Velciguat tablet and preparation method thereof

Abstract

The invention provides a Velciguat tablet and a preparation method thereof, and relates to the technical field of medicines. The Vilciguat tablet comprises the following components in percentage by mass: 3%-6% of Vilciguat, 40%-55% of lactose, 35%-50% of microcrystalline cellulose, 2%-4% of hydroxypropyl methylcellulose, 0.5%-1.5% of lauryl sodium sulfate, 1%-3% of croscarmellose sodium and 0.4%-0.8% of magnesium stearate. The granularity D90 of the vericiguat is 5-20 microns, the granularity D50 of the vericiguat is 2-10 microns, and the granularity D10 of the vericiguat is less than or equal to 2 microns; the preparation method comprises the following steps: carrying out wet granulation on the viriciguat, the lactose, the microcrystalline cellulose, the hydroxypropyl methylcellulose, the lauryl sodium sulfate and 40-60% by mass of the cross-linked sodium carboxymethyl cellulose; and then mixing and tabletting with the remaining components to prepare the Vilciguat tablet. The dissolution behavior of the Velciguat tablet is similar to that of an original developed preparation, and the dissolution effect consistent with that of the original developed preparation is achieved.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a Vericipirax tablet and a preparation method thereof. Background Art

[0002] Vericigum is a soluble guanylate cyclase (sGC) stimulator that can directly stimulate sGC. When nitric oxide (NO) is relatively or absolutely insufficient, it increases the level of intracellular cGMP (cyclic guanosine monophosphate) in a manner independent of nitric oxide, repairs the damaged NO-sGC-cGMP pathway, thereby relaxing smooth muscles, dilating blood vessels, improving myocardial and vascular function, and lowering blood pressure, thereby reducing the risk of heart failure and relieving symptoms such as dyspnea, coughing, and palpitations.

[0003] Vericipirat tablets are indicated for use in adult patients with symptomatic chronic heart failure with reduced ejection fraction (ejection fraction <45%) whose condition has stabilized after decompensated heart failure following intravenous treatment, to reduce the risk of hospitalization for heart failure or the need for emergency intravenous diuretic treatment.

[0004] The original drug of Vericipirab tablets is Verquvo from Bayer. The excipients used in the original drug are cross-linked sodium carboxymethyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate.

[0005] The particle size of the raw materials of the original drug of Vilicigu Tablets has not been made public, and raw materials of different particle sizes have an impact on the dissolution behavior of Vilicigu Tablets, thereby affecting the efficacy. The specific dosage ratio of each component in the original drug is also unclear, and the different dosages of the components will also affect the dissolution performance and efficacy of the drug preparation. At present, there are few studies on the active ingredients, excipient components, particle size of each component, and preparation methods of Vilicigu Tablets. Therefore, it is necessary to develop a Vilicigu Tablet drug with similar dissolution performance to the original drug and clear components and raw material particle size. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention provides a Vericipirax tablet and a preparation method thereof. By controlling the particle size, raw material components and preparation method of Vericipirax, the dissolution behavior of the prepared drug is similar to that of the original preparation, and the dissolution effect consistent with the original preparation is achieved, thereby providing a Vericipirax tablet with clear formula components for patients with heart failure.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] In one aspect, the present invention provides a Vericipirat tablet, which comprises, by mass fraction, 3%-6% Vericipirat, 40%-55% lactose, 35%-50% microcrystalline cellulose, 1%-4% hypromellose, 0.5%-1.5% sodium lauryl sulfate, 1%-4% cross-linked carboxymethyl cellulose sodium, and 0.4%-0.8% magnesium stearate;

[0009] The particle size of the Vericiguat is D90=5μm-20μm, D50=2μm-10μm, and D10≤2μm.

[0010] Preferably, the mass ratio of vericipirat to sodium dodecyl sulfate is 1:0.12-0.36.

[0011] Further preferably, the mass ratio of vericipirat to sodium dodecyl sulfate is 1:0.24.

[0012] Preferably, the mass ratio of the hypromellose to the cross-linked sodium carboxymethyl cellulose is 1:0.25-1.67.

[0013] Further preferably, the mass ratio of the hypromellose to the cross-linked sodium carboxymethyl cellulose is 1:0.33-1.67.

[0014] More preferably, the mass ratio of the hypromellose to the cross-linked sodium carboxymethyl cellulose is 1:0.42-1.

[0015] More preferably, the mass ratio of the hypromellose to the cross-linked sodium carboxymethyl cellulose is 1:0.33-0.67.

[0016] Preferably, the components of the Vericipiracil tablets include, by mass fraction, 4%-4.5% Vericipiracil, 42%-50% lactose, 40%-45% microcrystalline cellulose, 2.5%-3.5% hypromellose, 0.8%-1.2% sodium lauryl sulfate, 1.5%-2.5% cross-linked sodium carboxymethyl cellulose and 0.6%-0.7% magnesium stearate.

[0017] Further preferably, the components of the Vericipirax tablets include, by mass fraction, 4.17% Vericipirax, 46.33% lactose, 42.84% microcrystalline cellulose, 3% hypromellose, 1% sodium lauryl sulfate, 2% cross-linked sodium carboxymethyl cellulose, and 0.67% magnesium stearate.

[0018] Preferably, the particle size of the Vericipiracil is D90=6.9 μm-18.9 μm, D50=2.6 μm-7.8 μm, and D10=0.5 μm-1.7 μm.

[0019] More preferably, the particle size of the Vericiguat is D90=13.7 μm, D50=5.2 μm, and D10=1.1 μm.

[0020] Preferably, the Vericipiraq tablet further comprises a coating material.

[0021] Further preferably, the coating material is selected from gastric soluble film coating materials.

[0022] More preferably, the mass of the coating material is 2%-5% of that of the Vericipiracil tablets, i.e., the weight gain is 2%-5%; and the Vericipiracil tablets are tablet drugs without coating materials.

[0023] More preferably, the mass of the coating material is 3%-3.8% of the Vericipiracil tablets.

[0024] More preferably, the mass of the coating material is 3.3%-3.4% of the Vericipiracil tablets.

[0025] More preferably, the mass of the coating material is 3.33% of the Vericipiracil tablets.

[0026] In the present invention, the Vericigua is {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolyl[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamic acid methyl ester, the molecular formula is C 19 H 16 F2N8O2, molecular weight is 426.38.

[0027] On the other hand, the present invention provides a method for preparing the above-mentioned Vericigula tablets, comprising the steps of:

[0028] (1) crushing Viriciguat to obtain crushed Viriciguat;

[0029] (2) wet granulating 40% to 60% by weight of the vericipirat, lactose, microcrystalline cellulose, hypromellose, sodium lauryl sulfate and croscarmellose sodium crushed in step (1), drying and granulating to obtain granules;

[0030] (3) mixing the granules of step (2) with the remaining mass of cross-linked sodium carboxymethyl cellulose and magnesium stearate to obtain a mixture;

[0031] (4) tabletting to obtain Viriciguat tablets.

[0032] Preferably, in step (1), the pulverization is specifically performed by using a jet mill to pulverize the Vericiguat to obtain a particle size of D90 = 5 μm-20 μm, D50 = 2 μm-10 μm, and D10 ≤ 2 μm.

[0033] Preferably, in step (2), the amount of cross-linked sodium carboxymethyl cellulose used is 50% of the mass of cross-linked sodium carboxymethyl cellulose.

[0034] Preferably, in step (2), the wet granulation comprises the following steps: (2.1) mixing: in a wet granulator, a stirring speed of 50-200 rpm, a shearing speed of 600-1500 rpm, and mixing for 3-8 min; (2.2) adding liquid: in a wet granulator, a stirring speed of 100-150 rpm, a shearing speed of 1000-1600 rpm are set, water is sprayed into the wet granulator, and the liquid adding time does not exceed 5 min; (2.3) granulation: in a wet granulator, a stirring speed of 100-200 rpm, a shearing speed of 1000-2000 rpm, and high-speed shear granulation for 1.5-3 min are set to obtain a soft material.

[0035] Further preferably, in step (2), the wet granulation comprises the following steps: (2.1) mixing: in a wet granulator, the stirring speed is set to 100 rpm, the shear speed is set to 1000 rpm, and the mixing is performed for 5 min; (2.2) liquid addition: in a wet granulator, the stirring speed is set to 120 rpm, the shear speed is set to 1200 rpm, and water is sprayed into the wet granulator, and the liquid addition time does not exceed 5 min; (2.3) granulation: in a wet granulator, the stirring speed is set to 150 rpm, the shear speed is set to 1500 rpm, and high-speed shear granulation is performed for 2 min to obtain a soft material.

[0036] Preferably, the drying in step (2) needs to be performed until the moisture content is less than 2%.

[0037] Preferably, in step (2), the granulation is specifically performed by using a 1.0-1.5 mm sieve at 400-600 rpm.

[0038] Further preferably, in step (2), the granulation is specifically performed by using a 1.2 mm sieve at 500 rpm.

[0039] Preferably, step (3) is specifically as follows: mixing the granules of step (2) with the remaining mass of cross-linked sodium carboxymethyl cellulose for 10-20 minutes, and then mixing with magnesium stearate for 2-5 minutes to obtain a mixture.

[0040] Further preferably, step (3) specifically comprises: mixing the granules of step (2) with the remaining mass of cross-linked sodium carboxymethyl cellulose for 15 minutes, and then mixing with magnesium stearate for 3 minutes to obtain a mixture.

[0041] Preferably, the tableting process in step (4) is as follows: the tableting speed is 50,000-300,000 tablets / hour, and the hardness of the plain tablet is 30-60N.

[0042] Further preferably, the tableting process in step (4) has a hardness of 40-50N.

[0043] Preferably, step (4) further comprises a coating step after tabletting is completed: setting the tablet bed temperature to 40±5° C. and coating weight gain to 2%-5%.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The present invention controls the particle size, raw material component types and preparation method of Vericipirax so that the dissolution behavior of the obtained Vericipirax tablets is similar to that of the original preparation, thereby achieving a dissolution effect consistent with that of the original preparation. The present invention provides a Vericipirax tablet with clear formula components. DETAILED DESCRIPTION

[0046] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0047] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0048] The present invention is further described below by way of specific examples. Unless otherwise specified, the various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels.

[0049] In the following examples, cross-linked sodium carboxymethylcellulose was purchased from DuPont, USA, with a batch number of 2174212598; lactose was purchased from Shanghai Huamao Pharmaceutical Co., Ltd., with a batch number of 103-20240403; gastric soluble film coating premix was purchased from Shanghai Colorcon Coating Technology Co., Ltd., with a batch number of THL100535; microcrystalline cellulose was purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd., with a batch number of M221009 and a model number of KG-802; and hypromellose was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., with a model number of SH-E5. Products from different manufacturers have no significant effect on the effect.

[0050] Example 1

[0051] A formulation of Vericiguat tablets is shown in Table 1:

[0052] Table 1

[0053]

[0054] The particle size of Vericiguat is: D90 = 13.7 μm, D50 = 5.2 μm, D10 = 1.1 μm.

[0055] The preparation method of Vericipirax tablets is as follows:

[0056] (1) crushing Vericipiracil to obtain crushed Vericipiracil, the particle size of which is: D90=13.7 μm, D50=5.2 μm, and D10=1.1 μm;

[0057] (2) wet granulating 50% of the mass of the vericipirat, lactose, microcrystalline cellulose, hypromellose, sodium lauryl sulfate and croscarmellose sodium crushed in step (1), drying and granulating to obtain granules;

[0058] The process of wet granulation is as follows: (2.1) Mixing: wet granulator, set the stirring speed to 100 rpm, the shear speed to 1000 rpm, and mix for 5 minutes; (2.2) Liquid addition: wet granulator, set the stirring speed to 120 rpm, the shear speed to 1200 rpm, spray water into the wet granulator, and the liquid addition time shall not exceed 5 minutes; (2.3) Granulation: wet granulator, set the stirring speed to 150 rpm, the shear speed to 1500 rpm, and high-speed shear granulation for 2 minutes to obtain a soft material;

[0059] Drying: Place the soft material in a fluidized bed, set the fan frequency to 20Hz, the air inlet temperature to 70℃, and dry until the moisture content is less than 2% before discharging;

[0060] The granulation is specifically as follows: using a 1.2 mm sieve and 500 rpm for granulation;

[0061] (3) mixing the granules of step (2) with the remaining mass of cross-linked sodium carboxymethyl cellulose for 15 minutes, and then mixing with magnesium stearate for 3 minutes to obtain a mixture;

[0062] (4) Tableting: tableting speed: 150,000 tablets / hour; plain tablet hardness: 45±5N; coating: tablet bed temperature: 40±5°C; coating weight gain: 3.3% to obtain Vericiguat tablets.

[0063] Example 2

[0064] The difference from Example 1 is that the particle size of Vericipiracil is: D90=6.9 μm, D50=2.6 μm, D10=0.5 μm. The rest is the same as Example 1.

[0065] Example 3

[0066] The difference from Example 1 is that the particle size of Vericipirax is: D90=18.9 μm, D50=7.8 μm, D10=1.7 μm. The rest is the same as Example 1.

[0067] Example 4

[0068] The difference from Example 1 is that the mass ratio of Vericipirat to sodium dodecyl sulfate is 1:0.12. The rest is the same as Example 1. The formula of Vericipirat tablets is shown in Table 2.

[0069] Table 2

[0070]

[0071] Example 5

[0072] The difference from Example 1 is that the mass ratio of Vericipirat to sodium dodecyl sulfate is 1:0.36. The rest is the same as Example 1. The formula of Vericipirat tablets is shown in Table 3.

[0073] Table 3

[0074]

[0075] Example 6

[0076] The difference from Example 1 is that the mass ratio of hypromellose to croscarmellose sodium is 1:0.33. The rest is the same as Example 1. The formula of Vericiguat tablets is shown in Table 4.

[0077] Table 4

[0078]

[0079] Example 7

[0080] The difference from Example 1 is that the mass ratio of hypromellose to croscarmellose sodium is 1:1.67. The rest is the same as Example 1. The formula of Vericiguat tablets is shown in Table 5.

[0081] Table 5

[0082]

[0083] Comparative Example 1

[0084] The difference from Example 1 is that the particle size of Vericiguat is: D90 = 100.6 μm, D50 = 46.5 μm, D10 = 22.1 μm. The rest is the same as Example 1.

[0085] Comparative Example 2

[0086] The difference from Example 1 is that the particle size of Vericipirax is: D90=4.3 μm, D50=1.7 μm, D10=0.8 μm. The rest is the same as Example 1.

[0087] Comparative Example 3

[0088] The difference from Example 1 is that the binder hypromellose is replaced by povidone K30.

[0089] Comparative Example 4

[0090] The difference from Example 1 is that the mass ratio of Vericipirat to sodium dodecyl sulfate is 1:0.05. The rest is the same as Example 1. The formula of Vericipirat tablets is shown in Table 6.

[0091] Table 6

[0092]

[0093] Comparative Example 5

[0094] The difference from Example 1 is that the mass ratio of Vericipirat to sodium dodecyl sulfate is 1:1. The rest is the same as Example 1. The formula of Vericipirat tablets is shown in Table 7.

[0095] Table 7

[0096]

[0097] Comparative Example 6

[0098] The difference from Example 1 is that the mass ratio of hypromellose to croscarmellose sodium is 1:5. The rest is the same as Example 1. The formula of Vericiguat tablets is shown in Table 8.

[0099] Table 8

[0100]

[0101] Comparative Example 7

[0102] The difference from Example 1 is that the mass ratio of hypromellose to croscarmellose sodium is 1:0.2. The rest is the same as Example 1. The formula of Vericiguat tablets is shown in Table 9.

[0103] Table 9

[0104]

[0105] Comparative Example 8

[0106] Different from Example 1, the preparation method adopts one-step mixing:

[0107] Vericipirat, microcrystalline cellulose, hypromellose, sodium lauryl sulfate, cross-linked sodium carboxymethyl cellulose, and magnesium stearate were added into a mixer and mixed for 18 minutes; tableting was performed at a tableting speed of 150,000 tablets / hour and a plain tablet hardness of 45±5N; coating was performed by setting the tablet bed temperature to 40±5°C and coating weight gain to 3.3% to obtain Vericipirat tablets.

[0108] Test 1: Dissolution behavior test

[0109] Detection method: pH = 3.5 phosphate medium, dissolution method selects paddle method 50 rpm, and dissolution behavior (dissolution rate) detection is performed.

[0110] Evaluation index: The dissolution behavior in pH=3.5 medium is similar to that of the original product (f2>50).

[0111] The dissolution behavior test results of the original preparation Verquvo and the Vericipira tablets of various examples and comparative examples are shown in Table 10.

[0112] Table 10

[0113]

[0114] Note: f2 is calculated using all-point selection.

[0115] As can be seen from Table 10, the Vericipiraguat tablets of the present invention achieve the technical effect of dissolution behavior consistent with the quality of the original preparation. After the particle size of Vericipiraguat was changed in Comparative Examples 1 and 2, the dissolution behavior was inconsistent with the original preparation; after the proportions of the components in the prescriptions of Comparative Examples 3 to 7 were changed, the dissolution behavior was inconsistent with the original preparation; after the mixing process of Comparative Example 8 was changed, the dissolution behavior was inconsistent with the original preparation.

[0116] Test 2 Particle size detection

[0117] The particle size of the Vericipiracil raw material used in the present invention is obtained by the following method.

[0118] Instrument: Malvern laser particle size detector, MASTERSIZER3000.

[0119] method:

[0120] 1. See Table 11 for detection parameter settings:

[0121] Table 11

[0122] project Parameter settings Sample refractive index 1.53 Particle absorption rate 0.1 Evaluating light source stability 30s Background measurement duration 12s Sample measurement duration 12s Lower limit of shading 10％ Upper limit of opacity 25％ Stirring speed 2300rpm Ultrasound time 300s

[0123] 2. Preparation of dispersant solution: weigh 0.5g Tween 80 into 1L of water, stir and ultrasonicate to dissolve.

[0124] 3. Sample preparation

[0125] (1) Weigh 10 mg of sample (viriciguat raw material) into a 10 mL centrifuge tube, add an appropriate amount of dispersant and gently shake the sample to form a suspension.

[0126] (2) After the background measurement is completed, the sample solution is gradually added to the wet sampler until the shading degree is in the range of 10%-25%. The sample is mixed for 20-40 seconds while observing the shading degree. When the shading degree value is constant, the test begins.

[0127] (3) Perform three measurements on each batch of samples, record the values ​​of D10, D50, and D90, and calculate the average value.

[0128] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A Vericiguat tablet, characterized in that: The components, calculated by mass fraction, include: 3%-6% of Vericipiracil, 40%-55% of lactose, 35%-50% of microcrystalline cellulose, 2%-4% of hypromellose, 0.5%-1.5% of sodium lauryl sulfate, 1%-3% of cross-linked sodium carboxymethyl cellulose, and 0.4%-0.8% of magnesium stearate; The particle size of the Vericiguat is D90=5μm-20μm, D50=2μm-10μm, and D10≤2μm.

2. The Vericiguat tablet according to claim 1, characterized in that: The mass ratio of the vericipiracil and sodium lauryl sulfate is 1:0.12-0.36; the mass ratio of the hypromellose and croscarmellose sodium is 1:0.25-1.

67.

3. The Vericiguat tablet according to claim 2, characterized in that: The mass ratio of the vericipiracil and sodium lauryl sulfate is 1:0.24; the mass ratio of the hypromellose and croscarmellose sodium is 1:0.33-1.

67.

4. The Vericigula tablet according to claim 1, characterized in that: The components measured by mass fraction include: 4%-4.5% of Vericipiracil, 42%-50% of lactose, 40%-45% of microcrystalline cellulose, 2.5%-3.5% of hypromellose, 0.8%-1.2% of sodium lauryl sulfate, 1.5%-2.5% of cross-linked sodium carboxymethyl cellulose and 0.6%-0.7% of magnesium stearate.

5. The Vericipiraq tablet according to claim 4, characterized in that: The components calculated by mass fraction include: 4.17% of Vericipiracil, 46.33% of lactose, 42.84% of microcrystalline cellulose, 3% of hypromellose, 1% of sodium lauryl sulfate, 2% of cross-linked sodium carboxymethyl cellulose and 0.67% of magnesium stearate.

6. The Vericiguat tablet according to any one of claims 1 to 5, characterized in that: The particle size of the Vericipiracil is D90=6.9μm-18.9μm, D50=2.6μm-7.8μm, and D10=0.5μm-1.7μm.

7. The Vericipiraq tablet according to claim 6, characterized in that: The particle size of the Vericiguat is D90=13.7 μm, D50=5.2 μm, and D10=1.1 μm.

8. The Vericiguat tablet according to any one of claims 1 to 5, characterized in that: The components also include: coating materials.

9. The method for preparing the Vericigol tablets according to any one of claims 1 to 8, characterized in that: Includes steps: (1) crushing Viriciguat to obtain crushed Viriciguat; (2) wet granulating 40% to 60% by weight of the vericipirat, lactose, microcrystalline cellulose, hypromellose, sodium lauryl sulfate and croscarmellose sodium crushed in step (1), drying and granulating to obtain granules; (3) mixing the granules of step (2) with the remaining mass of cross-linked sodium carboxymethyl cellulose and magnesium stearate to obtain a mixture; (4) tabletting to obtain Viriciguat tablets.

10. The preparation method according to claim 9, characterized in that: In step (2), 50% of the mass of cross-linked sodium carboxymethyl cellulose is used for wet granulation; In step (2), the wet granulation process comprises the following steps: (2.1) Mixing: wet granulator, set stirring speed to 50-200 rpm, shear speed to 600-1500 rpm, and mix for 3-8 min; (2.2) Liquid addition: Set the stirring speed of the wet granulator to 100-150 rpm and the shear speed to 1000-1600 rpm. Spray water into the wet granulator. The liquid addition time should not exceed 5 min. (2.3) Granulation: wet granulator, set stirring speed 100-200 rpm, shear speed 1000-2000 rpm, high-speed shear granulation 1.5-3 min; Step (3) specifically comprises: mixing the granules of step (2) with the remaining mass of cross-linked sodium carboxymethyl cellulose for 10-20 minutes, and then mixing with magnesium stearate for 2-5 minutes to obtain a mixture; The tableting in step (4) is as follows: the tableting speed is 50,000-300,000 tablets / hour, and the hardness of the plain tablet is 30-60N; In step (4), after the tableting is completed, a coating step is also included: setting the tablet bed temperature to 40±5° C. and coating weight gain to 2%-5%.