HK1182638B - Solid pharmaceutical composition containing benzimidazole derivative - Google Patents

Description

Solid pharmaceutical composition comprising benzimidazole derivative

Technical Field

The invention relates to a solid pharmaceutical composition for improving the dissolution rate and/or stability of a medicament, a preparation method thereof and application thereof in preparing antihypertensive medicaments.

Background

Circulatory diseases, also known as cardiovascular diseases, refer to diseases of the heart, blood vessels and nervous mechanisms regulating blood circulation. Heart diseases and hypertension are the most common. Circulatory diseases are common diseases, and particularly account for a large proportion of internal diseases. The heart diseases are often delayed and not cured, the life and the labor are affected, the death rate is high, and the cardiovascular diseases occupy more prominent positions in the death cause of the population along with the control of infectious diseases. Circulatory diseases can be divided into congenital and acquired categories. Congenital cardiovascular diseases are caused by abnormal development of cardiac great vessels in the fetal period. Acquired cardiovascular diseases, such as coronary atherosclerotic heart disease, rheumatic heart disease, hypertension and hypertensive heart disease.

Angiotensin II causes vasoconstriction and raises blood pressure through angiotensin II receptors on the cell membrane. Thus, angiotensin II receptor antagonists may be effective drugs for the treatment of circulatory diseases such as hypertension and the like. The renin-angiotensin system is involved in controlling systemic blood pressure, body fluid amount, electrolyte balance, etc. in homeostasis together with the aldosterone system. Based on the fact that angiotensin II, which has a potent vasoconstrictive action, raises blood pressure via angiotensin II receptors located on cell membranes, the relationship between renin-angiotensin and hypertension has been revealed, and thus, antagonists of angiotensin II have been used to treat angiotensin-induced hypertension. Hitherto, ｃA drug having angiotensin II antagonistic activity has been administered clinically by oral administration, and as ｃA preferable chemical structure strongly expressing angiotensin II antagonistic activity, ｃA structure having an acid group such as tetrazolyl, carboxyl group and the like on ｃA biphenyl group side chain is known, and drugs having such structural characteristics as losartan, candesartan cilexetil, olmesartan medoxomil and the like (Ruth r.wexler et al, Journal of medicinal chemistry, vol.39, p.625(1996), JP- ｃA-4-364171, JP- ｃA-5-78328 and the like) have been clinically used. JP-A-5-271228 describes ｃA compound in which the acid group on the biphenyl side chain is ｃA 5-oxo-4, 5-dihydro-1, 2, 4-dithian-3-yl group, which shows ｃA long-term and strong angiotensin II antagonistic activity and antihypertensive activity after oral administration. Further, W003/047573 describes that the benzimidazole derivatives described in JP-A-5-271228 have insulin sensitizing activity in addition to angiotensin II receptor antagonistic activity.

Azilsartan (english name Azilsartan) is an angiotensin II receptor antagonist drug under development for treating hypertension, blocks the vasoconstriction effect of angiotensin II by selectively blocking the binding of angiotensin II to vascular smooth muscle AT1 receptor, is mostly used for treating hypertension, and is also the only angiotensin II receptor antagonist (sartan) drug in late-stage clinical use AT present.

Pharmaceutical products need to be effective, safe and stable. The effectiveness, safety and stability of a pharmaceutical product are closely related to the effectiveness and safety of the drug-effective ingredient itself, and are also very important due to the influence of the properties of the pharmaceutical product, such as the stability of the drug-effective ingredient in a preparation and the dissolution characteristics of the drug from the preparation. For example, even if a formulation satisfies a certain level of quality immediately after preparation, if a pharmaceutically effective ingredient in the formulation is decomposed over time, the formulation is problematic in terms of the effectiveness and safety of a pharmaceutical product. With respect to the dissolution characteristics of a drug from a preparation, when the drug is dissolved from the preparation too slowly, the drug may not reach an effective concentration in blood and may not achieve a desired effect. When the drug is dissolved too quickly, it may cause a rapid increase in blood concentration in the body, and the risk of side effects may also increase.

As a method for improving the stability of a pharmaceutically effective ingredient in a formulation, addition of a pH adjusting agent is known, and patent document CN101677961A discloses only a method using fumaric acid and sodium hydroxide, or monosodium fumarate as a stabilizer, together with the use of azilsartan medoxomil potassium salt as an active ingredient. Meanwhile, the patent document claims to improve the dissolution rate of the drug, but the given specific embodiments are dissolution tests under the condition of high pH (pH6.8), and the dissolution advantage in the human environment cannot be proved. The dissolution rate of the pharmaceutical composition provided by the patent application under the condition of low pH is measured, and the improvement effect is very limited.

CN101528262A discloses a solid pharmaceutical composition comprising a pharmaceutically active ingredient, a low melting point greasy substance and a low viscosity binder, and a method of improving the dissolution of the pharmaceutically active ingredient from the solid composition. The drug dissolution property of the solid dosage form containing the low-melting point grease-like substance is improved, but the specific implementation modes given by the solid dosage form are dissolution tests under the condition of high pH (pH6.8), and the dissolution advantage of the solid dosage form in the human environment cannot be proved. The dissolution rate of the pharmaceutical composition provided by the patent application under the condition of low pH is measured, and the improvement effect is very limited.

Disclosure of Invention

The invention aims to provide a solid pharmaceutical composition which comprises a compound represented by a formula (I) and is characterized by being capable of adjusting the dissolution rate and/or the stability of a medicament,

wherein the content of the first and second substances,

R¹is a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom capable of being deprotonated, R²Is a carboxyl group, and R³Is lower alkyl, preferably the compound of formula (I) is azilsartan;

the dissolution rate regulating amount is 5-100%, preferably 10-90%. The adjusting amount is an increasing amount or a reducing amount, the dissolution rate is the dissolution rate in a dissolution medium with the pH of 1-10, and the preferable pH is 4-8.

Wherein at least one inactive ingredient selected from the group consisting of ethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methacrylic acid-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropylcellulose acetate succinate and/or polyvinylacetate phthalate is included to adjust the dissolution rate, which inactive ingredient may be present on the surface of the pharmaceutical composition or dispersed within the pharmaceutical composition.

The inventors have surprisingly found that the addition of a co-solvent improves the dissolution of azilsartan very well. The cosolvent is selected from sodium carbonate, sodium bicarbonate, calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide, etc., preferably sodium carbonate and sodium bicarbonate.

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

The addition of some stabilizers may 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, monosodium maleate, monosodium fumarate, sodium tartrate, monosodium citrate, propyl gallate, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, butylated hydroxyanisole, sodium sulfite, sodium bisulfite, sodium metabisulfite and/or ascorbic acid, preferably maleic acid and 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 present invention, the stabilizer is added in an amount of 0.01% to 20%, preferably 0.01% to 10% by weight based on the total weight of the solid pharmaceutical composition.

In another aspect of the present invention there is provided a solid pharmaceutical composition comprising azilsartan, wherein the particle size d (0.5) of azilsartan is between 1 and 50 μm, d (0.9) is less than or equal to 150 μm; preferably d (0.5) is between 1 and 20 μm, d (0.9) is less than or equal to 80 μm; more preferably d (0.5) is between 1 and 10 μm, d (0.9) is less than or equal to 40 μm; most preferably d (0.5) is between 1 and 5 μm and d (0.9) is less than or equal to 15 μm.

Azilsartan dissolves well at high pH (e.g., pH6.8) but poorly at low pH (e.g., pH4.5), whereas the major absorption sites of azilsartan in the human body are the jejunum and duodenum, with pH around 4-7. The inventors have surprisingly found that treatment of azilsartan to the above particle size range is effective in improving its dissolution at low pH.

In a preferred embodiment of the invention, the solid pharmaceutical composition further comprises polyethylene glycol, preferably PEG4000 or PEG6000, more preferably PEG 6000. When the particle size of the azilsartan is reduced, the solid pharmaceutical composition tends to be unstable, and the inventor finds that the addition of polyethylene glycols effectively changes the situation and has the effect of stabilizing the composition. The content of the polyethylene glycol is not particularly limited, and in a further preferred embodiment of the present invention, it is 0.01% to 20%, preferably 0.01% to 10% by weight of the total composition.

In another preferred embodiment of the present 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 a mixture thereof can greatly improve the bioavailability of azilsartan. The content of said citric acid, sodium citrate, or mixtures thereof is not particularly limited, and in a further preferred embodiment of the invention it is between 0.01% and 20%, preferably between 0.01% and 10% of the total weight of the composition.

In another preferred embodiment of the present invention, the solid pharmaceutical composition further comprises a penetration enhancer selected from Sodium Dodecyl Sulfate (SDS), sodium lauryl sarcosinate, poloxamer, tween, span, polyoxyethylene hydrogenated castor oil, castor oil polyoxyl ester; the poloxamer can be poloxamer 188, poloxamer 407; the tween can be tween 20, tween 60 or tween 80. The addition of the penetration enhancer improves the absorption of the azilsartan in the body and improves the bioavailability of the azilsartan. The content of the penetration enhancer is not particularly limited, and in a further preferred embodiment of the present invention, it is 0.01% to 20%, more preferably 0.01% to 10% of the total weight of the composition.

Another preferred embodiment of the invention is that the compounds of formula (I) are occluded in the cavity of cyclodextrins and derivatives thereof to form inclusion compounds, wherein the cyclodextrin and its derivatives are selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, 2, 6-dimethyl beta-cyclodextrin, 2, 6-trimethyl beta-cyclodextrin, monosaccharide beta-cyclodextrin, disaccharide beta-cyclodextrin, maltotriosyl beta-cyclodextrin, dimonosyl beta-cyclodextrin, disaccharide beta-cyclodextrin, 2,3, 6-trimethoxy beta-cyclodextrin, 2-oxy- (2-hydroxypropyl) -beta-cyclodextrin and/or hydroxypropyl-beta-cyclodextrin, preferably beta-cyclodextrin and/or hydroxypropyl-beta-cyclodextrin. Further, the weight ratio of the compound represented by formula (I) to cyclodextrin is 1: 20-1: 2; preferably 1: 10-1: 4; more preferably 1: 8-1: 4.

another object of the present invention is a process for preparing said pharmaceutical composition, characterized by dispersing and/or embedding the compound represented by formula (I) in the components of the composition to form a solid composition.

Another object of the present invention is to provide the use of said pharmaceutical composition for the preparation of a medicament for the treatment of circulatory diseases, preferably hypertension.

Drawings

FIG. 1: influence of particle size of raw material on dissolution behavior of preparation

FIG. 2: effect of Inclusion on dissolution behavior of formulations

FIG. 3: effect of Co-solvent on dissolution behavior of formulations

FIG. 4: comparison of dissolution behavior of example 3 and comparative example 2

FIG. 5: effect of raw Material particle size on dissolution behavior of preparation 2

Detailed Description

Example 1

Azilsartan (64g) subjected to jet milling treatment (d (0.5) =2.61 μm, d (0.9) =5.24 μm) was uniformly mixed with mannitol (200g), microcrystalline cellulose (30g), and croscarmellose sodium (16g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. To the granulated granules, 3.3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (159.6 mg each)

Example 2

Azilsartan (64g) is mixed with beta-cyclodextrin (384g) uniformly, 768g of water is added, grinding is carried out for 6h to obtain a semisolid, and drying is carried out at 40 ℃ under reduced pressure to obtain a solid. Washing the obtained solid with appropriate amount of water and methanol, and drying under reduced pressure to obtain clathrate. Taking a proper amount of the inclusion compound (containing 32g of azilsartan), uniformly mixing with mannitol (100g), microcrystalline cellulose (15g) and croscarmellose sodium (8g), adopting 5% hydroxypropyl cellulose water solution as a binding agent, granulating, drying by a fluidized bed, and finishing granules by a 1.0mm screen. To the granulated granules, 3.3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 10.0mm punch to give a plain tablet having the following composition.

Composition of preparation (345.5 mg each)

Example 3

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g) and sodium carbonate (40g) are uniformly mixed, 5% hydroxypropyl cellulose water solution is used as a binding agent, granulation and fluidized bed drying are carried out, and granules are finished through a 1.0mm screen. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (156 mg each)

Example 4

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g) and sodium carbonate (40g) are mixed uniformly, and magnesium stearate (3 g) is added and mixed uniformly. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (per 151mg)

Example 5

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g), croscarmellose sodium (15g) and sodium lauryl sulfate (40g) are uniformly mixed, 5% hydroxypropyl cellulose water solution is used as a binding agent, granulation and fluidized bed drying are carried out, and granules are granulated through a 1.0mm screen. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (155 mg each)

Example 6

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g) and croscarmellose sodium (15g) are uniformly mixed, 5% hydroxypropyl cellulose aqueous solution (containing 2.5% citric acid and 0.83% sodium hydroxide) is used as a binding agent, and the mixture is granulated, dried by a fluidized bed and granulated by a 1.0mm screen. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (158.5 mg each)

Example 7

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g) and croscarmellose sodium (15g) are mixed uniformly, 5% hydroxypropyl cellulose aqueous solution (containing 2.5% maleic acid and 0.83% sodium hydroxide) is used as a binding agent, granulation and fluidized bed drying are carried out, and a 1.0mm screen mesh is used for size stabilization. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (158.5 mg each)

Example 8

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g) and croscarmellose sodium (15g) are uniformly mixed, 5% hydroxypropyl cellulose aqueous solution (containing 2.5% fumaric acid and 0.83% sodium hydroxide) is used as a binding agent, and the mixture is granulated, dried by a fluidized bed and granulated by a 1.0mm screen. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (158.5 mg each)

Example 9

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g) and croscarmellose sodium (15g) are uniformly mixed, 5% hydroxypropyl cellulose aqueous solution (containing 2.5% fumaric acid and 0.83% sodium hydroxide) is used as a binding agent, and the mixture is granulated, dried by a fluidized bed and granulated by a 1.0mm screen. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tabletted by a 9.0mm punch to give plain tablets. Dissolving methacrylic acid copolymer A and methacrylic acid copolymer B in 95% ethanol, stirring continuously until completely dissolved, slowly adding, and stirring continuously until dissolved for use. Adding pulvis Talci and triethyl citrate into the residual ethanol water solution, mixing, homogenizing for 10 min, slowly adding into the copolymer solution, and stirring for 30 min. The plain tablets were placed in a high-efficiency coating pan for coating to obtain coated tablets of the following composition.

Composition of the tablet core (317 mg each)

Composition of coating layer (332.9 mg each)

Example 10

Azilsartan (64g), mannitol (90g), microcrystalline cellulose (90g) and croscarmellose sodium (15g) are uniformly mixed, 5% hydroxypropyl cellulose aqueous solution (containing 2.5% fumaric acid and 0.83% sodium hydroxide) is used as a binding agent, and the mixture is granulated, dried by a fluidized bed and granulated by a 1.0mm screen. To the granulated granules, 3g of magnesium stearate was added and mixed well. The resulting mixture was tabletted by a 10.0mm punch to obtain plain tablets. Dissolving methacrylic acid copolymer A and methacrylic acid copolymer B in 95% ethanol, stirring continuously until completely dissolved, slowly adding, and stirring continuously until dissolved for use. Adding pulvis Talci and triethyl citrate into the residual ethanol water solution, mixing, homogenizing for 10 min, slowly adding into the copolymer solution, and stirring for 30 min. The plain tablets were placed in a high-efficiency coating pan for coating to obtain coated tablets of the following composition.

Composition of the tablet core (317 mg each)

Composition of coating layer (320.2 mg each)

Example 11

Azilsartan (64g), methacrylic acid copolymer type a (18.65g), methacrylic acid copolymer type B (55.95g), magnesium stearate (1.4g) were mixed uniformly, and the resulting mixture was tabletted by a 7.0mm punch to obtain plain tablets having the following composition.

Composition of preparation (per 140mg)

Example 12

Azilsartan (64g), calcium hydrogen phosphate (67.6g), pregelatinized starch (7g), magnesium stearate (1.4g) were uniformly mixed, and the resulting mixture was tableted by a 7.0mm punch to obtain plain tablets having the following composition.

Composition of preparation (per 140mg)

Example 13

Azilsartan (64g) is uniformly mixed with hydroxypropyl-beta-cyclodextrin (256g), 512g of water is added, grinding is carried out for 6h to obtain a semisolid, and reduced pressure drying is carried out at 40 ℃ to obtain a solid. Washing the obtained solid with appropriate amount of water and methanol, and drying under reduced pressure to obtain clathrate. Taking a proper amount of the inclusion compound (containing 32g of azilsartan), uniformly mixing with mannitol (100g), microcrystalline cellulose (15g) and croscarmellose sodium (8g), adopting 5% hydroxypropyl cellulose water solution as a binding agent, granulating, drying by a fluidized bed, and finishing granules by a 1.0mm screen. To the granulated granules, 3.3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 10.0mm punch to give a plain tablet having the following composition.

Composition of preparation (every 290mg)

Example 14

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =1.85 μm, d (0.9) =4.12 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Example 15

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =4.47 μm, d (0.9) =13.28 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Example 16

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =8.46 μm, d (0.9) =25.13 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Example 17

Azilsartan (80g) subjected to mechanical pulverization treatment (d (0.5) =17.94 μm, d (0.9) =56.82 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Example 18

Azilsartan (80g) subjected to mechanical pulverization treatment (d (0.5) =46.77 μm, d (0.9) =83.14 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g) and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Example 19

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =3.26 μm, d (0.9) =8.21 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and a 5% hydroxypropyl cellulose aqueous solution (containing polyethylene glycol 6000) was used as a binder to prepare granules, followed by fluidized bed drying and finishing with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (205.5 mg each)

Example 20

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =3.26 μm, d (0.9) =8.21 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Example 21

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =3.26 μm, d (0.9) =8.21 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated using a 5% hydroxypropyl cellulose aqueous solution (containing citric acid/sodium citrate) as a binder, followed by fluidized bed drying and granulation with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (per 209.5mg)

Example 22

Azilsartan (80g) subjected to jet milling treatment (d (0.5) =3.26 μm, d (0.9) =8.21 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and a 5% hydroxypropyl cellulose aqueous solution (containing poloxamer 188) was used as a binder to prepare granules, which were dried by a fluidized bed and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (per 209.5mg)

Comparative example 1

Azilsartan (64g) sieved by a 60-mesh sieve is uniformly mixed with mannitol (200g), microcrystalline cellulose (30g) and croscarmellose sodium (16g), and a hydroxypropyl cellulose aqueous solution is used as a binding agent to granulate, dry by a fluidized bed and granulate by a 1.0mm screen. To the granulated granules, 3.3g of magnesium stearate was added and mixed well. The resulting mixture was tableted by a 7.0mm punch to give a plain tablet having the following composition.

Composition of preparation (159.6 mg each)

Comparative example 2

See example 1 preparation of CN 101528262A.

Comparative example 3

Azilsartan (80g) subjected to nanocrystallization treatment (d (0.5) =290nm, d (0.9) =520nm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Comparative example 4

Azilsartan (80g) treated with an 80-mesh sieve (d (0.5) =61.2 μm, d (0.9) =144.8 μm) was uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g), and croscarmellose sodium (20g), and granulated with a 5% hydroxypropyl cellulose aqueous solution as a binder, fluidized bed-dried, and granulated with a 1.0mm mesh. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (199.5 mg each)

Comparative example 5

Azilsartan (80g) sieved by a 60-mesh sieve is uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g) and croscarmellose sodium (20g), 5% hydroxypropyl cellulose aqueous solution (containing polyethylene glycol 6000) is used as a binding agent, granulation and fluidized bed drying are carried out, and a 1.0mm screen mesh is used for finishing granules. 4.0g of magnesium stearate was added to the granulated material after finishing, and the mixture was mixed well. The resulting mixture was tableted by an 8.0mm punch to give a plain tablet having the following composition.

Composition of preparation (205.5 mg each)

Comparative example 6

Azilsartan (80g) sieved by a 60-mesh sieve is uniformly mixed with mannitol (250g), microcrystalline cellulose (37.5g) and croscarmellose sodium (20g), 5% hydroxypropyl cellulose aqueous solution (as a binder, granulation, fluidized bed drying, 1.0mm screen mesh granulation is adopted, 4.0g of magnesium stearate is added to granules after granulation, uniform mixing is carried out, and the obtained mixture is tabletted by an 8.0mm punch to obtain a plain tablet with the following composition.

Composition of preparation (199.5 mg each)

Experimental example 1

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

Referring to the method for determining the approximate solubility in Chinese pharmacopoeia 2010: to each medium was added a quantitative excess of azilsartan, vigorously shaken every 5 minutes at 25 ℃ for 30 seconds. After 30 minutes, filtration was carried out with a 0.45 μm microfiltration membrane and the azilsartan concentration in the subsequent filtrate was determined by HPLC.

Table 1 approximate solubility of azilsartan in different media

From the above results, it was found that pH4.5 acetate buffer solution + 5% sodium lauryl sulfate can satisfy the sink conditions for the formulation with the standard of 37mg or less, and pH6.8 phosphate buffer solution can satisfy the sink conditions for the formulation with the standard of 250mg or less.

Experimental example 2

The drug dissolution behavior evaluation conditions of the plain tablets obtained in example 1 and comparative example 1 were as follows:

dissolution medium: pH4.5 acetate buffer + 5% sodium dodecyl sulfate, pH6.8 phosphate buffer

Volume of dissolution medium: 900ml

The dissolution method comprises the following steps: referring to the dissolution determination method of the 2010 version of Chinese pharmacopoeia, the second dissolution determination method (namely paddle method) is selected, and the rotating speed is 50 rpm.

The dissolution profile determined by HPLC method is shown in FIG. 1.

As shown in fig. 1, the reduction of the particle size of the raw material can significantly improve the dissolution behavior of azilsartan under low pH conditions (pH 4.5).

Experimental example 3

The drug dissolution behavior evaluation conditions of the plain tablets obtained in example 2 and comparative example 1 were as follows:

dissolution medium: pH4.5 acetate buffer + 5% sodium dodecyl sulfate

Volume of dissolution medium: 900ml

The dissolution method comprises the following steps: referring to the dissolution determination method of the 2010 version of Chinese pharmacopoeia, the second dissolution determination method (namely paddle method) is selected, and the rotating speed is 50 rpm.

The dissolution profile determined by HPLC method is shown in FIG. 2.

As shown in fig. 2, after the inclusion compound is prepared by adopting beta-cyclodextrin as the inclusion material, the dissolution behavior of azilsartan under the condition can be remarkably improved.

Experimental example 4

The plain tablets obtained in example 2 and comparative example 1 were moisture-proof packed, placed at 40 ℃ and 60 ℃ respectively, and sampled for 7 days and 14 days respectively, and the amount of increase in the decomposition product was measured by the HPLC method, and the results are shown in Table 2.

TABLE 2 Effect of Inclusion on formulation stability

The result shows that the azilsartan stability can be improved and the degradation is inhibited after the inclusion compound is prepared by adopting the beta-cyclodextrin as the inclusion material.

Experimental example 5

The drug dissolution behavior evaluation conditions of the plain tablets obtained in example 3 and comparative example 1 were as follows:

dissolution medium: pH4.5 acetate buffer, pH4.5 acetate buffer + 5% sodium dodecyl sulfate

Volume of dissolution medium: 900ml

The dissolution method comprises the following steps: referring to the dissolution determination method of the 2010 version of Chinese pharmacopoeia, the second dissolution determination method (namely paddle method) is selected, and the rotating speed is 50 rpm.

The dissolution profile determined by HPLC method is shown in FIG. 3.

As shown in fig. 3, the dissolution behavior of azilsartan under the conditions can be significantly improved by using sodium carbonate as a cosolvent.

Experimental example 6

The plain tablets obtained in example 7 and comparative example 1 were moisture-proof packed, placed at 40 ℃ and 60 ℃ respectively, and sampled for 7 days and 14 days respectively, and the amount of increase in the decomposition product was measured by the HPLC method, and the results are shown in Table 3.

TABLE 3 Effect of stabilizers on formulation stability

The results show that the stability of the azilsartan can be obviously improved by adopting maleic acid and sodium hydroxide as stabilizing agents.

Experimental example 7

The plain sheets obtained in examples 6 and 8 and comparative example 1 were moisture-proof packed, placed at 40 ℃ and 60 ℃ respectively, and sampled for 7 days respectively, and the amount of increase in the decomposition product was measured by the HPLC method, and the results are shown in Table 4.

TABLE 4 Effect of stabilizers on formulation stability

The results show that the stability of the azilsartan can be improved by adopting fumaric acid or citric acid and sodium hydroxide as stabilizing agents.

Experimental example 8

The plain sheets obtained in examples 19 and 20 and comparative examples 5 and 6 were subjected to moisture-proof packaging, placed at 60 ℃ and sampled for 7 days and 14 days, respectively, and the amount of increase in the decomposition product was measured by the HPLC method, and the results are shown in Table 5.

TABLE 5 Effect of stabilizers on formulation stability

The results show that when the raw materials which are sieved by a 60-mesh sieve are adopted to prepare a sample, the polyethylene glycol 6000 can improve the stability of the azilsartan, but the effect is limited; when the sample is prepared by using the bulk drug with smaller particle size (through jet milling), the polyethylene glycol 6000 can play an unexpected effect of the stabilizer.

Experimental example 9

The evaluation conditions of the drug dissolution behavior of the plain tablets obtained in example 3 and comparative examples 1 and 2 were as follows:

dissolution medium: pH4.5 acetate buffer + 5% sodium dodecyl sulfate, pH6.8 phosphate buffer

Volume of dissolution medium: 900ml

The dissolution method comprises the following steps: referring to the dissolution determination method of the 2010 version of Chinese pharmacopoeia, the second dissolution determination method (namely paddle method) is selected, and the rotating speed is 50 rpm.

The dissolution profile determined by HPLC method is shown in FIG. 4.

As shown in fig. 4, the dissolution behavior of the technical scheme of the comparative example 2 is equivalent to that of the comparative example 1 under the condition of high pH (pH6.8), and the dissolution improving effect under the condition of low pH (pH4.5) is limited, which indicates that the effect of adding polyethylene glycol 6000 as a cosolvent is not significant. In example 3, sodium carbonate is used as a cosolvent, compared with comparative example 2, the dissolution behavior is equivalent under the condition of high pH (pH6.8), and the dissolution of azilsartan is better improved under the condition of low pH (pH4.5), so that the method has an unexpected effect.

Experimental example 10

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

dissolution medium: pH4.5 acetate buffer + 5% sodium dodecyl sulfate

Volume of dissolution medium: 900ml

The dissolution method comprises the following steps: referring to the dissolution determination method of the 2010 version of Chinese pharmacopoeia, the second dissolution determination method (namely paddle method) is selected, and the rotating speed is 50 rpm.

The dissolution profile is shown in FIG. 5.

As shown in fig. 5, the dissolution behavior of examples 14, 15, 16, 17, 18 and comparative example 4 was sequentially slower, but the dissolution rate of comparative example 3 was lower than that of example 14. It can be seen that the dissolution speed is faster and more sufficient as the particle size of the azilsartan raw material is smaller. However, the dissolution rate of the azilsartan crude drug is reduced after the particle size is reduced to a certain degree (for example, nanocrystallization), which is beyond the common knowledge of persons skilled in the art. Therefore, the particle size of the azilsartan raw material should be controlled within a certain range.

Experimental example 11

Examples 20 and 21 were each subjected to a human pharmacokinetic study. C of example 20 after oral administration of 40mg on an empty stomach_maxAnd AUC_(0-∞)4025 ng/ml and 26968 ng/ml x h, respectively, C of example 21_maxAnd AUC_(0-∞)4436 ng/ml and 36895 ng/ml × h, respectively. AUC of example 21_(0-∞)1.37 times that of example 20, it can be seen that the addition of citric acid/sodium citrate improves the bioavailability of the formulation.

Experimental example 12

Examples 20 and 22 were each subjected to a human pharmacokinetic study. C of example 20 after oral administration of 40mg on an empty stomach_maxAnd AUC_(0-∞)4025 ng/ml and 26968 ng/ml x h, respectively, C of example 22_maxAnd AUC_(0-∞)4559 ng/ml and 37725 ng/ml x h, respectively. AUC of example 22_(0-∞)Compared with 1.40 times of example 20, the addition of poloxamer 188 can improve the bioavailability of the preparation.

Claims (7)

1. A solid pharmaceutical composition comprising azilsartan, characterized in that it comprises a cosolvent, which is sodium carbonate.

2. The solid pharmaceutical composition of claim 1, wherein the cosolvent is present in an amount of 0.01% to 20% by weight of the total solid pharmaceutical composition.

3. The solid pharmaceutical composition of claim 1, wherein the cosolvent is present in an amount of 0.01% to 10% by weight of the total solid pharmaceutical composition.

4. The composition according to any one of claims 1 to 3, characterized by 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.

5. The composition according to claim 4, characterized in that the stabilizer is present in an amount ranging from 0.01% to 20% relative to the total weight of the composition.

6. The composition according to claim 5, wherein the stabilizer is present in an amount of 0.01% to 10% by weight based on the total weight of the composition.

7. Use of the pharmaceutical composition according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of a circulatory disorder, said disorder being hypertension.