Composition of alplsutentan and diuretic and preparation method of composition

Abstract

The invention belongs to the field of medicine, and particularly relates to a composition of alpoxidine and a diuretic and a preparation method of the composition, and the composition comprises the following components in parts by mass: 3-25 parts of alpoxidine, 3-25 parts of a diuretic, 20-80 parts of a filler, 0.5-5 parts of an adhesive, 1-5 parts of a disintegrating agent, 0.1-5 parts of a surfactant and 0.1-5 parts of a lubricant. The composition provided by the invention can improve the powder flowability, compressibility and sticking problems, enhance the adhesion resistance of particles, improve the dissolution speed and improve the bioavailability.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a composition of apixanthen and a diuretic and a preparation method thereof. Background Art

[0002] Apixanthen was approved in the United States in March 2024 for the treatment of hypertension. Apixanthen is a novel oral dual endothelin A / B receptor (ETA / ETB) antagonist that can effectively inhibit the binding of endothelin-1 (ET-1) to endothelin receptor A (ETA) and endothelin receptor B (ETB), thereby blocking the action of endothelin-1. Endothelin-1 is a potent vasoconstrictive peptide and a smooth muscle mitogen (promoting fibroplasia), which is produced by vascular endothelial cells and regulates vascular tone through receptors ETA and ETB. If the concentration of endothelin-1 in the systemic circulation increases, it can significantly increase vascular tone and peripheral vascular resistance, thereby increasing blood pressure. It can be seen that the endothelin pathway is related to the pathogenesis of hypertension. Apixanthen is the active metabolite of macitentan, has a longer half-life (48h vs 14h), can be used once a day to reduce blood pressure, and is the first endothelin receptor antagonist used for the treatment of hypertension.

[0003] When apixanthen is used to treat refractory hypertension, the most common adverse reaction is edema / fluid retention. According to the EMA document, 45% and 47% of the patients receiving apixanthen 12.5mg or 25mg treatment respectively need to use diuretics; to improve patient compliance and safety, combining apixanthen with thiazide diuretics can have a synergistic effect and offset adverse reactions: Thiazides are the most widely used diuretics in clinical practice and have a certain antihypertensive effect. As an adjuvant combination therapy, it has clinical benefits especially for elderly hypertension, isolated systolic hypertension or patients with heart failure; the combination of the two is expected to increase the effect and reduce the risk of death. Thiazides belong to medium-acting diuretics and can reduce the adverse reactions of edema / fluid retention of apixanthen. In addition, thiazide diuretics should be used with caution in patients with renal insufficiency, while apixanthen has a renal protection function; therefore, the combination of the two is expected to have a toxicity-reducing effect.

[0004] However, apixanthen is a poorly soluble drug. The data published by the FDA shows that its solubility in water is 2.6 μg / mL, its solubility in the pH 1.2 - 5 medium is 1.2 μg / mL, and its solubility in the pH 7.0 medium is 10.5 μg / ml, all of which are far less than the sink conditions. Its tablets require the addition of two surfactants, 0.05% CTAB (cetyltrimethylammonium bromide) + 0.5% Tween, for dissolution in the pH 6.8 medium.

[0005] However, during the preparation of existing apixanthen, problems such as electrostatic adsorption, poor anti-adhesion, and poor fluidity exist, resulting in: ① serious loss of the active pharmaceutical ingredient during the production process, significantly reducing the yield; ② poor fluidity of the powder, resulting in unqualified mixing uniformity; ③ during the process of preparing tablets, the phenomenon of sticking to the punch is obvious, resulting in an unattractive appearance defect, and the resulting preparations generally have problems of poor stability and poor patient compliance. Therefore, there is an urgent need to provide a composition of apixanthen and a diuretic and its preparation method to solve the problem of sticking to the punch during tabletting and effectively improve the dissolution behavior of the preparation. Summary of the Invention

[0006] To solve the above problems, the present invention provides a composition of apixanthen and a diuretic and its preparation method, which can improve the fluidity, compressibility and sticking to the punch problem of the powder, enhance the anti-adhesion of the granules, improve the dissolution rate and increase the bioavailability.

[0007] The preparation method of the present invention enables the granules to be quickly formed, effectively improves the fluidity, compressibility and sticking to the punch problem of the material, makes the in vitro dissolution similar to the reference, and the obtained tablets have stable and reliable quality.

[0008] The technical solution provided by the present invention is as follows;

[0009] A composition containing apixanthen and a diuretic, the composition is a tablet, and the composition includes the following components in parts by mass: 3-25 parts of apixanthen, 3-25 parts of diuretic, 20-80 parts of filler, 0.5-5 parts of binder, 1-5 parts of disintegrant, 0.1-5 parts of surfactant, and 0.1-5 parts of lubricant.

[0010] Further, the diuretic is a thiazide diuretic.

[0011] Further, the apixanthen is micronized, and the particle size ≤ 20 μm.

[0012] Further, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and starch;

[0013] The binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone;

[0014] The disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose;

[0015] The surfactant is selected from one or more of sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium cetyl sulfate, polysorbate 80, polysorbate 20, and polyethylene glycol;

[0016] The lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate.

[0017] The present invention also provides a method for preparing the composition of apixanthen and a diuretic as described above. The method is wet granulation and includes the following steps:

[0018] Add micronized apixanthen, diuretic, filler and disintegrant to a wet granulator for premixing. After premixing, add a binder solution for wet granulation, and continuously granulate by the way of atomizing and adding liquid with a peristaltic pump spray gun until it can be formed into a ball by hand and can be easily dispersed by light pressure to obtain wet granules; perform wet screening on the wet granules, and perform dry screening after drying; mix the granules after dry screening evenly with the disintegrant and lubricant to obtain an intermediate; compress the intermediate to obtain a composition tablet containing apixanthen and a diuretic.

[0019] Further, the particle size of the micronized apixanthen is below 20 μm.

[0020] Further, perform wet screening on the wet granules with a 4 mm * 4 mm aperture sieve of a screening machine, and control it at 30 HZ for wet screening.

[0021] Further, place the material after wet screening in an oven at 60 °C for drying, and stop drying when the moisture content is ≤ 3%.

[0022] Further, perform dry screening with a φ1.0 mm aperture sieve of a screening machine, and control it at 30 HZ for dry screening.

[0023] Further, mix the granules after dry screening evenly with the disintegrant and lubricant in a hopper mixer at 20 HZ for 10 min to obtain an intermediate.

[0024] Further, the preparation method includes the following steps:

[0025] 1. Add purified water to a beaker, start stirring, and add the binder while stirring until it is completely dissolved;

[0026] 2. Add micronized apixanthen, diuretic, filler, disintegrant to a wet granulator for premixing. After premixing, add a binder solution for wet granulation, and continuously granulate by the way of atomizing and adding liquid with a peristaltic pump spray gun until it can be formed into a ball by hand and can be easily dispersed by light pressure to obtain wet granules;

[0027] 3. Perform wet screening on the wet granules, place the material after wet screening in an oven or fluidized bed for drying, and then perform dry screening;

[0028] 4. Mix the granules after dry screening evenly with the disintegrant and lubricant to obtain an intermediate;

[0029] 5. Compress the intermediate to obtain a composition tablet containing apixanthen and a diuretic.

[0030] Beneficial effects

[0031] To improve the solubility of poorly soluble drugs, in the present invention, apixaban is micronized and a surfactant is added, which can significantly increase the dissolution rate, thereby improving the bioavailability and ensuring the drug efficacy. The composition of apixaban and diuretics described in the present invention has the advantages of synergistic effect, reducing adverse reactions and improving patient compliance.

[0032] The present invention uses wet granulation. By adding a surfactant and micronized active pharmaceutical ingredient in the formulation, it can improve the powder flowability, compressibility and sticking problems, enhance the anti-adhesion property of the granules, improve the dissolution rate and increase the bioavailability. Description of the Drawings

[0033] Figure 1 is the dissolution curve of the reference preparation and the self-made preparation in the medium of pH 6.8 + 0.05% CTAB + 0.5% Tween;

[0034] Figure 2 is the dissolution curve of the reference preparation and the self-made preparation in the medium of pH 6.8 + 0.05% CTAB + 0.5% Tween. Detailed Description of the Invention

[0035] Example 1

[0036] Apixaban is micronized, and a surfactant is added to the formulation, and the wet granulation process is used for preparation.

[0037]

[0038] Operation:

[0039] ① Micronization of the active pharmaceutical ingredient: Apixaban is pulverized to control the particle size below 20 μm;

[0040] ② Preparation of the binder: Weigh the prescribed amount of hydroxypropyl cellulose and add an appropriate amount of purified water to stir and dissolve;

[0041] ③ Premixing: Weigh the prescribed amounts of micronized apixaban, hydrochlorothiazide, lactose, sodium lauryl sulfate, and cross-linked carboxymethyl cellulose sodium (added internally) and mix them evenly in a wet granulator;

[0042] ④ Wet granulation: Atomize the premixed material and add the binder for granulation. The prepared soft material shows the state of "forming a ball when held in the hand and dispersing immediately when gently pressed" to obtain wet granules;

[0043] ⑤ Wet screening: Screen the wet granules through a 4 mm * 4 mm aperture sieve in a granule screening machine and control it at 30 HZ for wet screening;

[0044] ⑥ Drying: Place the wetted and granulated material on a tray, control the oven temperature at 60 °C for drying, monitor the moisture content with a rapid moisture analyzer. Stop drying and discharge the material when the moisture content is ≤ 3%.

[0045] ⑦ Dry granulation: Select a 1.0 mm aperture sieve mesh for the granulator, control at 30 HZ for dry granulation, and weigh.

[0046] ⑧ Total mixing: Mix the dry granules with the prescribed amount of cross-linked carboxymethyl cellulose sodium (added externally) and magnesium stearate in a hopper mixer at 20 HZ for 10 min to obtain the intermediate.

[0047] ⑨ After tableting, a composition of apixaban and a diuretic is obtained.

[0048] Example 2

[0049] Micronize apixaban, replace the filler with mannitol and microcrystalline cellulose, add a surfactant to the formulation, and prepare using the wet granulation process.

[0050]

[0051] Operation:

[0052] ① Micronization of raw materials: Crush apixaban, control the particle size below 20 μm.

[0053] ② Preparation of binder: Weigh the prescribed amount of hydroxypropyl cellulose and add an appropriate amount of purified water, stir and dissolve.

[0054] ③ Premixing: Weigh the prescribed amount of micronized apixaban, hydrochlorothiazide, mannitol, microcrystalline cellulose, sodium lauryl sulfate, and cross-linked carboxymethyl cellulose sodium (added internally), and mix evenly in a wet granulator.

[0055] ④ Wet granulation: Atomize the premixed material and add the binder for granulation. The resulting soft material should be in a state of "forming a ball when held in the hand and dispersing when lightly pressed" to obtain wet granules.

[0056] ⑤ Wet screening: Screen the wet granules through a 4 mm * 4 mm aperture sieve mesh of a granulator, control at 30 HZ for wet screening.

[0057] ⑥ Drying: Place the wetted and screened material on a tray, control the oven temperature at 60 °C for drying, monitor the moisture content with a rapid moisture analyzer. Stop drying and discharge the material when the moisture content is ≤ 3%.

[0058] ⑦ Dry screening: Select a 1.0 mm aperture sieve mesh for the granulator, control at 30 HZ for dry screening, and weigh.

[0059] ⑧ Total mixing: Mix the dry granules with the prescribed amount of cross-linked carboxymethyl cellulose sodium (added externally) and magnesium stearate in a hopper mixer at 20 HZ for 10 min to obtain the intermediate.

[0060] ⑨ After tabletting, a composition of apixaban and a diuretic is obtained.

[0061] Example 3

[0062] Apixaban was micronized, and the surfactant was replaced with polysorbate 80, and it was prepared by the wet granulation process.

[0063]

[0064] Operation:

[0065] ① Micronization of the active pharmaceutical ingredient: Apixaban was pulverized, and the particle size was controlled to be below 20 μm;

[0066] ② Preparation of the binder: Weighed the prescribed amount of hydroxypropyl cellulose and Tween 80, added an appropriate amount of purified water, and stirred until dissolved;

[0067] ③ Premixing: Weighed the prescribed amount of micronized apixaban, hydrochlorothiazide, lactose, and croscarmellose sodium (added internally), and mixed them evenly in a wet granulator;

[0068] ④ Wet granulation: Atomized the premixed material and added the binder for granulation. The prepared soft material was in the state of "forming a ball when held in the hand and dispersing when gently pressed", and wet granules were obtained;

[0069] ⑤ Wet screening: Screened the wet granules through a 4 mm * 4 mm aperture sieve of a granule screen, and controlled the wet screening at 30 HZ;

[0070] ⑥ Drying: Placed the wet-screened material on a tray, controlled the oven temperature at 60 °C for drying, and monitored the moisture content with a rapid moisture analyzer. When the moisture content was ≤ 3%, the drying was stopped and the material was discharged;

[0071] ⑦ Dry screening: Took a granule screen with a φ1.0 mm aperture sieve, controlled the dry screening at 30 HZ, and weighed;

[0072] ⑧ Total mixing: Mixed the dry granules with the prescribed amount of croscarmellose sodium (added externally) and magnesium stearate in a hopper mixer at 20 HZ for 10 min to obtain the intermediate;

[0073] ⑨ After tabletting, a composition of apixaban and a diuretic is obtained.

[0074] Comparative Example 1

[0075] Apixaban was micronized, no surfactant was added to the formulation, and it was prepared by the wet granulation process.

[0076]

[0077] Operation:

[0078] ① Micronization of API: Apixanthen was crushed to control the particle size below 20 μm;

[0079] ② Preparation of binder: Weighed the prescribed amount of hydroxypropyl cellulose and added appropriate purified water and stirred until dissolved;

[0080] ③ Premixing: Weighed the prescribed amount of micronized apixanthen, hydrochlorothiazide, lactose, croscarmellose sodium (added internally) and mixed evenly in a wet granulator;

[0081] ④ The operations of wet granulation, wet screening, drying, dry screening, total mixing and tableting were the same as those in Example 1.

[0082] Comparative Example 2

[0083] Apixanthen was not micronized, the formulation was added with a surfactant, and it was prepared by a wet granulation process.

[0084]

[0085] Operations:

[0086] ① Preparation of binder: Weighed the prescribed amount of hydroxypropyl cellulose and added appropriate purified water and stirred until dissolved;

[0087] ② Premixing: Weighed the prescribed amount of apixanthen, hydrochlorothiazide, lactose, sodium dodecyl sulfate, croscarmellose sodium (added internally) and mixed evenly in a wet granulator;

[0088] ③ The operations of wet granulation, wet screening, drying, dry screening, total mixing and tableting were the same as those in Example 1.

[0089] Comparative Example 3

[0090] Apixanthen was micronized, the formulation was added with a surfactant, and it was prepared by a direct powder compression process.

[0091]

[0092] Operations

[0093] ① Micronization of API: Apixanthen was crushed to control the particle size below 20 μm;

[0094] ② Premixing: Weighed the prescribed amount of micronized apixanthen, hydrochlorothiazide, lactose, hydroxypropyl cellulose, sodium dodecyl sulfate, croscarmellose sodium and mixed at 20 HZ for 20 min in a hopper mixer to obtain the premix;

[0095] ③ Total mixing: Added the prescribed amount of magnesium stearate to the premixed material and mixed at 20 HZ for 10 min in a hopper mixer to obtain the intermediate;

[0096] ④ Tableting.

[0097] Comparative Example 4

[0098] Apixantel was micronized, surfactants were added to the formulation, and dry granulation process was used for preparation.

[0099]

[0100] Operation

[0101] ① Micronization of API: Apixantel was pulverized to control the particle size below 20 μm;

[0102] ② Premixing: Weighed amounts of micronized apixantel, hydrochlorothiazide, lactose, hydroxypropyl cellulose, sodium lauryl sulfate, and cross-linked carboxymethyl cellulose sodium (added internally) were mixed in a hopper mixer at 20 Hz for 20 min to obtain a premix;

[0103] ③ Dry granulation: The premix was extruded into sheets in a dry granulator, and the sheet materials were subjected to primary screening and secondary screening. The feeding speed was controlled at 40 rpm, the roller speed at 5 rpm, the primary screening speed at 50 rpm, the secondary screening speed at 100 rpm, and the screen aperture at 1.2 mm;

[0104] ④ Total mixing: The materials after dry granulation were added with weighed amounts of cross-linked carboxymethyl cellulose sodium (added externally) and magnesium stearate and mixed in a hopper mixer at 20 Hz for 10 min to obtain an intermediate;

[0105] ④ Tabletting.

[0106] Table 1 Results of particle size, granule powder properties, and tablet content of apixantel in Examples 1, 2, and 3:

[0107]

[0108] Table 2 Comparison of dissolution curve results of reference preparation and Examples 1, 2, and 3 (paddle method, 50 rpm):

[0109]

[0110] Table 3 Results of particle size, granule properties, and tablet content of apixantel in Example 1 and Comparative Examples 1, 2, 3, and 4:

[0111]

[0112] Table 4 Comparison of dissolution curve results of Example 1 and Comparative Examples 1, 2, 3, and 4 (paddle method, 50 rpm):

[0113]

[0114] Result analysis:

[0115] The results in Table 1 and Table 2 show that the self-made preparations prepared in Examples 1, 2, and 3, which are samples with different fillers and surfactants respectively, are all prepared using the wet granulation process. Their particle fluidity, compressibility, and content uniformity of the tablets are all good, without sticking to the punch phenomenon; the in vitro dissolution is faster than that of the reference preparation.

[0116] The results in Table 4 show that for the self-made preparation prepared in Example 1, apixantel is micronized and a surfactant is added to the formulation. Compared with the reference preparation, Comparative Example 1 (no surfactant in the formulation), and Comparative Example 2 (the active ingredient is not micronized), it can significantly improve the in vitro dissolution rate, thereby improving the bioavailability in vivo. This shows that micronization of the active ingredient and addition of a surfactant to the formulation can significantly improve the dissolution rate.

[0117] The results in Table 3 show that compared with Comparative Example 3 (direct compression of powder process) and Comparative Example 4 (dry granulation process), Example 1 (wet granulation process) has better particle fluidity and particle size distribution, and there are no problems of sticking to the punch and loss of the active ingredient; the results in Table 4 show that the wet granulation process has a faster dissolution rate than the direct compression of powder and dry granulation processes.

[0118] Therefore, for apixantel tablets, micronization of the active ingredient and addition of a surfactant to the formulation can significantly improve the in vitro dissolution rate, thereby improving the bioavailability in vivo. The wet granulation process used in this product, compared with the direct compression of powder and dry granulation processes, can significantly improve the problem of adsorption loss of the active ingredient. At the same time, the particles have excellent fluidity and appropriate particle size distribution, ensuring the content uniformity of the total mixing and the content / content uniformity of the tablets.

Claims

1. A composition containing apixanthen and a diuretic, characterized in that, The composition is a tablet, and the composition comprises the following components in parts by mass: apixanthen 3 - 25 parts, diuretic 3 - 25 parts, filler 20 - 80 parts, binder 0.5 - 5 parts, disintegrant 1 - 5 parts, surfactant 0.1 - 5 parts, and lubricant 0.1 - 5 parts.

2. The composition comprising apixanthen and a diuretic according to claim 1, characterized in that, The diuretic is a thiazide diuretic.

3. The composition comprising apixanthen and a diuretic according to claim 1, wherein, The apixanthen is micronized, and the particle size is ≤20 μm.

4. The composition containing apixanthen and diuretic according to claim 1, wherein the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and starch; the binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; the disintegrant is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose; the surfactant is selected from one or more of sodium dodecyl sulfate, sodium dodecylbenzenesulfonate, sodium cetyl sulfate, polysorbate 80, polysorbate 20, and polyethylene glycol; the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate.

5. The preparation method of the composition of apixanthen and diuretic according to claim 1, characterized in that, The method is wet granulation, and the method comprises the following steps: Add micronized apixanthen, diuretic, filler, and disintegrant to a wet granulator for premixing. After premixing, add the binder solution for wet granulation, and continuously granulate by the way of atomizing and adding liquid with a peristaltic pump spray gun until it can form a ball in hand and can be easily dispersed by gentle pressing to obtain wet granules; perform wet screening on the wet granules, and perform dry screening after drying; mix the granules after dry screening with the disintegrant and lubricant evenly to obtain an intermediate; perform tableting on the intermediate to obtain a composition tablet containing apixanthen and diuretic.

6. The preparation method of the composition of apixaban and diuretics according to claim 1, characterized in that, The particle size of the micronized apixanthen is below 20 μm.

7. The preparation method of the composition of apixaban and diuretics according to claim 1, characterized in that, Perform wet screening on the wet granules with a 4 mm * 4 mm aperture sieve of a screening machine, and control at 30 HZ.

8. The preparation method of the composition of apixentan and a diuretic according to claim 1, characterized in that, Place the material after wet screening in an oven at 60 °C for drying, and stop drying when the moisture content is ≤3%.

9. The preparation method of the composition of apixanthen and diuretic according to claim 1, characterized in that, Perform dry screening with a φ1.0 mm aperture sieve of a screening machine, and control at 30 HZ.

10. The preparation method of the composition of apixaban and diuretics according to claim 1, characterized in that, Mix the granules after dry screening with the disintegrant and lubricant in a hopper mixer at 20 HZ for 10 min to obtain an intermediate.

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