Pharmaceutical composition of pyridoimidazolethiopropionic acid compound crystal form Form 13 and preparation method of tablets thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically to a pharmaceutical composition of a pyridoimidazole thiopropionic acid compound crystal form Form 13 and a method for preparing the tablets thereof. The pharmaceutical composition is composed of the following components by mass fraction: API: 5%-50% of pyridoimidazole thiopropionic acid compound crystal form Form 13; internal excipients: 44%-89% of filler, 2%-6% of disintegrant, 1% of glidant; external excipients: 0.5%-2% of lubricant. The preparation steps are pretreatment, premixing, granulation, total mixing, tableting and coating. The present invention preferably uses a compound of a micronized API (particle size D90≤10μm), combined with technical means such as screening the type of excipients and limiting the proportion of excipients to a certain range, to avoid the use of a solubilizer, while effectively improving the solubility of HY-0902 tablets, with good stability, and a simple production process to meet production requirements.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a method for preparing a pharmaceutical composition of a pyridine imidazole thiopropionic acid compound crystal form Form 13 and a tablet thereof. Background Art

[0002] Hyperuricemia is a metabolic disease characterized by elevated serum uric acid levels in the human body, which is associated with increased uric acid production or decreased uric acid excretion. Hyperuricemia is not only the main cause of gout, but is also closely related to the occurrence and development of diseases such as hypertension, atherosclerosis and chronic kidney disease.

[0003] Patent CN 115385907 A discloses a room temperature stable crystal form of a pyridoimidazolethiopropionic acid anti-gout compound and its preparation method. The chemical name is 2-((1-(4-cyclopropylnaphthalene-1-yl)-1H-imidazole[4,5-b]pyridin-2-yl)thio)propionic acid. The compound is used to treat gout and hyperuricemia, hereinafter referred to as HY-0902. The HY-0902 compound crystal form Form 13 is a crystal form that can exist stably at room temperature, which can reduce storage costs. The HY-0902 compound is easily soluble in N-methylpyrrolidone, slightly soluble in methanol and ethanol, very slightly soluble in acetonitrile, and almost insoluble in water. It is a poorly soluble drug.

[0004] Since the HY-0902 compound has the solubility characteristic of being almost insoluble in water, the key problem of HY-0902 tablets is that the dissolution rate of the HY-0902 compound in vivo and in vitro is too low. Therefore, it is urgent to improve the dissolution rate of HY-0902 tablets and ensure the oral bioavailability of HY-0902 tablets. Summary of the invention

[0005] In view of the deficiencies in the prior art, the object of the present invention is to provide a pharmaceutical composition of a pyridine imidazole thiopropionic acid compound crystal form Form 13.

[0006] The present invention also provides a method for preparing the tablets thereof, which avoids the use of a solubilizing agent by micronizing the raw material drug compound and combining technical means such as screening the types and proportions of auxiliary materials, while effectively improving the solubility of the compound, having good preparation stability, and having a simple production process, thereby meeting production requirements.

[0007] The pharmaceutical composition of the pyridoimidazolethiopropionic acid compound crystal form Form 13 of the present invention, the chemical name of the pyridoimidazolethiopropionic acid compound is: 2-((1-(4-cyclopropylnaphthalene-1-yl)-1H-imidazole[4,5-b]pyridine-2-yl)thio)propionic acid (HY-0902), and the structural formula is shown in Formula I below:

[0008]

[0009] Formula I;

[0010] For specific information about the crystalline compound, please refer to the contents disclosed in patent CN 115385907 A.

[0011] The pyridoimidazole thiopropionic acid compound crystal form Form 13 uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in 2θ angles is 6.53±0.2, 7.70±0.2, 9.84±0.2, 10.24±0.2, 11.36±0.2, 12.58±0.2, 13.10±0.2, 14.18±0.2, 15.30±0.2, 17.30±0.2, 18.00±0.2, 19.78±0.2, 20.0 There are characteristic peaks at 4±0.2, 21.04±0.2, 22.31±0.2, 23.18±0.2, 24.08±0.2, 25.08±0.2, 26.21±0.2, 27.21±0.2, 28.20±0.2, 29.08±0.2, 30.15±0.2, 31.15±0.2, 32.51±0.2, 34.53±0.2, 35.18±0.2, 36.02±0.2, and 37.58±0.2;

[0012] The XRPD data of the pyridoimidazolethiopropionic acid compound crystal form Form 13 placed under long-term (25°C ± 2°C, 65% RH ± 10% RH, open to light) and accelerated (40°C ± 2°C, 75% RH ± 10% RH, open to light) conditions for 10 days are as follows: Figure 5 As shown;

[0013] The DSC data of the pyridoimidazole thiopropionic acid compound crystal form Form 13 placed under long-term (25°C ± 2°C, 65% RH ± 10% RH, open to light) and accelerated (40°C ± 2°C, 75% RH ± 10% RH, open to light) conditions for 10 days are as follows: Figure 6 shown.

[0014] The pharmaceutical composition comprises the following components by mass fraction:

[0015] API: 5%-50% pyridoimidazolethiopropionic acid compound crystal form Form 13;

[0016] Added excipients: 44%-89% filler, 2%-6% disintegrant, 1% glidant;

[0017] Additional auxiliary materials: 0.5%-2% lubricant.

[0018] Tablets prepared from the pharmaceutical composition generally include two specifications, the small specification preferably has a mass content of HY-0902 compound (crystal form Form 13) of 5%, and the large specification preferably has a mass content of HY-0902 compound (crystal form Form 13) of 10%.

[0019] The pyridoimidazole thiopropionic acid compound crystal form Form 13 is micronized, and the particle size of the raw material drug D90 is ≤10 μm. The tablets prepared after the HY-0902 compound is micronized have a smooth appearance and can be quickly dissolved, meeting the dissolution requirements.

[0020] The filler is one of microcrystalline cellulose, silicified microcrystalline cellulose and cellulose-lactose.

[0021] Preferably, the disintegrant is croscarmellose sodium.

[0022] The lubricant is one of magnesium stearate and sodium stearyl fumarate.

[0023] The glidant is one of gel silicon dioxide and silicon dioxide.

[0024] It also includes a coating material, which accounts for 1%-5% of the total weight of the pharmaceutical composition; the coating material is one of the film coating premix (gastric soluble) Opadry Ⅰ and Opadry Ⅱ.

[0025] The method for preparing tablets of the pharmaceutical composition of the pyridoimidazolethiopropionic acid compound crystal form Form 13 of the present invention comprises the following steps:

[0026] (1) Preprocessing

[0027] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and the flow aid, sieve and set aside; sieve the filler and rinse the sieve; weigh the disintegrant and set aside;

[0028] (2) Premix

[0029] The material obtained in step (1) and the added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0030] (3) Screening

[0031] Screening the premixed materials and collecting the screened materials;

[0032] (4) Total mixing

[0033] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0034] (5) Tableting

[0035] The total mixed material is tableted to obtain plain tablets.

[0036] The method also includes coating the plain tablets and packaging them, and selecting moisture-proof and light-proof materials for packaging.

[0037] The sieving in step (1) is through a 40-60 mesh sieve, and the sieving in step (3) is through a 0.425 mm-0.8 mm round hole sieve.

[0038] Preferably, the hardness of the plain tablet is 50N-80N when the API content is 5%, 90N-120N when the API content is 10%, and 90N-120N when the API content is 50%.

[0039] The coating treatment may adopt coating powder or coating liquid, and the coating liquid is a solution prepared by film coating premix Opadry I or Opadry II, preferably with a mass concentration of 10%.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] (1) The pyridoimidazolethiopropionic acid compound crystal form Form 13 of the present invention was placed under long-term (25°C ± 2°C, 65% RH ± 10% RH, open to light) and accelerated (40°C ± 2°C, 75% RH ± 10% RH, open to light) conditions for 10 days, and the crystal form and melting point did not change significantly.

[0042] (2) The present invention avoids the use of solubilizers by micronizing the raw material drug compound and combining it with technical means such as screening the types and proportions of excipients. At the same time, it effectively improves the solubility of the compound, has good formulation stability, and has a simple production process, which meets production requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the XRPD comparison diagram of HY-0902 API before and after crushing;

[0044] Figure 2 XRPD comparison chart of HY-0902 API, Example 2, Example 3 HY-0902 tablets and blank tablets;

[0045] Figure 3 This is the XRPD comparison chart of the influencing factor test and the long-term 1-month stability test of HY-0902 tablets in Example 2;

[0046] Figure 4 This is the XRPD comparison diagram of the influencing factor test and the long-term 1-month stability test of HY-0902 tablets in Example 3;

[0047] Figure 5 It is the XRPD pattern of the pyridoimidazolethiopropionic acid compound crystal form Form 13 placed under long-term (25℃±2℃, 65%RH±10%RH, open to light) and accelerated (40℃±2℃, 75%RH±10%RH, open to light) conditions for 10 days;

[0048] Figure 6 This is the DSC graph of the pyridoimidazolethiopropionic acid compound crystal form Form 13 placed under long-term (25℃±2℃, 65%RH±10%RH, open to light) and accelerated (40℃±2℃, 75%RH±10%RH, open to light) conditions for 10 days. DETAILED DESCRIPTION

[0049] The present invention is further described below in conjunction with specific embodiments.

[0050] Unless otherwise specified, the experimental materials used in the following examples are all conventional pharmaceutical grade excipients.

[0051] All of the following HY-0902 were prepared by the method of Example 1 in patent CN 115385907 A.

[0052] The raw material information used in the examples and comparative examples is shown in Table 1 below:

[0053] Table 1 Raw material information

[0054]

[0055] Note: ① Cellulose-lactose is a mixture of microcrystalline cellulose and lactose in a mass ratio of 3:1.

[0056] For the plain tablets not specially described in the embodiments and comparative examples, when the API content is 5%, the hardness is 50N-80N, when the API content is 10%, the hardness is 90N-120N, and when the API content is 50%, the hardness is 90N-120N.

[0057] Example 1

[0058] HY-0902 tablets were prepared using the micronized bulk drug HY-0902 compound (particle size D90 ≤ 10 μm) according to the formulation shown in Table 2.

[0059] Table 2 Prescription of Example 1

[0060]

[0061] The preparation steps are as follows:

[0062] (1) Preprocessing

[0063] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0064] (2) Premix

[0065] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0066] (3) Whole grain

[0067] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0068] (4) Total mixing

[0069] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0070] (5) Tableting

[0071] The total mixed material is tableted to obtain plain tablets, and the tablet hardness is 90~120N (the tablet production is batch production, and the hardness of the sampling test is within 90~120N).

[0072] Example 2

[0073] HY-0902 tablets were prepared using the micronized bulk drug HY-0902 compound (particle size D90 ≤ 10 μm) according to the formulation shown in Table 3.

[0074] Table 3 Prescription of Example 2

[0075]

[0076] The preparation steps are the same as in Example 1.

[0077] Example 3

[0078] HY-0902 tablets were prepared using the micronized bulk drug HY-0902 compound (particle size D90 ≤ 10 μm) according to the formulation shown in Table 4.

[0079] Table 4 Prescription of Example 3

[0080]

[0081] The preparation steps are the same as in Example 1.

[0082] The above raw materials before and after pulverization, HY-0902 tablets prepared in Example 2 and Example 3, HY-0902 blank tablets and HY-0902 raw materials were subjected to crystal form detection. The results are shown in Figure 1-2 The HY-0902 tablet samples prepared in Example 2 and Example 3 were subjected to influencing factor tests and long-term stability tests according to the Appendix of Part II of the 2020 edition of the Chinese Pharmacopoeia, and the HY-0902 tablet crystal form was tested to investigate the tablet crystal form stability. The results are shown in Figure 3-4 .

[0083] The results show that the crystal form of HY-0902 does not change before and after crushing. The samples prepared by direct compression are consistent with the crystal form of the raw material, and the crystal form of the above-mentioned HY-0902 tablets (Example 2) has not changed after the influencing factors and long-term stability tests, and the crystal form of the raw material of this product has not changed after accelerated and long-term storage. Therefore, it is shown that the crystal form of the HY-0902 (crystal form Form 13) compound is relatively stable, and the HY-0902 tablets prepared by direct compression technology are relatively stable under high temperature, high humidity, light and other conditions. The crystal form of the HY-0902 tablets prepared by direct compression technology is also relatively stable under long-term stability conditions.

[0084] Comparative Example 1

[0085] HY-0902 tablets were prepared using the un-crushed bulk drug HY-0902 compound according to the prescription shown in Table 5.

[0086] Table 5 Prescription of Comparative Example 1

[0087]

[0088] The preparation steps are as follows:

[0089] (1) Preprocessing

[0090] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0091] (2) Premix

[0092] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0093] (3) Whole grain

[0094] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0095] (4) Total mixing

[0096] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0097] (5) Tableting

[0098] The total mixed material is tableted to obtain plain tablets.

[0099] The dissolution data of the HY-0902 tablets prepared in the above Comparative Example 1 and Example 1 in a pH 6.8 medium are shown in Table 6 below.

[0100] Table 6 Dissolution curves of HY-0902 tablets with different API particle sizes in pH 6.8 medium

[0101]

[0102] The results show that the dissolution curves of prescriptions with different API particle sizes in pH 6.8 medium are different. The particle size directly affects the drug dissolution. When the API particle size is reduced, the specific surface area increases and the dissolution is significantly improved. In terms of tablet appearance, the tablets pressed without API treatment have brown spots, while the tablets pressed after API particle size crushing have a smooth appearance, and are white or off-white tablets, which are more beautiful.

[0103] The above data show that when the particle size D90 of the API is controlled to be ≤10 μm, the prepared tablets have a smooth appearance and can effectively improve the dissolution rate of HY-0902 tablets.

[0104] Example 4

[0105] HY-0902 tablets were prepared using the micronized API HY-0902 compound (particle size D90 ≤ 10 μm) according to the formulation shown in Table 7. The tablet hardness was 90~120N.

[0106] Table 7 Prescription of Example 4

[0107] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Microcrystalline Cellulose 86 Croscarmellose Sodium 2 Magnesium Stearate 1 Silicon dioxide 1 total 100

[0108] The preparation steps are as follows:

[0109] (1) Preprocessing

[0110] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0111] (2) Premix

[0112] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0113] (3) Whole grain

[0114] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0115] (4) Total mixing

[0116] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0117] (5) Tableting

[0118] The total mixed material is tableted to obtain plain tablets.

[0119] Example 5

[0120] The micronized API HY-0902 compound (particle size D90 ≤ 10 μm) was used to prepare HY-0902 tablets according to the formulation in Table 8 below. The tablet hardness was 90-120N.

[0121] Table 8 Prescription of Example 5

[0122] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Microcrystalline Cellulose 82 Croscarmellose Sodium 6 Magnesium Stearate 1 Silicon dioxide 1 total 100

[0123] The preparation steps are as follows:

[0124] (1) Preprocessing

[0125] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (about 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0126] (2) Premix

[0127] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0128] (3) Whole grain

[0129] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0130] (4) Total mixing

[0131] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0132] (5) Tableting

[0133] The total mixed material is tableted to obtain a plain tablet. The dissolution data of the HY-0902 tablets prepared in the above Examples 1, 4 and 5 in a pH 6.8 medium are shown in Table 9 below.

[0134] Table 9 Dissolution curves of HY-0902 tablets with different disintegrant dosages in pH 6.8 medium

[0135]

[0136] The results showed that when the disintegrant dosage of HY-0902 tablets was in the range of 2% to 6%, it could meet the requirement of rapid dissolution.

[0137] Example 6

[0138] The micronized API HY-0902 compound (particle size D90 ≤ 10 μm) was used to prepare HY-0902 tablets according to the prescription in Table 10 below. The tablet hardness was 90-120N.

[0139] Table 10 Prescription of Example 6

[0140] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Microcrystalline Cellulose 84.5 Croscarmellose Sodium 4 Magnesium Stearate 0.5 Silicon dioxide 1 total 100

[0141] The preparation steps are as follows:

[0142] (1) Preprocessing

[0143] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0144] (2) Premix

[0145] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0146] (3) Whole grain

[0147] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0148] (4) Total mixing

[0149] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0150] (5) Tableting

[0151] The total mixed material is tableted to obtain plain tablets.

[0152] Example 7

[0153] The micronized API HY-0902 compound (particle size D90 ≤ 10 μm) was used to prepare HY-0902 tablets according to the prescription in Table 11 below. The tablet hardness was 90-120N.

[0154] Table 11 Prescription of Example 7

[0155] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Microcrystalline Cellulose 83 Croscarmellose Sodium 4 Magnesium Stearate 2 Silicon dioxide 1 total 100

[0156] The preparation steps are as follows:

[0157] (1) Preprocessing

[0158] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0159] (2) Premix

[0160] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0161] (3) Whole grain

[0162] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0163] (4) Total mixing

[0164] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0165] (5) Tableting

[0166] The total mixed material is tableted to obtain plain tablets.

[0167] The dissolution data of HY-0902 tablets prepared in the above Examples 1, 6 and 7 in a pH 6.8 medium are shown in Table 12 below.

[0168] Table 12 Dissolution curves of HY-0902 tablets with different lubricant dosages in pH 6.8 medium

[0169]

[0170] The results showed that the lubricant dosage of HY-0902 tablets in the range of 0.5% to 2% did not affect the dissolution of the tablets.

[0171] Example 8

[0172] HY-0902 tablets were prepared using the micronized bulk drug HY-0902 compound (particle size D90 ≤ 10 μm) according to the formulations in Tables 13 and 14 below.

[0173] (1) HY-0902 (crushed) accounts for 10%:

[0174] Table 13 Prescriptions with HY-0902 (crushed) accounting for 10%

[0175] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Microcrystalline Cellulose 84 Croscarmellose Sodium 4 Magnesium Stearate 1 Gel Silica 1 total 100

[0176] (2) HY-0902 (crushed) accounts for 5%:

[0177] Table 14 Prescriptions with HY-0902 (crushed) accounting for 10%

[0178] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 5 Microcrystalline Cellulose 89 Croscarmellose Sodium 4 Magnesium Stearate 1 Gel Silica 1 total 100

[0179] The preparation steps are as follows:

[0180] (1) Preprocessing

[0181] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0182] (2) Premix

[0183] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0184] (3) Whole grain

[0185] The premixed material is sieved, a 0.425 mm aperture sieve is selected, and the sieved material is collected;

[0186] (4) Total mixing

[0187] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0188] (5) Tableting

[0189] The total mixed material was tableted, and HY-0902 tablets with different hardness ranges were pressed respectively to investigate the friability and dissolution of tablets with different hardness.

[0190] The hardness test results of the HY-0902 tablets of different hardness prepared in the above Example 8 are shown in Tables 15 and 16 below.

[0191] Table 15 Hardness test results of HY-0902 sheets (HY-0902 accounts for 5%)

[0192]

[0193] Table 16 Hardness test results of HY-0902 sheets (HY-0902 accounts for 10%)

[0194]

[0195] The friability test results of the HY-0902 tablets prepared in Example 8 are shown in Table 17 below.

[0196] Table 17 Investigation on the brittleness of HY-0902 tablets with different hardness

[0197]

[0198] The results showed that when the hardness of HY-0902 tablets (HY-0902 accounted for 5%) was 30-50N and the hardness of HY-0902 tablets (HY-0902 accounted for 10%) was 70-90N, due to the low hardness, there was slight wear on the surface of the tablets during the friability test, which may affect the appearance of the tablets;

[0199] When the hardness of HY-0902 tablets (HY-0902 accounts for 5%) is 50-80N and the hardness of HY-0902 tablets (HY-0902 accounts for 10%) is 90-120N, the tablet hardness is moderate and the friability is qualified.

[0200] The dissolution data of HY-0902 tablets prepared in Example 8 above in a pH 6.8 medium are shown in Tables 18 and 19 below.

[0201] Table 18 Dissolution curves of HY-0902 tablets with different hardness (HY-0902 accounts for 5%)

[0202]

[0203] Table 19 Dissolution curves of HY-0902 tablets with different hardness (HY-0902 accounts for 10%)

[0204]

[0205] The results showed that with the increase of hardness, the initial dissolution rate decreased slightly, but it did not affect the rapid dissolution of HY-0902 tablets, and there was almost no difference in the endpoint dissolution.

[0206] In summary, the preferred hardness range of HY-0902 sheets (HY-0902 accounts for 5%) is 50-80N, and the preferred hardness range of HY-0902 sheets (HY-0902 accounts for 10%) is 90-120N.

[0207] Example 9

[0208] HY-0902 tablets were prepared according to the following Table 20 formulation.

[0209] Table 20 Prescription of Example 9

[0210] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Silicified Microcrystalline Cellulose 84 Croscarmellose Sodium 4 Magnesium Stearate 1 Silicon dioxide 1 total 100

[0211] The preparation steps are as follows:

[0212] (1) Preprocessing

[0213] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0214] (2) Premix

[0215] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0216] (3) Whole grain

[0217] The premixed material is sieved, a 0.425 mm aperture sieve is selected, and the sieved material is collected;

[0218] (4) Total mixing

[0219] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0220] (5) Tableting

[0221] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0222] Example 10

[0223] HY-0902 tablets were prepared according to the following Table 21 formulation.

[0224] Table 21 Prescription of Example 10

[0225] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Cellulose-Lactose 84 Croscarmellose Sodium 4 Magnesium Stearate 1 Silicon dioxide 1 total 100

[0226] The preparation steps are as follows:

[0227] (1) Preprocessing

[0228] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, pass through a 40-mesh sieve for later use; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) and pass through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0229] (2) Premix

[0230] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0231] (3) Whole grain

[0232] The premixed material is sieved, a 0.425 mm aperture sieve is selected, and the sieved material is collected;

[0233] (4) Total mixing

[0234] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0235] (5) Tableting

[0236] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0237] The dissolution data of HY-0902 tablets prepared in the above Examples 1, 9 and 10 in a pH 6.8 medium are shown in Table 22 below.

[0238] Table 22 Dissolution curves of HY-0902 tablets with different filler types in pH 6.8 medium

[0239]

[0240] The results showed that when the filler types of HY-0902 tablets were microcrystalline cellulose, silicified microcrystalline cellulose and cellulose-lactose, HY-0902 tablets could be rapidly dissolved.

[0241] Embodiment 11

[0242] HY-0902 coated tablets were prepared according to the formulation in Table 23 below.

[0243] Table 23 Prescription of Example 11

[0244]

[0245] The preparation steps are as follows:

[0246] (1) Preprocessing

[0247] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, sieve and set aside; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0248] (2) Premix

[0249] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0250] (3) Whole grain

[0251] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0252] (4) Total mixing

[0253] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0254] (5) Tableting

[0255] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0256] (6) Coating: Use coating powder (Opadry I) to coat the plain tablets separately.

[0257] Example 12

[0258] HY-0902 coated tablets were prepared according to the formulation in Table 24 below.

[0259] Table 24 Prescription of Example 12

[0260]

[0261] The preparation steps are as follows:

[0262] (1) Preprocessing

[0263] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, sieve and set aside; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0264] (2) Premix

[0265] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0266] (3) Whole grain

[0267] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0268] (4) Total mixing

[0269] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0270] (5) Tableting

[0271] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0272] (6) Coating: Use coating powder (Opadry Ⅱ) to coat the plain tablets.

[0273] The dissolution data of the HY-0902 coated tablets prepared in the above Examples 11 and 12 in a pH 6.8 medium are shown in Table 25 below.

[0274] Table 25 Dissolution curves of HY-0902 coated tablets with different coating powder types in pH 6.8 medium

[0275]

[0276] The results showed that there was no significant difference in the dissolution trend of HY-0901 coated tablets prepared with different coating powder types (Opadry I, Opadry II).

[0277] Embodiment 13

[0278] HY-0902 coated tablets were prepared according to the formulation in Table 26 below.

[0279] Table 26 Prescription of Example 13

[0280]

[0281] The preparation steps are as follows:

[0282] (1) Preprocessing

[0283] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, sieve and set aside; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0284] (2) Premix

[0285] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0286] (3) Whole grain

[0287] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0288] (4) Total mixing

[0289] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0290] (5) Tableting

[0291] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0292] (6) Coating and packaging: The plain tablets are coated and packaged.

[0293] Embodiment 14

[0294] HY-0902 coated tablets were prepared according to the formulation in Table 27 below.

[0295] Table 27 Prescription of Example 14

[0296] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Cellulose-Lactose 84 Croscarmellose Sodium 4 Magnesium Stearate 1 Gel Silica 1 total 100 Coating powder Opadry I 3%

[0297] The preparation steps are as follows:

[0298] (1) Preprocessing

[0299] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, sieve and set aside; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0300] (2) Premix

[0301] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0302] (3) Whole grain

[0303] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0304] (4) Total mixing

[0305] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0306] (5) Tableting

[0307] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0308] (6) Coating and packaging: The plain tablets are coated and packaged.

[0309] Embodiment 15

[0310] HY-0902 coated tablets were prepared according to the formulation in Table 28 below.

[0311] Table 28 Prescription of Example 15

[0312] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Cellulose-Lactose 84 Croscarmellose Sodium 4 Sodium stearyl fumarate 1 Gel Silica 1 total 100 Coating powder Opadry I 3%

[0313] The dosage of coating powder in Examples 9-13 is a percentage of the total weight of the pharmaceutical composition.

[0314] The preparation steps are as follows:

[0315] (1) Preprocessing

[0316] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, sieve and set aside; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0317] (2) Premix

[0318] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0319] (3) Whole grain

[0320] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0321] (4) Total mixing

[0322] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0323] (5) Tableting

[0324] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0325] (6) Coating and packaging: The plain tablets are coated and packaged.

[0326] The dissolution data of HY-0902 tablets prepared in the above Examples 13, 14 and 15 in a pH 6.8 medium are shown in Table 29 below.

[0327] Table 29 Dissolution curves of HY-0902 coated tablets with different excipient types in pH 6.8 medium

[0328]

[0329] The results show that, compared with the HY-0902 coated tablets of Example 13 and Example 14, since microcrystalline cellulose is a water-insoluble excipient and has a void structure, it adsorbs the raw material drug, resulting in reduced dissolution; after the filler is replaced by cellulose-lactose from microcrystalline cellulose, the dissolution rate and dissolution platform of the HY-0902 tablets can be improved.

[0330] In addition, when comparing the HY-0902 coated tablets of Example 14 and Example 15, there was no significant difference in dissolution between the two after replacing magnesium stearate with sodium stearyl fumarate.

[0331] Example 16

[0332] According to the prescription in Table 30 below, HY-0902 coated tablets were prepared.

[0333] Table 30 Prescription of Example 16

[0334] Name of raw materials Prescription composition and percentage HY-0902 (crushed) 10 Microcrystalline Cellulose 84 Croscarmellose Sodium 4 Magnesium Stearate 1 Gel Silica 1 total 100 Coating powder model OpadryI

[0335] The preparation steps are as follows:

[0336] (1) Preprocessing

[0337] Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and flow aid, sieve and set aside; take an appropriate amount of filler (accounting for 1 / 3 of the prescription amount) through a 40-mesh sieve, and rinse the sieve; weigh other added excipients according to the prescription ratio and set aside;

[0338] (2) Premix

[0339] The material obtained in step (1) and the remaining added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material;

[0340] (3) Whole grain

[0341] The premixed material is sieved, and a 0.8 mm round hole sieve is selected to collect the sieved material;

[0342] (4) Total mixing

[0343] Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material;

[0344] (5) Tableting

[0345] The total mixed material is tableted to obtain plain tablets with a tablet hardness of 90~120N.

[0346] (6) Coating: Weigh the gastric-soluble film coating premix and water to prepare a coating solution with a concentration of 10% for coating. Control the coating weight gain to 1%, 3% and 5%.

[0347] The effects of different coating weight gains on HY-0902 coated tablets were investigated. The results are shown in Table 31 below.

[0348] Table 31 Dissolution curves of HY-0902 coated tablets with different coating weight gain in pH 6.8 medium

[0349]

[0350] According to the dissolution comparison results of HY-0902 coated tablets with different coating weight gains in Example 16, as the coating weight gain increases from 1% to 5%, the dissolution of HY-0902 coated tablets slows down, which may affect the endpoint dissolution of the tablets.

[0351] Combined with the dissolution comparison results of Example 13 and Example 14, when water-soluble excipients are used as fillers, the dissolution trend is significantly improved. Therefore, it is considered that the filler in the prescription can be replaced by cellulose-lactose from microcrystalline cellulose to improve the dissolution rate and dissolution platform of HY-0902 coated tablets.

[0352] Embodiment 17

[0353] According to the prescription in Table 32 below, HY-0902 coated tablets (HY-0902 accounts for 5%) are prepared, and the tablet hardness is 50~80N.

[0354] Table 32 Prescription of Example 17

[0355]

[0356] The samples were subjected to accelerated and long-term stability tests according to the Appendix of Part II of the 2020 edition of the Chinese Pharmacopoeia. The dissolution data of the HY-0902 coated tablets (HY-0902 accounting for 5%) prepared in Example 17 above are shown in Tables 33 and 34 below.

[0357] Table 33 Dissolution of HY-0902 coated tablets (HY-0902 accounts for 5%) in accelerated stability test

[0358]

[0359] Table 34 Dissolution of HY-0902 coated tablets (HY-0902 accounts for 5%) in long-term stability test

[0360]

[0361] The results showed that the HY-0902 coated tablets (HY-0902 accounting for 5%) prepared in Example 17 were able to dissolve rapidly and had good stability during the accelerated and long-term stability tests.

[0362] Embodiment 18

[0363] According to the prescription in Table 35 below, HY-0902 coated tablets (HY-0902 accounts for 10%) are prepared, and the tablet hardness is 90~120N.

[0364] Table 35 Prescription of Example 18

[0365]

[0366] The samples were subjected to accelerated and long-term stability tests according to the Appendix of Part II of the 2020 edition of the Chinese Pharmacopoeia. The dissolution data of the HY-0902 coated tablets (HY-0902 accounting for 10%) prepared in Example 18 above are shown in Tables 36 and 37 below.

[0367] Table 36 Dissolution of HY-0902 coated tablets (HY-0902 accounts for 10%) in accelerated stability test

[0368]

[0369] Table 37 Dissolution of HY-0902 coated tablets (HY-0902 accounts for 10%) in long-term stability test

[0370]

[0371] The results showed that the HY-0902 coated tablets (HY-0902 accounting for 10%) prepared in Example 18 were able to dissolve rapidly and had good stability during the accelerated and long-term stability tests.

[0372] The HY-0902 (crystal form Form 13) compound used in the present invention and the HY-0902 tablets prepared therefrom have stable crystal forms and are not easily affected by light, high temperature, high humidity and preparation process. The present invention avoids the use of solubilizers by micronizing the compound of the API (particle size D90≤10 μm), combining the screening of excipient types, limiting the proportion of excipients within a certain range and other technical means, while effectively improving the solubility of the HY-0902 tablets, and the production process is simple, meeting the production requirements.

Claims

1. A pharmaceutical composition of a pyridoimidazolethiopropionic acid compound crystal form Form 13, characterized in that: The chemical name of the pyridoimidazolethiopropionic acid compound is: 2-((1-(4-cyclopropylnaphthalene-1-yl)-1H-imidazole[4,5-b]pyridine-2-yl)thio)propionic acid, and the structural formula is shown in Formula I below: Formula I; The pyridoimidazole thiopropionic acid compound crystal form Form 13 uses Cu-Ka radiation, and the X-ray powder diffraction spectrum expressed in 2θ angles is 6.53±0.2, 7.70±0.2, 9.84±0.2, 10.24±0.2, 11.36±0.2, 12.58±0.2, 13.10±0.2, 14.18±0.2, 15.30±0.2, 17.30±0.2, 18.00±0.2, 19.78±0.2, 20.0 There are characteristic peaks at 4±0.2, 21.04±0.2, 22.31±0.2, 23.18±0.2, 24.08±0.2, 25.08±0.2, 26.21±0.2, 27.21±0.2, 28.20±0.2, 29.08±0.2, 30.15±0.2, 31.15±0.2, 32.51±0.2, 34.53±0.2, 35.18±0.2, 36.02±0.2, and 37.58±0.2; The pharmaceutical composition comprises the following components by mass fraction: API: 5%-50% pyridoimidazolethiopropionic acid compound crystal form Form 13; Added excipients: 44%-89% filler, 2%-6% disintegrant; Additional auxiliary materials: 0.5%-2% lubricant; The pyridoimidazolethiopropionic acid compound crystal form Form 13 is micronized, and the particle size of the raw material drug D90 is ≤ 10 μm; The filler is cellulose-lactose C80; It also includes a coating material, which accounts for 1% to 5% of the total weight of the pharmaceutical composition; the coating material is a film coating premix Opadry Ⅰ; The disintegrant is croscarmellose sodium; The lubricant is one of magnesium stearate and sodium stearyl fumarate.

2. The pharmaceutical composition of the pyridoimidazolethiopropionic acid compound crystal form Form 13 according to claim 1, characterized in that: The internal auxiliary materials also include glidants.

3. The pharmaceutical composition of the pyridoimidazolethiopropionic acid compound crystal form Form 13 according to claim 2, characterized in that: The flow aid is a kind of silicon dioxide.

4. A method for preparing tablets of a pharmaceutical composition of a pyridoimidazolethiopropionic acid compound crystal form Form 13 according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) Preprocessing Weigh the micronized pyridoimidazolethiopropionic acid crystal form Form 13 compound and the flow aid, sieve and set aside; sieve the filler and rinse the sieve; weigh the disintegrant and set aside; (2) Premix The material obtained in step (1) and the added auxiliary materials are transferred to a hopper mixer and mixed evenly to obtain a premixed material; (3) Whole grain Screening the premixed materials and collecting the screened materials; (4) Total mixing Weigh the material obtained in step (3) above, weigh the additional auxiliary materials and add them to the sieved material, transfer the above materials together to a hopper mixer, mix them evenly, and obtain a total mixed material; (5) Tableting The total mixed material is tableted to obtain a plain tablet; The method also includes coating the plain tablets.

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