WO2012159552A1 - Solid pharmaceutical composition containing benzimidazole derivative - Google Patents

Abstract

A solid pharmaceutical composition containing a benzimidazole derivative and preparation method therefor, said solid pharmaceutical composition being used for regulating degrees of drug dissolution and/or improving stability, and the uses of same in the preparation of drugs for treating circulatory diseases.

Description

 Solid pharmaceutical composition comprising benzimidazole derivatives

 The present invention relates to a solid pharmaceutical composition for improving drug dissolution and/or stability, a process for the preparation thereof, and use for the preparation of an antihypertensive drug. Background technique

 Circulatory diseases, also known as cardiovascular diseases, refer to the heart, blood vessels, and diseases of the nervous system that regulate blood circulation. The most common cause of heart disease and high blood pressure. Circulatory diseases are common diseases, especially in medical diseases. Heart disease often persists, affecting life and labor, and the mortality rate is high. With the control of infectious diseases, cardiovascular disease is more prominent in the causes of death. Circulatory diseases can be divided into two major categories: congenital and acquired. Congenital cardiovascular disease is caused by abnormal development of the heart's large blood vessels during the fetal period. Acquired cardiovascular disease, such as coronary heart disease, rheumatic heart disease, high blood pressure and high blood pressure heart disease.

 Angiotensin II causes vasoconstriction through the angiotensin II receptor on the cell membrane and raises blood pressure. Thus, the angiotensin II receptor antagonist can be an effective drug for treating diseases of the circulatory system such as hypertension. The renin-angiotensin system, together with the aldosterone system, participates in the control of systemic blood pressure, body fluid volume, electrolyte balance, etc. in the homeostasis. Based on the fact that angiotensin II, which has potent vasoconstriction, raises blood pressure through the angiotensin II receptor located on the cell membrane, the relationship between renin-angiotensin and hypertension has been revealed, thereby, An antagonist of angiotensin II has been used to treat angiotensin-induced hypertension. To date, clinically, drugs having angiotensin-antagonism activity have been administered by oral administration as a preferred chemical structure for strongly expressing angiotensin II antagonistic activity, and it is known that an acid group such as tetrazole is present on a biphenyl side chain. The structure of a base group, a carboxyl group, etc., such as losartan, candesartan cilexetil, olmesartan medoxomil, etc. (Ruth R. Wexler et al, Journal of Medicinal Chemistry, vol. 39, etc.) are clinically used. p. 625 (1996), JP-A-4-364171 JP-A-5-78328, etc.). JP-A-5-271228 describes a compound in which the acid group on the biphenyl side chain is 5-oxo-4,5-dihydro-1,2,4-dioxa-3-yl, orally It shows long-term and intense angiotensin II antagonistic activity and antihypertensive activity after administration. Further, W003/047573 describes that the benimipro derivative described in JP-A-5-271228 has insulin sensitizing activity in addition to angiotensin II receptor antagonistic activity.

 Azisartan (English name Azilsartan) is an angiotensin-receptor antagonist drug in the development of hypertension that selectively blocks the binding of angiotensin II to vascular smooth muscle ATI receptors. Blocking the vasoconstrictor of angiotensin II, which is often used to treat hypertension, is also the only angiotensin II receptor antagonist (sartan) drug in the terminal clinical stage.

Pharmaceutical products need to be effective, safe and stable. The effectiveness, safety and stability of a pharmaceutical product are not only closely related to the effectiveness and safety of the medicinal ingredient itself, but also by the preparation of the pharmacy. The effects of properties, such as the stability of the medicinal ingredients in the formulation, and the dissolution characteristics of the drug from the formulation, are all important. For example, even if the formulation satisfies a certain level of quality immediately after preparation, if the medicinal ingredient in the formulation decomposes over time, the formulation is problematic depending on the effectiveness and safety of the drug product. For the dissolution characteristics of the drug from the formulation, when the drug is too slow to dissolve from the formulation, the drug may not reach an effective concentration in the blood and may not achieve the desired effect. When the drug is dissolved too fast, it may cause a rapid increase in blood drug concentration in the body, and the risk of side effects may also increase.

 For the method of improving the stability of the medicinal ingredient in the preparation, it is known to add a pH adjusting agent, and only the method of using fumaric acid and sodium hydroxide, or monosodium fumarate as a stabilizer is disclosed in the patent document CN101677961A. At the same time, the active ingredient is azisartan potassium salt. At the same time, the patent document claims to improve the dissolution of the drug, but the specific embodiment given is a dissolution test at a high pH (pH 6.8), which fails to demonstrate its dissolution advantage in the human environment. The dissolution of the pharmaceutical composition provided by this patent application under low pH conditions was measured, and it was found that the improvement effect was very limited.

 CN101528262A discloses a solid pharmaceutical composition comprising a medicinal active ingredient, a low-melting oily substance and a low-viscosity binder, and an improved dissolution property of a pharmaceutical preparation comprising a solid dosage form containing a low-melting oily substance, wherein the pharmaceutical active ingredient is improved, However, the specific implementations given are all dissolution tests at high pH (pH 6.8), which have failed to demonstrate their dissolution advantages in the human environment. The dissolution of the pharmaceutical composition provided by this patent application under low pH conditions was measured, and it was found that the improvement effect was very limited. Summary of the invention

 It is an object of the present invention to provide a solid pharmaceutical composition comprising a compound represented by the formula (I), which is characterized in that it is capable of being adjusted

 (I)

R ¹ is a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom deprotonated, R ² is a carboxyl group, and R ³ is a lower alkyl group, and preferably the compound of the formula (I) is azilsartan;

 The amount of dissolution adjustment is from 5% to 100%, preferably from 10% to 90%. The amount of adjustment is an amount of increase or decrease, and the degree of dissolution is a dissolution rate in the dissolution medium of ρ Η 1 to 10, preferably a pH of 4 to 8.

Containing at least one inactive ingredient selected from the group consisting of ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate neighbors Phthalic acid Ester, carboxymethylethylcellulose, methacrylic acid-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymer, methyl methacrylate - ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate and/or polyvinyl acetate phthalate, The inactive ingredient may be present on the surface of the pharmaceutical composition or dispersed within the pharmaceutical composition.

 The inventors were pleasantly surprised to find that the addition of a co-solvent can improve the dissolution of azilsartan. The co-solvent is selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide and the like, and sodium carbonate and sodium hydrogencarbonate are preferred.

 In a preferred embodiment of the invention, the cosolvent is added in an amount of from 0.01% to 20%, preferably from 0.01% to 10% by weight based on the total weight of the solid pharmaceutical composition.

 The addition of some stabilizers can improve the stability of solid pharmaceutical compositions such as maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, tartaric acid and sodium hydroxide, and maleic acid. Sodium, monosodium fumarate, sodium tartrate, monosodium citrate, propyl gallate, ethylenediaminetetraacetic acid, disodium edetate, butylated hydroxyanisole, sodium sulfite, sodium bisulfite, sodium metabisulfite And/or ascorbic acid, preferably maleic acid with sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, monosodium maleate, monosodium fumarate and/or monosodium citrate.

 In a preferred embodiment of the invention, the stabilizer is added in an amount of from 0.01% to 20%, preferably from 0.01% to 10%, based on the total weight of the solid pharmaceutical composition.

 Another aspect of the present invention provides a solid pharmaceutical composition containing azilsartan, wherein azilsartan has a particle diameter d (0.5) of between 1 and 50 μm, and d (0.9) is less than or equal to 150 μm; preferably d (0.5) between 1 and 20 μm, d (0.9) is less than or equal to 80 μm; more preferably d (0.5) is between 1-10 μm, d (0.9) is less than or equal to 40 μm; most preferably d (0.5) is at Between 5μηι, d (0.9) is less than or equal to 15μηι.

 Azilsartan has good dissolution at high ρΗ (such as ρΗ6.8), but it has poor dissolution at low ρΗ (such as ρΗ4.5). However, the most important absorption site of azilsartan in human body is jejunum and Duodenum, ρ Η value is about 4-7. The inventors have surprisingly found that the treatment of azilsartan to the above particle size range can effectively improve its dissolution at low ρΗ.

 In a preferred embodiment of the invention, the solid pharmaceutical composition further comprises polyethylene glycol, preferably PEG 4000 or PEG 6000, more preferably PEG 6000. When the particle size of azilsartan becomes smaller, the solid pharmaceutical composition tends to be unstable, and the inventors have found that the addition of polyethylene glycols effectively changes this condition and serves to stabilize the composition. effect. The content of the polyethylene glycol is not particularly limited, and in a further preferred embodiment of the invention, it is from 0.01% to 20%, preferably from 0.01% to 10% by weight based on the total mass of the composition.

In another preferred embodiment of the invention, the solid pharmaceutical composition further comprises citric acid, sodium citrate, or a mixture thereof. The inventors have noted that citric acid, sodium citrate, or mixtures thereof can substantially increase the bioavailability of azilsartan. The content of the citric acid, sodium citrate, or a mixture thereof is not particularly limited, and in a further preferred embodiment of the present invention, it is from 0.01% to 20%, preferably from 0.01% to 10%, based on the total amount of the composition. In another preferred embodiment of the present invention, the solid pharmaceutical composition further comprises a penetration enhancer selected from the group consisting of sodium dodecyl sulfate (SDS), sodium lauryl sarcosinate, Poloxamer, Tween, Span, polyoxyethylene hydrogenated castor oil, castor oil polyoxyl ester; poloxamer can be poloxamer 188, poloxamer 407; Tween can be Tween 20 Tween 60 and Tween 80. The addition of a penetration enhancer improves the absorption of azilsartan in the body and also increases its bioavailability. The content of the penetration enhancer is not particularly limited, and in a further preferred embodiment of the invention, it is from 0.01% to 20%, more preferably from 0.01% to 10%, based on the total amount of the composition.

 According to another preferred embodiment of the present invention, the compound of the formula (I) is encapsulated in a hole structure of a cyclodextrin and a derivative thereof, wherein the cyclodextrin and a derivative thereof are selected from the group consisting of α-cyclodextrin. , β-cyclodextrin, γ-cyclodextrin, sulfobutylether-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, 2,6-trimethyl β-cyclodextrin, monosaccharide Β-cyclodextrin, disaccharide β-cyclodextrin, maltotriosyl β-cyclodextrin, dimonosaccharide β-cyclodextrin, di-disaccharide β-cyclodextrin, 2,3, 6-trimethoxy β-cyclodextrin, 2-oxo-(2-hydroxypropyl)-β-cyclodextrin and/or hydroxypropyl-β-cyclodextrin, preferably β-cyclodextrin and/or Or hydroxypropyl-β-cyclodextrin. Further, the weight ratio of the compound represented by the formula (I) to the cyclodextrin is 1:20 to 1:2; preferably 1:10 to 1:4; more preferably 1:8 to 1:4.

 Another object of the present invention is a method of preparing the pharmaceutical composition, characterized in that

The compound represented by (I) is dispersed and/or embedded in each component of the composition to form a solid composition.

 Another object of the present invention is to provide a use of the pharmaceutical composition for the preparation of a medicament for treating diseases of the circulatory system, which is preferably hypertension. DRAWINGS

 Figure 1: Effect of particle size on dissolution behavior of the formulation

 Figure 2: Effect of inclusion complex on dissolution behavior of the formulation

 Figure 3: Effect of co-solvent on dissolution behavior of the formulation

 Figure 4: Example 3 and Comparative Example 2 Comparison of dissolution behavior

 Figure 5: Effect of raw material particle size on dissolution behavior of the formulation 2

 Example 1

 Azisartan (64g), with mannitol (200g), microcrystalline cellulose (30g), crosslinked carboxymethyl group, will be treated by jet milling (d ( 0.5 ) = 2.61μηι, d ( 0.9 ) = 5.24μηι) The sodium cellulose (16 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 3.3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 159.6mg)

 Azilsartan 32mg

Mannitol lOOmg Hydroxypropyl cellulose 3.0mg

 Microcrystalline cellulose 15mg

 Cross-linked sodium carboxymethyl cellulose 8mg

 Magnesium stearate 1.6mg Example 2

 Azilsartan (64 g) was mixed with β-cyclodextrin (384 g) uniformly, added with 768 g of water, ground for 6 h to a semi-solid state, and dried under reduced pressure at 40 ° C to give a solid. The obtained solid was washed with an appropriate amount of water and methanol, and dried under reduced pressure to give a clath. Take appropriate amount of inclusion complex (containing azilsartan 32g), mix with mannitol (100g), microcrystalline cellulose (15g), croscarmellose sodium (8g), using 5% hydroxypropyl fiber The aqueous solution of the solution is a binder, granulation, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 3.3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 10.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 345.5mg)

 Azisartan inclusion complex 216mg (containing azilsartan 32mg)

 Mannitol lOOmg

 Hydroxypropyl cellulose 3.0mg

 Microcrystalline cellulose 15mg

 Cross-linked sodium carboxymethyl cellulose 8mg

 Magnesium stearate 3.5mg Example 3

 Azilsartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), sodium carbonate (40g), using 5% hydroxypropyl The aqueous cellulose solution was a binder, granulated, fluidized bed dried, and 1.0 mm sieve granules. To the granules after the granules, 3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 156mg)

 Azilsartan 32mg

 Mannitol 45mg

 Hydroxypropyl cellulose 5mg

 Microcrystalline cellulose 45mg

 Cross-linked carboxymethylcellulose sodium 7.5mg

 Sodium carbonate 20mg

 Magnesium stearate 1.5mg Example 4

Azilsartan (64g), with mannitol (90g), microcrystalline cellulose (90g), cross-linked carboxymethyl fiber Sodium (15g) and sodium carbonate (40g) were mixed uniformly, and 3 g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 151mg)

 Azilsartan 32mg

 Mannitol 45mg

 Microcrystalline cellulose 45mg

 Cross-linked carboxymethylcellulose sodium 7.5mg

 Sodium carbonate 20mg

 Magnesium stearate 1.5mg Example 5

 Azisartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), sodium lauryl sulfate (40g), using 5 The aqueous solution of % hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and 1.0 mm sieve granules. 3 g of magnesium stearate was added to the granules after the granules, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 155mg)

 Azilsartan 32mg

 Mannitol 45mg

 Hydroxypropyl cellulose 4mg

 Microcrystalline cellulose 45mg

 Cross-linked carboxymethylcellulose sodium 7.5mg

 Sodium lauryl sulfate 20mg

 Magnesium stearate 1.5mg Example 6

 Azisartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), using 5% hydroxypropyl cellulose solution (including 2.5 % citric acid, 0.83% sodium hydroxide) as binder, granulation, fluidized bed drying, 1.0 mm sieve granules. To the whole granules, 3 g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0 mm punch to obtain a tablet having the following composition.

 Composition of the preparation (per 158.5mg)

 Azilsartan 32mg

 Mannitol 45mg

 Hydroxypropylcellulose 4.5mg

 Citric acid 2.25mg

Sodium hydroxide 0.75mg Microcrystalline cellulose 45mg

 Cross-linked carboxymethylcellulose sodium 7.5mg

 Sodium lauryl sulfate 20mg

 Magnesium stearate 1.5mg Example 7

 Azisartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), using 5% hydroxypropyl cellulose solution (including 2.5 % maleic acid, 0.83% sodium hydroxide) as binder, granulation, fluidized bed drying, 1.0 mm sieve granules. To the whole granules, 3 g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0 mm punch to obtain a tablet having the following composition.

 Composition of the preparation (per 158.5mg)

 Azilsartan 32mg

 Mannitol 45mg

 Hydroxypropylcellulose 4.5mg

 Maleic acid 2.25mg

 Sodium hydroxide 0.75mg

 Microcrystalline cellulose 45mg

 Cross-linked carboxymethylcellulose sodium 7.5mg

 Sodium lauryl sulfate 20mg

 Magnesium stearate 1.5mg Example 8

 Azisartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), using 5% hydroxypropyl cellulose solution (including 2.5 % fumaric acid, 0.83% sodium hydroxide) as binder, granulation, fluidized bed drying, 1.0 mm sieve granules. To the whole granules, 3 g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0 mm punch to obtain a tablet having the following composition.

 Composition of the preparation (per 158.5mg)

 Azilsartan 32mg

 Mannitol 45mg

 Hydroxypropylcellulose 4.5mg

 Fumaric acid 2.25mg

 Sodium hydroxide 0.75mg

 Microcrystalline cellulose 45mg

Cross-linked carboxymethylcellulose sodium 7.5mg Sodium lauryl sulfate 20mg

 Magnesium stearate 1.5 mg Example 9

 Azisartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), using 5% hydroxypropyl cellulose solution (including 2.5 % fumaric acid, 0.83% sodium hydroxide) as binder, granulation, fluidized bed drying, 1.0 mm sieve granules. To the whole granules, 3 g of magnesium stearate was added and mixed well. The resulting mixture was tableted through a 9.0 mm punch to obtain a plain tablet. The methacrylic acid copolymer type A and the methacrylic acid copolymer type B were dissolved in 95% ethanol, continuously stirred until completely dissolved, and slowly added, stirring was continued until dissolution, and it was used. The talc powder and triethyl citrate were added to the remaining aqueous ethanol solution, and after mixing, they were homogenized for 10 minutes, and then slowly added to the copolymer solution, and stirring was continued for 30 minutes. The tablet was placed in a high-efficiency coating pan for coating to obtain a coated tablet of the following composition.

 Core composition (per 317mg)

 Azilsartan 64mg

 Mannitol 90mg

 Hydroxypropyl cellulose 9mg

 Fumaric acid 4.5mg

 Sodium hydroxide 1.5mg

 Microcrystalline cellulose 90mg

 Cross-linked carboxymethylcellulose sodium 15mg

 Sodium lauryl sulfate 40mg

 Magnesium stearate 3mg

 Composition of the coating layer (per 332.9mg)

 Chip core 317mg

 Methacrylic acid copolymer type A 2.48mg

 Methacrylic acid copolymer type B 7.44mg

 Talc 4.96mg

 Triethyl citrate 0.99 mg Example 10

Azisartan (64g), mixed with mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g), using 5% hydroxypropyl cellulose solution (including 2.5 % fumaric acid, 0.83% sodium hydroxide) as binder, granulation, fluidized bed drying, 1.0 mm sieve granules. 3 g of magnesium stearate was added to the granules after the granules, and the mixture was uniformly mixed. The resulting mixture was tableted through a 10.0 mm punch to obtain a plain tablet. The methacrylic acid copolymer type A and the methacrylic acid copolymer type B were dissolved in 95% ethanol, continuously stirred until completely dissolved, and slowly added, stirring was continued until dissolution, and it was used. Add talc powder and triethyl citrate to the remaining ethanol water The solution, after mixing, was homogenized for 10 minutes and then slowly added to the copolymer solution, and stirring was continued for 30 minutes. The tablet was placed in a high-efficiency coating pan for coating to obtain a coated tablet of the following composition.

 Core composition (per 317mg)

 Azilsartan 64mg

 Mannitol 90mg

 Hydroxypropyl cellulose 9mg

 Fumaric acid 4.5mg

 Sodium hydroxide 1.5mg

 Microcrystalline cellulose 90mg

 Cross-linked carboxymethylcellulose sodium 15mg

 Sodium lauryl sulfate 40mg

 Magnesium stearate 3mg

 Composition of the coating layer (per 320.2mg)

 Chip core 317mg

 Methacrylic acid copolymer type B 1.98mg

 Talc powder 0.99mg

 Triethyl citrate 0.20 mg Example 11

 Azisartan (64 g), methacrylic acid copolymer type A (18.65 g), methacrylic acid copolymer type B (55.95 g), magnesium stearate (1.4 g) were uniformly mixed, and the resulting mixture was washed through 7.0 mm. The head was pressed to obtain a plain tablet having the following composition.

 Composition of the preparation (per 140mg)

 Azilsartan 64mg

 Methacrylic acid copolymer type A 18.65mg

 Methacrylic acid copolymer type B 55.95mg

 Magnesium stearate 1.4 mg Example 12

 Azisartan (64 g), calcium hydrogen phosphate (67.6:), pregelatinized starch (7 g), magnesium stearate (1.4 g) were uniformly mixed, and the resulting mixture was passed through a 7.0 mm punch to obtain a pigment having the following composition. sheet.

 Composition of the preparation (per 140mg)

 Azilsartan 64mg

 Calcium hydrogen phosphate 67.6mg

Pregelatinized starch Vmg Stearic acid: 1.4 mg larger Example 13

 Azilsartan (64 g) was mixed with hydroxypropyl-β-cyclodextrin (256 g) uniformly, and 512 g of water was added thereto, and the mixture was ground for 6 hours to a semi-solid state, and dried under reduced pressure at 40 ° C to obtain a solid. The obtained solid was washed with an appropriate amount of water and methanol, and dried under reduced pressure to give a clath. Take appropriate amount of inclusion complex (containing azilsartan 32g), mix with mannitol (100g), microcrystalline cellulose (15g), croscarmellose sodium (8g), using 5% hydroxypropyl fiber The aqueous solution of the solution is a binder, granulation, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 3.3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 10.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 290 mg)

 Azilsartan inclusion complex 161mg (containing azilsartan 32mg) mannitol lOOmg

 Hydroxypropyl cellulose 3.0mg

 Microcrystalline cellulose 15mg

 Cross-linked sodium carboxymethyl cellulose 8mg

 Magnesium stearate 3.0 mg Example 14

 Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 1.85μηι, d ( 0.9 ) = 4.12μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Magnesium stearate 2mg Example 15

Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 4.47μηι, d ( 0.9) = 13.28μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the granules after the granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was compressed by a 8.0 mm punch. To a plain tablet with the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose 10mg

 Magnesium stearate 2mg

Example 16

 Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 8.46 m, d ( 0.9 ) = 25.13 μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Magnesium stearate 2mg Example 17

 Mechanical treatment (d ( 0.5 ) = 17.94 μιη, d ( 0.9 ) = 56.82 μηι) of azilsartan (80 g), with mannitol (250 g), microcrystalline cellulose (37.5 g), cross-linked carboxy Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

Cross-linked carboxymethyl cellulose sodium lOmg Magnesium stearate 2 mg Example 18

 Mechanical pulverization treatment ((1 (0.5) = 46.77μηι, (1 (0.9) = 83.14μηι) of azilsartan (80g), with mannitol (250g), microcrystalline cellulose (37.5g), Sodium carboxymethylcellulose (20g) is uniformly mixed, using 5% hydroxypropylcellulose aqueous solution as binder, granulating, fluidized bed drying, 1.0mm mesh granules. Adding hard to granules after granules 4.0 g of magnesium oleate was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Magnesium stearate 2mg Example 19

 Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 3.26μηι, d ( 0.9 ) = 8.21μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose (containing polyethylene glycol 6000) was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 205.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Polyethylene glycol 6000 6mg

 Magnesium stearate 2mg Example 20

Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 3.26μηι, d ( 0.9 ) = 8.21μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the granules after the granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was compressed by a 8.0 mm punch. To a plain tablet with the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Magnesium stearate 2mg Example 21

 Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 3.26μηι, d ( 0.9 ) = 8.21μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose (containing citric acid/sodium citrate) was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve was granulated. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 209.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Citric acid 5mg

 Sodium Citrate 5mg

 Magnesium stearate 2mg Example 22

 Azisartan (80g), mannitol (250g), microcrystalline cellulose (37.5g), cross-linked carboxylate will be treated by jet milling (d ( 0.5 ) = 3.26μηι, d ( 0.9 ) = 8.21μηι) Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose (containing poloxamer 188) was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 209.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

Microcrystalline cellulose 18.75mg Cross-linked sodium carboxymethyl cellulose 10mg

 Poloxamer 188 10mg

 Magnesium stearate 2mg Comparative example 1

 Azisartan (64 g) using a 60 mesh sieve was mixed with mannitol (200 g) and microcrystalline cellulose (30 g of croscarmellose sodium (16 g) uniformly, using a hydroxypropylcellulose aqueous solution. Adhesive, granulation, fluidized bed drying, 1.0 mm sieve granules. 3.3 g of magnesium stearate was added to the granules after granulation, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain the following composition. Tablets.

 Composition of the preparation (per 159.6mg)

 Azilsartan 32mg

 Mannitol lOOmg

 Hydroxypropyl cellulose 3.0mg

 Microcrystalline cellulose 15mg

 Cross-linked sodium carboxymethyl cellulose 8mg

 Magnesium stearate 1.6mg Comparative example 2

 See Example 1 of CN101528262A for preparation. Comparative example 3

 Azilsartan (80 g with mannitol (250 g), microcrystalline cellulose (37.5 g), croscarmellose sodium (d ( 0.5 ) = 290 d ( 0.9 ) = 520) will be used ( 20g) Mix evenly, use 5% hydroxypropyl cellulose aqueous solution as binder, granulate, fluidized bed drying, 1.0mm mesh granules. Add 4.0g of magnesium stearate to the granules after granules, mix evenly The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Magnesium stearate 2mg Comparative example 4

Azisartan (80g) treated with 80 mesh sieve (d ( 0.5 ) = 61.2μηι, (1 ( 0.9) =144.8μηι) Blended with mannitol (250g), microcrystalline cellulose (37.5g), croscarmellose sodium (20g), 5% hydroxypropyl cellulose solution as binder, granulation, fluidized bed Dry, 1.0mm mesh. To the granules after the granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Magnesium stearate 2mg Comparative example 5

 Azisartan (80g) using a 60 mesh sieve, mixed with mannitol (250g), microcrystalline cellulose (37.5g), croscarmellose sodium (20g), using 5% hydroxypropyl The aqueous cellulose solution (containing polyethylene glycol 6000) was used as a binder, granulated, fluidized bed drying, and 1.0 mm sieve granules. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.

 Composition of the preparation (per 205.5mg)

 Azilsartan 40mg

 Mannitol 125mg

 Hydroxypropyl cellulose 3.75mg

 Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose lOmg

 Polyethylene glycol 6000 6mg

 Stearic acid: day 2mg Comparative example 6

 Azisartan (80g) using a 60 mesh sieve, mixed with mannitol (250g), microcrystalline cellulose (37.5g), croscarmellose sodium (20g), using 5% hydroxypropyl Aqueous cellulose solution (for binder, granulation, fluidized bed drying, 1.0 mm sieve granules. Add 4.0 g of magnesium stearate to the granules after granulation, and mix well. The resulting mixture is passed through a 8.0 mm punch. The tablets were obtained as a plain tablet having the following composition.

 Composition of the preparation (per 199.5mg)

 Azilsartan 40mg

 Mannitol 125mg

Hydroxypropyl cellulose 3.75mg Microcrystalline cellulose 18.75mg

 Cross-linked sodium carboxymethyl cellulose 10mg

 Magnesium stearate 2mg Experimental example 1

 The approximate solubility of azilsartan in different media was determined as shown below.

 Refer to the Chinese Pharmacopoeia 2010 version of the approximate solubility determination method: Add an excess of acesartan to each of the quantitative media, and shake vigorously for 30 seconds every 5 minutes at 25 °C. After 30 minutes, it was filtered through a 0.45 μηι microporous membrane, and the concentration of azilsartan in the filtrate was determined by HPLC.

 Table 1 Approximate solubility of azilsartan in different media

 From the above results, it can be seen that ρΗ4.5 acetate buffer + 5% sodium dodecyl sulfate can meet the leakage condition of the preparation of the specification of 37 mg or less, and the pH 6.8 phosphate buffer can satisfy the leakage of the preparation of the specification of 250 mg or less. condition. Experimental example 2

 The drug dissolution behavior evaluation conditions of the tablets obtained in Example 1 and Comparative Example 1 were as follows: Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate, pH 6.8 phosphate buffer dissolution medium Volume: 900ml

 Dissolution method: According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.

 The dissolution profile was determined by HPLC as shown in Figure 1.

As shown in Figure 1, the reduction of the particle size of the raw material significantly improved the dissolution behavior of azilsartan under low pH conditions (pH 4.5). Experimental example 3

 The drug dissolution behavior evaluation conditions of the tablets obtained in Example 2 and Comparative Example 1 were as follows: Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate

 Dissolution medium volume: 900ml

 Dissolution method: According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.

 The dissolution profile was determined by HPLC as shown in Fig. 2.

 As shown in Fig. 2, the preparation of the inclusion complex using β-cyclodextrin as the inclusion material can significantly improve the dissolution behavior of azilsartan under these conditions. Experimental example 4

 The plain tablets obtained in Example 2 and Comparative Example 1 were moisture-proof packaged, and placed at 40 ° C and 60 ° C, respectively, and sampled at 7 days and 14 days, respectively, and the amount of decomposition products was measured by HPLC method. See Table 2.

 Table 2 Effect of inclusion complexes on formulation stability

 Inhibition of degradation. Experimental example 5

 The drug dissolution behavior evaluation conditions of the tablets obtained in Example 3 and Comparative Example 1 were as follows: Dissolution medium: ρΗ4.5 acetate buffer, ρΗ4.5 acetate buffer + 5% sodium dodecyl sulfate dissolution Media volume: 900ml

 Dissolution method: According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.

 The dissolution profile was determined by HPLC as shown in Fig. 3.

As shown in Figure 3, the use of sodium carbonate as a co-solvent significantly improved the dissolution behavior of azilsartan under these conditions. Experimental example 6 The plain tablets obtained in Example 7 and Comparative Example 1 were moisture-proof packaged and placed at 40 ° C and 60 ° C respectively, and sampled at 7 days and 14 days, respectively, and the amount of decomposition products was measured by HPLC method. See Table 3.

 Table 3 Effect of stabilizers on formulation stability

 The results showed that the use of maleic acid and sodium hydroxide as stabilizers can significantly improve the stability of azilsartan. Experimental example 7

 The plain tablets obtained in Examples 6, 8 and Comparative Example 1 were moisture-proof packaged and placed under 40 ° C and 60 ° C cattle, respectively, and sampled at 7 days, and the amount of decomposition products was determined by HPLC method. Table 4. Table 4 Effect of stabilizers on formulation stability

实验例 8

Experimental Example 8

 The plain tablets obtained in Examples 19 and 20 and Comparative Examples 5 and 6 were moisture-proof packaged and placed at 60 ° C, respectively, and sampled at 7 days and 14 days, respectively, and the amount of decomposition products was measured by HPLC method. See Table 5.

 Table 5 Effect of stabilizers on formulation stability

The results show that polyethylene glycol 6000 can improve the stability of azilsartan when preparing samples with 60 mesh sieve materials, but the effect is limited. When preparing samples with smaller particle size raw materials (by jet milling), Ethylene Glycol 6000 can have an unexpected stabilizer effect. Experimental Example 9

 The evaluation conditions of the drug dissolution behavior of the tablets obtained in Example 3 and Comparative Examples 1 and 2 were as follows: Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate, pH 6.8 phosphate buffer Dissolution medium volume: 900ml

 Dissolution method: According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.

 The dissolution profile was determined by HPLC as shown in Fig. 4.

 As shown in Fig. 4, the dissolution scheme of Comparative Example 2 was comparable to that of Comparative Example 1 at high pH (pH 6.8), and the improvement of dissolution at low pH (pH 4.5) was limited, indicating that polyethylene was added. Alcohol 6000 is not significant as a cosolvent. Example 3 Using sodium carbonate as a co-solvent compared to Comparative Example 2 The dissolution behavior was comparable at high pH (pH 6.8), and the dissolution of azilsartan was better at low pH (pH 4.5). Unexpected effect. Experimental example 10

 The evaluation conditions of the drug dissolution behavior of the tablets obtained in Examples 14, 15, 16, 17, 18 and Comparative Examples 3 and 4 were as follows:

 Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate

 Dissolution medium volume: 900ml

 Dissolution method: According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.

 The dissolution profile is shown in Figure 5.

 As shown in Fig. 5, the dissolution behaviors of Examples 14, 15, 16, 17, 18 and Comparative Example 4 were sequentially slowed, but the dissolution rate of Comparative Example 3 was lower than that of Example 14. It can be seen that as the particle size of the raw material of azilsartan becomes smaller, the dissolution rate is faster and more sufficient. However, after the particle size of the azilsartan drug substance is reduced to a certain extent (such as nanocrystallization treatment), the dissolution rate is decreased, which is beyond the common knowledge of the practitioners in the field. Therefore, the particle size of the azisartan raw material should be controlled within a certain range. Experimental example 11

Examples 20 and 21 were performed on human pharmacokinetic studies, respectively. After 40 mg orally on an empty stomach, the _Cmax and AUC of Example 20 were 4025 ng/ml and 26968 ng/ml*h, respectively, and the _Cmax and AUC of Example 21 were 4436 ng/ml and 36895 ng/ml*h, respectively. The AUC of Example 21 _(which is 1.37 times that of Example 20, shows that the addition of citric acid/sodium citrate improves the bioavailability of the formulation. Experimental Example 12 Examples 20 and 22 were performed on human pharmacokinetic studies, respectively. After 40 mg orally on an empty stomach, the _Cmax and AUC of Example 20 were 4025 ng/ml and 26968 ng/ml*h, respectively, and the _Cmax and AUC of Example 22 were 4559 ng/ml and 37725 ng/ml*h, respectively. The AUC of Example 22 _(which is 1.40 times that of Example 20, shows that the addition of Poloxamer 188 improves the bioavailability of the formulation.

Claims

Claims: A solid pharmaceutical composition comprising a compound represented by the formula (I), characterized by comprising a co-solvent selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide or a mixture of them, preferably sodium carbonate,

 (I) Wherein R ¹ is a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom deprotonated, R ² is a carboxyl group, and R ³ is. Lower alkyl. The solid pharmaceutical composition according to claim 1, wherein the compound of the formula (I) is azisartan. The solid pharmaceutical composition according to claim 2, wherein the co-solvent is used in an amount of from 0.01% to 20%, preferably from 0.01% to 10% based on the total amount of the solid pharmaceutical composition. The composition according to any one of claims 1 to 3, further comprising a stabilizer selected from the group consisting of maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and Sodium hydroxide, monosodium maleate, monosodium fumarate and/or monosodium citrate; preferably the stabilizer is used in an amount of from 0.01% to 20% by weight based on the total weight of the composition; more preferably from 0.01% to 10%. 5. A solid pharmaceutical composition comprising azilsartan, wherein the azartan has a particle size d (0.5) of between 1 and 50 μηι, d (0.9) of less than or equal to 150 μηΐ; preferably d (0.5) of 1 Between -20μηι, d (0.9) is less than or equal to 80μηι; more preferably d (0.5) is between 1-10μηι, d (0.9) is less than or equal to 40μηι; most preferably d (0.5) is between 1-5μηι, d (0.9) Less than or equal to 15μηι. 6. Composition according to claim 5, characterized in that it further comprises polyethylene glycol, preferably PEG4000 or PEG6000, more preferably PEG6000. 7. The composition according to claim 6, wherein the content of the polyethylene glycol is a composition 0.01%-20%, preferably 0.01%-10% of the total weight  8. The composition of claim 5 further comprising citric acid or sodium citrate, or a mixture thereof; preferably said citric acid or sodium citrate, or a mixture thereof, based on the total weight of the composition From 0.01% to 20%, more preferably from 0.01% to 10%.  9. The composition of claim 5 further comprising a penetration enhancer selected from the group consisting of sodium lauryl sulfate, sodium lauryl sarcosinate, poloxamer, spit Warm, Span, polyoxyethylene hydrogenated castor oil, castor oil polyoxyl ester; preferably poloxamer is poloxamer 188 and / or poloxamer 407, more preferably poloxamer 188; preferably Tween It is Tween 20, Tween 60, and/or Tween 80, and Tween 80 is more preferable.  10. Composition according to claim 9, characterized in that the penetration enhancer is present in an amount of from 0.01% to 20%, more preferably from 0.01% to 10% by weight based on the total weight of the composition.  The use of the pharmaceutical composition according to any one of claims 1 to 10 for the preparation of a medicament for treating diseases of the circulatory system, wherein the disease is preferably hypertension.