WO2009146608A1 - Pharmaceutical compositions containing imidazole-5-carboxylic acid derivatives and preparation method and use thereof - Google Patents

Abstract

Pharmaceutical compositions for treating hypertension are provided. The compositions contain pharmaceutically acceptable salts of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-methyl] imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester as active ingredient and pharmaceutically acceptable carriers or diluents. The preparation methods and use in the production of anti-hypertension agent of the compositions are also provided.

Description

 Pharmaceutical composition containing imidazole-5-carboxylic acid derivative, preparation method and use thereof

 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.

 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.

 With the development and marketing of losartan potassium, various pharmaceutical research and development institutions and companies have successively carried out structural studies of Ang II receptor antagonists. 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. Among them, 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.

Submitted by the applicant on February 20, 2006, published on August 29, 2007 In Chinese patent application CN200610023991.0, a series of imidazole-5-carboxyindole derivatives are described, which are structurally characterized in that the 5-position of the imidazole ring is a sebacate structure, and such compounds have potent angiotensin II. Antagonist and anti-hypertensive activity. In this patent application, the following compounds are specifically disclosed: 2-butyl-4-chloro-1 -[2'-(1 Η-tetrazol-5-yl)-indole, fluorene-biphenyl-A Imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester.

 In the application PCT/CN2006/003301 filed by the applicant on December 6, 2006, a group of compounds having the basic structure as shown in Formula II is provided. This application is hereby incorporated by reference in its entirety.

式 II 式中， R选自氢、 C1-C4直链或支链烷基、 或 C3-C7环烷基； 其中，所述的烷基或环烷基是未取代的或被 1-3个以下取代基所取 代： F、 Cl、 Br, 或 OH;

In the formula, 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.

 2-butyl-4-chloro-1 -[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid,

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'-(1Η-tetrazol-5-yl)-indole, Γ-biphenyl-methyl]imidazole- 5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester has the advantage of a more economical metabolic pathway and safer use. Applicants'2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazol-5-carboxylic acid, 1- [ (Isopropoxy)carbonyloxy]nonyl ester has been extensively studied to further improve the solubility, bioavailability and formulation suitability of the substance, and to obtain a pharmaceutical composition suitable for clinical use. Can meet the needs of clinical treatment. Summary of the invention

 Pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-methyl]imidazole-5 in the pharmaceutical composition of the present invention - a pharmaceutically acceptable salt of a carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester, which is economical, safe to use, has excellent solubility and physicochemical stability, and is better Bioavailability, suitable for use as a drug, especially a therapeutic agent.

 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'-(1Η-tetrazol-5-yl)-indole, Γ- 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'-(1Η-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 granulation method using ethanol as a binder is preferred, and more preferably Fluidized bed wet granulation particle preparation step.

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'-(1Η-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. In particular, it is used in reducing blood pressure in mammals, especially primates, and more particularly in human patients. At the same time, the present invention provides the use of the pharmaceutical composition described in the manufacture of a medicament for lowering blood pressure in a mammal. Definition As used herein, the term "active ingredient" or "pharmacologically active ingredient" refers to 2-butyl-4-chloro-1-[2'-(1Η-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 Η-tetrazol-5-yl)-indole described in the relevant part of the present invention, A pharmaceutically acceptable salt of Γ-biphenyl-indenyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonyl ester.

 As used herein, 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.

 As used herein, the term "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.

 In this context, the term "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%. At the same time, in this article, 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. For impurities that need to be quantitatively checked, 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.

In this paper, the term "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. The term "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. To further understand, in certain circumstances, the dose of the active ingredient is determined by oral dose or by the level of the drug determined in the blood.

 The percentages and ratios (ratio) used herein are based on weight unless otherwise stated. Pharmaceutical composition

 The present invention provides 2-butyl-4-chloro-1-[2'-(1Η-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'-(1Η-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.

 In one embodiment, the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-1,1 '-biphenyl-methyl]imidazole- 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 Η-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'-(1Η-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.

2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1-[( One embodiment of a pharmaceutical composition of a pharmaceutically acceptable salt of isopropoxy)carbonyloxy]nonyl ester is: Prepared as an oral liquid formulation, for example: an emulsion, a suspension, a sugar Pulp, tincture, suspension, solution, etc. 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, and the colorant is selected from artificial Or synthetic pigments, etc. In oral liquid preparations, the active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-methyl]imidazol-5-carboxylate The pharmaceutically acceptable salt of the acid, 1-[(isopropoxy)carbonyloxy]methyl ester, 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'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazol-5-carboxylic acid, 1 - [( Another embodiment of 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.

 When prepared as an oral solid preparation, 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. It is very advantageous that 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.

In one embodiment of the oral solid formulation, 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. In one embodiment of the oral solid formulation, 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.

 In one embodiment of the oral solid formulation, 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.

 In one embodiment of the oral solid formulation, 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.

 In one embodiment of the oral solid formulation, 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.

 In one embodiment of the oral solid formulation, 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.

Of course, 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. For such a formulation which is expected to disintegrate rapidly, 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.

 Suitable 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). This method of dissolving in water before taking it is very beneficial for patients who are not accustomed to taking solid preparations such as capsules, tablets, and tablets. In the case of the use of effervescent disintegrating tablets, the applicant has surprisingly discovered such a group of formulas through a large number of extensive tests: pharmacologically active ingredients account for 5%-15% of the total weight of the formulation, effervescent disintegrants account for 35%-60% of the total weight of the preparation, sodium carboxymethylcellulose accounts for 5%-15% of the total weight of the preparation, microcrystalline cellulose accounts for 10%-50% of the total weight of the preparation, and the lubricant accounts for 0% of the total weight of the preparation. 1%-5%, wherein 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. During the "related substances, experimental determination methods or during the accelerated test (40 °C, RH75%) for 1-3 months, it was found that the relevant impurity content of the active ingredient of the agent conforming to the above formulation was remarkably low.

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.

 Preferably, in the solid oral preparation, the active ingredient 2-butyl-4-chloro-1 -[2'-(1 Η-tetrazol-5-yl)-indole, hydrazine-biphenyl-methyl]imidazole The pharmaceutically acceptable salt of the 5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester, 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'-(1Η-tetrazol-5-yl)-indole, Γ - 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, For example, 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. During the "related substances" experimental determination method or during the accelerated test (40 ° C, RH 75%) for 1-3 months, it was found that the relevant impurities of the active ingredients of the pharmaceutical preparations satisfying the above formulation were significantly lower.

 In a particularly preferred embodiment of the invention, the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl - mercapto imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxymethyl ester potassium salt accounts for 30%-60% of the total weight of the solid preparation, and microcrystalline cellulose accounts for the total weight of the solid preparation. 20%-67%, cross-linked polyvinylpyrrolidone accounts for 1%-10% of the total weight of the solid preparation, and polyvinylpyrrolidone accounts for 0%-10% of the total weight of the solid preparation (when present, preferably 1%-10%) ), magnesium stearate is from 0.1% to 5% by weight based on the total weight of the solid preparation. In the "related substance" experimental measurement method or in the accelerated test (40 ° C, RH 75%) for 1-3 months, it was found that the relevant impurity content of the active ingredient of the agent conforming to the above formulation was remarkably low.

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. The present inventors have unexpectedly discovered that when an aqueous solution is used as a binder, such as a PVPP XL (crospovidone) aqueous solution, 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. Conventional wet granulation using alcohol as a binder solvent, such as high shear granulation, has no effect on the impurity content of the formulation during sieving. Further, the inventors have found that the use of an aqueous solution or an alcohol solution of the binder does not affect the impurity content of the resulting preparation when the fluidized bed granulation method is used. Therefore, in the present invention, 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.

 In the dry granulation, 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. When granulating by this method, 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. In the fluidized state, the mixture is hooked, and the binder liquid is sprayed into the appropriate concentration to make the powder condense into granules. After repeated spraying and drying, when the size of the granules meets the requirements, the spraying is stopped, and the hot air drying is continued until The moisture content of the granules meets the requirements. In preparing the preparation of the present invention, 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. Among them, 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.

 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. Among them, 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. A fluidized bed wet granulation method for filling plastic bottles.

 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. It is also possible to change the release behavior by coating other functional coating layers, such as an intumescent layer, an isolating layer, a controlled release layer, and the like. The 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.

The present invention 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, 1 - [( Another embodiment of a pharmaceutical composition of a pharmaceutically acceptable salt of isopropoxy)carbonyloxy]nonyl ester is: Preparation of a parenteral injection administration formulation. "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.

 The present invention 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1 - [( Pharmaceutical 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.

 From the standpoint of ease of preparation and administration, preferred pharmaceutical 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'-(1Η-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. And the present invention 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, 1- [ An oral solid composition of a pharmaceutically acceptable salt of (isopropoxy)carbonyloxy]nonyl ester has good formulation properties, good stability, and high bioavailability.

 As will be readily understood by those skilled in the art, for solid oral preparations, the enumeration of the above substances does not constitute a limitation of the technical solution, and the excipients used in other solid preparations not enumerated may also be applicable to the present scheme. It is therefore also included in this scenario.

 In the pharmaceutical composition of the present invention, 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. For example, 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.

However, it should be understood that 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.

 The invention is further illustrated in detail below by way of specific examples. As will be appreciated by those skilled in the art, the embodiments and examples set forth in the present invention are provided by way of example only and do not constitute a selection of a carrier or a diluent in a particular embodiment, a method of preparing the composition, and Limitations on the use of the composition. detailed description

 (a) 2-butyl-4-chlorosodium [2'-(1-tetrazol-5-yl)-1, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1-[ (different Preparation of pharmaceutically acceptable salts of propoxy)carbonyloxy]decyl ester

Known (for example, see CN200610023991.0) 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:

Preparation of 2-butyl-4-chloro-1-[2'-(1-triphenylnonyl-tetrazol-5-yl)-1, fluorenyl-biphenyl-indenyl]imidazole-5 by literature -carboxylic acid, 2-butyl-4-chloro-1-[2'-(1-tritylmethyl-tetrazol-5-yl)-1, indole-biphenyl-group was added sequentially to a 100 ml single-mouth bottle Base imidazole-5-carboxylic acid, 0.523 g, ₂ C0 ₃ 0.124 g, 5 ml of hydrazine, hydrazine-dimethylacetamide, stirred at room temperature for 20 min, and added 0.562 g of isopropoxy chlorodecanoate at room temperature, 45- The reaction was carried out at 50 ° C for 16 h. After completion of the reaction, the mixture was filtered, and 30 ml of water was added to the filtrate, and 5 ml of a 4 mol/L hydrochloric acid solution was added thereto, and the mixture was reacted at room temperature for 16 hours. The reaction was stopped, and the aqueous solution of sodium hydrogencarbonate was added to adjust the pH of the reaction mixture to pH 6 - 7, and turbidity appeared, ethyl acetate was extracted, and the organic phase was washed with saturated brine, dried and concentrated to give 2-butyl-4-chloro-1- 2'-(1H-tetrazol-5-yl)-1, fluorenyl-biphenyl-methyl]imidazole-5-carboxylic acid, [(isopropoxy)carbonyloxy] decyl ester 0.436g, below Call compound one. On this basis, 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. By way of example, 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. Example 1 2-Butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, 1- [ Preparation of potassium salt of (isopropoxy)carbonyloxy]methyl ester

 In a 100 ml three-necked flask, 2-butyl-4-chloro-1-[2'-(1-tetradec-5-yl)-1,1'-biphenyl-indenyl]imidazol-5-carboxylate was added. Acid, 1-[(isopropoxy)carbonyloxy]decyl ester 2.50 g (4.52 mmol) and tetrahydrofuran (THF) 25 ml. After stirring and stirring, 0.645 g of potassium trimethylsilanolate (4.52 mmol, 90% content, Aldrich) dissolved in 15 ml of THF was added, and the mixture was reacted at room temperature for 28 h at room temperature.

After the completion of the reaction, a small amount of white floc was obtained in the reaction mixture, which was filtered, and the filtrate was concentrated under reduced pressure to give a white solid. Recrystallization from a mixed solution of isopropyl ether and ethanol (3:1 v/v) gave 1.42 g of 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1. Potassium salt of Γ-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester, yield 53%, hereinafter referred to as compound 2. Example 2 2-Butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-1,1'-biphenyl-methyl]imidazole-5-carboxylic acid, 1- Preparation of sodium salt of [(isopropoxy)carbonyloxy]nonyl ester

 Take 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1- [( Propyl)carbonyloxy]methyl ester 2.5 g (4.53 mmol), dissolved in 15 ml of anhydrous tetrahydrofuran (THF) dried with sodium metal at room temperature, and added with 1.0 M sodium tridecylsilanol dichloride The methane solution was 4.6 ml and reacted at 25 ° C for 24 h. The volume of the reaction solution was further concentrated to 1/2, and it was allowed to stand for 48 hours, and a white solid was precipitated. After filtration, a crude product of 0.923 g was obtained in a yield of 35.5 %. Recrystallization from ethanol isopropyl ether gave 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1,1'-biphenyl-methyl]imidazole-5 -carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester sodium salt 0.563 g, hereinafter referred to as compound III. Example 3 2-Butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazole-5-carboxylic acid, 1- [ Preparation of calcium salt of (isopropoxy)carbonyloxy]methyl ester

 2-butyl-4-chloro-1-[2'-(1-tetrazole-5-yl)-1, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid,

To a solution of 1-[(isopropoxy)carbonyloxy]decyl ester 2.212g (4mmol), 15ml of anhydrous decyl alcohol was added, and then 0.148g (2mmol) of calcium hydroxide was added thereto, and the temperature was raised to 3CTC, and the reaction was carried out for 20 hours. Filtration, and the filtrate was concentrated to dryness to dryness crystals crystals crystals crystals crystalssssssssssssssssss -1, Γ-biphenyl-methyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]decyl ester calcium salt 1.77 g, yield 77.1%, below Call compound IV. (b) 2-Butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-1, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, 1- [ Study on the Dissolution Behavior of Potassium, Sodium and Calcium Salts of (Isopropoxy)carbonyloxy]decyl Ester

 The solubility of the compound obtained in (a) in water and methanol, respectively, is defined by the Chinese Pharmacopoeia (2005 edition, Part 2). The results are shown in Table 1 below: Table 1

Note: slightly soluble, means that the lg compound can be dissolved in a solvent of lOOml-l OOOml;

 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

 Taking the potassium salt as an example, the stability of this type of salt was investigated. The details are as follows: Thermal stability test

 A small amount of compound 2 was taken and stored at 60 ° C under high temperature, and its purity was measured on days 0, 5, and 10. The experimental results are shown in Table 2 below: Table 2

 Test compound

Detection time (days) 0 5 10 Purity (%) 100.08 99.77 99.39 From the above experimental results, it is known that it is 60. When C was stored under a high temperature environment, the purity of the compound 2 was only slightly decreased, indicating that the present invention provides the compound 2 with good thermal stability. Light stability experiment

 A small amount of compound 2 was taken and stored under illumination of 45001x ± 5001x, and the purity of compound 2 was measured on days 0, 5, and 10. The experimental results are shown in Table 3 below: Table 3

从上述实验结果可知在照度为 45001x ± 5001x光照环境下保存， 化 合物二的纯度几乎不变， 这表明了本发明提供的化合物二具有优异的 光稳定性。 吸湿性实验

From the above experimental results, it was found that the purity of the compound 2 was almost unchanged when the illuminance was 45001x ± 5001x, and the compound 2 provided by the present invention had excellent photostability. Hygroscopicity experiment

 A small amount of compound 2 was taken and stored in a high humidity environment with a humidity of 92.5%, and the purity of compound 2 was measured on days 0, 5, and 10. The experimental results are shown in Table 4 below: Table 4

从上述实验结果可知在湿度为 92.5 %高湿环境下保存， 化合物二 的纯度几乎不变， 这表明了本发明提供的化合物二在高湿环境下非常 稳定。

From the above experimental results, it was found that the purity of the compound 2 was almost unchanged under the humidity of 92.5% in a high-humidity environment, which indicates that the compound 2 provided by the present invention is very stable in a high-humidity environment.

The above test results indicate that 2-butyl-4-chloro-1-[2'-(tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid provided by the present invention , potassium of 1-[(isopropoxy)carbonyloxy]methyl ester The salt form is stable under high temperature, light or high humidity environment, and has excellent formulation adaptability, and is suitable for preparation for clinical use.

(iii) 2-Butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-indole, fluorenyl-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[ Study on Pharmacological Action of Potassium Salt of (Isopropoxy)carbonyloxy]decyl Ester

 Hereinafter, 2-butyl-4-chloro-1-[2'-(1-tetrazol-5-yl)-indole, fluorenyl-biphenyl-indenyl]imidazol-5-carboxylic acid, 1-[ The potassium salt of (isopropoxy)carbonyloxy]nonyl ester is a representative active ingredient, and the pharmacological action of the salt of this type and related medical uses are investigated. Absorption experiment

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'-(1Η-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 concentration of 1-[2'-(1Η-tetrazol-5-yl)-1,1 '-biphenyl-methyl]imidazole-5-carboxylic acid), based on the drug concentration-time curve, the metabolite EXP3174 was calculated. Pharmacokinetic parameters, correlations between the main pharmacokinetic parameters (^^ and !;.^ and doses, the results show that: in the dose range of 3.0 mg / kg - 27 mg / kg, C _max and AUQM values Increased dose and increased force. Blood pressure lowering activity experiment

 2-butyl-4-chloro-1-[2'-(1 Η-tetrazol-5-yl)-oxime was used in the rat spontaneous hypertension model (SHR) at 15 mg/kg and 30 mg/kg. , Γ-biphenyl-methyl]imidazol-5-carboxylic acid, potassium salt of 1-[(isopropoxy)carbonyloxy]nonyl ester was suspended in physiological saline for administration, before and after administration The blood pressure decreased by 10 mm Hg and 20 mm Hg, respectively. The results showed that the compound was orally administered at a dose of 15 mg/kg or more, and the blood pressure was significantly reduced in rats. Bioavailability experiment

Four SD rats were intragastrically administered with compound 2 at a dose of 10.72 mg/kg, and four SD rats were intravenously administered with EXP3174 at a dose of 7.9 mg/kg to measure EXP3174 in rat plasma. The drug concentration was studied and the absolute bioavailability of rats after intragastric administration of Compound II was studied. The results are shown in Table 5 below.

化合物二的原形直接给药后， 以同样的动物模型和计算方法， 测 定生物利用度为 4.1 %。

After the original form of the compound 2 was directly administered, the bioavailability was determined to be 4.1% by the same animal model and calculation method.

 Conclusion: The mean absolute bioavailability was 26.7% calculated by AUQM, and the bioavailability increased by 6.5 times compared with the direct administration of the compound dimorphism.

(iv) containing 2-butyl-4-chloro-1-[2'-(1 Η-tetrazol-5-yl)-1,1 '-biphenyl-methyl]imidazole-5-carboxylic acid, 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' -(1Η-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

羧曱基纤维素钠 小于 10%

Carboxymethyl cellulose sodium is less than 10%

 Magnesium stearate less than 6%

 Pregelatinized starch less than 15%

 Calcium hydrogen phosphate dihydrate less than 22%

 Polyvinylpyrrolidone (PVP 29/32 ) less than 5% Example 4 Powder

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, 1- [(isopropyl Oxy)carbonyloxy]decyl ester potassium salt 10 g

 Lactose 40 g

 Preparation: Separate the 60 mesh sieve separately, gradually add the prescription amount of lactose according to the equal amount of addition method, until the mixture is evenly distributed, and the powder of the drug is obtained by dispensing. In this scheme, an appropriate amount of flavoring agent, odorant, and preservative may also be added as needed. Example 5 Granules

 Prescription:

 2-butyl-4-chloro-1 -[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1-[(isopropyl Oxy)carbonyloxy]methyl ester potassium salt 10 g

 Starch 10 g

 Sucrose 10 g

 Carboxymethyl starch sodium 2 g

 70% starch slurry

 Preparation: Separate the 60 mesh sieve separately, mix the drug with starch, sucrose and sodium carboxymethyl starch uniformly, add appropriate amount of starch slurry to make soft material, sieve with 14 mesh, dry at 60 °C for 4 hours, 14 mesh sieve Granules, granules of the drug are dispensed. In this solution, it is also necessary to add an appropriate amount of flavoring agent, odorant and preservative. Example 6 Capsule

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid,

1- [(Isopropoxy)carbonyloxy]decyl ester sodium salt 15 g Microcrystalline cellulose 17 g,

 Lactose 15 g

 Sodium carboxymethyl starch 2 g

 Magnesium stearate 1 g

 10% crospovidone (PVPK30) ethanol solution

 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%. Whole grain, put into the No. 1 capsule, that is. The prepared capsule had a dissolution rate of 95.5% in 45 minutes. Example 7 Tablet

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester calcium salt 10 g

 Microcrystalline cellulose 15 g

 Lactose 15 g

 Cross-linked povidone 5 g

 Magnesium stearate 1 g

 Preparation: The drug and each excipient were thoroughly pulverized through a 60 mesh sieve, mixed, and directly compressed. The prepared tablets were smooth and friable, and the dissolution rate was 93.7% in 45 minutes. Example 8 Tablet

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorenyl-biphenyl-indenyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester sodium salt 10 g

 Lactose 20 g

 Hydroxypropylmethylcellulose 101 15g

 Sodium carboxymethyl starch 4 g

 Magnesium stearate 1 g

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. Example 9 Tablet

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorenyl-biphenyl-methyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]decyl ester potassium salt 5 g

 Povidone ( Plasdone K-29/32 ) 5 g

 Microcrystalline cellulose 20 g

 Lactose 20 g

 Cross-linked povidone 4 g

 Magnesium stearate 4 g

 Preparation: The drug and povidone (Plasdone K-29/32) were dissolved in an appropriate amount of methanol, spray-dried, and the spray-dried sample was mixed with the rest of the material, and compressed, and the dissolution was determined to be 95.5% at 45 minutes. Comparative 10' tablet

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester sodium salt 150.2 g

 Microcrystalline cellulose MCC101 260.0 g

 Lactose 20.0 g

 PVPP XL 40.0 g

 Magnesium stearate 3.4 g

 Water amount

Preparation: 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, and PVPP XL are uniformly mixed. An appropriate amount of water soft material is added, and the wet granulation is carried out through a 22 mesh sieve. The oven was dried in an oven at a temperature of 60 ° C, and sieved with a 30-mesh sieve. The obtained granules were mixed with magnesium stearate and pressed into 1,000 pieces. According to the "stability investigation, the "related substances" experiment, the main impurity content in the raw material drug is 0.09%, and the impurity content in the preparation is 0.79%. Example 10 Tablet

 Prescription -

2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorenyl-biphenyl-indenyl]imidazole-5-carboxylic acid, 1- [(isopropyl Oxy)carbonyloxy]methyl ester sodium salt 150.2 g

 Microcrystalline cellulose MCC101 260.0 g

 Lactose 20.0 g

 PVPP XL 40.0 g

 Magnesium stearate 3.4 g

 Preparation: 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%. Example 11 Tablet

 Prescription

₂ -butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]decyl ester potassium salt 20 g

 Microcrystalline cellulose 20 g

 Lactose 15 g

 Cross-linked povidone 5 g

 Magnesium stearate 1 g

 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. Comparative example 1 Γ tablets

 Prescription

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester potassium salt 20 g

 Pregelatinized starch 20 g

 Calcium hydrogen phosphate dihydrate 15 g

Cross-linked povidone 5 g Magnesium stearate 1 g

 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.

从上述实验结果可知在加速试验条件下， 没有采用本发明配方制 得的片剂的杂质增长快， 含量高， 在加速试验进行 1 个月时其杂质含 量显著高于本发明配方所制得的片剂杂质含量。 对比例 12， 片剂

From the above experimental results, it can be seen that under the accelerated test conditions, the tablets which were not prepared by using the formulation of the present invention have a rapid increase in impurities and a high content, and the impurity content thereof is significantly higher than that of the formulation of the present invention at the accelerated test for 1 month. Tablet impurity content. Comparative example 12, tablet

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorenyl-biphenyl-methyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester potassium salt ".4 g

 Microcrystalline cellulose MCC101 76.0 g

 PVPP XL (internal force) 2.8 g

 PVPP XL (plus) 4.2 g

 PVP 29/32 4.2 g

 Magnesium stearate 0.9 g

 Water amount

 Preparation:

 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.

Add API, microcrystalline cellulose, PVPP XL for internal addition to the high shear granulator, Start the mixing paddle to mix the hooks, slowly add the binder to the material during the stirring, and start the cutting knife to prepare the wet granules. The wet granules were dried in an oven at a temperature of 60 ° C, and sieved with a 30 mesh sieve, and added to the added PVPP XL, magnesium stearate, mixed, and pressed into 1000 pieces. Example 12 Tablet

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]decyl ester potassium salt 53.4 g

 Microcrystalline cellulose MCC101 76.0 g

 PVPP XL (plus) 2.8 g

 PVPP XL (plus) 4.2 g

 PVP 29/32 4.2 g

 Magnesium stearate 0.9 g

 Water amount

 Preparation:

 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.

 After preheating the fluidized bed (WBF-2 type, Chongqing Yingge Granulation Coating Technology Co., Ltd.), 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.

 Determination of related substances in the accelerated test preparations for Comparative Example 12 and Example 12

 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%

 February 1.16%

 March 1.28%

Example 12 08% in October February 0.61%

 March 0.66% From the above experimental results, it can be seen that under the accelerated test conditions, the impurities produced by the high shear granulation process have a fast growth and high content, and the impurity content is about the fluidized bed at the accelerated test for 3 months. Granulation was made twice as much as tablets. Example 13 Oral Disintegration Tablets

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1-[(isopropyl Oxy)carbonyloxy]methyl ester sodium salt 5 g

 Mannitol 10 g

 Microcrystalline cellulose 10 g

 Cross-linked povidone 2.25 g

 Magnesium stearate 0.25 g

 Lemon Flavor 0.12 g

 Aspartame 0.12 g

 Talc 0.2 g

 Preparation: Mix the drug with mannitol and crush it by 80 mesh. The other ingredients are crushed through a 60 mesh sieve, mixed evenly, and directly compressed. The tablet was disintegrated in 5 ml of distilled water for 3 minutes. Example 14 Effervescent Tablets

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester potassium salt 20 g

 Tartaric acid 50 g

 Sodium bicarbonate 56 g

 Carboxymethyl cellulose sodium 20 g

 Microcrystalline cellulose 30 g

 Talc powder 6 g

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. Example 15 Effervescent Tablets

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]decyl ester potassium salt 80 g

 Tartaric acid 130 g

 Sodium bicarbonate 135 g

 Sodium carboxymethyl cellulose 50 g

 Microcrystalline cellulose 130 g

 Talc 5 g

 Magnesium stearate 5 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. According to the "related substance" experiment, the main impurity content in the raw material drug was 0.09%, and the impurity content in the preparation was 0.27%. Example 16 Suppository

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1 - [(isopropyl Oxy)carbonyloxy]methyl ester sodium salt 10g

 Cocoa butter 60g

 PEG6000 60g

 Polosham 188 5g

 Stearic acid 5g

Preparation: The drug was pulverized through an 80 mesh sieve, added to a cocoa butter melted by heating in a water bath at 80-90 ° C, stirred to homogenize uniformly, until the drug powder completely disappeared, and prepared as a suppository. Example 17 Pellets

 Pill core prescription:

 2-butyl-4-chloro-1 -[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-indenyl]imidazole-5-carboxylic acid, 1-[(isopropyl Oxy)carbonyloxy]methyl ester potassium salt 5 g

 Microcrystalline cellulose 20 g

 Low substituted hydroxypropyl cellulose 10 g

 Magnesium stearate 1 g

 Sodium lauryl sulfate 1 g

 Separation coating solution:

 Hydroxypropyl decyl cellulose ( Pharmacoat 606 ) 13g

 Polyethylene glycol 400 2.6g

 Talc 6.5g

 Water amount

 Preparation: 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.

 Dissolving hydroxypropyl fluorenyl cellulose in water, adding polyethylene glycol 400, dispersing talc powder therein to prepare a separation layer coating liquid, and spraying the prepared pellets with a fluidized bed bottom to coat weight gain It is 4%. The bagging layer pellets were dried at 40 ° C for 30 min to obtain pellets. The dissolution was determined to be 88.7% at 45 minutes. Example 18 Injection

 Prescription:

 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]decyl ester potassium salt 5 g

 Water for injection 45 g

 Preparation: The drug is dissolved in water for injection, filtered and sterilized, and placed in an ampoule. Example 19 Syrup

prescription: 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, indole-biphenyl-indenyl]imidazole-5-carboxylic acid,

1-[(Isopropoxy)carbonyloxy]methyl ester potassium salt 10 g

 70% sucrose solution 40 g

 Sorbic acid 3 g

 Vitamin C 5 g

 Preparation: The drug and other excipients are dissolved in a 70% sucrose solution, dispensed into a dark glass container, and sterilized.

 All documents and publications mentioned herein are hereby incorporated by reference in their entirety in their entirety. In view of the above-described details of the present disclosure, those skilled in the art can make various modifications, changes and changes in the present invention without departing from the spirit and scope of the invention. Within the limits defined by the book.

Claims

Rights request A pharmaceutical composition having a blood pressure lowering action comprising a pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, anthracene-biphenyl a pharmaceutically acceptable salt of 1-methyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]methyl ester, and a pharmaceutically acceptable diluent or carrier material, The pharmacologically active ingredient is present in an amount of from 0.1% to 99%, preferably from 1% to 80% by weight of the pharmaceutical composition.  The pharmaceutical composition according to claim 1, wherein the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole , Γ-biphenyl-indenyl]imidazol-5-carboxylic acid, pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]nonyl ester in the pharmaceutical composition has a weight of 5 Mg - 400 mg.  The pharmaceutical composition according to claim 1, wherein the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole , Γ-biphenyl-fluorenyl] imidazole-5-carboxylic acid, The pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]methyl ester is selected from one of a potassium salt, a sodium salt or a calcium salt of the pharmacologically active ingredient.  The pharmaceutical composition according to claim 1, wherein the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole , Γ-biphenyl-fluorenyl] imidazole-5-carboxylic acid, The pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]nonyl ester is selected from the potassium salt of the pharmacologically active ingredient.  The pharmaceutical composition according to claim 1, which is in the form of an oral liquid preparation, wherein the oral liquid preparation is selected from the group consisting of a suspension, a syrup, a solution, an expectorant, and the dilution. The agent is selected from the group consisting of water, physiological saline, ethanol solution, polyethylene glycol, edible oil, and further optionally contains one or more of a preservative, an antioxidant, a flavoring agent, a flavoring agent or a coloring agent.  The pharmaceutical composition according to claim 1, which is in the form of an injection, the diluent being selected from the group consisting of water for injection, isotonic saline, and non-toxic non-volatile oil.  7. The pharmaceutical composition according to claim 1, which is in the form of a suppository, the carrier being selected from the group consisting of cocoa butter or polyethylene glycol.  The pharmaceutical composition according to claim 1, which is in the form of a solid preparation selected from the group consisting of a tablet, a capsule, a powder, a granule, and a dry suspension, and the pharmacologically active ingredient 2-butyl-4-chloro-1 -[2'-(1Η-tetrazol-5-yl)-1,1'-biphenyl-indenyl]imidazol-5-carboxylic acid, 1- [(iso a pharmaceutically acceptable salt of a propoxy)carbonyloxy]decyl ester, based on the total weight of the pharmaceutical composition From 1% to 80%, the carrier material comprises one or more of a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a flavoring agent, and a coloring agent.  The pharmaceutical composition according to claim 8, wherein the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, Γ-biphenyl-indenyl]imidazol-5-carboxylic acid, pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]nonyl ester, 5%-70% by weight of the total solid preparation .  10. The composition according to claim 8, wherein the carrier material other than the binder has a loss on drying of less than 20%, wherein the filler is selected from one or more of the following: 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, hydroxide Aluminum, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose; a disintegrant selected from one or more of the following: starch, sodium carboxymethyl starch, hydroxypropyl starch, crosslinked carboxymethyl a cellulose sodium, a crosslinked polyvinylpyrrolidone, a low-substituted hydroxypropyl fluorenyl cellulose, and an effervescent disintegrant such as a mixture of tartaric acid and sodium hydrogencarbonate; the surfactant being selected from one or more of the following: Species: sodium lauryl 3⁄4, poloxamer, tween, cetyltrimethylammonium bromide, sodium lauryl sulfate, sodium stearyl sulfonate, polyoxyethylene higher fatty alcohol, sucrose ester, Sorbitol fatty ester, soybean Fat, alginic acid, sodium alginate, colloidal magnesium aluminum silicate; binder selected from one or more of the following: hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, starch Pulp, dextrin, glucose and its syrup, sucrose and its syrup, lactose and its syrup, fructose and its syrup, sorbitol, gelatin glue, gum arabic, sassafras, microcrystalline cellulose, water, ethanol, Isopropanol, preferably a combination of one or more of polyvinylpyrrolidone, ethanol, isopropanol, water, starch slurry, microcrystalline cellulose, particularly preferably a combination of polyvinylpyrrolidone and water, polyvinylpyrrolidone and ethanol a combination, and a composition of polyvinylpyrrolidone, water and ethanol; the lubricant is selected from one or more of the following: stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, Glyceryl monostearate, palm stearin, magnesium lauryl sulfate, polyethylene glycol, sodium stearyl fumarate. 1 1. The pharmaceutical composition according to claim 8, wherein the pharmacologically active ingredient 2-butyl-4-chloro-1-[2'-(1Η-tetrazol-5-yl)-indole, Γ -biphenyl-indenyl]imidazol-5-carboxylic acid, the pharmaceutically acceptable salt of 1-[(isopropoxy)carbonyloxy]nonyl ester is from 30% to 60% by weight based on the total weight of the 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. 0.1% to 5% by weight of the total body preparation.  12. The pharmaceutical composition according to claim 11, wherein 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, low-substituted hydroxypropyl decyl cellulose, croscarmellose sodium or sodium carboxymethyl starch; the binder is selected from the group consisting of microcrystalline cellulose, carboxy a combination of sodium decyl cellulose, a combination of polyvinylpyrrolidone and water, a combination of polyvinylpyrrolidone and ethanol, or a combination of polyvinylpyrrolidone, water and ethanol; the lubricant is selected from the group consisting of magnesium stearate and talc.  The pharmaceutical composition according to claim 12, wherein the pharmacologically active ingredient is 2-butyl-4-chloro-1-[2'-(1 Η-tetrazol-5-yl)-indole, Γ-biphenyl-indenyl]imidazol-5-carboxylic acid, 1-[(isopropoxy)carbonyloxy]nonanoate potassium salt, 30%-60% by weight of the total solid preparation; The material comprises microcrystalline cellulose, crosslinked polyvinylpyrrolidone, magnesium stearate, and optionally polyvinylpyrrolidone, wherein the microcrystalline cellulose accounts for 20% to 67% of the total weight of the solid preparation; the crosslinked polyvinylpyrrolidone accounts for solids. 1% to 10% by weight of the total formulation; polyvinylpyrrolidone is 0% to 10% by weight based on the total weight of the solid preparation; 0.1% to 5% by weight based on the total weight of the magnesium stearate solid preparation.  The pharmaceutical composition according to claim 10, wherein the pharmacologically active ingredient comprises 5% to 15% by weight of the total preparation, and the carrier material comprises an effervescent disintegrant, sodium carboxymethylcellulose, micro a crystalline cellulose and a lubricant, wherein the effervescent disintegrant is selected from the group consisting of tartaric acid and sodium hydrogencarbonate, wherein the ratio of tartaric acid to sodium hydrogencarbonate is 1: 0.8-1.2, accounting for 35%-60% of the total weight of the preparation. The sodium carboxymethyl cellulose accounts for 5%-15% of the total weight of the preparation; the microcrystalline cellulose accounts for 10%-50% of the total weight of the preparation; the lubricant accounts for 0.1%-5 of the total weight of the preparation. %.  15. The pharmaceutical composition according to claim 8, wherein the granules, tablets, capsules are wet granulated by including dry granulation, fluidized bed wet granulation, or other wet using a nonaqueous solvent as a binder The method of the granulation step is prepared.  16. The pharmaceutical composition according to claim 8, wherein the granules, tablets, and capsules are prepared by a method comprising a fluidized bed wet granulation step.  17. The pharmaceutical composition according to claim 8, wherein the tablet is prepared by a method of directly compressing a powder, wherein the gelatin is prepared by a method of directly filling a powder.  18. Use of a pharmaceutical composition according to claim 1 for the manufacture of a medicament for reducing blood pressure in a mammal. 19. The use according to claim 18, wherein the pharmaceutical composition has a reduction Further active ingredients for the action of blood pressure in mammals are used in combination.  The use according to claim 19, wherein the further active ingredient having a blood pressure lowering effect on a mammal is one or more selected from the group consisting of a diuretic, an angiotensin converting enzyme inhibitor, and a calcium ion antagonist.  The method of producing a pharmaceutical composition according to claim 1, which is produced into a corresponding pharmaceutical agent by a conventional method.  The preparation method according to claim 21, wherein the pharmaceutical composition is in the form of a solid preparation selected from the group consisting of a tablet, a capsule, a powder, a granule, and a dry suspension, and the pharmacologically active ingredient is 2-butyl. 4- 4-Chloro-1-[2,-(1H-tetrazol-5-yl)-1, fluorene-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxy) The pharmaceutically acceptable salt of the carbonyloxy]nonyl ester is from 1% to 80% by weight based on the total weight of the pharmaceutical composition, and the carrier material includes a filler, a disintegrant, a binder, a lubricant, and a surface active agent. One or more of a dose, a flavoring agent, a flavoring agent, and a coloring agent.  23. The production method according to claim 22, wherein the preparation method comprises dry granulation, fluidized bed wet granulation, or a particle preparation step of another wet granulation method using a nonaqueous solvent as a binder, wherein The particle preparation step of dry granulation, fluidized bed wet granulation, or other conventional wet granulation method using ethanol as a binder is preferred, and the fluidized bed wet granulation granule preparation step is more preferred.