CN118356426A

CN118356426A - Pharmaceutical composition containing fused ring compound and preparation method and application thereof

Info

Publication number: CN118356426A
Application number: CN202410069923.6A
Authority: CN
Inventors: 杨汝磊; 田军峰; 李亚雷; 石松安; 田广辉; 沈敬山
Original assignee: Wangshan Wangshui Lianyungang Pharmaceutical Co ltd; Suzhou Wangshan Wangshui Biopharmaceutical Co ltd
Current assignee: Wangshan Wangshui Lianyungang Pharmaceutical Co ltd; Suzhou Wangshan Wangshui Biopharmaceutical Co ltd
Priority date: 2023-01-18
Filing date: 2024-01-17
Publication date: 2024-07-19
Also published as: WO2024153130A1

Abstract

The invention relates to a pharmaceutical composition containing a fused ring compound, a preparation method and application thereof. The pharmaceutical composition comprises: a compound of formula i, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof; and, an auxiliary material; wherein the auxiliary materials comprise a filler and an optional lubricant, and the filler is starch substances. The pharmaceutical composition has the advantages of simple prescription components, high stability, easy storage, good dissolution and disintegration effects, low cost and the like.

Description

Pharmaceutical composition containing fused ring compound and preparation method and application thereof

Cross Reference to Related Applications

The present application claims priority from chinese patent application No. 2023100593311 filed 1/18 in 2023, entitled "pharmaceutical composition comprising a bicyclic compound, and methods of preparing and using the same", the entire contents of which are incorporated herein by reference.

Technical Field

The invention relates to the technical field of biological medicine, in particular to a pharmaceutical composition containing a fused ring compound, and a preparation method and application thereof.

Background

Depression is a widespread, sustained onset chronic disease with a lifetime prevalence of about 16% worldwide. Despite the great progress in the development of antidepressants, there are many clinical needs such as rapid onset of drug action, prevention of recurrence, improvement of cognitive impairment in patients with depression, etc. Despite the market for a few drugs in the area of major depression, only about 30-40% of patients respond to first line therapy, and these drugs remain ineffective or poorly effective in more than 30% of patients.

Patent document WO2020239073A1 discloses a series of compounds having very high antidepressant pharmacological activity in vivo, the structural general formula of which is shown as follows:

Wherein, specifically disclosed are compounds of formula I:

The compound has high affinity to 5-HT3 receptor, can act on monoamine transporter/5-hydroxytryptamine receptor, and has great potential in treating depression. However, there is no report on the related preparation containing the compound as an active ingredient.

In view of this, the present invention has been made.

Disclosure of Invention

The compound of the formula I has stable property and can keep better stability under the conditions of high temperature, high humidity, illumination and the like. Although the compound itself is stable, it was found during formulation studies that the compound is susceptible to degradation during formulation. After intensive studies, it was found that conventionally added excipients (e.g., microcrystalline cellulose, lactose, etc.) change their stability and accelerate their degradation. In order to solve the above-mentioned problems, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, which is simple in composition and stable in quality, and has desired pharmacological activity and few side effects. The application also provides a commercially feasible method for preparing the pharmaceutical composition, and the prepared pharmaceutical preparation has stable and reliable quality.

It is an object of the present invention to provide a pharmaceutical composition comprising a fused ring compound.

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

It is a further object of the present invention to provide a pharmaceutical formulation comprising the pharmaceutical composition.

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

In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:

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

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

An auxiliary material;

Wherein the auxiliary materials comprise a filler and an optional lubricant, and the filler is starch substances.

Pharmaceutically acceptable salts of the compounds of formula I and stereoisomers thereof mean that the compounds of formula I or stereoisomers thereof are converted into the therapeutically active, non-toxic salt forms by treatment with a suitable acid. Such as hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, nitrate, phosphate or acid phosphate, perchlorate, formate, 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, camphordate or camphorsulfonate, and the like. Conversely, the salt form may also be converted to the free base form by treatment with a base.

Solvates (including salt solvates) of the compounds of formula I and stereoisomers thereof are for example hydrates, alkoxides and the like.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula i is one or more selected from the group consisting of hydrochloride, maleate, and sulfate salts of the compound of formula i.

The filler is starch substance, including starch, modified starch, starch enzymolysis and/or hydrolysis products and other starch related substances.

In some embodiments, the filler is a mixture of one or more selected from the group consisting of starch, pregelatinized starch, dextrin, and betacyclodextrin; preferably 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 to play a role in glidant and anti-adhesive.

According to some embodiments of the invention, the auxiliary material comprises a starch-based filler and optionally a lubricant, and the auxiliary material does not comprise microcrystalline cellulose, lactose, mannitol, calcium (anhydrous) hydrogen phosphate, and the like.

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 of magnesium stearate, sodium stearyl fumarate, silicon dioxide and talc; more preferably sodium stearyl fumarate, silica or talc.

In some embodiments, the pharmaceutical composition comprises, in weight percent:

a compound of formula i, a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, from 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%),

0.1% -3% (E.g., 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%) of lubricant.

0.1 to 10 percent of compound of formula I, stereoisomer or pharmaceutically acceptable salt or solvate thereof,

88 To 99.7 percent of filling agent,

0.2 To 2 percent of lubricant.

In a specific embodiment, the pharmaceutical composition comprises, in weight percent:

0.1 to 10 percent of hydrochloride of the compound of the formula I,

88 To 99.7 percent of dextrin,

0.2 To 2 percent of magnesium stearate.

0.1 to 10 percent of hydrochloride of the compound of the formula I,

88 To 99.7 percent of pregelatinized starch,

0.2 To 2 percent of magnesium stearate/silicon dioxide/hydrogenated castor oil/talcum powder.

0.1 to 10 percent of hydrochloride of the compound of the formula I,

88 To 99.7 percent of pregelatinized starch,

Sodium stearyl fumarate 0.2-2%, preferably 0.2-1%.

According to the invention, the auxiliary material may optionally comprise, in addition to the filler and optionally the lubricant, a complexing agent (metal ion chelating agent).

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

In some embodiments, the adjunct further includes a complexing agent, such as EDTA-2Na, for example, can comprise 0.1% to 5% complexing agent by weight percent. The complexing agent can complex potential iron ions in the material, so that the stability is improved.

90 To 99.9 percent of filler.

0.1 to 10 percent of hydrochloride of the compound of the formula I,

90 To 99.9 percent of pregelatinized starch.

In the present invention, the percentages of the above components are percentages based on the total weight of the composition unless otherwise specified.

In a second aspect, the present invention provides a method for preparing the pharmaceutical composition, the method comprising: wet granulating, dry granulating or direct mixing; preferably, the preparation method is a direct mixing process; the specific process steps of the direct mixing process comprise: the compound of the formula I, the stereoisomer or the pharmaceutically acceptable salt or the solvate thereof and the required auxiliary materials are sieved, the compound of the formula I, the stereoisomer or the pharmaceutically acceptable salt or the solvate thereof and the required auxiliary materials are mixed, and the obtained mixture is prepared by tabletting or capsule filling.

In a third aspect, the present invention provides a pharmaceutical formulation, in particular an oral solid formulation, comprising the pharmaceutical composition described above.

In some embodiments, the oral solid formulations are tablets, granules and capsules, preferably granules and capsules.

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

The beneficial effects are that:

the application innovatively provides a pharmaceutical composition taking a compound shown in the formula I as an active ingredient, which has the advantages of simple prescription ingredients, no microcrystalline cellulose, lactose, mannitol, calcium hydrophosphate and the like which are added conventionally, high stability, easy storage, excellent dissolution and disintegration effects, low cost, simple preparation process, and the like, and is beneficial to amplified production.

The present invention has been described in detail hereinabove, but the above embodiments are merely exemplary in nature and are not intended to limit the present invention. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or summary or the following examples.

Unless explicitly stated otherwise, numerical ranges throughout this application include any subrange therein and any numerical value incremented by the smallest subunit in which a given value is present. Unless explicitly stated otherwise, numerical values throughout this application represent approximate measures or limits to include minor deviations from the given value and ranges of embodiments having about the stated value and having the exact value noted. Except in the operating examples provided last, all numerical values of parameters (e.g., amounts or conditions) in this document (including the appended claims) should be construed in all cases as modified by the term "about" whether or not "about" actually appears before the numerical value. "about" means that the recited value allows for slight imprecision (with some approximation to the exact value; approximately or reasonably close to the value; approximated). "about" as used herein at least means variations that can be produced by ordinary methods of measuring and using these parameters if the imprecision provided by "about" is not otherwise understood in the art with this ordinary meaning. For example, "about" may include a change 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%.

Drawings

FIG. 1 shows the dissolution profile of the respective salt capsules of the compounds of formula I of examples 8-12 in a dissolution medium at pH 4.5.

Detailed Description

The invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention as claimed.

Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.

The compounds of formula I are prepared by the method described in example 2 of the WO2020239073A1 patent.

The hydrochloride of the compound of the formula I is prepared by the following method: 0.5g of the compound of formula I (free base) was added to acetonitrile (5 mL), and the mixture was dissolved by heating and stirring. Adding concentrated hydrochloric acid (1.0 eq), stirring at 50+ -5deg.C for half an hour, precipitating a large amount of solid, stirring for 1 hr, cooling to 10+ -5deg.C, stirring for 1 hr, filtering, collecting filter cake, and oven drying at normal pressure 55+ -5deg.C.

The sulfate of the compound of the formula I is prepared by the following method: to 0.5g of the compound of formula I (free base) was added absolute ethanol (5 ml), and the mixture was warmed and dissolved. Adding concentrated sulfuric acid (1.1 eq), stirring at 50+ -5deg.C for half an hour, precipitating a large amount of solid, continuing stirring at 50+ -5deg.C for 1 hour, cooling to 10+ -5deg.C, stirring for 1 hour, filtering, collecting filter cake, and oven drying at normal pressure 55+ -5deg.C.

The maleate salt of the compound of the formula I is prepared by the following method: to 0.5g of the compound of formula I (free base) was added absolute ethanol (5 ml), and the mixture was warmed and dissolved. Maleic acid (1.2 eq) is added, stirring is carried out for half an hour at 50+/-5 ℃ and a large amount of solid is precipitated, stirring is continued for 1 hour at 50+/-5 ℃, cooling is carried out to 10+/-5 ℃ and stirring is carried out for 1 hour, filtering is carried out, filter cakes are collected, and the products are obtained by drying at the normal pressure of 55+/-5 ℃.

Pregelatinized starch is available from calek (Shanghai) trade company, lot number IN543543; the dextrin is from Anhui mountain river pharmaceutic adjuvant Co., ltd, and the batch number is 201220; magnesium stearate comes from Anhui mountain river pharmaceutic adjuvant Co., ltd, batch number 200404; sodium stearyl fumarate was obtained from the company Mida chemical pharmaceutical Co., ltd (Taiwan) under the lot number S96-0094.

Examples

Example 1

Table 1 example 1 formulation

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

1) Preparing raw materials and auxiliary materials: weighing all raw materials and auxiliary materials according to the theoretical amount, sieving the hydrochloride of the compound shown in the formula I by a 60-mesh sieve, and sieving the auxiliary materials by a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: adding the compound hydrochloride of the formula I and dextrin into a mixer, mixing for 20min, and adding magnesium stearate and mixing for 1min;

3) Filling the capsule: the capsule No. 4 was filled in a theoretical amount (100 mg).

Examples 2 to 6

Table 2 examples 2-6 formulations (unit mg)

Note that: N/A indicates that there is no such item.

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

1) Preparing raw materials and auxiliary materials: weighing all raw materials and auxiliary materials according to theoretical dosage (the dosage corresponding to each raw material and auxiliary material in the table above), sieving the raw material compound hydrochloride with a 60-mesh sieve, and sieving the auxiliary materials with a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: adding the compound hydrochloride of the formula I and pregelatinized starch into a mixer, mixing for 20min, and adding magnesium stearate/silicon dioxide/talcum powder/hydrogenated castor oil, mixing for 1min;

3) Filling the capsule: and filling the medicine with a No. 4 capsule according to the theoretical filling amount.

Examples 7 to 12

Table 3 examples 7 to 12 formulations

Table 3 is a formulation of the compound of formula I in different composition ratios, and capsules containing the compound of formula I were made according to the formulation composition in table 3 and the following preparation steps:

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

2) Mixing raw materials and auxiliary materials: adding the compound hydrochloride or maleate of the formula I and pregelatinized starch into a mixer, mixing for 20min, and adding sodium stearyl fumarate, mixing for 1min;

Examples 13 to 16

Table 4 examples 13 to 16 formulations

* And (3) injection: the amount of the compound of formula I is reduced according to the molecular weight of the different salt forms so as to contain an equivalent amount of the free base.

Table 4 is a formulation of different salt forms of the compounds of formula I, and particles of the compositions containing the compounds of formula I were prepared according to the formulation composition in table 4 and following preparation steps:

1) Preparing raw materials and auxiliary materials: weighing all raw materials according to the theoretical dosage, sieving the raw materials (the compound of the formula I or the salt thereof) with a 60-mesh sieve, and sieving the auxiliary materials (except EDTA-2 Na) with a 20-mesh sieve;

2) Preparing a wetting agent: adding EDTA-2Na with a formula amount into a proper amount of purified water, and stirring until the EDTA-2Na is completely dissolved;

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

4) And (3) drying: adding the wet particles into a fluidized bed for drying until the drying weight loss is less than 7%;

5) Finishing: granulating the dried granules by a crushing granulator with a screen of 1.5 mm;

6) Mixing: adding sodium stearyl fumarate into the granulated dry granules, and mixing for 1min.

Example 17

Table 5 example 17 formulation

Note that: N/A indicates that there is no such item.

The raw materials and the auxiliary materials are weighed according to the dosage of the table 5, and the compound hydrochloride of the formula I is evenly mixed with pregelatinized starch after passing through a 60-mesh sieve.

Comparative examples 1 to 3

Table 6 comparative examples 1-3 formulations

Note that: N/A indicates that there is no such item.

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

1) Preparing raw materials and auxiliary materials: weighing all raw materials and auxiliary materials according to the theoretical amount, sieving the raw material compound hydrochloride of the formula I with a 60-mesh sieve, and sieving the auxiliary materials with a 20-mesh sieve;

2) Mixing raw materials and auxiliary materials: adding the compound hydrochloride of the formula I and lactose monohydrate or microcrystalline cellulose into a mixer, mixing for 20min, and adding magnesium stearate or sodium stearyl fumarate, and mixing for 1min;

3) Tabletting: the resulting mixture was re-tableted according to the theoretical tablet.

Comparative example 4

Table 7 comparative example 4 formulation

Note that: purified water is a wetting agent for wet granulation, which is removed during drying and is not included in a single dose.

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

2) Adhesive preparation: adding the pregelatinized starch with the formula amount into a proper amount of purified water, and fully stirring until the pregelatinized starch is uniformly dispersed;

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

6) Mixing: adding magnesium stearate into the dried granules after finishing, and mixing for 1min;

7) Tabletting: the resulting mixture was re-tableted according to the theoretical tablet.

Comparative example 5

Table 8 comparative example 5 formulation

The raw materials and the auxiliary materials are weighed according to the dosage of Table 8, and the compound hydrochloride of the formula I is evenly mixed with anhydrous calcium hydrophosphate after being sieved by a 60-mesh sieve.

Experiment 1 stability test

1. Samples of examples 1-6 and comparative examples 1-3 (without any package, only spread in a weighing bottle) were placed under accelerated test conditions (40.+ -. 2 ℃ C./RH 75.+ -. 5.0%), sampled at 0 day, 2 days, 1 week and 2 weeks, respectively, and examined for changes in the relevant substances, and only samples of 2 days were examined, as the relevant substances of comparative examples 1, 2 and 3 grew too fast, and the relevant substance detection results are shown in Table 10.

2. Samples of examples 3, 7 to 9 and comparative examples 3 and 4 (without any package, only spread in a weighing flask) were placed under high temperature (60 ℃), high humidity (RH 92.5%) and light (5000 lux, 90. Mu.w/cm ²) test conditions, respectively, and sampled for 0 day and 10 days, respectively, and the change of the relevant substances was examined, and the test results are shown in Table 11.

3. The samples (double aluminum packages) of examples 10 to 16 and comparative example 4 were placed under the test conditions of 40.+ -. 2 ℃ and RH 75.+ -. 5.0%, and were sampled at 0 day, 1 month, 2 months and 3 months, respectively, and the change of the relevant substances was examined, and the sample of comparative example 4 was examined for only 1 month since the relevant substances grew too fast, and the results of the relevant substances were shown in Table 12.

4. Samples of example 17 and comparative example 5 (without any packaging, only spread in a weighing flask) were placed under high temperature (60 ℃) conditions, sampled at 0 day and 1 week and 2 weeks, respectively, and the change in the relevant substances was examined, and the results are shown in Table 13.

5. Method for detecting substance

The method is measured according to high performance liquid chromatography (China pharmacopoeia 2020 edition four general rules 0512). Phenylsilane-bonded silica gel as filler (Waters XSelect CSH PHENYL-Hexyl,4.6mm×150mm,3.5 μm or column with comparable performance); gradient elution was carried out according to Table 9 using 0.01mol/L potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate, 1L of water was added to dissolve, pH was adjusted to 2.5 with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B; the detection wavelength is 230nm; the flow rate is 1.0ml per minute; the column temperature is 35 ℃; precisely measuring 20 μl of each of the reference solution, the sample solution and the blank auxiliary material solution, respectively injecting into a liquid chromatograph, and recording the chromatogram.

TABLE 9 flow gradient elution

Time (minutes)	Mobile phase a (%)	Mobile phase B (%)
			0	95	5
6	95	5
			11	90	10
29	50	50
			39	20	80
47	20	80
			48	95	5
58	95	5

TABLE 10 stability test results for examples 1-6 and comparative examples 1-3

TABLE 11 stability test results for examples 3, 7-9 and comparative examples 3 and 4

Note that: the light conditions were 5000lux, 90. Mu.w/cm ².

Table 12 stability test results for examples 10 to 16 and comparative example 4

TABLE 13 stability test results for example 17 and comparative example 5

Experiment 2 disintegration and dissolution test

1) Disintegration experimental method

According to the disintegration time limit checking method of the four parts <0921> of Chinese pharmacopoeia, a lifting type disintegration apparatus and a 1000ml beaker are adopted, the position of a hanging basket is adjusted to enable a screen to be 25mm away from the bottom of the beaker when the hanging basket descends to a low point, water with the temperature of 37 ℃ +/-1 ℃ is contained in the beaker, the screen is 15mm below the water surface when the water level is adjusted to enable the hanging basket to ascend to a high point, and the top of the hanging basket cannot be immersed in solution. And 6 grains of the sample are taken, and a baffle plate (preventing floating) is added into the glass tube of the hanging basket respectively, and a disintegration tester is started for inspection.

2) Dissolution test method

According to the second method (paddle method) of dissolution and release measurement of <0931> in the four parts of Chinese pharmacopoeia, the rotating speed is set to be 50rpm, the sampling time points are 10min, 15min, 30min and 45min, the circulating volume is 10ml, and the sampling volume is 1ml. Measuring 900ml of dissolution medium into each dissolution cup, taking 6 particles of test sample (placed in a dry sedimentation basket) after the temperature of the dissolution medium is constant at 37+/-0.5 ℃, respectively putting the test sample into 6 dissolution cups, immediately starting a dissolution instrument, sampling until a specified sampling time point, filtering the dissolution liquid by a PES (polyether sulfone) filter membrane with the thickness of 45 mu m, and detecting by HPLC (high performance liquid chromatography).

According to high performance liquid chromatography (China Pharmacopeia 2020 edition, fourth edition, general rule 0512), octadecylsilane chemically bonded silica is used as filler (Agilent ZORBAX SB-C18,4.6mm×150mm,3.5 μm or chromatographic column with equivalent efficacy); taking 0.05% phosphoric acid solution-acetonitrile as a mobile phase (70:30) as a mobile phase; the detection wavelength is 248nm; the flow rate is 1.0ml per minute; the column temperature is 35 ℃; sample pan temperature control 10 ℃ (only 0.1mg gauge); isocratic elution was performed for 6 minutes. Precisely measuring 10 μl (0.1 mg standard 100 μl) of the control solution and the test solution, injecting into a liquid chromatograph, and recording the chromatogram. The relative standard deviation of the continuous 5-needle peak area of the control solution should be no more than 2.0%. The cumulative elution amount at each time point was calculated by the external standard method using the peak area. The results are shown in Table 14 and FIG. 1.

Table 14 results of detection of time period for dissolution and disintegration of capsules of compound of formula I

Analysis of results:

1) As can be seen from the test results in Table 10, the unpackaged samples were left for 2 weeks under the test conditions of 40.+ -. 2 ℃ RH 75.+ -. 5.0%, and the relevant substances in examples 1 to 6 (using pregelatinized starch, dextrin filler, magnesium stearate, silica, talc or hydrogenated castor oil as lubricants) increased by 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 left to stand under the same conditions for 2 days, the relevant substances increased by more than 26%. It can be seen that examples 1 to 6 have remarkable stability advantages compared with comparative examples 1 to 3, showing that when starch-based substances (gelatinized starch, dextrin, etc.) are used as fillers, the stability of the products is significantly better than that of lactose, microcrystalline cellulose, etc. as fillers; the effect of different lubricants (magnesium stearate, silica, talc or hydrogenated castor oil) on the stability of the product was not significantly different. From the test results in Table 13, the compatibility of pregelatinized starch with the drug substance (example 17) was significantly better than the compatibility of anhydrous dibasic calcium phosphate with the drug substance (comparative example 5).

2) As can be seen from the test results in Table 11, the unpackaged samples were left for 10 days under high temperature (60 ℃ C.), high humidity (RH 92.5%) or light (5000 lux, 90. Mu.w/cm ²), and the relevant substances of example 3 (different from the lubricant of example 8) and examples 7 to 9 (different formula ratios of the compound of formula I) increased by less than 0.5%; under the same conditions, the increase amounts of the related substances of comparative example 3 (microcrystalline cellulose as filler) were 4.25%, 12.78% and 28.72%, respectively; the relevant substances of comparative example 4 (lactose monohydrate and microcrystalline cellulose as fillers, pregelatinized starch as binder) increased by 3.84%, 11.35% and 27.11%, respectively. It can be seen that example 3 and examples 7-9 have significant stability advantages over comparative examples 3 and 4, indicating that the stability of the products with pregelatinized starch as filler is better than that with lactose, microcrystalline cellulose.

3) As can be seen from the test results in Table 12, the aluminum pouch package samples were left for 3 months under the test conditions of 40+ -2deg.C/RH 75+ -5.0%, and the relevant substances in examples 10-16 (different salt forms of the compound of formula I) all increased less than 0.5%; under the same conditions, the relevant substances of comparative example 4 had increased by 29.89% for one month. It can be seen that examples 10 to 16 have significant stability advantages over comparative example 4. The stability of the compound of the formula I in different salt forms is not obviously different, and the stability of the product taking pregelatinized starch as a filler is better than that of the product taking lactose and microcrystalline cellulose as fillers.

4) In addition to stability, as can be seen from the data in table 14, the compound preparation of formula I of the present invention has good dissolution and disintegration, and can be effectively used in clinic.

The above embodiments are only for illustrating the technical solution of the present invention, and are not limited thereto. Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present invention as defined in the claims; and such modifications or substitutions are intended to be within the scope of the present invention as defined by the claims.

Claims

1. A pharmaceutical composition, the pharmaceutical composition comprising:

An auxiliary material;

2. The pharmaceutical composition according to claim 1, wherein the filler is one or more selected from the group consisting of starch, pregelatinized starch, dextrin and betacyclodextrin.

3. The pharmaceutical composition according to claim 1, wherein the lubricant is one or more selected from the group consisting of 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, silica, magnesium stearate, and talc.

4. A pharmaceutical composition according to any one of claims 1-3, characterized in that it comprises, in weight percent:

0.1 to 20 percent of compound of formula I, stereoisomer or pharmaceutically acceptable salt or solvate thereof,

77 To 99.8 percent of filling agent,

0.1% -3% Of lubricant;

Preferably, the pharmaceutical composition comprises, in weight percent:

88 To 99.7 percent of filling agent,

0.2 To 2 percent of lubricant.

5. A pharmaceutical composition according to any one of claims 1-3, wherein the adjuvant further comprises EDTA-2Na.

6. A pharmaceutical composition according to any one of claims 1-3, characterized in that: the pharmaceutically acceptable salt of the compound of the formula I is one or more selected from hydrochloride, maleate and sulfate of the compound of the formula I.

7. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 6, wherein the process is wet granulation, dry granulation or direct mixing; preferably the method is direct mixing.

8. The method according to claim 7, comprising the steps of:

1) Sieving a compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a solvate thereof, and the adjuvant;

2) Mixing the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt or its solvate with the adjuvants, and making into tablet or capsule.

9. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-6;

Preferably, the pharmaceutical formulation is an oral solid formulation;

More preferably, the oral solid preparation is a tablet, a granule, and a capsule;

Particularly preferably, the oral solid preparation is a capsule or a granule.

10. Use of a pharmaceutical composition according to any one of claims 1-6 or a pharmaceutical formulation according to claim 9 for the preparation of an antidepressant.