Allisartan medoxomil composition and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and provides an allisartan medoxomil composition and a preparation method thereof. In the research and development process of allisartan medoxomil tablets, the inventor finds that the dissolution rate of allisartan medoxomil can be improved and the stability of allisartan medoxomil can be ensured by mixing the allisartan medoxomil compound and the caprylic / capric polyethylene glycol glyceride; especially, the tablet prepared from the allisartan medoxomil pharmaceutical composition is high in dissolution rate, good in stability, simple in preparation process and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an allisartan medoxomil composition and a preparation method thereof. Background Art

[0002] Alisartan medoxomil (CAS: 947331-05-7), chemical name 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy]-methyl ester, is a new type of angiotensin II receptor antagonist. Alisartan medoxomil has low toxicity and better antihypertensive effect than similar products (such as losartan). Alisartan medoxomil exerts its antihypertensive effect by metabolizing in the body to generate active metabolite 5-carboxylic acid losartan (EXP3174). The structural formula of Alisartan medoxomil was first disclosed in Chinese patent CN200680000397.8.

[0003]

[0004] CN200710093852.X discloses the preparation of Alisartan medoxomil tablets and capsules, and the solubility measured at 45 minutes by dissolution detection is more than 95%. Tablet prescription: Alisartan 5g, Plasdone K-29 / 3210g, Polyplasdone XL (A) 26g, microcrystalline cellulose 10g, lactose 10g, Polyplasdone XL (B) 3g, sodium stearyl fumarate 0.5g. The drug and plasdone are dissolved in a mixture of an appropriate amount of acetone and ethanol (v / v 1:1). Polyplasdone XL (A) is added to a fluidized bed. The prepared solution is sprayed into the fluidized bed in the form of a top spray through a spray gun for granulation. After drying, the dried material is fully mixed with other materials and then tableted. The average weight of the tablet is 250 mg. The solubility measured at 45 minutes is 96.7%.

[0005] CN200880001668.0 discloses a series of preparations containing allisartan medoxomil, wherein Examples D1 to D6 disclose an allisartan medoxomil solid dispersion and a preparation method thereof, wherein the allisartan medoxomil solid dispersion is prepared by a fluidized bed top spray method. This method is complex and generally requires a relatively long drying time to avoid excessive residual organic solvents, and is not the best process for preparing solid dispersions.

[0006] CN201510254020.6 and CN201510334498.X further optimized the formulations based on patent CN200880001668.0 and provided two improved solid dispersions of ollisartan medoxomil. However, the technical improvements did not involve changes in the preparation process. Therefore, the process still has the defects of complex fluidized bed top spraying process and relatively long process time.

[0007] CN201610379945.8 provides an improved allisartan medoxomil solid dispersion, which realizes a hot melt extrusion preparation process through a prescription design, and realizes the technical advantages of the hot melt extrusion process such as simple preparation and short time, ensures the dissolution performance of the solid dispersion, and further develops an allisartan medoxomil preparation based on this. Although the obtained solid dispersion solves the technical problem of dissolution, it does not solve the technical problem of impurity content.

[0008] CN201610373232.0 provides an allisartan medoxomil pharmaceutical composition, which facilitates the preparation of allisartan medoxomil into nano-sized particles stably dispersed in the pharmaceutical composition by a grinding process through the stabilization and protection of the prescription, and exists as stable nanoparticles in the subsequent process; the present invention also provides an allisartan medoxomil preparation, which has the characteristics of high loading capacity and high stability. However, the process is complicated, and the average particle size of allisartan medoxomil nanoparticles varies greatly, making it difficult to ensure the stability of the process.

[0009] CN202310041083.8 discloses a compound preparation of Alisartan medoxomil, which is made of the following raw materials in weight ratio, including 25-55% of Alisartan medoxomil, 0.15-0.5% of glidant, 0.2-13% of stabilizer, 4-35% of protective agent, 0.5-4.8% of adhesive, 5-28% of disintegrant, and 0.2-3% of lubricant. Its invention implementation scheme can effectively ensure the disintegration and dissolution of the drug, and the dissolution rate level is stable, and a stable blood drug concentration can be maintained, thereby reducing the number of dosing times, extending the interval between medications, and reducing treatment costs. The invention does not solve the problem of improving the dissolution of the drug.

[0010] Alisartan ester has poor water solubility, and after oral administration, it is slowly dissolved in the gastrointestinal tract, poorly absorbed, and has low bioavailability. At present, the prior art prepares Alisartan ester into a solid dispersion, which is the main means to improve the dissolution performance of the oral preparation of Alisartan ester. Traditional solid dispersion preparation methods include: melting method, solvent method, grinding method, spray drying method, etc. In addition, the prior art prepares various amorphous and crystalline forms of Alisartan ester and micronizes the raw material of Alisartan ester to solve the problem of Alisartan ester.

[0011] Based on the above patent applications, the preparation of the current allisartan medoxomil preparation is not convenient enough, and some tablets of allisartan medoxomil dissolve slowly, take effect slowly, and have low bioavailability. The effectiveness of the patient's medication cannot be guaranteed. Summary of the invention

[0012] The purpose of the present invention is to provide an allisartan medoxomil composition and a preparation method thereof in view of the above-mentioned defects of the prior art. In particular, the tablets prepared from the allisartan medoxomil pharmaceutical composition of the present invention have high dissolution, good stability, simple preparation process, and are suitable for industrial production.

[0013] Specifically, the present invention is achieved through the following technical solutions:

[0014] A pharmaceutical composition of allisartan medoxomil, comprising allisartan medoxomil, caprylic acid capric acid macrogol glyceride, a filler, a disintegrant, and a lubricant.

[0015] Preferably, in the allisartan medoxomil pharmaceutical composition, the weight ratio of allisartan medoxomil to caprylic / capric macrogol glyceride is 1:0.2-0.6.

[0016] Further preferably, in the allisartan medoxomil pharmaceutical composition, the weight ratio of allisartan medoxomil to caprylic / capric macrogol glyceride is 1:0.3-0.5.

[0017] Preferably, the filler is one or more of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, and calcium hydrogen phosphate. More preferably, lactose and microcrystalline cellulose are mixed.

[0018] Preferably, the disintegrant is one or more of cross-linked carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone sodium, and low-substituted hydroxypropyl cellulose. Cross-linked polyvinylpyrrolidone is further preferred.

[0019] The amount of the excipients such as fillers, disintegrants, binders, etc. is the conventional amount in the art. Preferably, the weight ratio of allisartan medoxomil to filler is 1:0.2-0.8; the weight ratio of allisartan medoxomil to disintegrant is 1:0.4-0.8.

[0020] Preferably, the lubricant is one or more of magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, and micro-powder silica gel. Magnesium stearate is further preferred. The amount of lubricant used is based on the amount known in the art that can achieve a lubricating effect, and the preferred weight ratio of allisartan ester to lubricant is 1:0.02-0.1.

[0021] The oliskitan medoxomil pharmaceutical composition of the present invention is made into a solid preparation, which can be a capsule, tablet, bead, granule, ball, lozenge, pill or gel.

[0022] Preferably, the present invention also provides a tablet containing the olisartan medoxomil pharmaceutical composition.

[0023] The present invention also provides a method for preparing an allisartan medoxomil tablet, which comprises the following steps:

[0024] a. dissolving caprylic acid capric acid macrogol glyceride in 95% ethanol to prepare a caprylic acid capric acid macrogol glyceride solution;

[0025] b. Adding olisartan medoxomil and disintegrant to the fluidized bed, adding caprylic acid capric acid macrogol glyceride solution to granulate and dry;

[0026] c. The dry granules are granulated by a granulator;

[0027] d. Add additional disintegrant, filler, lubricant and mix;

[0028] e. The above mixed powder is tableted to obtain Alisartan medoxomil tablets.

[0029] Among them, preferably, the mass ratio of the internal disintegrant to the external disintegrant is 1:0.5-1.5, and more preferably 1:1.

[0030] The caprylic acid capric acid macrogol glycerides are prepared into a caprylic acid capric acid macrogol glycerides solution with a mass fraction of 3% to 5%.

[0031] The present invention provides a new pharmaceutical composition of Allisartan medoxomil. The inventors found in the process of developing Allisartan medoxomil tablets that mixing Allisartan medoxomil compounds and caprylic acid capric acid macrogol glyceride can improve the solubility of Allisartan medoxomil and ensure the stability of Allisartan medoxomil. Therefore, further research was conducted to obtain a preparation method of the Allisartan medoxomil tablets of the present invention, which was granulated by a fluidized bed wet method, and had significant dissolution effect and stability. The method for preparing the tablets is simple and easy to operate, and avoids the influence of the solid dispersion preparation method of the prior art on the stability of Allisartan medoxomil. The Allisartan medoxomil tablets and preparation method of the present invention are suitable for industrial production. DETAILED DESCRIPTION

[0032] The beneficial effects of the present invention are further described by the following examples. These examples are for illustrative purposes only and should not be construed as limiting the present invention. Obvious improvements and modifications made to the present invention by those skilled in the art are also within the scope of protection of the present invention.

[0033] The following examples are used to prepare Alisartan Medoxomil tablets. The operations not described are conventional preparation operations.

[0034] Example 1

[0035] Prescription single dose

[0036] Alisartan medoxomil 240mg

[0037] Caprylic / capric macrogol glycerides 96 mg

[0038] Lactose 96mg

[0039] Microcrystalline cellulose 48mg

[0040] Crospovidone 144mg

[0041] Magnesium stearate 12mg

[0042] Preparation process:

[0043] Caprylic capric acid macrogol glyceride is dissolved in 95% ethanol to prepare a caprylic capric acid macrogol glyceride solution with a mass fraction of 3% to 5%; Alisartan medoxomil and 1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone are added to a fluidized bed for mixing, and the caprylic capric acid macrogol glyceride solution is added for granulation and drying; the dry granules are granulated with a granulator; lactose, microcrystalline cellulose, 1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone and magnesium stearate are added for mixing; the mixed powder is pressed into tablets to obtain the Alisartan medoxomil tablets.

[0044] Example 2

[0045] Prescription single dose

[0046] Alisartan medoxomil 240mg

[0047] Caprylic / capric macrogol glycerides 48 mg

[0048] Lactose 96mg

[0049] Microcrystalline cellulose 48mg

[0050] Crospovidone 144mg

[0051] Magnesium stearate 12mg

[0052] Preparation process: Same as Example 1

[0053] Example 3

[0054] Prescription single dose

[0055] Alisartan medoxomil 240mg

[0056] Caprylic / capric macrogol glycerides 120 mg Lactose 96 mg

[0057] Microcrystalline cellulose 48mg

[0058] Crospovidone 144mg

[0059] Magnesium stearate 12mg

[0060] Preparation process: same as Example 1 Example 4

[0061] Prescription single dose

[0062] Alisartan medoxomil 240mg

[0063] Caprylic / capric macrogol glycerides 168 mg Lactose 96 mg

[0064] Microcrystalline cellulose 48mg

[0065] Crospovidone 144mg

[0066] Magnesium stearate 12mg

[0067] Preparation process: same as Example 1 Example 5

[0068] Prescription single dose

[0069] Alisartan medoxomil 240mg

[0070] Caprylic / capric macrogol glycerides 24 mg

[0071] Lactose 96mg

[0072] Microcrystalline cellulose 48mg

[0073] Crospovidone 144mg

[0074] Magnesium stearate 12mg

[0075] Preparation process: same as Example 1 Example 6

[0076] Prescription single dose

[0077] Alisartan medoxomil 240mg

[0078] Caprylic / capric macrogol glycerides 96 mg

[0079] Mannitol 128mg

[0080] Pregelatinized starch 64mg

[0081] Croscarmellose sodium 192mg

[0082] Magnesium stearate 12mg

[0083] Preparation process: dissolve caprylic acid capric acid macrogol glyceride in 95% ethanol to prepare caprylic acid capric acid macrogol glyceride solution with a mass fraction of 3% to 5%; add olmesartan medoxomil and 1 / 2 of the prescription amount of cross-linked sodium carboxymethyl cellulose to the fluidized bed for mixing, add the caprylic acid capric acid macrogol glyceride solution to granulate, and dry; granulate the dry granules with a granulator; add mannitol, pregelatinized starch, 1 / 2 of the prescription amount of cross-linked sodium carboxymethyl cellulose, and magnesium stearate to mix; mix the powder and press the tablets to obtain olmesartan medoxomil tablets.

[0084] Comparative Example 1

[0085] Prescription single dose

[0086] Alisartan medoxomil 240mg

[0087] Lactose 96mg

[0088] Microcrystalline cellulose 48mg

[0089] Crospovidone 144mg

[0090] Magnesium stearate 12mg

[0091] Preparation process:

[0092] Alisartan medoxomil and 1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone are added to a fluidized bed for mixing, and 95% ethanol solution is added for granulation, and the mixture is dried; the dry granules are granulated with a granulator; lactose, microcrystalline cellulose, 1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone, and magnesium stearate are added for mixing; the mixed powder is tableted to obtain the Alisartan medoxomil tablets.

[0093] Verification Example Dissolution Determination and Stability Study of Alisartan Medoxomil Tablets:

[0094] 1. Detection methods for related substances:

[0095] Determine according to high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition), or according to the detection method for related substances of Alisartan Medoxomil Tablets in Part II of the Chinese Pharmacopoeia 2020 Edition.

[0096] Determination method: Accurately measure the test solution, control solution and reference substance solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Limit: If there are impurity peaks in the chromatogram of the test solution, the impurity I peak, impurity II peak and impurity III peak are calculated by peak area according to the external standard method. Impurity II shall not exceed 0.3%, impurity I and impurity III shall not exceed 0.2%, and the peak area of ​​other single impurities shall not be greater than the main peak area of ​​the control solution (0.1%), and the total amount of impurities shall not exceed 1.0%. Chromatographic peaks smaller than the main peak area of ​​the sensitivity solution are ignored.

[0097] 2. Dissolution determination method: According to the second method (paddle method) of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, the above-prepared preparations were compared with Examples 1-6 and Comparative Example 1 and the marketed single-prescription preparation Alisartan Medoxomil Tablets (Specification 240 mg, trade name: ) for dissolution determination. Dissolution conditions: Take phosphate buffer (take 750ml of 0.1mol / L hydrochloric acid solution and 250ml of 0.2mol / L sodium phosphate solution, mix well, and adjust the pH value to 6.8±0.05 with 2mol / L hydrochloric acid solution or 2mol / L sodium hydroxide solution if necessary) 900ml as dissolution medium, the speed is 50 revolutions per minute, operate according to the law, and after 15 minutes, take a sample to measure its dissolution. Determination method: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 256nm according to the UV-visible spectrophotometry (General Rule 0401), and calculate the dissolution amount of each tablet.

[0098] 3. Stability test accelerated conditions: 40±2℃, 75%±5%RH accelerated time: 6 months.

[0099] Table 1 Investigation and measurement results of examples and comparative examples

[0100]

[0101]

[0102] As can be seen from the table, the samples of Examples 1-6 obtained by the present invention can maintain good stability and dissolution rate for a long time compared with the existing marketed products. According to the data of 6 months of investigation, compared with Example 1, in which no caprylic acid capric acid macrogol glyceride was added, the stability of the obtained preparation was poor, especially the impurity peaks I, II and III all exceeded the standard limits, and the dissolution rate was unqualified.

Claims

1. An allisartan medoxomil pharmaceutical composition, characterized in that: The pharmaceutical composition comprises allisartan medoxomil, caprylic acid capric acid macrogol glyceride, a filler, a disintegrant and a lubricant.

2. The olisartan medoxomil pharmaceutical composition according to claim 1, characterized in that In the described allisartan medoxomil pharmaceutical composition, the weight ratio of allisartan medoxomil to caprylic acid capric acid macrogol glyceride is 1:0.2-0.

6.

3. The pharmaceutical composition of olisartan medoxomil according to claim 1, characterized in that: The filler is one or more of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, and calcium hydrogen phosphate; more preferably, lactose and microcrystalline cellulose are mixed.

4. The pharmaceutical composition of olisartan medoxomil according to claim 1, characterized in that The disintegrant is one or more of cross-linked carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium, and low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone is more preferred.

5. The pharmaceutical composition of olisartan medoxomil according to claim 1, characterized in that: The weight ratio of allisartan medoxomil to filler is 1:0.2-0.8; the weight ratio of allisartan medoxomil to disintegrant is 1:0.4-0.

8.

6. The pharmaceutical composition of olisartan medoxomil according to claim 1, characterized in that: The lubricant is one or more of magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, and micro-powdered silica gel; magnesium stearate is further preferred; the amount of lubricant used is based on the amount known in the art that can achieve a lubricating effect, and the preferred weight ratio of allisartan medoxomil to lubricant is 1:0.02-0.

1.

7. The pharmaceutical composition of olisartan medoxomil according to claim 1, characterized in that: The alisartan medoxomil pharmaceutical composition is made into a solid preparation in the form of capsules, tablets, beads, granules, balls, lozenges, pills or gelatin.

8. A method for preparing tablets of the olisartan medoxomil pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: a. dissolving caprylic acid capric acid macrogol glyceride in 95% ethanol to prepare a caprylic acid capric acid macrogol glyceride solution; b. Adding olisartan medoxomil and disintegrant to the fluidized bed, adding caprylic acid capric acid macrogol glyceride solution to granulate and dry; c. The dry granules are granulated by a granulator; d. Add additional disintegrant, filler, lubricant and mix; e. The above mixed powder is tableted to obtain Alisartan medoxomil tablets.

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