An aliskiren composition and a method for preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and provides an alisartan composition and a preparation method thereof. The inventors find that mixing the alisartan compound and caprylocaproyl macrogolglycerides can improve the dissolution of alisartan and ensure the stability of alisartan during the development of alisartan tablets. In particular, the tablet prepared by using the alisartan pharmaceutical composition of the application has high dissolution, good stability and simple preparation process, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparation, and particularly relates to an alisartan composition and a preparation method thereof. BACKGROUND

[0002] Alisartan (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 has small toxicity and better antihypertensive effect than the same type of product (such as losartan). Alisartan exerts antihypertensive effect by generating active metabolite 5-carboxylic acid losartan (EXP3174) in vivo. The structural formula of alisartan is disclosed for the first time in Chinese patent CN200680000397.8.

[0003]

[0004] CN200710093852.X discloses the preparation of alisartan tablet and capsule. The solubility is more than 95% at 45 minutes by dissolution detection. The tablet prescription is as follows: alisartan 5 g, Plasdone K-29 / 32 10 g, Polyplasdone XL(A) 26 g, microcrystalline cellulose 10 g, lactose 10 g, Polyplasdone XL(B) 3 g, and sodium stearyl fumarate 0.5 g. The drug and plasdone are dissolved in a mixture 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 by a spray gun in a top spray form for granulation. After drying, the dried material is mixed with other materials, and then tabletted. The average weight of the tablet is 250 mg. The solubility is 96.7% at 45 minutes.

[0005] CN200880001668.0 discloses a series of formulations containing alisartan. Examples D1-D6 disclose a solid dispersion of alisartan and a preparation method thereof. The solid dispersion of alisartan is prepared by a fluidized bed top spray method. The process is complex. In order to avoid excessive organic solvent residue, a relatively long drying time is usually required, and the method is not the best process for preparing a solid dispersion.

[0006] CN201510254020.6 and CN201510334498.X further optimize the formulation prescription based on patent CN200880001668.0, providing two improved solid dispersions of aliskiren, but the technical improvement does not involve changes in the preparation process, so the method still has the defects of complex fluidized bed top spraying process and relatively long process time.

[0007] CN201610379945.8 provides an improved solid dispersion of aliskiren, which is prepared by hot melt extrusion process through prescription design, and has the technical advantages of simple preparation, short time, etc., ensuring the dissolution performance of the solid dispersion, and further developing an aliskiren preparation. The obtained solid dispersion solves the technical problem of dissolution, but does not solve the technical problem of impurity content.

[0008] CN201610373232.0 provides an aliskiren pharmaceutical composition, which is prepared into nanoscale particles by grinding process through the stabilizing and protecting effect of the prescription, and exists as stable nanoparticles in the subsequent process; the invention also provides an aliskiren preparation with high loading capacity and high stability. However, the process is complex, the average particle size of aliskiren nanoparticles varies greatly, and it is difficult to ensure the stability of the process.

[0009] CN202310041083.8 discloses a compound aliskiren preparation made of the following weight ratio of raw materials, including aliskiren 25-55%, glidant 0.15-0.5%, stabilizer 0.2-13%, protective agent 4-35%, binder 0.5-4.8%, disintegrant 5-28%, lubricant 0.2-3%. The invention can effectively ensure the disintegration and dissolution of the drug, and the dissolution rate is stable, and the blood drug concentration can be maintained stable, so as to reduce the frequency of administration, prolong the medication interval and reduce the treatment cost. The invention does not solve the problem of improving the dissolution of the drug.

[0010] Aliskiren has poor water solubility, and after oral administration, it is slowly dissolved in the gastrointestinal tract and poorly absorbed, with low bioavailability. The existing technology prepares aliskiren into a solid dispersion, which is the main means to improve the dissolution performance of aliskiren oral preparation. Traditional solid dispersion preparation methods include: melting method, solvent method, grinding method, spray drying method, etc. In addition, the existing technology prepares various amorphous, crystalline and micronized aliskiren raw materials to solve the problem of aliskiren.

[0011] In summary of the above patent applications, the preparation of aliskiren ester is not convenient, and some aliskiren ester tablets have slow dissolution, slow effect and low bioavailability. The effectiveness of the patient's medication cannot be guaranteed. SUMMARY

[0012] The present application aims at the above-mentioned defects of the prior art, and provides an aliskiren ester composition and a preparation method thereof. In particular, the aliskiren ester pharmaceutical composition prepared by the present application has high dissolution, good stability and simple preparation process, and is suitable for industrial production.

[0013] Specifically, the present application is realized by the following technical scheme:

[0014] An aliskiren ester pharmaceutical composition, which comprises aliskiren ester, caprylocaproyl macrogolglycerides, a filler, a disintegrant and a lubricant.

[0015] Preferably, in the aliskiren ester pharmaceutical composition, the weight ratio of aliskiren ester to caprylocaproyl macrogolglycerides is 1:0.2-0.6.

[0016] Further preferably, in the aliskiren ester pharmaceutical composition, the weight ratio of aliskiren ester to caprylocaproyl macrogolglycerides 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. Further preferably, lactose and microcrystalline cellulose are mixed.

[0018] Preferably, the disintegrant is one or more of croscarmellose sodium, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose. Further preferably, crospovidone is used.

[0019] The amount of the excipients such as the filler, the disintegrant and the binder is the conventional amount in the art. Preferably, the weight ratio of aliskiren ester to the filler is 1:0.2-0.8, and the weight ratio of aliskiren ester to the 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 micronized silica. Further preferably, magnesium stearate is used. The amount of the lubricant used is the amount known in the art that can achieve the lubricating effect, and preferably, the weight ratio of aliskiren ester to the lubricant is 1:0.02-0.1.

[0021] The aliskiren ester pharmaceutical composition of the present application can be prepared into a solid preparation, which can be a capsule, a tablet, a bead, a granule, a pellet, a lozenge, a pill or a gum.

[0022] Preferably, the present application also provides a tablet of alosartan l-prodrug pharmaceutical composition.

[0023] The present application also provides a preparation method of alosartan l-prodrug tablet, which comprises the following steps:

[0024] a. dissolve caprylocaproyl polyoxylglycerols in 95% ethanol to prepare a caprylocaproyl polyoxylglycerols solution;

[0025] b. add alosartan l-prodrug, internal disintegrant to a fluidized bed, granulate with the caprylocaproyl polyoxylglycerols solution, and dry;

[0026] c. size the dried granules with a sizer;

[0027] d. add external disintegrant, filler, lubricant, and mix;

[0028] e. compress the above mixed powder to obtain alosartan l-prodrug tablet.

[0029] 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 caprylocaproyl polyoxylglycerols is prepared into a caprylocaproyl polyoxylglycerols solution with a mass fraction of 3%-5%.

[0031] The present application provides a new alosartan l-prodrug pharmaceutical composition. The inventors found that mixing alosartan l-prodrug compound and caprylocaproyl polyoxylglycerols can improve the dissolution of alosartan l-prodrug and ensure the stability of alosartan l-prodrug during the development of alosartan l-prodrug tablet. Further research led to the preparation method of alosartan l-prodrug tablet of the present application, which significantly improves the dissolution and stability through fluidized bed wet granulation. The preparation method of the present application is simple and easy to operate, and avoids the influence of the preparation method of solid dispersion in the prior art on the stability of alosartan l-prodrug. The alosartan l-prodrug tablet and the preparation method of the present application are suitable for industrial production. DETAILED DESCRIPTION

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

[0033] The following examples are for preparing alosartan l-prodrug tablet. Operations not described are conventional preparation operations.

[0034] Example 1

[0035] Prescription single dose

[0036] Alosartan l-prodrug 240mg

[0037] Caprylic / capric macrogol glycerides 96mg

[0038] Lactose 96mg

[0039] Microcrystalline cellulose 48mg

[0040] Crospovidone 144mg

[0041] Magnesium stearate 12mg

[0042] Preparation process:

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

[0044] Example 2

[0045] Prescription single dose

[0046] Alisartan medoxomil 240mg

[0047] Caprylic / capric macrogol glycerides 48mg

[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 120mg Lactose 96mg

[0057] Microcrystalline cellulose 48mg

[0058] Crospovidone 144mg

[0059] Magnesium stearate 12mg

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

[0061] Prescribed single dose

[0062] Aliskiren 240 mg

[0063] Capryol 168 mg Lactose 96 mg

[0064] Microcrystalline cellulose 48 mg

[0065] Crospovidone 144 mg

[0066] Magnesium stearate 12 mg

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

[0068] Prescribed single dose

[0069] Aliskiren 240 mg

[0070] Capryol 24 mg

[0071] Lactose 96 mg

[0072] Microcrystalline cellulose 48 mg

[0073] Crospovidone 144 mg

[0074] Magnesium stearate 12 mg

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

[0076] Prescribed single dose

[0077] Aliskiren 240 mg

[0078] Capryol 96 mg

[0079] Mannitol 128 mg

[0080] Pre-gelatinized starch 64 mg

[0081] Croscarmellose sodium 192 mg

[0082] Magnesium stearate 12 mg

[0083] Preparation process: dissolve Capryol in 95% ethanol to prepare a Capryol solution with a mass fraction of 3% to 5%; add Aliskiren, 1 / 2 of the prescribed amount of croscarmellose sodium to a fluidized bed mixer, granulate with the Capryol solution, and dry; use a granulator to granulate the dry granules; mix with mannitol, pre-gelatinized starch, 1 / 2 of the prescribed amount of croscarmellose sodium, and magnesium stearate; mix the powder and press into tablets to obtain Aliskiren tablets.

[0084] Comparative Example 1

[0085] Prescribed single dose

[0086] Aliskiren 240 mg

[0087] Lactose 96 mg

[0088] Microcrystalline cellulose 48 mg

[0089] Crospovidone 144 mg

[0090] Magnesium stearate 12 mg

[0091] Preparation process:

[0092] Aliskiren, 1 / 2 prescription amount of crospovidone, is added to the fluidized bed mixer, granulated with 95% ethanol solution, and dried; the dry granules are sized with a sizer; lactose, microcrystalline cellulose, 1 / 2 prescription amount of crospovidone, and magnesium stearate are mixed; the powder is mixed and pressed into tablets to obtain aliskiren tablets.

[0093] Verification of dissolution determination and stability investigation of aliskiren tablets:

[0094] 1. Detection method of related substances:

[0095] Determined by reference to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512), or according to the detection method of related substances of aliskiren tablets in Chinese Pharmacopoeia 2020 Edition Part II.

[0096] Determination method: accurately measure the test solution, control solution and reference solution, respectively inject into the liquid chromatograph, 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, the impurity II shall not exceed 0.3%, the impurity I and the impurity III shall not exceed 0.2%, the peak area of other single impurity shall not be greater than the peak area of the main peak of the control solution (0.1%), and the total amount of impurities shall not exceed 1.0%. Chromatographic peaks less than the main peak area of the sensitivity solution are ignored.

[0097] 2. Dissolution determination method: according to Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931 Second Method (Paddle Method), the above prepared preparation products are determined for Examples 1-6 and Comparative Example 1, as well as the single preparation aliskiren tablets (specification 240 mg, trade name: Dissolution test was carried out. Dissolution condition: 900 ml of phosphate buffer (750 ml of 0.1 mol / L hydrochloric acid solution and 250 ml of 0.2 mol / L sodium phosphate solution were mixed, and pH value was adjusted to 6.8±0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution as necessary) was used as dissolution medium, rotation speed was 50 rotations per minute, and dissolution test was carried out according to the law. After 15 minutes, sample was taken to measure dissolution. Determination method: test product solution and control product solution were taken, and absorbance was measured at 256 nm wavelength by UV-visible spectrophotometry (general rule 0401), and dissolution amount of each tablet was calculated.

[0098] 3. Stability investigation Accelerated condition: 40±2℃, 75%±5% RH Acceleration time: 6 months.

[0099] Table 1 Investigation and determination results of samples 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 application can keep good stability and dissolution rate for a long time. After 6 months of investigation data, the comparative example 1 without the addition of capryol 90 obtains a preparation with poor stability, especially the impurity I peak, impurity II peak and impurity III peak all exceed the limit of the standard, and the dissolution rate is 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; In the described allisartan medoxomil pharmaceutical composition, the weight ratio of allisartan medoxomil to caprylic / capric macrogol glyceride is 1:0.2-0.6; The filler is one or more of microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch, and calcium hydrogen phosphate; 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; 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; The lubricant is one or more of magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, and micro-powder silica gel.

2. The pharmaceutical composition of Alisartan medoxomil according to claim 1, characterized in that The filler is a mixture of lactose and microcrystalline cellulose.

3. The pharmaceutical composition of Alisartan medoxomil according to claim 1, characterized in that The disintegrant is cross-linked polyvinylpyrrolidone.

4. The pharmaceutical composition of Alisartan medoxomil according to claim 1, characterized in that The lubricant is magnesium stearate; the amount of the lubricant used is based on the amount known in the art that can achieve a lubricating effect.

5. The pharmaceutical composition of allisartan medoxomil according to claim 1, characterized in that The weight ratio of allisartan medoxomil to lubricant is 1:0.02-0.

1.

6. The pharmaceutical composition of allisartan medoxomil according to claim 1, characterized in that The alisartan medoxomil pharmaceutical composition is prepared into solid preparations in the form of capsules, tablets, granules, lozenges, pills or gelatin.

7. A method for preparing tablets of the allisartan medoxomil pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: a. Caprylic acid capric acid macrogol glycerides were dissolved in 95% ethanol to prepare a caprylic acid capric acid macrogol glycerides solution; b. Alisartan medoxomil, added disintegrant to the fluidized bed, added caprylic acid capric acid macrogol glyceride solution granulation, and dried; c. The dry granules are granulated using a granulator; d. Add additional disintegrant, filler, lubricant and mix; e. The mixed powder is tableted to obtain Alisartan medoxomil tablets.

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