WO2024153130A1 - Pharmaceutical composition comprising cyclic compound, preparation method therefor, and use thereof - Google Patents

Abstract

A pharmaceutical composition comprising a cyclic compound, a preparation method therefor, and a use thereof. The pharmaceutical composition comprises: a compound of formula (I), and a stereoisomer or pharmaceutically acceptable salt or solvate thereof; and an adjuvant. The adjuvant comprises a filler and an optional lubricant, wherein the filler is a farinaceous substance. The pharmaceutical composition has the advantages such as simple prescription ingredients, high stability, easy storage, excellent dissolution and disintegration effects, and low costs.

Description

A pharmaceutical composition containing a cyclopentane compound and its preparation method and application

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Chinese patent application No. 2023100593311 filed on January 18, 2023, entitled “A pharmaceutical composition comprising a cyclic compound, a preparation method and an application thereof”, the entire contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to the field of biomedicine technology, and in particular to a pharmaceutical composition comprising a cyclic compound, and a preparation method and application thereof.

Background technique

Depression is a widespread, persistent chronic disease with a lifetime prevalence of approximately 16% worldwide. Although great progress has been made in the development of antidepressants, there are still many clinical needs, such as rapid onset of drug effects, prevention of relapse, and improvement of cognitive impairment in patients with depression. Although there are many drugs on the market for severe depression, only about 30-40% of patients respond to first-line treatment, and these drugs still have no effect or low efficacy on more than 30% of patients.

Patent document WO2020239073A1 discloses a series of compounds having high antidepressant pharmacological activity in vivo, and the general structural formula thereof is shown below:

Among them, specifically disclosed are compounds of formula I:

The compound has a high affinity for 5-HT3 receptors and can act on monoamine transporters/5-hydroxytryptamine receptors at the same time, and has great potential in treating depression. However, there are currently no reports on related preparations with the compound as an active ingredient.

In view of this, the present invention is proposed.

Summary of the invention

The compound of formula I has stable properties and can maintain relatively good stability under conditions such as high temperature, high humidity, and illumination. Although the compound itself is stable, it was found during the preparation research process that the compound is prone to degradation during the preparation process. After in-depth research, it was found that conventionally added excipients (such as microcrystalline cellulose and lactose, etc.) will change its stability and accelerate its degradation. In order to solve the above-mentioned technical problems, the present application provides a pharmaceutical composition containing a therapeutically effective amount of the compound of formula I with simple ingredients and stable quality, and has the desired pharmacological activity and less side effects. The present application also provides a method for preparing the pharmaceutical composition that is feasible in commercial production, and the quality of the prepared pharmaceutical preparation is stable and reliable.

One of the objects of the present invention is to provide a pharmaceutical composition comprising a paracyclic compound.

The second object of the present invention is to provide a method for preparing the pharmaceutical composition.

The third object of the present invention is to provide a pharmaceutical preparation comprising the pharmaceutical composition.

A fourth object of the present invention is to provide an application of the pharmaceutical composition or the pharmaceutical preparation in the preparation of antidepressant drugs.

In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

In a first aspect, the present invention provides a pharmaceutical composition comprising a paracyclic compound, the pharmaceutical composition comprising:

A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof; and,

Excipients;

Wherein, the auxiliary materials include a filler and an optional lubricant, wherein the filler is a starch substance.

The pharmaceutically acceptable salts of the compounds of formula I and their stereoisomers refer to the compounds of formula I or their stereoisomers which are converted into therapeutically active non-toxic salt forms by treating them with appropriate acids, such as hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, nitrate, phosphate or acid phosphate, perchlorate, format, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, maleate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, ascorbate, camphorate or camphorsulfonate, etc. Conversely, the salt form can also be converted into the free base form by treating it with a base.

Solvates of the compounds of formula I and their stereoisomers (including solvates of salts) are, for example, hydrates, alcoholates and the like.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from the hydrochloride of the compound of formula I, One or more of a maleate salt of a compound of formula I and a sulfate salt of a compound of formula I.

The filler of the present invention is a starch material, including starch, modified starch, starch enzymatic hydrolysis and/or hydrolysis products and other starch-related materials.

In some embodiments, the filler is a mixture of one or more selected from starch, pregelatinized starch, dextrin, beta-cyclodextrin; preferably, it is a mixture of one or more selected from starch, pregelatinized starch, dextrin.

The lubricant is an optional component and can be a pharmaceutical excipient known in the art that can play a flow-aiding and anti-adhesive role.

According to some embodiments of the present invention, the auxiliary material includes a starch filler and an optional lubricant, and the auxiliary material does not contain microcrystalline cellulose, lactose, mannitol and (anhydrous) calcium hydrogen phosphate.

In some embodiments, the lubricant is a mixture of one or more selected from magnesium stearate, sodium stearyl fumarate, stearic acid, silicon dioxide, hydrogenated vegetable oil (e.g., hydrogenated castor oil) and talc; preferably a mixture of one or more selected from magnesium stearate, sodium stearyl fumarate, silicon dioxide and talc; more preferably sodium stearyl fumarate, silicon dioxide or talc.

In some embodiments, the pharmaceutical composition comprises, by weight percentage:
0.1% to 20% (e.g.
1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 16%, 18%),
Filler 77%～99.8% (e.g.
80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%),
Lubricant 0.1% to 3% (e.g.
0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%).

In some embodiments, the pharmaceutical composition comprises, by weight percentage:
The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or solvate 0.1% to 10%,
Filler 88%～99.7%,
Lubricant 0.2%～2%.

In a specific embodiment, the pharmaceutical composition comprises, by weight percentage:
The hydrochloride of the compound of formula I 0.1% to 10%,
Dextrin 88%～99.7%,
Magnesium stearate 0.2%～2%.

In a specific embodiment, the pharmaceutical composition comprises, by weight percentage:
The hydrochloride of the compound of formula I 0.1% to 10%,
Pregelatinized starch 88%～99.7%,
Magnesium stearate/silicon dioxide/hydrogenated castor oil/talc 0.2%～2%.

In a specific embodiment, the pharmaceutical composition comprises, by weight percentage:
The hydrochloride of the compound of formula I 0.1% to 10%,
Pregelatinized starch 88%～99.7%,
Sodium stearyl fumarate 0.2% to 2%, preferably 0.2% to 1%.

According to the invention, the auxiliary materials may optionally include complexing agents (metal ion chelators) in addition to fillers and optional lubricants.

According to the present invention, the auxiliary material may consist of a filler, an optional lubricant and an optional complexing agent.

In some embodiments, the auxiliary material further includes a complexing agent, such as EDTA-2Na, for example, in terms of weight percentage, 0.1% to 5% of the complexing agent may be included. The complexing agent may complex potential iron ions in the material to improve stability.

In a specific embodiment, the pharmaceutical composition comprises, by weight percentage:

In some embodiments, the pharmaceutical composition comprises, by weight percentage:
The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or solvate 0.1% to 10%,
Filler 90%～99.9%.

In a specific embodiment, the pharmaceutical composition comprises, by weight percentage:
The hydrochloride of the compound of formula I 0.1% to 10%,
Pregelatinized starch 90%～99.9%.

In the present invention, unless otherwise specified, the percentage of each component mentioned above is based on the total weight of the composition.

In a second aspect, the present invention provides a method for preparing the pharmaceutical composition, the method comprising: wet granulation, dry granulation or direct mixing process; preferably, the method is a direct mixing process; the specific process steps of the direct mixing process include: screening the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or its solvate and the required excipients, mixing the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or its solvate with the required excipients, and preparing the obtained mixture by tableting or capsule filling.

In a third aspect, the present invention provides a pharmaceutical preparation, particularly an oral solid preparation, comprising the above pharmaceutical composition.

In some embodiments, the oral solid preparation is a tablet, a granule, and a capsule, preferably a granule and a capsule.

In a fourth aspect, the present invention provides a use of the pharmaceutical composition or pharmaceutical preparation in the preparation of an antidepressant drug.

Beneficial effects:

The present application innovatively provides a pharmaceutical composition with a compound of formula I as an active ingredient. The pharmaceutical composition not only has a simple prescription composition and does not contain conventionally added microcrystalline cellulose, lactose, mannitol and (anhydrous) calcium hydrogen phosphate, but also has the advantages of high stability, easy storage, excellent dissolution and disintegration effects and low cost, and a simple preparation process, which is conducive to large-scale production.

The present invention has been described in detail above, but the above embodiments are only illustrative in nature and are not intended to limit the present invention. In addition, this article is not limited by any theory described in the above prior art or invention content or the following examples.

Unless otherwise expressly stated, the numerical ranges throughout the application documents include any subranges therein and any numerical values incremented by the smallest subunit of a given value therein. Unless otherwise expressly stated, the numerical values throughout the application documents represent approximate measurements or limitations of the range of embodiments including slight deviations from the given values and having approximately the values mentioned and having the exact values mentioned. Except for the working examples provided at the end of the detailed description, all numerical values of parameters (e.g., quantities or conditions) in this application document (including the appended claims) should be understood in all cases as modified by the term "approximately", regardless of whether "approximately" actually appears before the numerical value. "Approximately" means that the numerical value described allows for slight imprecision (some close to precision in the value; approximately or reasonably close to the value; approximately). If the imprecision provided by "approximately" is not understood in this ordinary sense in the art, the "approximately" used herein at least represents the variation that can be produced by ordinary methods of measuring and using these parameters. For example, "approximately" can include a variation of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1% or less than or equal to 0.5%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a dissolution curve of each salt capsule of the compound of formula I in Examples 8-12 in a dissolution medium of pH 4.5.

Detailed ways

The present invention is further described below in conjunction with examples. It should be noted that the following examples are provided for illustrative purposes only and do not constitute a limitation on the scope of protection claimed for the present invention.

Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, methods in the art.

The compound of formula I is prepared according to the method of Example 2 in WO2020239073A1 patent.

The hydrochloride of the compound of formula I is prepared by the following method: 0.5 g of the compound of formula I (free base) is added to acetonitrile (5 mL), heated and stirred to dissolve. Concentrated hydrochloric acid (1.0 eq) is added, and stirred at 50±5°C for half an hour, a large amount of solid is precipitated, and stirring is continued for 1 hour, then the temperature is lowered to 10±5°C and stirred for 1 hour, filtered, the filter cake is collected, and dried at 55±5°C under normal pressure to obtain the product.

The sulfate of the compound of formula I is prepared by the following method: add anhydrous ethanol (5 ml) to 0.5 g of the compound of formula I (free base), stir and dissolve at elevated temperature, add concentrated sulfuric acid (1.1 eq), stir at 50±5°C for half an hour, a large amount of solid precipitates, continue stirring at 50±5°C for 1 hour, cool to 10±5°C and stir for 1 hour, filter, collect the filter cake, and dry at 55±5°C at normal pressure to obtain the obtained product.

The maleate salt of the compound of formula I is prepared by the following method: add anhydrous ethanol (5 ml) to 0.5 g of the compound of formula I (free base), stir and dissolve at elevated temperature, add maleic acid (1.2 eq), stir at 50±5°C for half an hour, a large amount of solid precipitates, continue stirring at 50±5°C for 1 hour, cool to 10±5°C and stir for 1 hour, filter, collect the filter cake, and dry at 55±5°C at normal pressure to obtain the product.

Pregelatinized starch came from Colorcon (Shanghai) Trading Co., Ltd., batch number IN543543; dextrin came from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number 201220; magnesium stearate came from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number 200404; sodium stearyl fumarate came from Shengda Chemical Pharmaceutical Co., Ltd. (Taiwan), batch number S96-0094.

Example

Example 1

Table 1 Example 1 Formula

Capsules containing the compound of formula I were prepared according to the formulation composition in Table 1 and the following preparation steps:

1) Preparation of raw materials and auxiliary materials: all raw materials and auxiliary materials are weighed according to the theoretical amount, the hydrochloride of the compound of formula I is sieved through a 60-mesh sieve, and the auxiliary materials are sieved through a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: Add the hydrochloride of the compound of formula I and dextrin into a mixer and mix for 20 minutes, then add magnesium stearate and mix for 1 minute;

3) Capsule filling: Use No. 4 capsules to fill according to the theoretical filling amount (100 mg).

Embodiments 2 to 6

Table 2 Examples 2 to 6 formulations (unit: mg)

Note: N/A means no such item.

Capsules containing the compound of formula I were prepared according to the formulation composition in Table 2 and the following preparation steps:

1) Preparation of raw materials and auxiliary materials: all raw materials and auxiliary materials are weighed according to the theoretical amount (the amount of each raw material and auxiliary material in the above table), the hydrochloride of the raw material formula I compound is sieved through a 60-mesh sieve, and the auxiliary materials are sieved through a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: Add the hydrochloride of the compound of formula I and pregelatinized starch into a mixer and mix for 20 minutes, then add magnesium stearate/silicon dioxide/talc/hydrogenated castor oil and mix for 1 minute;

3) Capsule filling: Use No. 4 capsules to fill according to the theoretical capacity.

Examples 7 to 12

Table 3 Examples 7 to 12 Formulations

Table 3 shows the formula of the compound composition of formula I with different composition ratios. The capsule containing the compound composition of formula I is prepared according to the formula composition in Table 3 and the following preparation steps:

1) Preparation of raw materials and auxiliary materials: All raw materials and auxiliary materials are weighed according to the theoretical amount, the hydrochloride and maleate of the raw material compound of formula I are sieved through a 60-mesh sieve, and the auxiliary materials are sieved through a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: Add the hydrochloride or maleate of the compound of formula I and pregelatinized starch into a mixer and mix for 20 minutes, then add sodium stearyl fumarate and mix for 1 minute;

3) Capsule filling: Use No. 4 capsules to fill according to the theoretical capacity.

Embodiments 13 to 16

Table 4 Examples 13 to 16 formulations

*Note: The amount of the compound of formula I is converted according to the molecular weight of different salt forms to contain an equal amount of free base.

Table 4 shows the composition formula of different salt forms of the compound of formula I. The composition particles containing the compound of formula I are prepared according to the composition in Table 4 and the following preparation steps:

1) Preparation of raw materials and auxiliary materials: all raw materials and auxiliary materials are weighed according to the theoretical amount, the raw material (the compound of formula I or its salt) is passed through a 60-mesh sieve, and the auxiliary materials (except EDTA-2Na) are passed through a 20-mesh sieve;

2) Preparation of wetting agent: Add the formulated amount of EDTA-2Na into an appropriate amount of purified water and stir until completely dissolved;

3) Wet granulation: Add the salt or free base of the compound of formula I and pregelatinized starch into a wet granulator, and slowly add EDTA-2Na aqueous solution under stirring to granulate;

4) Drying: Add the wet granules into a fluidized bed and dry them until the loss on drying is less than 7%;

5) Granulation: The dried granules are granulated by a 1.5 mm sieve crusher;

6) Mixing: Add sodium stearyl fumarate to the dry granules after granulation and mix for 1 minute.

Embodiment 17

Table 5 Example 17 formulation

Note: N/A means no such item.

The raw materials and auxiliary materials were weighed according to the amounts shown in Table 5. The hydrochloride of the compound of formula I was passed through a 60-mesh sieve and mixed evenly with the pregelatinized starch.

Comparative Examples 1 to 3

Table 6 Comparative Examples 1 to 3 Formulations

Note: N/A means no such item.

Tablets containing the hydrochloride salt of the compound of formula I were prepared according to the formulation composition in Table 6 and the following preparation steps:

1) Preparation of raw materials and auxiliary materials: all raw materials and auxiliary materials are weighed according to the theoretical amount, the raw material hydrochloride of the compound of formula I is sieved through a 60-mesh sieve, and the auxiliary materials are sieved through a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: Add the hydrochloride of the compound of formula I and lactose monohydrate or microcrystalline cellulose into a mixer and mix for 20 minutes, then add magnesium stearate or sodium stearyl fumarate and mix for 1 minute;

3) Tableting: The obtained mixture is compressed into tablets according to the theoretical tablet weight.

Comparative Example 4

Table 7 Comparative Example 4 Formula

Note: Purified water is the wetting agent for wet granulation and is removed during the drying process. It is not included in the single dose.

Tablets containing the hydrochloride salt of the compound of formula I were prepared according to the formulation composition in Table 7 and the following preparation steps:

1) Preparation of raw materials and auxiliary materials: all raw materials and auxiliary materials are weighed according to the theoretical amount, the raw material hydrochloride of the compound of formula I is sieved through a 60-mesh sieve, and the auxiliary materials are sieved through a 20-mesh sieve;

2) Preparation of adhesive: Add the formulated amount of pregelatinized starch to an appropriate amount of purified water and stir thoroughly until evenly dispersed;

3) Wet granulation: Add the hydrochloride of the compound of formula I, lactose monohydrate and microcrystalline cellulose into a wet granulator, and slowly add the pregelatinized starch suspension to granulate under stirring;

4) Drying: Add the wet granules into a fluidized bed and dry them until the loss on drying is less than 7%;

5) Granulation: The dried granules are granulated by a 1.5 mm sieve crusher;

6) Mixing: Add magnesium stearate to the dry granules after granulation and mix for 1 minute;

7) Tableting: The obtained mixture is compressed into tablets according to theoretical tablet weight.

Comparative Example 5

Table 8 Comparative Example 5 Formula

The raw materials and auxiliary materials were weighed according to the amounts shown in Table 8. The hydrochloride of the compound of formula I was passed through a 60-mesh sieve and mixed evenly with anhydrous calcium hydrogen phosphate.

Experiment 1: Stability test

1. The samples of Examples 1-6 and Comparative Examples 1-3 (without any packaging, only spread flat in a weighing bottle) were placed under accelerated test conditions (40±2°C/RH75±5.0%), and samples were taken at 0 days, 2 days, 1 week and 2 weeks respectively to investigate the changes in related substances. Since the related substances in Comparative Examples 1, 2 and 3 increased too fast, only samples for 2 days were tested. The results of related substance detection are shown in Table 10.

2. The samples of Examples 3, 7-9 and Comparative Examples 3 and 4 (without any packaging, just spread flat in a weighing bottle) were placed under high temperature (60°C), high humidity (RH 92.5%) and light (5000 lux, 90 μw/cm ² ) test conditions, and samples were taken on day 0 and day 10 to examine the changes in related substances. The test results are shown in Table 11.

3. The samples of Examples 10-16 and Comparative Example 4 (double aluminum packaging) were placed under test conditions of 40±2°C/RH75±5.0%, and samples were taken at 0 day, 1 month, 2 months and 3 months respectively to examine the changes in related substances. Since the related substances in Comparative Example 4 increased too fast, only samples for 1 month were tested. The results of related substance detection are shown in Table 12.

4. The samples of Example 17 and Comparative Example 5 (without any packaging, just spread flat in a weighing bottle) were placed under high temperature (60°C) conditions, and samples were taken at 0 day, 1 week, and 2 weeks respectively to examine the changes in related substances. The test results are shown in Table 13.

5. Related substances detection methods

Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Use phenylsilane bonded silica gel as filler (Waters XSelect CSH Phenyl-Hexyl, 4.6mm×150mm, 3.5μm or chromatographic column with equivalent performance); use 0.01mol/L potassium dihydrogen phosphate solution (take 1.36g of potassium dihydrogen phosphate, add 1L of water to dissolve, and adjust the pH value to 2.5 with phosphoric acid) as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to Table 9; the detection wavelength is 230nm; the flow rate is 1.0ml per minute; the column temperature is 35℃; accurately measure 20μl of each of the reference solution, test solution and blank excipient solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

Table 9 Fluidity Gradient Elution

Table 10 Stability test results of Examples 1-6 and Comparative Examples 1-3

Table 11 Stability test results of Examples 3, 7-9 and Comparative Examples 3 and 4

Note: The illumination conditions are 5000 lux, 90 μw/cm ² .

Table 12 Stability test results of Examples 10 to 16 and Comparative Example 4

Table 13 Stability test results of Example 17 and Comparative Example 5

Experiment 2 Disintegration and dissolution test

1) Disintegration test method

According to the disintegration time limit test method of Part IV of the Chinese Pharmacopoeia <0921>, a lifting disintegrator is used, with a 1000ml beaker. The position of the hanging basket is adjusted so that when it drops to the lowest point, the screen is 25mm from the bottom of the beaker. The beaker is filled with water at a temperature of 37℃±1℃. The water level is adjusted so that when the hanging basket rises to the highest point, the screen is 15mm below the water surface. The top of the hanging basket cannot be submerged in the solution. Take 6 test samples and put them into the glass tubes of the above hanging baskets respectively. Add baffles in the tubes (to prevent floating), and start the disintegrator for inspection.

2) Dissolution test method

According to the second method (paddle method) of the dissolution and release rate determination method of the fourth volume of the Chinese Pharmacopoeia <0931>, the speed was set to 50rpm, the sampling time points were 10min, 15min, 30min and 45min, the circulation volume was 10ml, and the sampling volume was 1ml. 900ml of dissolution medium was measured and put into each dissolution cup. After the temperature of the dissolution medium was constant at 37℃±0.5℃, 6 pellets of the test sample (placed in a dry sinker basket) were taken and put into 6 dissolution cups respectively, and the dissolution instrument was immediately started. Samples were taken at the specified sampling time points, and the dissolution solution was filtered through a 45μm PES filter membrane and detected by HPLC.

Determine according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512), use octadecylsilane bonded silica gel as filler (Agilent ZORBAX SB-C18, 4.6mm×150mm, 3.5μm or chromatographic column with equivalent performance); 0.05% phosphoric acid solution-acetonitrile as mobile phase (70:30); detection wavelength is 248nm; flow rate is 1.0ml per minute; column temperature is 35℃; sample plate temperature is controlled at 10℃ (only 0.1mg specification); isocratic elution is 6 minutes. Accurately measure 10μl of the reference solution and the test solution (100μl for 0.1mg specification) and inject them into the liquid chromatograph to record the chromatogram. Reference solution The relative standard deviation of the peak area of 5 consecutive injections of the solution should not be greater than 2.0%. The cumulative dissolution amount of each tablet at each time point was calculated by the external standard method using the peak area. The results are shown in Table 14 and Figure 1.

Table 14 Dissolution and disintegration time test results of the compound of formula I capsule

Result analysis:

1) From the test results in Table 10, it can be seen that when the unpackaged samples were placed under the test conditions of 40±2℃/RH75±5.0% for 2 weeks, the growth amount of related substances in Examples 1-6 (with pregelatinized starch, dextrin filler, magnesium stearate, silicon dioxide, talcum powder or hydrogenated castor oil as lubricant) was less than 1%; the samples of Comparative Example 1 (with lactose monohydrate as filler), Comparative Example 2 (with microcrystalline cellulose as filler) and Comparative Example 3 (with microcrystalline cellulose as filler) were placed under the same conditions for 2 days, and the growth amount of related substances exceeded 26%. It can be seen that compared with Comparative Examples 1-3, Examples 1-6 have significant stability advantages, indicating that when starchy substances (gelatinized starch, dextrin, etc.) are used as fillers, the product stability is significantly better than that of lactose, microcrystalline cellulose, etc. as fillers; there is no significant difference in the influence of different lubricants (magnesium stearate, silicon dioxide, talcum powder or hydrogenated castor oil) on product stability. From the test results in Table 13, it can be seen that the compatibility of pregelatinized starch with the raw material drug (Example 17) is significantly better than the compatibility of anhydrous calcium hydrogen phosphate with the raw material drug (Comparative Example 5).

2) From the test results in Table 11, it can be seen that when the unpackaged samples were placed under high temperature (60°C), high humidity (RH 92.5%) or light (5000lux, 90μw/ ^cm2 ) conditions for 10 days, the growth amount of related substances in Example 3 (different lubricants from Example 8) and Examples 7-9 (different formula ratios of compounds of Formula I) was less than 0.5%; under the same conditions, the growth amounts of related substances in Comparative Example 3 (using microcrystalline cellulose as filler) were 4.25%, 12.78% and 28.72% respectively; the growth amounts of related substances in Comparative Example 4 (using lactose monohydrate and microcrystalline cellulose as fillers and pregelatinized starch as binder) were 3.84%, 11.35% and 27.11% respectively. It can be seen that compared with Comparative Examples 3 and 4, Examples 3 and Examples 7-9 have significant stability advantages, indicating that the stability of the product using pregelatinized starch as filler is better than that using lactose and microcrystalline cellulose as fillers.

3) From the test results in Table 12, it can be seen that the aluminum bag packaging samples were placed under the test conditions of 40±2℃/RH75±5.0% for 3 months, and the growth amount of related substances in Examples 10 to 16 (compounds of formula I in different salt forms) was less than 0.5%; under the same conditions, The growth amount of related substances in Comparative Example 4 has reached 29.89% in one month. It can be seen that compared with Comparative Example 4, Examples 10 to 16 have significant stability advantages. It shows that there is no significant difference in the stability of the compound of formula I in different salt forms investigated, and the stability of the product with pregelatinized starch as a filler is better than that with lactose and microcrystalline cellulose as fillers.

4) In addition to stability, it can be seen from the data in Table 14 that the preparation of the compound of formula I of the present invention also has good solubility and disintegration, which can effectively meet clinical use.

The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may be modified, or some or all of the technical features thereof may be replaced by equivalents, without departing from the spirit and essence of the claims of the present invention; and these modifications or replacements are still within the scope defined by the claims of the present invention.

Claims (10)

A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof; and, Excipients;
Wherein, the auxiliary materials include a filler and an optional lubricant, wherein the filler is a starch substance. The pharmaceutical composition according to claim 1, characterized in that the filler is one or more selected from starch, pregelatinized starch, dextrin and beta-cyclodextrin. The pharmaceutical composition according to claim 1, characterized in that the lubricant is one or more selected from magnesium stearate, sodium stearyl fumarate, stearic acid, silicon dioxide, hydrogenated vegetable oil and talc; Preferably, the lubricant is one or more selected from sodium stearyl fumarate, silicon dioxide, magnesium stearate and talc. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, in terms of weight percentage, the pharmaceutical composition comprises:
The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or solvate thereof 0.1% to 20%,
Filler 77%～99.8%,
Lubricant 0.1%～3%; Preferably, in terms of weight percentage, the pharmaceutical composition comprises:
The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or solvate 0.1% to 10%,
Filler 88%～99.7%,
Lubricant 0.2%～2%. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the excipient further comprises EDTA-2Na. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the pharmaceutically acceptable salt of the compound of formula I is one or more selected from the group consisting of the hydrochloride of the compound of formula I, the maleate of the compound of formula I and the sulfate of the compound of formula I. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that the method is wet granulation, dry granulation or direct mixing; preferably the method is direct mixing. The method according to claim 7, characterized in that it comprises the following steps: 1) sieving the compound of formula I, its stereoisomer or pharmaceutically acceptable salt or solvate thereof and the auxiliary materials; 2) The compound of formula I, its stereoisomer or pharmaceutically acceptable salt or solvate thereof is mixed with the auxiliary materials, and the obtained mixture is prepared by tableting or capsule filling. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 6; Preferably, the pharmaceutical preparation is an oral solid preparation; More preferably, the oral solid preparation is a tablet, a granule or a capsule; Particularly preferably, the oral solid preparation is a capsule or a granule. Use of the pharmaceutical composition according to any one of claims 1 to 6 or the pharmaceutical preparation according to claim 9 in the preparation of an antidepressant drug.