration to make the powder condense into granules.
  • the spraying is stopped, and the hot air drying is continued until The moisture content of the granules meets the requirements.
  • the inlet air temperature is preferably 35-75 ° C, and the temperature in the drying stage may be higher than the granulation stage in the preferred range.
  • a suitable concentration of the binder liquid is preferably a combination of polyvinylpyrrolidone and water in the present invention, or a combination of polyvinylpyrrolidone, water and ethanol, and polyvinylpyrrolidone accounts for 2-8% by weight of the total amount of the binder liquid.
  • the granules prepared according to the method preferably have a moisture content of less than 3%.
  • the other wet granulation method in which the nonaqueous solvent is used as a binder is pharmaceutically acceptable
  • the non-aqueous solvent which is easily volatilized such as ethanol, isopropanol or propylene glycol, is used as a binder, and the wet granules are prepared by a conventional wet granulation method other than the fluidized bed granulation method, and dried.
  • the binder may also comprise a solid binder such as hydroxypropylcellulose, ethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose.
  • the solid binder may be dissolved or suspended in the nonaqueous solvent to prepare a binder liquid.
  • the other wet granulation methods may be selected by a sieve granulation method, an extrusion granulation mechanism granule, a sway granulation mechanism granule, a high shear granulation mechanism granule, and the like.
  • a suitable preparation method can be selected according to the experimental conditions.
  • the preparation method of the tablet can be carried out by a conventional preparation method such as direct powder tableting, tableting after wet granulation, and tableting after dry granulation.
  • a direct tableting method of powder, a tablet after dry granulation, a tablet after wet granulation in a fluidized bed, or a method of tableting after other wet granulation methods using a nonaqueous solvent as a binder is preferred, and fluidization is particularly preferred.
  • a method of tableting after wet granulation of a bed is particularly preferred.
  • the preparation method of the capsule can be carried out by a conventional preparation method, such as a powder-filled mash, a wet granulation, a capsule, and a dry granulation.
  • a powder-filled crucible, a capsule after dry granulation, a capsule after wet granulation in a fluidized bed, or another wet granulation method using a non-aqueous solvent as a binder is preferred.
  • the oral solid pharmaceutical composition of the present invention may also be a coated pellet.
  • Embodiments which may be employed include coating the surface of the blank pellet core into pellets, or mixing the medicament with a suitable carrier.
  • the pellet core is then coated with other coating layers.
  • the carrier material used for preparing the pellet core mainly comprises a filler and a binder, and the filler is selected from the group consisting of sucrose, starch, dextrin, beeswax, fatty acid, povidone, methyl cellulose, cellulose acetate, polyacrylic resin, acetic acid.
  • the cellulose phthalate, hydroxypropyl cellulose, etc., the binder is selected, for example, from polyethylene glycol, shellac or the like.
  • pellets may be packaged in a divided dose for clinical administration, or a suitable excipient may be further added, and the capsule may be prepared or compressed into tablets according to a conventional preparation method.
  • Non-oral injection preparation includes preparations suitable for subcutaneous injection, intravenous injection, intraperitoneal injection, intravenous drip injection, using a suitable dispersing agent or lubricant and suspending agent, as is conventional in the art.
  • Injectable preparations such as sterile injectable aqueous or oily suspensions, may be prepared.
  • Useful liquid diluents include, but are not limited to, water, isotonic saline, non-toxic, non-volatile oils, and the like.
  • compositions of pharmaceutically acceptable salts of isopropoxy)carbonyloxy]nonyl ester may also include other embodiments, for example, may also be prepared for topical administration in vitro, such as lotions, creams and gels. Etc., or intracavitary medications, such as suppositories. For suppositories, it can be used in the rectum or other channels. It can be mixed with a suitable non-irritating excipient. The excipient is solid at room temperature, and it is liquid at the intestinal temperature to dissolve and release the drug. In the rectum, the excipients are, for example, cocoa butter or polyethylene glycol.
  • compositions are solid compositions, especially tablets, solid filled capsules.
  • Oral administration is preferred from the viewpoint of ease of administration. Therefore, the present invention particularly provides a 2-butyl-4-chloro-1-[2'-(1 ⁇ -tetrazol-5-yl)-1,1'-biphenyl-indenyl]imidazole-5- Oral solid composition of a pharmaceutically acceptable salt of a carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester.
  • An oral solid composition of a pharmaceutically acceptable salt of (isopropoxy)carbonyloxy]nonyl ester has good formulation properties, good stability, and high bioavailability.
  • the content of the pharmacologically active ingredient may be 5 mg - 400 mg, preferably one third or one half of the daily dose of the human body, or a multiple of the daily dose, that is, the unit composition may contain a dose of about The amount is used to form a daily dose.
  • the general animal effective dose and human dose conversion method can be 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg according to the results of animal experiments. 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, or 400 mg.
  • the particular dosage level for any particular patient depends on a number of factors: the type or extent of cellular or physiological response to be achieved, the activity of the particular substance or composition being used, the particular substance or combination used. , the patient's age, weight, general state of health, sex and diet, time of administration, route of administration and rate of excretion of the shield, duration of treatment, combination with or use of the particular substance And similar factors well known in the medical field. treatment
  • the pharmaceutical composition obtained by the present invention can be used for the preparation of a medicament for treating cardiovascular diseases in mammals, particularly primates, more particularly humans, and particularly for lowering blood pressure.
  • the present invention provides a method of treating the hypertension of a mammal, particularly a primate, more particularly a human, comprising administering a composition comprising a pharmacologically effective amount or a therapeutically effective amount of the active ingredient to a patient individual,
  • the method of administration can be by oral, injection or other means. It can be administered once a day or two to three times.
  • the present invention also encompasses the use of a pharmaceutical composition obtained by the present invention in combination with a further active ingredient having a blood pressure lowering effect on a mammal, wherein the further active ingredient having a blood pressure lowering effect on a mammal is selected from the group consisting of a diuretic, an angiotensin converting enzyme One or more of an inhibitor, a calcium ion antagonist.
  • 2-butyl-4-chloro-1-[2'-(1-tetrazol- 5 -yl)_1, 1'-biphenyl-indenyl]imidazole- 5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester can be prepared by the following method:
  • 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1,1'-biphenyl-indenyl]imidazol-5-carboxylate can be prepared.
  • Various pharmaceutically acceptable salts of the acid, 1-[(isopropoxy)carbonyloxy]methyl ester can be prepared.
  • 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1,1'-biphenyl-indenyl]imidazol-5-carboxylic acid The preparation of potassium, sodium and calcium salts of 1-[(isopropoxy)carbonyloxy]nonyl ester is explained.
  • Soluble means that the lg compound can be dissolved in a solvent of 1 ml to 10 ml. From the above test results, 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, The solubility of potassium, sodium and calcium salts of 1-[(isopropoxy)carbonyloxy]decyl ester is significantly better than that of the prototype 2-butyl-4-chloro-1-[2'-(1-tetrazole) -5-yl)-1, fluorenyl-biphenyl-indenyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester. Stability study
  • Beagle dogs were used as test animals, and each group of six animals was treated with 3.0 mg/kg, 9.0 mg/kg and 27 mg/kg of 2-butyl-4-chloro-1 -[2'-(1 ⁇ -four Zin-5-yl)-indole, fluorene-biphenyl-methyl] imidazole-5-carboxylic acid, potassium salt of 1-[(isopropoxy)carbonyloxy]nonyl ester suspended in physiological saline
  • Single-dose intragastric administration blood samples were taken at set time points in each dose group, plasma was separated and prepared, and the metabolite EXP3174 (2-butyl-4-chloro- in plasma) was determined by liquid chromatography-tandem mass spectrometry.
  • the bioavailability was determined to be 4.1% by the same animal model and calculation method.
  • a pharmaceutical composition of a pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]nonyl ester is exemplified below, and the present invention contains 2-butyl-4-chloro-1-[2' -(1 ⁇ -tetrazol-5-yl)-1,1'-biphenyl-methyl]imidazol-5-carboxylic acid, 1- [(isopropoxy)carbonyloxy]methyl ester pharmaceutically
  • the medicinal and acceptable compositions of the acceptable salts are described.
  • Table 6 lists some of the drying weight loss of the carrier materials used in the following formulation examples: Table 6
  • Carboxymethyl cellulose sodium is less than 10%
  • Preparation The drug is mixed with lactose and crushed through a 80 mesh sieve.
  • the microcrystalline cellulose, sodium carboxymethyl starch, and the PVPK30 ethanol solution are added to a pre-comminuted 80 mesh sieve to prepare a soft material, which is prepared by a rocking granulator.
  • the granules are dried at 50-60 ° C until the granules have a moisture content of less than 3%.
  • the prepared capsule had a dissolution rate of 95.5% in 45 minutes.
  • Preparation Mix the drug with the prescribed amount of lactose, fully smash, pass 60 mesh sieve, add the prescribed amount of hydroxypropyl thioglycolate 101 and sodium carboxymethyl starch, mix well, add appropriate amount of steam
  • the distilled water is made into a soft material, and the granules are sieved by a 14-mesh sieve.
  • the wet granules are dried by hot air at 60 ° C for 4 hours, sieved into a 14-mesh sieve, and the prescribed amount of magnesium stearate is added, and the mixture is uniformly mixed, and the tablet is obtained.
  • the prepared tablets were smooth and friable, and the dissolution rate was 85.5% in 45 minutes.
  • the API is pulverized through an 80 mesh sieve, the carrier material is passed through a 60 mesh sieve, and the API, microcrystalline cellulose, lactose, PVPP XL are uniformly mixed, and the dry granulation mechanism is used to add the magnesium stearate to the obtained granules. Evenly, pressed into 1000 pieces. According to the "related substance" experiment, the main impurity content in the raw material was 0.09%, and the impurity content in the preparation was 0.39%.
  • Preparation The drug and each excipient are thoroughly pulverized through a 60 mesh sieve, uniformly mixed, and directly compressed.
  • the prepared tablets have a smooth surface and a good friability test.
  • Test conditions for the relevant substances in the accelerated test preparations for Comparative Example 1 1 and Example 1 1 The test articles were placed at 40 ° C under an accelerated test condition of RH 75% for 1 month. Table 7 below shows the test results.
  • Adhesive configuration PVP 29/32 was dissolved in an appropriate amount of water and diluted with water to a 4% aqueous solution of PVP 29/32.
  • Adhesive configuration PVP 29/32 was dissolved in an appropriate amount of water and diluted with water to a 4% aqueous solution of PVP 29/32.
  • the API, microcrystalline cellulose, PVPP XL for internal addition is added to the fluidized bed, and the inlet air temperature is 40. °C, the binder was added by bottom spray to prepare wet granules, dried, added to the added PVPP XL, magnesium stearate, mixed and pressed into 1000 pieces.
  • Test conditions The test piece was placed at 40 ° C and RH 75%. Table 8 below shows the test results. Table 8
  • Test sample Placement time Total impurity Example 12 0 month 0.46%
  • Magnesium stearate 2 g Preparation: The drug, tartaric acid, sodium carboxymethylcellulose, microcrystalline cellulose drug is mixed through a 16 mesh sieve, granulated in a solution of 7% povidone isopropanol, dried, sieved through a 30 mesh sieve; sodium bicarbonate It is pulverized through a 30 mesh sieve, mixed with the prepared granules, and added with talc powder, magnesium stearate, and uniformly mixed, and the tablet is obtained by effervescent tablets.
  • Pill core prescription
  • the drug is pulverized to 80 mesh, and the remaining carrier materials are separately pulverized through a 60 mesh sieve.
  • the sodium lauryl sulfate is dissolved in an appropriate amount of water, and the drug, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and stearic acid are prepared.
  • the magnesium acid is uniformly mixed, the soft material is prepared by using sodium lauryl sulfate solution, the pellets are prepared by using an extrusion spheronization apparatus, the pellets are dried at 60 ° C, sieved, and 18 to 24 mesh pellets are placed in a fluidized bed. In the middle of the isolation layer.
  • Preparation The drug and other excipients are dissolved in a 70% sucrose solution, dispensed into a dark glass container, and sterilized.

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Abstract

La présente invention concerne des compositions pharmaceutiques pour le traitement de l’hypertension. Les compositions contiennent des sels pharmaceutiquement acceptables de l’acide 2-butyl-4-chloro-1-[2'-(1H-tétrazol-5-yl)-1,1'-biphényl-méthyl] imidazole-5-carboxylique, un ester 1-[(isopropoxy)carbonyloxy]méthyl comme principe actif et des supports ou diluants pharmaceutiquement acceptables. L’invention concerne également des procédés de préparation et l’utilisation des compositions dans la production d’agent anti-hypertension.
PCT/CN2009/000629 2008-06-05 2009-06-05 Compositions pharmaceutiques contenant des dérivés de l’acide imidazole-5-carboxylique et leur procédé de préparation et leur utilisation WO2009146608A1 (fr)

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WO2015192722A1 (fr) * 2014-06-20 2015-12-23 深圳信立泰药业股份有限公司 Cristal d'allisartan isoproxil, méthode de préparation associée et composition pharmaceutique le contenant

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CN111018841B (zh) * 2013-11-01 2023-04-07 深圳信立泰药业股份有限公司 阿利沙坦酯无定形及其制备方法及含所述无定形的药物组合物
US11655240B1 (en) 2022-05-10 2023-05-23 Beijing Grand Johamu Pharmaceutical Company, Ltd. Crystal form of compound and fumaric acid, pharmaceutical composition and method for treating coronavirus-induced diseases
CN117159556A (zh) * 2022-05-27 2023-12-05 北京远大九和药业有限公司 一种药物组合物及其制备方法和用途

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WO2005023182A2 (fr) * 2003-08-28 2005-03-17 Nitromed, Inc. Composes cardiovasculaires nitroses et nitrosyles, compositions et procedes d'utilisation correspondants
WO2006115187A1 (fr) * 2005-04-22 2006-11-02 Daiichi Sankyo Company, Limited Produit pharmaceutique pour la prévention ou le traitement d'une maladie métabolique osseuse
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JP2017518351A (ja) * 2014-06-20 2017-07-06 シェンヅェン サルブリス ファーマシューティカルズ カンパニー リミテッドＳｈｅｎｚｈｅｎ Ｓａｌｕｂｒｉｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ アリサルタン・イソプロキシル結晶、その製造方法及び該結晶を含む医薬組成物
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