A sulanolone pharmaceutical composition, capsule and preparation method

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically discloses a sulanolone pharmaceutical composition, capsule and preparation method. The present invention uses silicified microcrystalline cellulose and mannitol as diluents, cross-linked sodium carboxymethyl cellulose as a disintegrant, and adds colloidal silicon dioxide as a glidant, and sodium stearyl fumarate as a lubricant, and prepares sulanolone capsules by dry granulation. The prepared sulanolone capsules have a faster dissolution rate, and compared with the reference preparation, the stability is significantly improved during storage, and the dissolution rate is also improved to a certain extent, which helps to increase the absorption and bioavailability of the product, and can achieve a good replacement for the original research product, and the preparation process is simple, the repeatability is good, and it is easy to realize industrial large-scale production, and it has a high value of promotion and application.

Description

Technical Field

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

[0002] Zuranolone is a white to off-white, non-hygroscopic crystalline solid with a molecular formula of C 25 H 35 N3O2, molecular weight is 409.57, chemical name is 1-[(3α,5β)-3-hydroxy-3-methyl-20-oxo-19-norpregnane-21-yl]-1H-pyrazole-4-carbonitrile, and its chemical structure is as follows.

[0003]

[0004] Currently, about 1 in 8 people worldwide suffers from mental illness, among which depression is one of the most common mental illnesses, with about 280 million patients worldwide. At the same time, nearly 2 / 3 of patients with depression cannot get adequate relief from existing treatments. This reflects that mental health problems represented by depression face severe unmet treatment needs. Postpartum depression (PPD) is one of the most common complications during and after pregnancy. PPD can have serious negative effects on women, including severe functional impairment, depression and / or loss of interest in newborns, as well as related depressive symptoms such as loss of appetite, difficulty sleeping, movement disorders, inattention, lack of energy and inferiority.

[0005] Although many antidepressants are available, most of them work mainly by affecting the signaling of monoamine neurotransmitters (such as serotonin, norepinephrine, and dopamine), and it usually takes 2 to 6 weeks to see mood improvements. PPD is most severe in the first month after delivery, so most patients fail to get adequate relief after taking the above-mentioned drugs.

[0006] Shuranolone is an oral neuroactive steroid gamma-aminobutyric acid type A (GABAA) receptor positive allosteric modulator, mainly used to treat major depressive disorder (MDD) and PPD. The GABA system is the main inhibitory signaling pathway in the brain and central nervous system (CNS) and plays an important role in regulating CNS function. Shuranolone targets brain networks responsible for functions such as emotion, arousal, behavior, and cognition. In patients with MDD, it may help to quickly rebalance dysregulated neuronal networks to help restore brain function.

[0007] Related preparations of sulanolone have been launched in the United States in 2023 in the form of hard capsules with a trade name of ZURZUVAE. There are few public documents on sulanolone preparations in the prior art. The fluidity of sulanolone raw materials is poor, and the bulk density of materials is low, which is not conducive to the molding of preparations. At the same time, sulanolone is slightly soluble in ethyl acetate, methanol, and ethanol, and is almost insoluble in water. Due to its poor solubility, the dissolution of the preparation product is low. Therefore, it is necessary to develop a sulanolone pharmaceutical composition to solve the problems of poor fluidity, poor formability, and low solubility of the preparation product during the preparation process. Summary of the invention

[0008] Aiming at the problems of poor material fluidity, poor formability and low product solubility in the preparation process of existing sulanolone preparations, the present invention provides a sulanolone pharmaceutical composition, a capsule and a preparation method.

[0009] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0010] A sulanolone pharmaceutical composition comprising sulanolone, silicified microcrystalline cellulose, a diluent, a glidant, cross-linked sodium carboxymethyl cellulose and a lubricant;

[0011] Wherein, the silicified microcrystalline cellulose is 10% to 20% of the total mass of the sulanolone pharmaceutical composition;

[0012] The cross-linked sodium carboxymethyl cellulose is 3% to 10% of the total mass of the sulanolone pharmaceutical composition;

[0013] The particle size D90 of the sulanolone is 0.2 μm to 40 μm.

[0014] Relative to the prior art, the sulanolone pharmaceutical composition provided by the present invention uses silicified microcrystalline cellulose as a diluent, which has a regular shape and particle form, can be better mixed with sulanolone and other excipients, and improves the fluidity of sulanolone in the preparation process. At the same time, silicified microcrystalline cellulose can adsorb sulanolone molecules on its surface and inside the pores, reducing the contact of active ingredients with external factors (such as oxygen, light and moisture), thereby helping to improve the stability of the drug; furthermore, cross-linked carboxymethyl cellulose sodium is used as a disintegrant, and sulanolone of a specific particle size is selected, which can increase the dissolution rate of sulanolone, and effectively solve the problem of low dissolution of sulanolone preparations. The pharmaceutical composition provided by the present invention can improve the dissolution rate, stability and oral bioavailability of sulanolone preparations, and provide safer and more efficient drugs for the clinical treatment of depression and postpartum depression, with high promotion and application value.

[0015] Furthermore, the diluent is mannitol.

[0016] Mannitol can improve the fluidity of sulanolone in the preparation process, improve the mixing uniformity of sulanolone and excipients, and at the same time, it can also improve the solubility of sulanolone in the medium, thereby increasing the dissolution rate of the drug.

[0017] Furthermore, the lubricant includes sodium stearyl fumarate.

[0018] Sodium stearyl fumarate 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.

[0019] Furthermore, the glidant is colloidal silicon dioxide.

[0020] The preferred glidant is combined with silicified microcrystalline cellulose and mannitol to significantly improve the fluidity of sulanolone during the preparation process and improve the processability of the preparation of sulanolone.

[0021] Furthermore, the average particle size of the silicified microcrystalline cellulose is 50 μm to 200 μm.

[0022] Preferably, the average particle size of the silicified microcrystalline cellulose is 90 μm to 160 μm.

[0023] Furthermore, the particle size D90 of the sulanolone is 2 μm to 20 μm.

[0024] The particle size of silicified microcrystalline cellulose matches that of sulanolone, which can improve the dispersion and uniformity of material mixing during the preparation process, and plays a very important role in ensuring the uniformity and release characteristics of the sulanolone content in the preparation.

[0025] Furthermore, the diluent is 55% to 75% of the total mass of the sulanolone pharmaceutical composition.

[0026] Furthermore, the glidant is 0.5% to 2% of the total mass of the sulanolone pharmaceutical composition.

[0027] The addition amount of the preferred diluent and glidant can increase the dispersion surface area of ​​the API, thereby increasing the dissolution rate of the product.

[0028] Furthermore, the lubricant is 0.5% to 2.5% of the total mass of the sulanolone pharmaceutical composition.

[0029] The present invention also provides a sulanolone capsule, which is prepared from any one of the above-mentioned sulanolone pharmaceutical compositions.

[0030] As a specific embodiment of the present invention, the sulanolone capsule contains 20.0-30.0 mg (single dose) of sulanolone, preferably 25.0 mg.

[0031] As a specific embodiment of the present invention, each sulanolone capsule comprises: sulanolone 20-30 mg, silicified microcrystalline cellulose 25-35 mg, mannitol 100-180 mg, cross-linked sodium carboxymethyl cellulose 5-20 mg, colloidal silicon dioxide 1-5 mg, and sodium stearyl fumarate 1-4 mg.

[0032] The present invention also provides a method for preparing the above-mentioned sulanolone capsule, comprising the following steps:

[0033] S1, mixing sulanolone, silicified microcrystalline cellulose, a diluent, a glidant and cross-linked sodium carboxymethyl cellulose uniformly to obtain a premixed material;

[0034] S2, dry granulating the premixed material to obtain granules;

[0035] S3, mixing the granules and lubricant evenly, and filling the mixture into capsule shells to obtain sulanolone capsules.

[0036] The preparation method of the sulanolone capsule provided by the present invention adopts dry granulation, has a simple preparation process, and the prepared sulanolone capsule has good stability and high solubility, and can achieve a good replacement for the original product.

[0037] As a specific embodiment of the present invention, the capsule shell is a gelatin hard capsule, and the capsule shell contains gelatin, titanium dioxide and iron oxide.

[0038] Furthermore, the sulanolone capsule provided by the present invention is suitable for treating postpartum depression.

[0039] It should be noted that wet granulation can also be adopted in S2 of the present invention.

[0040] The present invention uses silicified microcrystalline cellulose and mannitol as diluents, cross-linked sodium carboxymethyl cellulose as a disintegrant, adds colloidal silicon dioxide as a glidant, and sodium stearyl fumarate as a lubricant, and prepares sulanolide capsules through dry granulation. The prepared sulanolide capsules have a faster dissolution rate, and compared with the reference preparation, the stability is significantly improved during the storage process, and the dissolution rate is also improved to a certain extent, which helps to increase the absorption and bioavailability of the product, and can achieve a good replacement for the original research product. The preparation process is simple, the repeatability is good, and it is easy to realize industrial mass production, and it has a high value of promotion and application. DETAILED DESCRIPTION

[0041] 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.

[0042] In order to better illustrate the present invention, further examples are given below.

[0043] Example 1

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

[0045]

[0046]

[0047] The preparation method of the above-mentioned Shuranolone capsule is as follows:

[0048] S1, adding sulanolone, silicified microcrystalline cellulose, mannitol, colloidal silicon dioxide and cross-linked sodium carboxymethyl cellulose into a mixer, and mixing them evenly to obtain a premixed material;

[0049] S2, dry granulating the premixed material using a dry granulator to obtain granules;

[0050] S3, mixing the granules and sodium stearyl fumarate evenly, and filling the mixture into hollow hard gelatin capsule shells to obtain sulanolone capsules.

[0051] Example 2

[0052] This embodiment provides a sulanolide capsule, and the prescription dosage (single dose) is shown in the following table:

[0053]

[0054] The preparation method of the above-mentioned Shuranolone capsule is as follows:

[0055] S1, adding sulanolone, silicified microcrystalline cellulose, mannitol, colloidal silicon dioxide and cross-linked sodium carboxymethyl cellulose into a mixer, and mixing them evenly to obtain a premixed material;

[0056] S2, dry granulating the premixed material using a dry granulator to obtain granules;

[0057] S3, mixing the granules and sodium stearyl fumarate evenly, and filling the mixture into hollow hard gelatin capsule shells to obtain sulanolone capsules.

[0058] Example 3

[0059] This embodiment provides a sulanolide capsule, and the prescription dosage (single dose) is shown in the following table:

[0060]

[0061] The preparation method of the above-mentioned Shuranolone capsule is as follows:

[0062] S1, adding sulanolone, silicified microcrystalline cellulose, mannitol, colloidal silicon dioxide and cross-linked sodium carboxymethyl cellulose into a mixer, and mixing them evenly to obtain a premixed material;

[0063] S2, dry granulating the premixed material using a dry granulator to obtain granules;

[0064] S3, mixing the granules and sodium stearyl fumarate evenly, and filling the mixture into hollow hard gelatin capsule shells to obtain sulanolone capsules.

[0065] Comparative Example 1

[0066] This comparative example provides a sulanolone capsule, which is different from Example 2 only in that the amount of silicified microcrystalline cellulose in Example 2 is reduced. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0067]

[0068] The sulanolone capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0069] Comparative Example 2

[0070] This comparative example provides a sulanolone capsule, which is different from Example 2 only in that the amount of cross-linked sodium carboxymethyl cellulose in Example 2 is reduced. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0071]

[0072]

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

[0074] Comparative Example 3

[0075] This comparative example provides a sulanolone capsule, which is different from Example 2 only in that the particle size of sulanolone in Example 2 is changed. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0076]

[0077] The sulanolone capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0078] Comparative Example 4

[0079] This comparative example provides a sulanolone capsule, which is different from Example 2 only in that the silicified microcrystalline cellulose in Example 2 is replaced by microcrystalline cellulose. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0080]

[0081] The sulanolone capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0082] Comparative Example 5

[0083] This comparative example provides a sulanolone capsule, which is different from Example 2 only in that the cross-linked carboxymethylcellulose sodium in Example 2 is replaced by cross-linked polyvinylpyrrolidone. The specific prescription dosage (single tablet dosage) is shown in the following table:

[0084]

[0085]

[0086] The sulanolone capsules were prepared in exactly the same manner as in Example 2, which will not be described in detail herein.

[0087] Quality Research

[0088] 1. Dissolution curve

[0089] According to the second method under the fourth part of the "Dissolution and Release Determination Method" of the 2020 edition of the Chinese Pharmacopoeia, the rotation speed was 75r, and the dissolution medium was 900mL of 50mM pH6.8 sodium phosphate buffer containing 0.3% SDS, and the dissolution curve of the sulanolone capsules prepared in Examples 1 to 3 of the present invention and the original product (trade name: ZURZUVAE; specification: 30mg) was investigated. The results are shown in Table 1.

[0090] Table 1 Dissolution curve in 50 mM sodium phosphate buffer at pH 6.8 containing 0.3% SDS

[0091]

[0092] The experimental results show that the products of Examples 1 to 3 have similar dissolution trends to the original product, and their dissolution amounts in 20 minutes are all greater than 80%, solving the problem of low dissolution.

[0093] When the amount of silicified microcrystalline cellulose in Comparative Example 1 is adjusted outside the scope of the present invention, the material formability and hardness during the dry granulation process are poor, and the roller pressure needs to be increased to meet the use requirements. The dissolution curve results of the preparation product show that the dissolution trend of the prepared product is inconsistent with the original research, the 20-minute dissolution amount does not reach more than 80%, and the dissolution performance is poor. The dissolution curve results of Comparative Example 2 show that the product prepared outside the dosage range of the disintegrant of the present invention has a dissolution trend inconsistent with the original research, the 20-minute dissolution amount does not reach more than 80%, and the dissolution performance is poor. The dissolution curve results of Comparative Example 3 show that the product prepared using the raw material outside the particle size range of sulanolone of the present invention has a dissolution trend inconsistent with the original research, the 20-minute dissolution amount does not reach more than 80%, and the dissolution performance is poor. Comparative Examples 4 to 5 adjusted the material types of the auxiliary material silicified microcrystalline cellulose and the disintegrant cross-linked carboxymethyl cellulose sodium, respectively. The dissolution results showed that the dissolution trend after adjusting the auxiliary material types was significantly inconsistent with the original research, and the dissolution amount in 20 minutes did not reach more than 80%, and the dissolution performance was poor.

[0094] By replacing the particle size of the sulanolone raw material in Example 2 of the present invention with other particle sizes, as long as D90 is in the range of 0.2 μm to 40 μm, the dissolution effect equivalent to that of Example 1 or Example 3 can be achieved.

[0095] Powder properties testing

[0096] The angle of repose, bulk density and tap density of the total mixed powder prepared in Examples 1 to 3 of the present invention and S3 in Comparative Example 1 were tested. The results are shown in Table 2.

[0097] Table 2 Test results of powder properties of Examples 1 to 3 and Comparative Example 1

[0098] sample Angle of repose Bulk density (g / mL) Tap density (g / mL) Example 1 36.7 0.47 0.61 Example 2 37.2 0.46 0.60 Example 3 36.8 0.47 0.61 Comparative Example 1 39.5 0.36 0.50

[0099] The bulk density and repose angle test results show that the particles prepared in the embodiment of the present invention have a lower repose angle, increased bulk density and tap density, and better material fluidity. In Comparative Example 1, the amount of silicified microcrystalline cellulose used is lower than the range specified in the present invention, and the prepared particles have a larger repose angle, worse fluidity, and lower bulk density and tap density.

[0100] Stability testing

[0101] The sulanolone capsules prepared in Examples 1 to 3 and the original product were placed without packaging at 60° C. + 75% RH for 30 days, and then the changes in related substances in the samples were detected by HPLC. The results are shown in Table 3.

[0102] Table 3 Test results of related substances in Examples 1 to 3 and original research samples placed at 60°C + 75% RH for 30 days

[0103]

[0104] The experimental results show that the sulanolone capsule product prepared in the embodiment of the present invention and the original product are placed under 60°C + 75% RH conditions for 30 days. The stability of the product prepared in the embodiment of the present invention is significantly improved and is better than the original product, and can be a good substitute for the original product.

[0105] 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 sulanolone pharmaceutical composition, characterized in that: Includes sulanolone, silicified microcrystalline cellulose, diluents, glidants, croscarmellose sodium, and lubricants; Wherein, the silicified microcrystalline cellulose is 10% to 20% of the total mass of the sulanolone pharmaceutical composition; The cross-linked sodium carboxymethyl cellulose is 3% to 10% of the total mass of the sulanolone pharmaceutical composition; The particle size D90 of the sulanolone is 0.2 μm to 40 μm.

2. The sulanolone pharmaceutical composition according to claim 1, wherein the diluent is mannitol; and / or The lubricant comprises sodium stearyl fumarate; and / or The glidant is colloidal silicon dioxide.

3. The sulanolone pharmaceutical composition according to claim 1, characterized in that: The average particle size of the silicified microcrystalline cellulose is 50 μm to 200 μm.

4. The sulanolone pharmaceutical composition according to claim 3, characterized in that: The average particle size of the silicified microcrystalline cellulose is 90 μm to 160 μm.

5. The sulanolone pharmaceutical composition according to claim 1, characterized in that: The particle size D90 of the sulanolone is 2 μm to 20 μm.

6. The sulanolone pharmaceutical composition according to claim 1 or 2, characterized in that: The diluent accounts for 55% to 75% of the total mass of the sulanolone pharmaceutical composition.

7. The sulanolone pharmaceutical composition according to claim 1 or 2, characterized in that: The glidant is 0.5% to 2% of the total mass of the sulanolone pharmaceutical composition.

8. The sulanolone pharmaceutical composition according to claim 1 or 2, characterized in that: The lubricant accounts for 0.5% to 2.5% of the total mass of the sulanolone pharmaceutical composition.

9. A sulanolone capsule, characterized in that: The composition is prepared from the sulanolone pharmaceutical composition according to any one of claims 1 to 8.

10. A method for preparing the sulanolone capsule according to claim 9, characterized in that: The steps include: S1, mixing sulanolone, silicified microcrystalline cellulose, a diluent, a glidant and cross-linked sodium carboxymethyl cellulose uniformly to obtain a premixed material; S2, dry granulating the premixed material to obtain granules; S3, mixing the granules and lubricant evenly, and filling the mixture into capsule shells to obtain sulanolone capsules.

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