A seladepa pharmaceutical composition, its preparation and preparation method

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically discloses a sladepam pharmaceutical composition, a preparation thereof and a preparation method thereof. The sladepam pharmaceutical composition provided by the present invention selects mannitol and microcrystalline cellulose as diluents, and controls the content of microcrystalline cellulose in the diluent, which can not only improve the uniformity of mixing API with other excipients, improve the uniformity of preparation content, but also improve the stability of the drug during storage; at the same time, butylated hydroxytoluene is selected as an antioxidant to reduce the possibility of degradation of sladepam during preparation, storage and transportation, further improve the stability of the preparation, thereby ensuring the consistency and reliability of drug efficacy; cross-linked sodium carboxymethyl cellulose is selected as a disintegrant, which can increase the dissolution rate of sladepam in the medium, control the dissolution process of sladepam, and make it reach a dissolution rate consistent with the original research.

Description

Technical Field

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

[0002] Seladelpar is a single enantiomer of the R configuration and exists in the form of lysine salt dihydrate. Seladelpar lysine salt dihydrate is a white to off-white powder with a molecular formula of C 21 H 23 F3O5S·C6H 14 N2O2·2H2O, molecular weight is 626.7g / mol, and its chemical structure is as follows.

[0003]

[0004] Siladepag is a peroxisome proliferator-activated receptor (PPAR)-δ agonist. Pharmacological activities potentially relevant to therapeutic effects include inhibition of bile acid synthesis through activation of PPARδ, a nuclear receptor expressed in most tissues including the liver. Published studies have shown that siladepag activates PPARδ to reduce bile acid synthesis through fibroblast growth factor 21 (FGF21)-dependent downregulation of CYP7A1, a key enzyme in the synthesis of bile acids from cholesterol. It is suitable for combination therapy with ursodeoxycholic acid (UDCA) for the treatment of adult primary cholangitis (PBC) that is inadequately responsive to UDCA, or for the treatment of patients who cannot tolerate UDCA.

[0005] Siladepam-related preparations have been launched in the United States in 2024 in the form of hard capsules with the trade name Livdelzi. Siladepam has poor stability during the preparation process, especially in a hot and humid environment, the stability of the contents of the capsule is extremely unstable and easy to degrade. At present, there are few public documents on Siladepam preparations, and there is no public document on Siladepam preparations to solve the above problems. Therefore, it is necessary to develop a Siladepam pharmaceutical composition and preparation thereof with good stability and good dissolution performance. Summary of the invention

[0006] Aiming at the problem that the existing sladepam preparations have poor stability during preparation, especially in a hot and humid environment, the stability of the contents of the capsules is extremely unstable and easy to degrade, the present invention provides a sladepam pharmaceutical composition, a preparation thereof and a preparation method thereof.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] A sladepam pharmaceutical composition, comprising sladepam or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a glidant, an antioxidant and a lubricant;

[0009] Wherein, the diluent comprises mannitol and microcrystalline cellulose, and the microcrystalline cellulose accounts for 20% to 40% of the total mass of the seladespa pharmaceutical composition;

[0010] The disintegrant is cross-linked sodium carboxymethyl cellulose; and the antioxidant is butylated hydroxytoluene.

[0011] Compared with the prior art, the sladepam pharmaceutical composition provided by the present invention selects mannitol and microcrystalline cellulose as diluents, and controls the content of microcrystalline cellulose in the diluent, which can not only improve the uniformity of mixing of API and other excipients, improve the uniformity of preparation content, but also improve the stability of the drug during storage; at the same time, butylated hydroxytoluene is selected as an antioxidant to reduce the possibility of degradation of sladepam during preparation, storage and transportation, further improve the stability of the preparation, thereby ensuring the consistency and reliability of drug efficacy; cross-linked sodium carboxymethyl cellulose is selected as a disintegrant, which can increase the dissolution rate of sladepam in the medium, control the dissolution process of sladepam, and make it reach a dissolution rate consistent with the original research.

[0012] The invention uses a variety of excipients to reasonably match, and microcrystalline cellulose and mannitol work together to improve the dilution effect and take into account the fluidity and stability of sladepam in the preparation process; the antioxidant works together with the excipients to further improve the chemical stability of sladepam in the preparation and storage process, and improves the quality of the sladepam pharmaceutical preparation as a whole; and the dissolution process is controlled by the synergistic effect of cross-linked sodium carboxymethyl cellulose and other excipients, so that the pharmaceutical composition can achieve a dissolution rate consistent with that of the original research, thereby achieving effective substitution for the original research, and providing more safe drug options for combined treatment with ursodeoxycholic acid (UDCA) for adult primary cholangitis (PBC) with poor efficacy to UDCA, or for treating patients who cannot tolerate UDCA.

[0013] Furthermore, the glidant is colloidal silicon dioxide.

[0014] The preferred glidant is combined with microcrystalline cellulose and mannitol to significantly improve the fluidity of seladespam during the preparation process and increase the uniformity of the drug content.

[0015] Furthermore, the lubricant is magnesium stearate.

[0016] Magnesium stearate can improve the fluidity of drug powder or granules, prevent the particles from sticking to each other, and make the material flow more smoothly in the equipment. At the same time, it can ensure that the drug powder or granules are evenly filled into the capsule, avoiding uneven filling or excessive differences in capsule weight, which is beneficial to improving the consistency of product quality.

[0017] Furthermore, the diluent accounts for 80% to 93% of the total mass of the seladespa pharmaceutical composition.

[0018] Furthermore, the sladepam pharmaceutical composition comprises the following components in parts by weight: 14.1 parts of sladepam lysine salt dihydrate, 280 parts to 325 parts of diluent, 7 parts to 35 parts of disintegrant, 1.7 parts to 7 parts of glidant, 0.1 parts to 1.5 parts of antioxidant, and 1.7 parts to 7 parts of lubricant;

[0019] Wherein, the diluent contains 140 to 260 parts of mannitol and 70 to 140 parts of microcrystalline cellulose.

[0020] Preferably, the sladepam pharmaceutical composition comprises the following components in parts by weight: 14.1 parts of sladepam lysine salt dihydrate, 245 parts to 255 parts of mannitol, 70 parts to 75 parts of microcrystalline cellulose, 5 parts to 10 parts of cross-linked sodium carboxymethyl cellulose, 0.1 parts to 0.2 parts of butylated hydroxytoluene, 2 parts to 3 parts of colloidal silicon dioxide, and 4 parts to 5 parts of magnesium stearate.

[0021] More preferably, the sladepam pharmaceutical composition comprises the following components in parts by mass: 14.1 parts of sladepam lysine salt dihydrate, 251.8 parts of mannitol, 70 parts of microcrystalline cellulose, 7 parts of cross-linked sodium carboxymethyl cellulose, 0.1 parts of butylated hydroxytoluene, 2.65 parts of colloidal silicon dioxide, and 4.35 parts of magnesium stearate.

[0022] The present invention also provides a sladepam pharmaceutical preparation, which is prepared from any of the sladepam pharmaceutical compositions described above.

[0023] Furthermore, the dosage form of the seladespa pharmaceutical preparation is capsule or tablet.

[0024] Specifically, if the dosage form is a tablet, the prescription of the selapid preparation also includes a gastric-soluble film coating premix, and the gastric-soluble film coating premix may include a colorant, titanium dioxide, and iron oxide.

[0025] Exemplarily, the dosage form of the seladepa pharmaceutical preparation provided by the present invention is a capsule.

[0026] The present invention also provides a method for preparing the above-mentioned Seladepa capsules, comprising the following steps:

[0027] S1, mixing siladepa or its pharmaceutically acceptable salt, a diluent, a disintegrant, a glidant and an antioxidant uniformly to obtain a premixed material;

[0028] S2, dry granulating the premixed material and granulating the premixed material to obtain granules;

[0029] S3, mixing the granules and lubricant evenly, and filling the mixture into a capsule shell to obtain a Sladoppa drug preparation.

[0030] The preparation method of the sladepam capsule provided by the present invention adopts dry granulation, has a simple preparation process, and the prepared sladepam capsule has good stability and a dissolution rate consistent with the original research product, can achieve a good replacement for the original research product, and provide more drug options for treating bile duct diseases.

[0031] Furthermore, in S2, a 24-mesh sieve is used for granulation.

[0032] As a specific embodiment of the present invention, the capsule shell is a gelatin hard capsule, and the capsule shell contains a colorant, titanium dioxide and iron oxide.

[0033] The present invention uses microcrystalline cellulose and mannitol as diluents, uses cross-linked sodium carboxymethyl cellulose as a disintegrant, and adds butylated hydroxytoluene as an antioxidant. At the same time, by controlling the content of microcrystalline cellulose in the diluent, sladepam capsules are prepared by dry granulation. The dissolution curve of the prepared sladepam capsules is similar to that of the original research, and compared with the original research, the stability is significantly improved during the storage process, and a good replacement for the original research product can be achieved, thereby providing more drug options for patients with cholangiopathy, and reducing the drug cost of patients, and having a high clinical application value. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0035] In order to better illustrate the present invention, further examples are given below.

[0036] Example 1

[0037] This embodiment provides a seladespa capsule, and the prescription dosage (single dose) is shown in the following table:

[0038] Components Mass / mg Sladopterin lysine salt dihydrate 14.1 Mannitol 198.95 Microcrystalline Cellulose 112 Croscarmellose Sodium 17.5 Butylated Hydroxytoluene 0.45 Colloidal Silica 3.5 Magnesium Stearate 3.5 total 350

[0039] The preparation method of the above-mentioned Sladepam capsule is as follows:

[0040] S1, adding sladopterin lysine salt dihydrate, microcrystalline cellulose, mannitol, colloidal silicon dioxide, butylated hydroxytoluene and cross-linked sodium carboxymethyl cellulose into a mixer, and mixing for 8 minutes at a stirring speed of 200 rpm and a shear speed of 500 rpm to obtain a premixed material;

[0041] S2, dry granulating the premixed material using a dry granulator, and sieving using a 24-mesh screen to obtain granules;

[0042] S3, mixing the granules and magnesium stearate uniformly, and filling the mixture into hollow gelatin hard capsule shells to obtain Sladoppa capsules.

[0043] Example 2

[0044] This embodiment provides a seladespa capsule, and the prescription dosage (single dose) is shown in the following table:

[0045] Components Mass / mg Sladopterin lysine salt dihydrate 14.1 Mannitol 251.8 Microcrystalline Cellulose 70 Croscarmellose Sodium 7 Butylated Hydroxytoluene 0.1 Colloidal Silica 2.65 Magnesium Stearate 4.35 total 350

[0046] The preparation method of the above-mentioned Sladepam capsule is as follows:

[0047] S1, adding sladopterin lysine salt dihydrate, microcrystalline cellulose, mannitol, colloidal silicon dioxide, butylated hydroxytoluene and cross-linked sodium carboxymethyl cellulose into a mixer, and mixing for 8 minutes at a stirring speed of 200 rpm and a shear speed of 500 rpm to obtain a premixed material;

[0048] S2, dry granulating the premixed material using a dry granulator, and sieving using a 24-mesh screen to obtain granules;

[0049] S3, mixing the granules and magnesium stearate uniformly, and filling the mixture into hollow gelatin hard capsule shells to obtain Sladoppa capsules.

[0050] Example 3

[0051] This embodiment provides a seladespa capsule, and the prescription dosage (single dose) is shown in the following table:

[0052] Components Mass / mg Sladopterin lysine salt dihydrate 14.1 Mannitol 154.6 Microcrystalline Cellulose 140 Croscarmellose Sodium 33.25 Butylated Hydroxytoluene 1.05 Colloidal Silica 4.35 Magnesium Stearate 2.65 total 350

[0053] The preparation method of the above-mentioned Sladepam capsule is as follows:

[0054] S1, adding sladopterin lysine salt dihydrate, microcrystalline cellulose, mannitol, colloidal silicon dioxide, butylated hydroxytoluene and cross-linked sodium carboxymethyl cellulose into a mixer, and mixing for 8 minutes at a stirring speed of 200 rpm and a shear speed of 500 rpm to obtain a premixed material;

[0055] S2, dry granulating the premixed material using a dry granulator, and sieving using a 24-mesh screen to obtain granules;

[0056] S3, mixing the granules and magnesium stearate uniformly, and filling the mixture into hollow gelatin hard capsule shells to obtain Sladoppa capsules.

[0057] Comparative Example 1

[0058] This comparative example provides a seladespa capsule, which is different from Example 2 only in that butylated hydroxytoluene is replaced with an equal amount of sodium metabisulfite. The specific formula is as follows:

[0059] Components Mass / mg Sladopterin lysine salt dihydrate 14.1 Mannitol 251.8 Microcrystalline Cellulose 70 Croscarmellose Sodium 7 Sodium metabisulfite 0.1 Colloidal Silica 2.65 Magnesium Stearate 4.35 total 350

[0060] Sladepam capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0061] Comparative Example 2

[0062] This comparative example provides a sladepam capsule, which is different from Example 2 in that the cross-linked carboxymethyl cellulose sodium is replaced with an equal amount of dry starch. The specific formula is as follows:

[0063]

[0064]

[0065] Sladepam capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0066] Comparative Example 3

[0067] This comparative example provides a sladepam capsule, which is different from Example 2 only in that the dosage of microcrystalline cellulose and mannitol is changed, but the total diluent dosage is kept the same. The specific prescription is as follows:

[0068] Components Mass / mg Sladopterin lysine salt dihydrate 14.1 Mannitol 275.95 Microcrystalline Cellulose 35 Croscarmellose Sodium 7 Butylated Hydroxytoluene 0.1 Colloidal Silica 2.65 Magnesium Stearate 4.35 total 350

[0069] Sladepam capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0070] Comparative Example 4

[0071] This comparative example provides a sladepam capsule, which is different from Example 2 in that the microcrystalline cellulose is replaced with an equal amount of pregelatinized starch. The specific formula is as follows:

[0072] Components Mass / mg Sladopterin lysine salt dihydrate 14.1 Mannitol 251.8 Pregelatinized starch 70 Croscarmellose Sodium 7 Butylated Hydroxytoluene 0.1 Colloidal Silica 2.65 Magnesium Stearate 4.35 total 350

[0073] Sladepam capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0074] Quality Research

[0075] 1. Dissolution curve

[0076] According to the second method under the fourth part of the "Dissolution and Release Determination Method" of the 2020 edition of the Chinese Pharmacopoeia, a standard medium pH 3.0 citrate buffer medium containing 0.05% CTAB was selected, and the paddle method was used at a speed of 75r / min to investigate the dissolution curves of Examples 1 to 3 of the present invention and the original product (trade name: Livdelzi; specification 10mg) Comparative Examples 2 to 4. The results are shown in Table 1.

[0077] Table 1 Dissolution curve in citrate buffer containing 0.05% CTAB at pH 3.0

[0078]

[0079]

[0080] The experimental results show that the products of Examples 1 to 3 have similar dissolution trends as the original product in a citrate buffer medium containing 0.05% CTAB at pH 3.0, and their dissolution amounts in 90 minutes are all greater than 85%. The dissolution amounts of the products prepared in Comparative Examples 2 to 4 after changing the type of disintegrant, filler or the amount of microcrystalline cellulose did not reach 85% in 90 minutes, which is not similar to the original product.

[0081] Stability testing

[0082] The sladepam capsules prepared in Examples 1 to 3, Comparative Examples 1 and 4, and the original product were placed without packaging at 40°C + 75% RH for 7 days, 14 days and 30 days, and then the content and changes in related substances of the samples were detected by HPLC. The results are shown in Tables 2 and 3.

[0083] Table 2 Content test results

[0084] sample Example 1 Example 2 Example 3 Original research products Comparative Example 1 Comparative Example 4 Initial content% 100.1 99.8 100.2 99.6 99.7 99.8 7 days content% 99.9 99.6 99.9 99.3 98.3 98.7 14 days content% 99.8 99.5 99.9 98.9 97.4 98.0 30 days content% 99.6 99.1 99.8 98.4 95.3 97.1

[0085] The experimental results show that the samples of Examples 1 to 3 were placed under 40°C + 75% RH conditions without packaging for 1 month, and the content of the products did not show a significant downward trend, and the stability was good. The samples of Comparative Examples 1 and 4 were placed under 40°C + 75% RH conditions for 1 month, and compared with the examples, the content showed a significant downward trend, and the stability was poor.

[0086] Table 3 Test results of related substances

[0087]

[0088] The experimental results show that the stability of the samples of comparative examples 1 and 4 was significantly changed after being placed under 40°C + 75% RH for 1 month, and the total amount of related substances increased by about 3.8% and 2.4%. After the samples of Examples 1 to 3 were placed under 40°C + 75% RH for 1 month, there was no significant change trend in the related substances compared with the comparative examples, and the products prepared in the examples had good stability. Moreover, compared with the original research, the stability of the sladepam prepared in the examples of the present invention was improved to a certain extent, so it can achieve a good replacement for the original research.

[0089] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A seladepa pharmaceutical composition, characterized in that: It includes sladepam or its pharmaceutically acceptable salt, a diluent, a disintegrant, a glidant, an antioxidant and a lubricant; Wherein, the diluent comprises mannitol and microcrystalline cellulose, and the microcrystalline cellulose accounts for 20% to 40% of the total mass of the seladespa pharmaceutical composition; The disintegrant is cross-linked sodium carboxymethyl cellulose; and the antioxidant is butylated hydroxytoluene.

2. The seladepa pharmaceutical composition according to claim 1, wherein the glidant is colloidal silicon dioxide.

3. The seladepa pharmaceutical composition according to claim 1, characterized in that: The lubricant is magnesium stearate.

4. The sladepam pharmaceutical composition according to claim 1, characterized in that: The diluent accounts for 80% to 93% of the total mass of the sladepam pharmaceutical composition.

5. The seladepa pharmaceutical composition according to claim 1 or 4, characterized in that: The sladepam pharmaceutical composition comprises the following components in parts by weight: 14.1 parts of sladepam lysine salt dihydrate, 280 parts to 325 parts of diluent, 7 parts to 35 parts of disintegrant, 1.7 parts to 7 parts of glidant, 0.1 parts to 1.5 parts of antioxidant, and 1.7 parts to 7 parts of lubricant; Wherein, the diluent contains 140 to 260 parts of mannitol and 70 to 140 parts of microcrystalline cellulose.

6. The sladepam pharmaceutical composition according to claim 5, characterized in that: The sladepam pharmaceutical composition comprises the following components in parts by weight: 14.1 parts of sladepam lysine salt dihydrate, 245 parts to 255 parts of mannitol, 70 parts to 75 parts of microcrystalline cellulose, 5 parts to 10 parts of cross-linked sodium carboxymethyl cellulose, 0.1 parts to 0.2 parts of butylated hydroxytoluene, 2 parts to 3 parts of colloidal silicon dioxide, and 4 parts to 5 parts of magnesium stearate.

7. A seladepa pharmaceutical preparation, characterized in that: The invention is prepared from the sladepam pharmaceutical composition according to any one of claims 1 to 6.

8. The sladepam pharmaceutical preparation according to claim 7, characterized in that Its dosage form is capsule or tablet.

9. The sladepam pharmaceutical preparation according to claim 8, characterized in that Its dosage form is capsule.

10. A method for preparing the sladepam pharmaceutical preparation according to claim 9, characterized in that: The steps include: S1, mixing siladepa or its pharmaceutically acceptable salt, a diluent, a disintegrant, a glidant and an antioxidant uniformly to obtain a premixed material; S2, dry granulating the premixed material and granulating the premixed material to obtain granules; S3, mixing the granules and lubricant evenly, and filling the mixture into a capsule shell to obtain a Sladoppa drug preparation.

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