GK001 solid preparation as well as preparation method and application thereof

Abstract

The invention provides a GK001 solid preparation as well as a preparation method and application thereof. The solid preparation comprises the following components: a GK001 amorphous solid dispersion, an excipient, a diluent, a disintegrating agent and a lubricant, the GK001 has a structure as shown in a formula I which is described in the specification. According to the invention, GK001 is creatively prepared into a solid preparation in the form of amorphous solid dispersion, and the solid preparation has excellent stability and fluidity and high oral availability. The preparation is moderate in hardness and stable in quality, the process requirements are met, and the friability and disintegration time limit both meet the requirements; the dissolution rate of the preparation is basically consistent with the drug content, the plasma exposure is high, and the oral dose of the drug and the plasma exposure are in a linear relationship.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a GK001 solid dosage form, its preparation method, and its application. Background Technology

[0002] Depression is a serious mental disorder characterized primarily by persistent sadness, loss of interest, and reduced pleasure in daily activities. Patients may experience a range of emotional, cognitive, and physical symptoms, including fatigue, sleep disturbances, changes in appetite, difficulty concentrating, and low self-esteem. Depression not only severely impacts the personal lives of individuals but also places a burden on families and society, significantly affecting the global disease burden. Approximately 300 million people worldwide suffer from depression, with about 50 million cases in China.

[0003] Existing technologies have developed various medications and behavioral therapies to treat depression. However, due to the complexity of the etiology of depression, significant heterogeneity exists among patients despite similar diagnoses. Consequently, current treatments still show poor efficacy in most patients. For example, selective serotonin reuptake inhibitors (SSRIs) often require a long time to achieve therapeutic effects and are frequently accompanied by severe side effects, leading to poor patient adherence. Furthermore, the type of drug formulation and the method of administration can also significantly impact treatment outcomes.

[0004] US11285161B2 and CN111840300A disclose the selective cholecystokinin beta-receptor antagonist GK001 (also known as YM002), which has a good therapeutic effect on depression after injection. Although injection administration has a rapid onset of action and high bioavailability, this method of administration can cause physical pain to patients, resulting in poor patient compliance, and is particularly unsuitable for patients who need long-term medication. Therefore, the development of a solid oral dosage form for the new drug GK001 is of great significance. Oral medication is convenient to use and will not cause physical discomfort to patients. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a GK001 solid dosage form, its preparation method, and its application. The solid dosage form provided by the present invention has good stability, disintegration and dissolution properties, and exhibits high oral bioavailability.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a GK001 solid dosage form, wherein the components of the solid dosage form include a GK001 amorphous solid dispersion, an excipient, a diluent, a disintegrant, and a lubricant;

[0008] The GK001 has the structure shown in Formula I:

[0009]

[0010] GK001 (also known as YM002), chemically named (R)-1-[2,3-dihydro-1-(2'-methylbenzoylmethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]-3-(3-tolyl)urea, is a selective cholecystokinin beta-receptor antagonist. It can effectively alleviate depressive symptoms by blocking the formation of long-term effects in the amygdala of the brain. GK001 itself is almost insoluble in water and has poor oral absorption. It exists in B-form and amorphous states. The B-form has a melting point of 197-199℃ and has good stability and flowability. However, solid dosage forms made from B-form GK001 have poor oral bioavailability and cannot achieve the same efficacy as the amorphous GK001 at the same dose. Preparing solid dosage forms from amorphous GK001 requires solving problems such as stability and flowability during the formulation process.

[0011] This invention creatively prepares GK001 into a solid dosage form as an amorphous solid dispersion, exhibiting excellent stability and flowability, and high oral bioavailability. The dosage form has moderate hardness, stable quality, meets process requirements, and its friability and disintegration time both meet the requirements. The dissolution rate of the dosage form is essentially consistent with the drug content, and the plasma exposure is high, with a linear relationship between the oral drug dose and the plasma exposure.

[0012] In this invention, the active ingredient GK001 can be in B crystal form or amorphous state. The specific formulation of this invention can load any crystal form of GK001 active ingredient with the aforementioned good effects.

[0013] Preferably, the solid dosage form comprises, by weight, 15-25 parts of GK001 amorphous solid dispersion, 45-55 parts of excipient, 20-30 parts of diluent, 4-10 parts of disintegrant and 0.5-3 parts of lubricant.

[0014] The weight percentages of the GK001 amorphous solid dispersion can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 parts, etc.

[0015] The excipient can be present in weight parts of 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 parts, etc.

[0016] The weight percentage of the diluent can be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 parts, etc.

[0017] The disintegrant can be expressed in parts by weight of 4, 4.2, 5, 5.5, 6, 6.7, 7, 8, 9, or 10 parts, etc.

[0018] The lubricant can be present in parts by weight of 0.5, 0.8, 1, 1.2, 1.5, 1.7, 2, 2.5, or 3 parts, etc.

[0019] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0020] Preferably, the GK001 amorphous solid dispersion is prepared by a method comprising the following steps:

[0021] GK001 and the carrier were mixed and dissolved in an organic solvent. After spray drying and baking, the amorphous solid dispersion of GK001 was obtained.

[0022] Preferably, the mass ratio of GK001, the carrier, and the organic solvent is (0.5-5):(1.5-10):(85-98).

[0023] The specific point values ​​in (0.5-5) can be 0.5, 0.7, 1, 1.2, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5 or 5, etc.

[0024] The specific point values ​​in (1.5-10) can be 1.5, 2, 3, 4, 5, 6, 7, 8, 9 or 10, etc.

[0025] The specific point values ​​in (85-98) can be 85, 87, 90, 91, 92, 93, 94, 95, 96, 97 or 98, etc.

[0026] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0027] Preferably, the carrier comprises any one or a combination of at least two of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, or vinylpyrrolidone vinyl acetate copolymer.

[0028] The present invention preferably uses hydroxypropyl methylcellulose succinate as the carrier of GK001, and the solid dosage form prepared therefrom has high stability, flowability and oral bioavailability.

[0029] Preferably, the organic solvent includes any one or a combination of at least two of methanol, dichloromethane, acetone, ethanol, or ethyl acetate.

[0030] GK001 dissolves completely within 10 minutes in the aforementioned organic solvents, resulting in solid dosage forms with good performance. Among these, the combination of methanol and dichloromethane produces the best-performing solid dosage form; the combination of acetone and ethanol exhibits a good balancing effect; and the combination of acetone and ethyl acetate provides good drying efficiency.

[0031] Preferably, the organic solvent includes methanol and dichloromethane.

[0032] The present invention preferably uses methanol and dichloromethane to prepare the amorphous solid dispersion of GK001, and the solid dosage form prepared thereby has high stability, flowability and oral bioavailability.

[0033] Preferably, the mass ratio of methanol to dichloromethane is 1:(1.5-5).

[0034] The specific point values ​​in (1.5-5) can be 1.5, 1.7, 2, 2.3, 2.5, 2.8, 3, 3.5, 4, 4.5 or 5, etc.

[0035] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0036] Preferably, the nitrogen flow rate for spray drying is 0.08-0.1 MPa, for example, 0.08 MPa, 0.082 MPa, 0.085 MPa, 0.087 MPa, 0.09 MPa, 0.093 MPa, 0.095 MPa, 0.098 MPa, or 0.1 MPa; the inlet air temperature is 75-90℃, for example, 75℃, 77℃, 80℃, 82℃, 85℃, 88℃, or 90℃; and the fan parameters are 0.2-0.85 m. 3 / min, for example, can be 0.2m 3 / min, 0.3m 3 / min, 0.4m 3 / min, 0.5m 3 / min, 0.6m 3 / min, 0.7m 3 / min, 0.8m 3 / min or 0.85m 3 / min, etc.; the pump speed is 14.1-27.9 mL / min, for example, it can be 14.1 mL / min, 15 mL / min, 16 mL / min, 17 mL / min, 18 mL / min, 19 mL / min, 20 mL / min, 22 mL / min, 25 mL / min or 27.9 mL / min, etc.

[0037] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0038] This invention optimizes the parameters of spray drying, which significantly improves the recovery rate of wet materials, reaching up to 98%. The entire spraying process is smooth, the spray gun is unblocked, and the drying is thorough.

[0039] Preferably, the drying temperature is 40-60℃, for example, 40℃, 42℃, 45℃, 57℃, 50℃, 53℃, 55℃, 58℃ or 60℃; the drying time is 22-26h, for example, 22h, 22.5h, 23h, 23.5h, 24h, 24.5h, 25h, 25.5h or 26h.

[0040] This invention optimizes the drying parameters, resulting in a significant increase in the recovery rate of dry materials, reaching up to 97.2%.

[0041] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0042] Preferably, the excipient comprises any one or a combination of at least two of microcrystalline cellulose, colloidal silica, or sucrose fatty acid esters.

[0043] Preferably, the excipients include microcrystalline cellulose and colloidal silica.

[0044] The present invention preferably uses microcrystalline cellulose and colloidal silica as excipients, which have a synergistic effect, and the prepared solid dosage form has high stability, flowability and oral bioavailability.

[0045] Preferably, the mass ratio of microcrystalline cellulose to colloidal silica is (1-10):(30-50).

[0046] The specific point values ​​in (1-10) can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, etc.

[0047] The specific point values ​​in (30-50) can be 30, 32, 35, 37, 40, 43, 45, 48 or 50, etc.

[0048] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0049] Preferably, the diluent comprises any one or a combination of at least two of mannitol, lactose, fructose, sorbitol, or sucrose.

[0050] Preferably, the disintegrant comprises any one or a combination of at least two of crospovidone, sodium glycolate starch, sodium crospovidone carboxymethyl cellulose, or low-substituted hydroxypropyl cellulose.

[0051] Preferably, the lubricant comprises any one or a combination of at least two of magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, sodium lauryl sulfate, or sodium stearate fumarate.

[0052] Preferably, the dosage form of the solid preparation includes any one of tablets, capsules, granules, pills, powders, or granules.

[0053] In a second aspect, the present invention provides a method for preparing a solid dosage form as described in the first aspect, the method comprising:

[0054] (1) Mix the GK001 amorphous solid dispersion and excipients and sieve them; sieve the diluent, disintegrant and lubricant separately;

[0055] (2) The sieved GK001 amorphous solid dispersion, excipient, diluent and disintegrant are mixed, a portion of lubricant is added, granulation is performed, the remaining lubricant is added, and tableting is performed to obtain the solid preparation.

[0056] The preparation method of the solid dosage form of this invention has a short cycle and low production cost, making it suitable for large-scale industrial production.

[0057] Preferably, the mass ratio of the partial lubricant to the remaining lubricant is 1:(1.5-3).

[0058] The specific point values ​​in (1.5-3) can be 1.5, 1.7, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3, etc.

[0059] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0060] Thirdly, the present invention provides the use of solid dosage forms as described in the first aspect in the preparation of antidepressant drugs.

[0061] Compared with the prior art, the present invention has the following beneficial effects:

[0062] This invention creatively prepares GK001 into a solid dosage form as an amorphous solid dispersion, exhibiting excellent stability and flowability, and high oral bioavailability. The dosage form has moderate hardness, stable quality, meets process requirements, and its friability and disintegration time both meet the requirements. The dissolution rate of the dosage form is essentially consistent with the drug content, and the plasma exposure is high, with a linear relationship between the oral drug dose and the plasma exposure. Attached Figure Description

[0063] Figure 1 X-ray powder diffraction pattern for the preparation of the GK001 amorphous solid dispersion provided in Example 1;

[0064] Figure 2 Scanning electron microscope image of the GK001 amorphous solid dispersion provided in Example 1;

[0065] Figure 3 X-ray powder diffraction patterns of the GK001 amorphous solid dispersion provided in Example 1 after being placed in environments of 25°C and 60%RH and 40°C and 75%RH for one month.

[0066] Figure 4 X-ray powder diffraction patterns of the GK001 amorphous solid dispersion provided in Example 1 after being placed in environments of 25°C and 60%RH and 40°C and 75%RH for 3 months.

[0067] Figure 5 The forced swimming test results of the GK001 solid dosage form provided in Example 1 are shown in the figure.

[0068] Figure 6 The image shows the tail suspension test results of the GK001 solid dosage form provided in Example 1. Detailed Implementation

[0069] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0070] Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels. GK001 involved in the specific embodiments is in an amorphous state.

[0071] The sources of materials used in the following specific embodiments are as follows:

[0072] Raw material name Purchase manufacturer model GK001 MedChemExpress HY-103355 Hydroxypropyl methylcellulose acetate succinate Sigma-Aldrich 71138-97-1 Hydroxypropyl methylcellulose Sigma-Aldrich 423238 Vinylpyrrolidone vinyl acetate copolymer Shanghai Chengyu Biotechnology Co., Ltd. 25086-89-9 Microcrystalline cellulose 102 Huzhou Linghu Xinwang Chemical Co., Ltd. PH-102 Colloidal silica 200Pharma Evonik 112945-52-57631-86-9 Mannitol 100SD Jiangsu Xidian Pharmaceutical Excipients Co., Ltd. 69-65-8 Cross-linked polyvinylpyrrolidone XL-10 Quzhou Jianhua Nanhang Pharmaceutical Co., Ltd. 9003-39-8 magnesium stearate Peter Greven 433487

[0073] Preparation Example 1

[0074] This preparation example provides an amorphous solid dispersion GK001, which is prepared by a method comprising the following steps:

[0075] By weight, 2 parts of GK001 and 6 parts of hydroxypropyl methylcellulose acetate succinate were mixed and dissolved thoroughly in 21 parts of methanol and 71 parts of dichloromethane. The solution was then spray-dried with the following settings: nozzle size 0.7 mm, cleaning frequency 1 time / min, condensation temperature -20℃, nitrogen flow rate 0.09 MPa, inlet air temperature 80℃, and fan parameters 0.5 m. 3The pumping speed was 20 mL / min; then it was dried at 50 °C for 24 h to obtain the GK001 amorphous solid dispersion.

[0076] Preparation Example 2

[0077] This preparation example provides an amorphous solid dispersion GK001, which is prepared by a method comprising the following steps:

[0078] By weight, 1.25 parts of GK001 and 3.75 parts of hydroxypropyl methylcellulose acetate succinate were mixed and dissolved thoroughly in 38 parts of methanol and 57 parts of dichloromethane. The solution was then spray-dried with the following settings: nozzle size 0.7 mm, cleaning frequency 1 time / min, condensation temperature -20℃, nitrogen flow rate 0.08 MPa, inlet air temperature 75℃, and fan parameters 0.2 m. 3 The pumping speed was 14.1 mL / min; then it was dried at 40 °C for 26 h to obtain the GK001 amorphous solid dispersion.

[0079] Preparation Example 3

[0080] This preparation example provides an amorphous solid dispersion GK001, which is prepared by a method comprising the following steps:

[0081] By weight, 1 part GK001 and 2 parts hydroxypropyl methylcellulose acetate succinate were mixed and dissolved thoroughly in 24 parts methanol and 73 parts dichloromethane. The solution was then spray-dried with the following settings: nozzle size 0.7 mm, cleaning frequency 1 time / min, condensation temperature -20℃, nitrogen flow rate 0.1 MPa, inlet air temperature 90℃, and fan parameters 0.85 m. 3 The pumping speed was 27.9 mL / min; then it was dried at 60 °C for 22 h to obtain the GK001 amorphous solid dispersion.

[0082] Preparation Example 4

[0083] This preparation example provides an amorphous solid dispersion GK001, which differs from Preparation Example 1 only in that "21 parts methanol and 71 parts dichloromethane" are replaced with "21 parts acetone and 71 parts ethanol", while the other raw materials and steps remain unchanged.

[0084] Preparation Example 5

[0085] This preparation example provides an amorphous solid dispersion called GK001, which differs from Preparation Example 1 only in that "21 parts methanol and 71 parts dichloromethane" are replaced with "21 parts acetone and 71 parts ethyl acetate", while the other raw materials and steps remain unchanged.

[0086] Preparation Example 6

[0087] This preparation example provides an amorphous solid dispersion GK001, which differs from Preparation Example 1 only in that "21 parts methanol and 71 parts dichloromethane" are replaced with "21 parts ethanol and 71 parts trichloromethane", while the other raw materials and steps remain unchanged.

[0088] Preparation Example 7

[0089] This preparation example provides an amorphous solid dispersion called GK001, which differs from Preparation Example 1 only in that "21 parts methanol and 71 parts dichloromethane" are replaced with "92 parts methanol", while the other raw materials and steps remain unchanged.

[0090] Preparation Example 8

[0091] This preparation example provides an amorphous solid dispersion called GK001, which differs from Preparation Example 1 only in that "21 parts methanol and 71 parts dichloromethane" are replaced with "92 parts dichloromethane", while the other raw materials and steps remain unchanged.

[0092] Preparation Example 9

[0093] This preparation example provides an amorphous solid dispersion called GK001, which differs from Preparation Example 1 only in that "6 parts of hydroxypropyl methylcellulose acetate succinate" is replaced with "6 parts of hydroxypropyl methylcellulose", while the other raw materials and steps remain unchanged.

[0094] Preparation Example 10

[0095] This preparation example provides an amorphous solid dispersion called GK001, which differs from Preparation Example 1 only in that "6 parts of hydroxypropyl methylcellulose acetate succinate" is replaced with "6 parts of vinylpyrrolidone vinyl acetate copolymer", while the other raw materials and steps remain unchanged.

[0096] Example 1

[0097] This embodiment provides a GK001 solid dosage form, which comprises the following components in parts by weight:

[0098]

[0099] Its preparation methods include:

[0100] (1) Mix the GK001 amorphous solid dispersion and excipients and pass them through a 50-mesh sieve; pass the diluent and disintegrant through a 50-mesh sieve respectively, and pass the lubricant through a 30-mesh sieve;

[0101] (2) Mix the above-mentioned sieved GK001 amorphous solid dispersion, excipient, diluent and disintegrant, and add 0.5 parts of lubricant for lubrication; then perform dry granulation, setting the feeding speed to 15 rpm and the roller pressure to 50 kg / cm. 2The roller speed is 6 rpm, the granulation speed is 150 rpm, the primary granulation screen is a 5 mm round hole screen, and the secondary granulation screen is 0.8 mm in size; then add 1 part of lubricant for lubrication; finally, use a 6 mm round shallow concave punch to compress the tablets to obtain the solid dosage form.

[0102] Example 2

[0103] This embodiment provides a GK001 solid dosage form, which comprises the following components in parts by weight:

[0104]

[0105] Its preparation methods include:

[0106] (1) Mix the GK001 amorphous solid dispersion and excipients and pass them through a 50-mesh sieve; pass the diluent and disintegrant through a 50-mesh sieve respectively, and pass the lubricant through a 30-mesh sieve;

[0107] (2) Mix the above-mentioned sieved GK001 amorphous solid dispersion, excipient, diluent and disintegrant, and add 0.5 parts of lubricant for lubrication; then perform dry granulation, setting the feeding speed to 15 rpm and the roller pressure to 50 kg / cm. 2 The roller speed is 6 rpm, the granulation speed is 150 rpm, the primary granulation screen is a 5 mm round hole screen, and the secondary granulation screen is 0.8 mm in size; 1.5 parts of lubricant are added for lubrication; finally, a 6 mm round shallow concave punch is used for tableting to obtain the solid dosage form.

[0108] Example 3

[0109] This embodiment provides a GK001 solid dosage form, which comprises the following components in parts by weight:

[0110]

[0111] Its preparation methods include:

[0112] (1) Mix the GK001 amorphous solid dispersion and excipients and pass them through a 50-mesh sieve; pass the diluent and disintegrant through a 50-mesh sieve respectively, and pass the lubricant through a 30-mesh sieve;

[0113] (2) Mix the above-screened GK001 amorphous solid dispersion, excipient, diluent, and disintegrant, and add 1 part of lubricant for lubrication; then perform dry granulation, setting the feeding speed to 15 rpm and the roller pressure to 50 kg / cm². 2The roller speed is 6 rpm, the granulation speed is 150 rpm, the primary granulation screen is a 5 mm round hole screen, and the secondary granulation screen is 0.8 mm in size; 1.5 parts of lubricant are added for lubrication; finally, a 6 mm round shallow concave punch is used for tableting to obtain the solid dosage form.

[0114] Examples 4-10

[0115] This embodiment provides a GK001 solid dosage form, which differs from Example 1 only in that "the GK001 amorphous solid dispersion provided in Preparation Example 1" is replaced with an equal number of "GK001 amorphous solid dispersions provided in Preparation Examples 4-10", while the other raw materials and steps remain unchanged.

[0116] Example 11

[0117] This embodiment provides a GK001 solid dosage form, which differs from Example 1 only in that: microcrystalline cellulose 102 is not added to the excipients, and its reduced amount is allocated to colloidal silica 200Pharma in proportion, while the other raw materials and steps remain unchanged.

[0118] Example 12

[0119] This embodiment provides a GK001 solid dosage form, which differs from Example 1 only in that: colloidal silica 200Pharma is not added to the excipients, and its reduced amount is allocated to microcrystalline cellulose 102 in proportion, while the other raw materials and steps remain unchanged.

[0120] Comparative Example 1

[0121] This comparative example provides a GK001 solid dosage form, which differs from Example 1 only in that "20 parts of the GK001 amorphous solid dispersion provided in Example 1" are replaced with "5 parts of GK001", while the other raw materials and steps remain unchanged.

[0122] Test Example 1

[0123] The amorphous solid dispersion GK001 provided in Preparation Example 1 was subjected to the following tests: X-ray powder diffraction (XRPD) ( Figure 1 The analysis showed that the GK001 amorphous solid dispersion was an amorphous powder; differential scanning calorimetry (mDSC) showed that the sample had only one glass transition midpoint at 107.3℃, indicating that GK001 and hydroxypropyl methylcellulose acetate succinate can form a uniform amorphous state, demonstrating good miscibility; particle size analysis (PSD) showed that 10% of the amorphous particles were less than 4.94 μm, 50% were less than 20.3 μm, and 90% were less than 52.4 μm; scanning electron microscopy (SEM) showed that... Figure 2 The results showed that the amorphous particles were raisin-shaped.

[0124] Test Example 2

[0125] The long-term stability of the GK001 amorphous solid dispersion provided in Preparation Example 1 was tested: 2g of test sample was placed in a sealed bag (inner packaging was a double-layer LDPE bag, tied tightly with a cable tie; outer packaging was an aluminum foil bag, heat-sealed; 1g of desiccant was added between the inner and outer packaging); then placed in environments of 25℃ + 60% RH and 40℃ + 75% RH for 1 month and 3 months respectively, and then X-ray powder diffraction (XRPD), differential scanning calorimetry (mDSC), moisture, related substances, and content were detected. RRT0.16, RRT0.88, RRT0.98, and RRT1.02 were identified as impurities.

[0126] XRPD( Figure 3-4 The test results showed that after being placed in environments of 25℃ + 60% RH and 40℃ + 75% RH for 1 month or 3 months, the test samples remained amorphous particles. As shown in Table 1, after being placed in environments of 25℃ + 60% RH and 40℃ + 75% RH for 1 month or 3 months, the appearance, related substances, content, and glass transition midpoint of the test samples did not change significantly, with only a slight increase in moisture content. This indicates that the prepared GK001 amorphous solid dispersion is relatively stable, meets the stability requirements, and can be used for the preparation of solid dosage forms.

[0127] Table 1

[0128]

[0129] Test Example 3

[0130] In the preparation of the GK001 solid dosage form in Examples 1-12 and Comparative Example 1, equal amounts of samples were taken for particle size analysis before tableting. The angle of repose was measured using a Ningbo Ruike angle of repose meter (model FT-104B) according to GB / T11986-1989. The tap density was measured using the 2020 edition of the Chinese Pharmacopoeia's methods for determining bulk density and tapped density, and the Karl index was calculated as follows: Karl index = (tapered density - bulk density) / tapped density × 100%. The Karl index reflects the compressibility and filling properties of the powder, while the angle of repose reflects the flowability of the powder. A larger Karl index indicates better compressibility but poorer flowability; a smaller Karl index indicates better filling and flowability but poorer compressibility; and a smaller angle of repose indicates better flowability.

[0131] The test results are shown in Table 2. GK001, when prepared as an amorphous solid dispersion, exhibits balanced flowability and compressibility, meeting the requirements of the production process. No flakes appear and it does not stick to the rollers. The carrier of GK001, the organic solvent used for drug dissolution, and the type of excipient further affect the above properties.

[0132] Table 2

[0133] Test sample Carr's index (%) Angle of repose (°) Example 1 28.7 39.58 Example 2 30.4 42.31 Example 3 29.7 43.73 Example 4 34.6 52.51 Example 5 32.2 49.24 Example 6 43.2 50.48 Example 7 36.5 47.82 Example 8 37.3 48.46 Example 9 39.8 44.92 Example 10 38.2 48.49 Example 11 41.4 51.35 Example 12 38.1 48.78 Comparative Example 1 18.3 27.51

[0134] Test Example 4

[0135] The GK001 solid dosage forms provided in Examples 1-12 and Comparative Example 1 were subjected to the following tests: (1) The tablet weight and thickness of the samples were measured, and the tablet diameter was a fixed value of 6 mm; (2) The hardness of the samples was measured using a PYD-1 tablet hardness tester (Bestco Pharmaceutical Co., Ltd., Tianjin), and the test was repeated 10 times and the average value was taken; (3) The radial destructive force of the samples was measured using a YPJ-200B tablet hardness tester (Shanghai Huanghai Pharmaceutical Testing Instrument Factory) to evaluate the tensile strength; the tensile strength reflects the formability of the powder, and the greater the tensile strength, the better. (4) Use CJY-300B tablet friability tester (Shanghai Huanghai Pharmaceutical Instrument Factory) to test the friability of the sample; Friability refers to the reduction in mass of the particles or particle fragments during mechanical stress treatment. The lower the friability, the less likely the particles are to be deformed or damaged; (5) Disintegration time limit: Refer to the disintegration time limit test method in General Chapter 0921 of Part IV of the Chinese Pharmacopoeia 2020 edition; (6) Dissolution: Refer to the paddle method in the dissolution determination method in General Chapter 0931 of Part IV of the Chinese Pharmacopoeia 2020 edition.

[0136] The test results are shown in Table 3-4. GK001, when prepared as an amorphous solid dispersion, exhibits excellent formability, moderate hardness, and is not easily deformed. Its dissolution rate and disintegration time meet the requirements. The carrier of GK001, the organic solvent used for drug dissolution, and the type of excipient further affect the above properties.

[0137] Table 3

[0138] Test sample Tablet weight (mg) Thickness (mm) Hardness (N) Tensile strength (MPa) Friability (%) Disintegration timeout (s) Example 1 99.59 3.36 78.44 2.47826307 0.07 40 Example 2 102.48 3.52 59.23 1.78627437 0.21 68 Example 3 99.34 3.41 60.15 1.87253675 0.24 73 Example 4 103.26 3.68 41.12 1.18619034 0.73 93 Example 5 102.33 3.57 41.96 1.24771777 0.57 99 Example 6 102.48 3.62 36.53 1.07124843 0.91 89 Example 7 108.21 3.57 34.36 1.02172504 1.04 94 Example 8 107.78 3.74 40.32 1.14445315 0.77 98 Example 9 104.11 3.53 42.82 1.28771886 0.49 86 Example 10 103.74 3.59 42.31 1.25111628 0.54 92 Example 11 105.21 3.49 41.48 1.26171835 0.51 100 Example 12 101.45 3.43 42.63 1.31938126 0.45 104 Comparative Example 1 110.65 3.55 25.16 0.75236985 1.22 101

[0139] Table 4

[0140]

[0141] Test Example 5

[0142] Male C57BL / 6 mice were randomly divided into groups of 10 each and housed under a 12h / 12h light / dark cycle with free access to water. After 5 days of acclimatization, the mice were given the following medications: (1) the experimental group received oral administration of GK001 solid formulation provided in Example 1; (2) the blank control group received a 5% DMSO / 0.5% HPMC solution prepared with physiological saline as the solvent; and (3) the positive control group received oral administration of fluoxetine. Animals were administered the medication via gavage 23, 4.5, 1, and 0.5 hours before the 6-minute forced swimming test and tail suspension test. During the tests, the animals were video-recorded, and the immobility time during the last 4 minutes of forced swimming and the entire 6 minutes of tail suspension was automatically analyzed and quantified using Smart3.0 video tracking software (Panlab, Spain).

[0143] Forced swimming test: The forced swimming apparatus was made of transparent plexiglass (30cm high, 12cm in diameter, water depth 20±1cm, water temperature 25±1℃). Mice were acclimatized for 15 minutes the day before the test; during the test, the mice were placed in the apparatus. The forced swimming experiment is a classic antidepressant drug screening model; effective antidepressants can significantly reduce the immobility time of mice during forced swimming.

[0144] Tail suspension test: A self-made tail suspension box was used. Each box (18cm long × 18cm wide × 29cm high) had a hook fixed to the top. A long tape was tied to the animal's tail 1cm from the tip, and the animal was suspended from the hook for 6 minutes, with video recording. The tail suspension test is a classic antidepressant drug screening model. Effective antidepressants can significantly reduce the immobility time of mice in the tail suspension test.

[0145] Test results are as follows Figure 5-6 As shown (the horizontal axis represents the dosage relative to mouse body weight), the GK001 solid formulation provided by this invention has high plasma exposure and oral bioavailability, and can exert its efficacy rapidly after oral administration, achieving an antidepressant effect at an oral dose of 1 mg / kg.

[0146] Test Example 6

[0147] Sprague-Dawley rats were randomly divided into groups of 10 each and housed under a 12h / 12h light / dark cycle with free access to water. After 5 days of acclimatization, the rats were administered the drug orally via gavage in the solid formulation of GK001 provided in Example 1 or Comparative Example 1, using deionized water containing 5% (v / v) Kolliphor HS15 as the solvent. 0.25 mL of whole blood was collected from the tail vein and jugular vein at each time point before administration and at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration to determine the blood drug concentration.

[0148] Among them, Cmax Maximum plasma concentration (T) refers to the highest plasma concentration of a drug that can be achieved after administration; max Time to peak concentration (AUC) refers to the time required for a drug to reach its maximum blood concentration after administration. last The area under the plasma concentration-time curve from the time of administration (0h) to the last measurable plasma concentration point represents the total exposure of the drug in the body during this period; F is the bioavailability, which refers to the proportion and rate at which the drug is absorbed and enters the systemic circulation, and measures the effective dose of the administered dose that ultimately reaches the site of action (systemic circulation).

[0149] The test results are shown in Table 5. The GK001 solid dosage form provided by this invention has high plasma exposure and oral bioavailability.

[0150] Table 5

[0151]

[0152] This invention illustrates a GK001 solid dosage form, its preparation method, and its application through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0153] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0154] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A GK001 solid dosage form, characterized in that, The solid dosage form comprises GK001 amorphous solid dispersion, excipients, diluents, disintegrants, and lubricants. The GK001 has the structure shown in Formula I:

2. The solid dosage form according to claim 1, characterized in that, The solid dosage form comprises, by weight, 15-25 parts of GK001 amorphous solid dispersion, 45-55 parts of excipient, 20-30 parts of diluent, 4-10 parts of disintegrant, and 0.5-3 parts of lubricant.

3. The solid dosage form according to claim 1 or 2, characterized in that, The GK001 amorphous solid dispersion is prepared by a method comprising the following steps: GK001 and the carrier were mixed and dissolved in an organic solvent. After spray drying and baking, the amorphous solid dispersion of GK001 was obtained.

4. The solid dosage form according to claim 3, characterized in that, The mass ratio of GK001, the carrier, and the organic solvent is (0.5-5):(1.5-10):(85-98); Preferably, the carrier comprises any one or a combination of at least two of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, or vinylpyrrolidone vinyl acetate copolymer.

5. The solid dosage form according to claim 3 or 4, characterized in that, The organic solvent includes any one or a combination of at least two of methanol, dichloromethane, acetone, ethanol, or ethyl acetate; Preferably, the organic solvent includes methanol and dichloromethane; Preferably, the mass ratio of methanol to dichloromethane is 1:(1.5-5).

6. The solid dosage form according to any one of claims 3-5, characterized in that, The drying temperature is 40-60℃, and the time is 22-26h.

7. The solid dosage form according to any one of claims 1-6, characterized in that, The excipients include any one or a combination of at least two of microcrystalline cellulose, colloidal silica, or sucrose fatty acid esters. Preferably, the excipients include microcrystalline cellulose and colloidal silica; Preferably, the diluent comprises any one or a combination of at least two of mannitol, lactose, fructose, sorbitol, or sucrose; Preferably, the disintegrant comprises any one or a combination of at least two of crospovidone, sodium glycolate starch, sodium crospovidone carboxymethyl cellulose, or low-substituted hydroxypropyl cellulose; Preferably, the lubricant comprises any one or a combination of at least two of magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, sodium lauryl sulfate, or sodium stearate fumarate.

8. The method for preparing solid dosage forms according to any one of claims 1-7, characterized in that, The method includes: (1) Mix the GK001 amorphous solid dispersion and excipients and sieve them; sieve the diluent, disintegrant and lubricant separately; (2) The sieved GK001 amorphous solid dispersion, excipient, diluent and disintegrant are mixed, a portion of lubricant is added, granulation is performed, the remaining lubricant is added, and tableting is performed to obtain the solid preparation.

9. The method according to claim 8, characterized in that, The mass ratio of the partial lubricant to the remaining lubricant is 1:(1.5-3).

10. The use of the solid dosage form according to any one of claims 1-7 in the preparation of antidepressant drugs.

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