Pharmaceutical composition of analgesic compound and preparation method therefor

Abstract

Provided are a pharmaceutical composition of an analgesic compound and a preparation method therefor. The pharmaceutical composition can be prepared into a liquid injection or a lyophilized powder. The pharmaceutical composition has a controllable particle size and a narrow distribution range, features good stability, and can be used for intravenous injection and achieves a rapid onset of action, thereby effectively replacing the use of opioid analgesics and reducing addiction. In addition, the composition does not contain excipients having a sustained-release function, thereby providing higher safety.

Description

Pharmaceutical compositions of analgesic compounds and their preparation methods

[0001] Citation of relevant applications

[0002] This disclosure claims priority to Chinese Patent Application No. 202411686694.9, filed on November 22, 2024, entitled "Pharmaceutical Composition of Analgesic Compound and Preparation Method thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of pharmaceutical preparations, specifically relating to a pharmaceutical composition of an analgesic compound and its preparation method. Background Technology

[0004] The global prevalence of pain is currently estimated at 35% to 45%. According to the "China Pain Medicine Development Report (2020)," there are over 300 million chronic pain patients in my country, and this number is increasing by 10-20 million annually. While pain does not directly threaten life like other diseases, it can lead to a decline in quality of life and may contribute to suicide, premature death, Alzheimer's disease, depression, and anxiety.

[0005] The pathogenesis of pain is relatively complex, which makes many treatments less than satisfactory. Existing pain medications often suffer from problems such as low tolerability, poor long-term safety, and potential drug abuse. Furthermore, moderate to severe pain can lead to opioid dependence. In 2016, the U.S. Food and Drug Administration (FDA) issued a warning to restrict the use of opioid analgesics.

[0006] NaV1.8 is a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons, playing a crucial role in pain signal transduction in the peripheral nervous system and serving as a major selective target for pain management. NaV1.8 inhibitors produce analgesia by blocking the transmission of pain signals from the peripheral to the central nervous system. A prime example is VX-548 from Vertex Pharmaceuticals in the United States. Its Phase III clinical trial showed positive results, demonstrating that VX-548 does not produce addictive effects compared to opioids in the treatment of moderate to severe acute pain. VX-548 has received Fast Track designation and Breakthrough Therapy designation from the FDA for the treatment of moderate to severe acute pain. VX-548 may become the first drug with a novel mechanism of action for the treatment of acute pain in over two decades, filling a gap in the non-opioid acute pain medication market.

[0007] Currently, VX-548 is only available in oral formulations, and there is no injectable form in China to meet the high clinical demand. This is because oral formulations have issues such as slow onset of analgesia and are unsuitable for postoperative swallowing. Therefore, there is a need to develop an injectable form that is rapidly effective and convenient for clinical use. This disclosure provides a method for preparing a VX-548-based suspension injection and its formulation. After formulation screening, a nano-suspension with controllable particle size, narrow distribution, and good stability can be obtained. It can rapidly take effect after intravenous injection and can effectively replace the use of opioid analgesics, reducing the risk of addiction. Summary of the Invention

[0008] A first aspect of this disclosure provides a pharmaceutical composition comprising an active ingredient having the structure of formula (I) and a pharmaceutically acceptable excipient selected from one or more of wetting agents, stabilizers, pH adjusters, osmotic pressure regulators, and lyophilization protectants.

[0009] in:

[0010] X 2a It is N, N + -O - or CR 2a ;

[0011] X 4a It is N, N + -O - or CR 4a ;

[0012] X 5a It is N, N + -O - or CR 5a ;

[0013] X 6a It is N, N + -O - or CR 6a ;

[0014] Each R is independently H or a C1-C6 alkyl group;

[0015] R 2a R 4a R 5a and R 6a Each is independently H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group;

[0016] R 4b1 and R 4b2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;

[0017] R5b1 and R 5b2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl;

[0018] X 3c Is it N or CR? 3c ;

[0019] X 4c Is it N or CR? 4c ;

[0020] X 5c Is it N or CR? 5c ;

[0021] X 6c Is it N or CR? 6c ;

[0022] R 2c It is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl group is optionally substituted with 1-2 halogen groups;

[0023] L 1 It is a key or an O;

[0024] L 2 It is a bond or a C1-C6 alkylene group;

[0025] R 3c It is H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group;

[0026] R 4c It is H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group;

[0027] R 5c It is H, a halogen, a C1-C6 alkyl, or a C1-C6 haloalkyl; and

[0028] R 6c It is H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group;

[0029] The constraint is X 2a X 4a X 5a and X 6a No more than two of them are N or N + -O - ;and

[0030] The constraint is X 3c X4c X 5c and X 6c No more than one of them is N.

[0031] In some embodiments, the active ingredient is compound A with the following structure or an acceptable pharmaceutical salt thereof:

[0032] In some embodiments, the active ingredient is VX-548.

[0033] In some embodiments, the pharmaceutical composition is a liquid formulation.

[0034] In some embodiments, the pharmaceutical composition is an injectable formulation.

[0035] In some embodiments, the pharmaceutical composition is a nanosuspension.

[0036] In some implementations, the nanosuspension is used for intravenous injection.

[0037] In some embodiments, the pharmaceutical composition comprises the following components by weight percentage:

[0038] The active ingredient content is 2.5%–30%, preferably 5%–20%;

[0039] A wetting agent of 0.1% to 5%, preferably 0.2% to 3%; and

[0040] The remainder is water for injection.

[0041] In some embodiments, the pharmaceutical composition further comprises 0.1% to 5%, preferably 0.2% to 2%, of a stabilizer.

[0042] In some embodiments, the pharmaceutical composition further comprises a pH adjuster of 0-1%, preferably 0%-0.5%.

[0043] In some embodiments, the pharmaceutical composition further comprises 0% to 10% of an osmotic pressure regulator.

[0044] In some embodiments, the wetting agent is selected from one or more of the following: bile salts, sodium oleate, polyethylene glycol 15-hydroxystearate (HS 15), polysorbates (e.g., Tween 20, 40, 60, 80), dehydrated sorbitan fatty acid esters (e.g., Span 20, 40, 60, 80), poloxamer, sodium lauryl sulfate, monoglycerides, polyoxyethylene castor oil, and lecithin.

[0045] In some embodiments, the wetting agent is selected from one or more of cholates and sodium oleate.

[0046] In some embodiments, the wetting agent is selected from one or more of deoxycholic acid, glycocholic acid, ursodeoxycholic acid, or sodium oleate.

[0047] In some embodiments, the stabilizer is selected from one or more of povidone (e.g., PVP K12, PVPK17, PVPK30), cyclodextrin, sodium carboxymethyl cellulose and its sodium salt, polyethylene glycol, hydroxypropyl methylcellulose, and polyethylene glycol 1000 vitamin E succinate (TPGS).

[0048] In some embodiments, the stabilizer is povidone.

[0049] In some embodiments, the stabilizer is selected from one or more of PVP K12, PVPK17, and PVPK30.

[0050] In some embodiments, the pH adjuster is selected from one or more of sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium citrate, and tartrate.

[0051] In some embodiments, the pH adjuster is sodium hydroxide.

[0052] In some embodiments, the osmotic pressure regulator is selected from one or more of sucrose, mannitol, glycerol, sodium chloride, and glucose.

[0053] In some embodiments, the osmotic pressure regulator is selected from one or more of sucrose, mannitol, and glycerol.

[0054] In some embodiments, the osmotic pressure regulator is selected from one or more of sucrose and glycerol.

[0055] In some embodiments, the pharmaceutical composition meets one or more of the following conditions:

[0056] (1) The pharmaceutical composition further comprises 0-1% of a pH adjuster;

[0057] (2) The pharmaceutical composition further comprises 0% to 10% of an osmotic pressure regulator;

[0058] (3) The wetting agent is selected from one or more of the following: bile salts, sodium oleate, polyethylene glycol 15-hydroxystearate, polysorbate, sorbitan fatty acid ester, poloxamer, sodium lauryl sulfate, monoglyceride, polyoxyethylene castor oil, and lecithin.

[0059] (4) The wetting agent is selected from one or more of cholates and sodium oleate;

[0060] (5) The wetting agent is selected from one or more of deoxycholic acid, glycocholic acid, ursodeoxycholic acid and sodium oleate;

[0061] (6) The stabilizer is selected from one or more of the following: povidone, cyclodextrin, sodium carboxymethyl cellulose and its sodium salt, polyethylene glycol, hydroxypropyl methylcellulose, and polyethylene glycol 1000 vitamin E succinate (TPGS);

[0062] (7) The pH adjuster is selected from one or more of sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium citrate and tartrate.

[0063] (8) The osmotic pressure regulator is selected from one or more of sucrose, mannitol, glycerol, sodium chloride, and glucose.

[0064] In a second aspect, this disclosure provides a pharmaceutical composition comprising:

[0065] 10-60% active ingredients;

[0066] Wetting agent 0.1-10%; and

[0067] 40-90% freeze-drying protectant;

[0068] The active ingredient is a compound with the structure shown in formula (I) or an acceptable pharmaceutical salt thereof.

[0069] In some embodiments, the active ingredient is compound A or an acceptable pharmaceutical salt thereof.

[0070] In some embodiments, the pharmaceutical composition is a solid dosage form.

[0071] In some embodiments, the pharmaceutical composition is a lyophilized formulation.

[0072] In some embodiments, the pharmaceutical composition is a lyophilized powder formulation.

[0073] In some embodiments, the pharmaceutical composition further includes at least one of a stabilizer or a pH adjuster.

[0074] In some embodiments, the wetting agent is selected from one or more of the following: bile salts, sodium oleate, polysorbates (e.g., Tween 20, 40, 60, 80), dehydrated sorbitan fatty acid esters (e.g., Span 20, 40, 60, 80), poloxamer, sodium lauryl sulfate, monoglycerides, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate (HS15), and lecithin.

[0075] In some embodiments, the freeze-drying protectant is selected from one or more of sucrose, trehalose, mannitol, lactose, maltose, glucose, glycerol, sorbitol, and albumin.

[0076] In some embodiments, the freeze-drying protectant is selected from one or both of sucrose and trehalose.

[0077] In some embodiments, the freeze-drying protectant is trehalose and glucose.

[0078] In some embodiments, the freeze-drying protectant is sucrose and mannitol.

[0079] In some embodiments, the stabilizer is selected from one or more of polyvinylpyrrolidone (PVP K12, PVP K17, PVPK30), carboxymethyl cellulose and its sodium salt, polyethylene glycols (e.g., polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000), and poloxamers (e.g., poloxamer 188, poloxamer 407).

[0080] In some embodiments, the pH adjuster is selected from at least one of sodium hydroxide, hydrochloric acid, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium acetate, sodium bicarbonate, citric acid, and acetic acid.

[0081] In some embodiments, the method for preparing the pharmaceutical composition includes the following steps:

[0082] Step 1-1: Dissolve the wetting agent in water to form solution A;

[0083] Steps 1-2: Disperse the active ingredient into solution A, stir until homogeneous, and form suspension B;

[0084] Steps 1-3: Obtain sample C or sample D by treating suspension B through ball milling, high-pressure homogenization, or microfluidic jet processing;

[0085] Steps 1-4: Add the remaining excipients to sample C or sample D, stir until completely dissolved, and then dispense to obtain the drug composition.

[0086] In some implementations, steps 1-3 further include the following operations:

[0087] Suspension B was placed in a ball mill and milled according to the specified parameters. After a certain period of time, the particle size of the suspension sample was monitored. Once the target particle size was reached, sample C was collected.

[0088] In some implementations, steps 1-3 further include the following operations:

[0089] Pour suspension B into a high-pressure homogenizer or microfluidic system, gradually adjust the pressure, and periodically check the particle size. Once the target particle size is reached, collect sample C.

[0090] In some implementations, steps 1-3 further include the following operations:

[0091] Suspension B is placed in a ball mill for ball milling. After a certain period of time, the particle size of the suspension sample is monitored. Once the target particle size is reached, sample C is collected. Sample C is then poured into a high-pressure homogenizer or microjet, the pressure is adjusted, and the particle size is monitored periodically. Once the target particle size is reached, sample D is collected.

[0092] In some implementations, the particle size of suspension B after steps 1-3 is reduced.

[0093] In some embodiments, the method for preparing the pharmaceutical composition includes the following steps:

[0094] Step 2-1: Dissolve the wetting agent in water to form solution A;

[0095] Step 2-2: Disperse the active ingredient into solution A to form suspension B;

[0096] Steps 2-3: Treat suspension B by ball milling, high-pressure homogenization and / or micro-jet homogenization;

[0097] Steps 2-4: Add the remaining excipients to sample D, stir until completely dissolved, dispense into vials, and freeze-dry to obtain the drug composition.

[0098] In some embodiments, step 2-2 further includes a step of mixing thoroughly.

[0099] In some implementations, steps 2-3 further include the following steps:

[0100] The suspension B was ball-milled, and the particle size of the suspension sample was monitored after a certain period of time. Once the target particle size was reached, sample C was collected.

[0101] In some implementations, steps 2-3 further include the following steps:

[0102] Pour suspension B into a high-pressure homogenizer or microfluidic system, gradually adjust the pressure, and periodically check the particle size. Once the target particle size is reached, collect sample C.

[0103] In some implementations, steps 2-3 further include the following steps:

[0104] Suspension B is placed in a ball mill for ball milling. After a certain period of time, the particle size of the suspension sample is monitored. Once the target particle size is reached, sample C is collected. Sample C is then poured into a high-pressure homogenizer or microjet, the pressure is adjusted, and the particle size is monitored periodically. Once the target particle size is reached, sample D is collected.

[0105] In some embodiments, the size of the grinding balls used in steps 1-3 or 2-3 is 0.1mm to 0.5mm, preferably 0.1mm to 0.4mm, for example 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm.

[0106] In some embodiments, the amount of grinding balls used in steps 1-3 or 2-3 is 50% to 70% of the filling amount of the ball mill cavity, preferably 60% to 70%.

[0107] In some embodiments, the ball milling speed in steps 1-3 or steps 2-3 is 1000 rpm to 3000 rpm, preferably 1500 rpm to 2000 rpm.

[0108] In some embodiments, the pump speed for ball milling in steps 1-3 or 2-3 is 100 ml / min to 500 ml / min, preferably 200 ml / min to 400 ml / min.

[0109] In some embodiments, the homogenization pressure in steps 1-3 or steps 2-3 is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1000 bar, and even more preferably not less than 1500 bar.

[0110] In some implementations, the homogenization time in steps 1-3 or steps 2-3 is not less than 10 minutes, preferably not less than 20 minutes, more preferably not less than 1 hour, and even more preferably not less than 3 hours.

[0111] In some implementations, the homogenization pressure in steps 1-3 or steps 2-3 is not less than 500 bar, preferably not less than 800 bar, more preferably not less than 1200 bar, and even more preferably not less than 2000 bar.

[0112] In some implementations, the number of homogenization cycles in steps 1-3 or steps 2-3 is not less than 10, preferably not less than 20, and more preferably not less than 30.

[0113] In some implementations, the freeze-drying in steps 2-4 includes pre-freezing, primary drying, and desorption drying.

[0114] In some embodiments, the set temperature of the pre-freezing process is -5 to -100°C; preferably -10 to -80°C; more preferably -20 to -60°C, for example -20°C, -30°C, -40°C, -50°C, or -60°C.

[0115] In some implementations, the primary drying process is divided into three stages.

[0116] In some embodiments, the first stage of the primary drying process is set at a temperature of -5 to -40°C; preferably -10 to -35°C; more preferably -15 to -30°C; for example, -15°C, -20°C, -25°C or -30°C.

[0117] In some embodiments, the set temperature of the second stage of the primary drying process is -1 to -15°C; preferably -3 to -10°C, for example -3°C, -4°C, -5°C, -6°C, -7°C, -8°C or -10°C.

[0118] In some embodiments, the set temperature of the third stage of the primary drying process is 1 to 15°C; preferably 3 to 10°C, for example 3°C, 4°C, 5°C, 6°C, 7°C, 8°C or 10°C.

[0119] In some embodiments, the first stage of the primary drying process is set for 30 to 240 minutes, preferably 60 to 180 minutes, and more preferably 90 to 150 minutes, for example, 90 minutes, 120 minutes, or 150 minutes.

[0120] In some embodiments, the set time for the second or third stage of the primary drying process is independently 10 to 120 minutes, preferably 30 to 90 minutes, more preferably 40 to 80 minutes, for example 40 minutes, 50 minutes, 60 minutes, 70 minutes, or 80 minutes.

[0121] In some embodiments, the duration of the first stage of the primary drying process is 12 to 36 hours, preferably 18 to 30 hours, and more preferably 22 to 26 hours, for example 22 hours, 23 hours, 24 hours, 25 hours, or 26 hours.

[0122] In some embodiments, the duration of the second or third stage of the primary drying process is independently 1 to 24 hours, preferably 6 to 18 hours, more preferably 9 to 15 hours, for example 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, or 15 hours.

[0123] In some embodiments, the set temperature of the analytical drying step is 1 to 60°C, preferably 10 to 50°C, more preferably 20 to 40°C, for example 25°C, 30°C, 35°C, or 40°C.

[0124] In some implementations, the set time for the analytical drying step is 10 to 120 minutes, preferably 30 to 90 minutes, and more preferably 40 to 80 minutes, for example 40 minutes, 50 minutes, 60 minutes, 70 minutes, or 80 minutes.

[0125] In some implementations, the duration of the analytical drying step is 1 to 24 hours, preferably 4 to 12 hours, for example 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours.

[0126] In some embodiments, the particle size Z-Average of the pharmaceutical composition is in the range of 100 nm to 800 nm, preferably 100 nm to 600 nm. This application also provides the use of the pharmaceutical composition in the preparation of medicaments for the prevention and / or treatment of NaV1.8-related diseases, preferably pain.

[0127] This application also provides the pharmaceutical composition for the prevention and / or treatment of NaV1.8-related diseases, preferably, the NaV1.8-related diseases being pain.

[0128] This application also provides pharmaceutical compositions as described in any of the above, for the prevention and / or treatment of NaV1.8-related diseases, preferably, said NaV1.8-related diseases being pain.

[0129] This application also provides methods for preventing and / or treating NaV1.8-related diseases, including administering an individual a preventive and / or therapeutically effective amount of the pharmaceutical composition, preferably, the NaV1.8-related disease being pain.

[0130] In some implementations, the pain is selected from, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain (e.g., pain from bunion removal, hernia repair, or abdominoplasty), visceral pain, etc., especially postoperative pain.

[0131] In some embodiments, the pharmaceutical composition is used simultaneously, alone, or sequentially in combination with other therapeutic or preventative agents.

[0132] In some implementations, the additional therapeutic or preventative agent is an analgesic.

[0133] As used in this article, the term "effective amount" refers to an amount sufficient to achieve the desired preventive or therapeutic effect, such as an amount that reduces one or more symptoms associated with the disease to be treated.

[0134] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that the dose value can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the nanoinjection of this disclosure.

[0135] The amount of the pharmaceutical composition administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. In some cases, a dose level not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0136] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or improve the condition or illness to which such term applies, or the progression of one or more symptoms of such condition or illness.

[0137] The term "prevention" refers to suppressing and delaying the onset of disease, including not only prevention before the disease develops, but also prevention of recurrence after treatment.

[0138] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this disclosure, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0139] Compared with the prior art, this disclosure has the following beneficial effects:

[0140] The pharmaceutical compositions and / or formulations disclosed herein exhibit controllable particle size and narrow distribution range, good stability, and can be used for intravenous injection. They provide rapid onset of action, effectively replacing opioid analgesics and reducing the risk of addiction. Furthermore, the pharmaceutical compositions and / or formulations disclosed herein do not contain excipients with sustained-release function, resulting in higher safety. The preparation process has good repeatability and is easy to scale up for industrial production. Detailed Implementation

[0141] The following detailed description of specific embodiments further illustrates the above-described content of this disclosure. However, it should not be construed as limiting the scope of the subject matter of this disclosure to the following examples. All technical solutions implemented based on the above-described content of this disclosure fall within the scope of this disclosure.

[0142] Example 1. Preparation of suspension

[0143] Weigh 0.245g of sodium hydroxide, add 118g of purified water, stir to dissolve, then add 2.4g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.4mm grinding beads, add the drug solution to the ball mill for ball milling, the ball milling parameters are: 1500rpm, pump speed: 200ml / min, condensate circulation temperature: 10℃. After ball milling for 2 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 222.3nm. Collect the ball milling liquid, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.4g of polyvinylpyrrolidone K30 and 8g of sucrose are added to 31.6g of water, stirred until completely dissolved, then add 40g of the ball milling liquid just collected, stir evenly to obtain a suspension, the sample average particle size Z-Average was measured to be 220.8nm.

[0144] Example 2. Preparation of suspension

[0145] Weigh 0.258g of sodium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of glycocholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; add the drug solution to a high-pressure homogenizer for homogenization, the homogenization parameters are: initially low pressure, 0-500 bar, gradually increase, 30 min; then change the pressure to 1500 bar, homogenize for 2 h, then take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 266.8nm. Collect the homogenized drug solution, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.4g of polyvinylpyrrolidone K12 and 4g of glycerin are added to 35.6g of water, stirred until completely dissolved, then add 40g of the homogenized drug solution just collected, stir evenly to obtain a suspension, the average particle size Z-Average of the sample is measured to be 274.6nm.

[0146] Example 3. Preparation of suspension

[0147] Weigh 0.214g of sodium hydroxide, add 118g of purified water, stir to dissolve, then add 2.1g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.1mm grinding beads, add the drug solution to the ball mill for ball milling, the ball milling parameters are: 1500rpm, pump speed: 150ml / min, condensate circulation temperature: 10℃. After ball milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 164.3nm. Collect the ball milling liquid, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.32g of polyvinylpyrrolidone K30 and 4.8g of sucrose are added to 34.88g of water, stirred until completely dissolved, then add 40g of the ball milling liquid just collected, stir evenly to obtain a suspension, the average particle size Z-Average of the sample is measured to be 190.6nm.

[0148] Example 4. Preparation of suspension

[0149] Weigh 0.155g of sodium hydroxide, add 126g of purified water, stir to dissolve, then add 1.8g of glycocholic acid, stir until completely dissolved, then add 22.5g of raw material, stir to disperse evenly; weigh 206g of 0.3mm grinding beads, add the drug solution to the ball mill for ball milling, the ball milling parameters are: 1500rpm, pump speed: 400ml / min, condensate circulation temperature: 10℃. After ball milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 210.5nm. Collect the ball milling liquid, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.12g of polyvinylpyrrolidone K12 and 3.6g of sucrose are added to 16.28g of water, stirred until completely dissolved, then add 40g of the ball milling liquid just collected, stir evenly to obtain a suspension, the average particle size Z-Average of the sample is measured to be 213.8nm.

[0150] Example 5. Preparation of suspension

[0151] Weigh 0.306g of sodium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of ursodeoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.3mm grinding beads, add the solution to a ball mill for ball milling, the ball milling parameters are: 2000rpm, pump speed: 200ml / min, condensate circulation temperature: 10℃. After ball milling for 2 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 215.5nm. The ball-milled solution is then added to a high-pressure homogenizer for homogenization, the homogenization parameters are: 1500bar, homogenize for 20 minutes, and take a sample again for particle size analysis using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 164.3nm. After collecting the homogenized drug solution, another excipient solution was prepared. The specific weighings were as follows: 0.4g of polyvinylpyrrolidone K30 and 4.8g of sucrose were added to 34.8g of water and stirred until completely dissolved. Then, 40g of the homogenized drug solution was added and stirred evenly to obtain a suspension. The average particle size Z-Average of the sample was measured to be 180.5nm.

[0152] Example 6. Preparation of Suspension

[0153] Weigh 9g of Tween 80, add 111g of purified water, stir until completely dissolved, then add 30g of raw material and stir to disperse evenly. Weigh 206g of 0.4mm milling beads, add the drug solution to the ball mill and mill. The milling parameters are: 1500rpm, pump speed: 200ml / min, and condensate circulation temperature: 5℃. After milling for 4 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size Z-Average = 232.4nm. Collect the milling liquid and prepare another excipient solution. The specific weighing is as follows: 0.4g of polyvinylpyrrolidone K17 and 4g of sucrose are added to 35.6g of water, stirred until completely dissolved, then add 40g of the collected milling liquid and stir evenly to obtain a suspension. The average particle size Z-Average of the sample was measured to be 266.2nm.

[0154] Example 7. Preparation of Suspension

[0155] Weigh 6g of HS15, add 114g of purified water, stir until completely dissolved, then add 30g of raw material and stir to disperse evenly. Weigh 206g of 0.4mm grinding beads, add the drug solution to the ball mill and ball mill. The ball milling parameters are: 1500rpm, pump speed: 150ml / min, and condensate circulation temperature: 5℃. After ball milling for 4 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size Z-Average = 228.7nm. Collect the ball milling liquid, and at the same time prepare another excipient solution. The specific weighing is as follows: 0.4g of polyvinylpyrrolidone K17 and 4g of sucrose are added to 35.6g of water, stirred until completely dissolved, then add 40g of the collected ball milling liquid, stir evenly to obtain a suspension, and the average particle size Z-Average of the sample is measured to be 250.5nm.

[0156] Example 8. Preparation of suspension

[0157] Weigh 1.8g of sodium oleate, add 118.2g of purified water, stir to dissolve, then add 30g of raw material and stir to disperse evenly. Weigh 206g of 0.3mm grinding beads, add the solution to a ball mill for grinding. The grinding parameters are: 1500rpm, pump speed: 150ml / min, and condensate circulation temperature: 10℃. After grinding for 2 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size Z-Average = 239.4nm. The milled solution is then added to a high-pressure homogenizer for homogenization. The homogenization parameters are: 1500bar. After homogenization for 20 minutes, take a sample and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size Z-Average = 198.8nm. After collecting the homogenized drug solution, another excipient solution was prepared. The specific weighing was as follows: 0.4g of polyvinylpyrrolidone K17 and 4g of sucrose were added to 35.6g of water and stirred until completely dissolved. Then, 40g of the homogenized drug solution was added and stirred evenly to obtain a suspension. The average particle size of the sample was measured to be Z-Average = 200.2nm.

[0158] Example 9. Preparation of suspension

[0159] Weigh 0.306g of sodium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.4mm milling beads, add the solution to a ball mill for milling, the milling parameters are: 1500rpm, pump speed: 150ml / min, condensate circulation temperature: 10℃. After milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 210.6nm. After collecting the ball milling slurry and stirring it evenly, the drug solution was added to a microfluidic jet for homogenization. The homogenization parameters were 2000 bar and 30 cycles. After that, a sample was taken and the particle size was measured using a Malvern nanoparticle size analyzer. The average particle size Z-Average was 168.8 nm. The homogenized drug solution was collected, and another excipient solution was prepared at the same time. The specific weighing was as follows: 0.4 g of polyvinylpyrrolidone K17 and 4 g of sucrose were added to 35.6 g of water and stirred until completely dissolved. Then, 40 g of the ball milling slurry that had just been collected was added and stirred evenly to obtain a suspension. The average particle size Z-Average of the sample was measured to be 214.6 nm.

[0160] Example 10. Preparation of suspension

[0161] Weigh 0.263g of sodium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of glycocholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.3mm milling beads, add the drug solution to the ball mill for milling, the milling parameters are: 2000rpm, pump speed: 150ml / min, condensate circulation temperature: 10℃. After milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 212.5nm. Collect the milled drug solution, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.4g of polyvinylpyrrolidone K17 and 4g of sucrose are added to 35.6g of water, stirred until completely dissolved, then add 40g of the homogenized drug solution just collected, stir evenly to obtain a suspension, the average particle size Z-Average of the sample is measured to be 210.3nm.

[0162] Example 11. Preparation of suspension

[0163] Weigh 0.430g of potassium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.3mm ball milling beads, add the drug solution to the ball mill for ball milling, the ball milling parameters are: 1500rpm, pump speed: 150ml / min, condensate circulation temperature: 10℃. After ball milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 215.8nm. Collect the ball-milled drug solution, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.4g of polyvinylpyrrolidone K17 and 4g of sucrose are added to 35.6g of water, stirred until completely dissolved, then add 40g of the homogenized drug solution just collected, stir evenly to obtain a suspension, the average particle size Z-Average of the sample is measured to be 220.3nm.

[0164] Example 12. Stability testing of formulation particle size

[0165] The particle size and resuspensibility of the samples prepared in Examples 6-11 were measured at 0 days and 30 days, respectively. After being placed at room temperature or 30°C for 30 days, the samples could be mixed within 1 minute by shaking. The particle size results are shown in Table 1.

[0166] Table 1 Screening of wetting agents for injectable products

[0167] The results in Table 1 show that although different wetting agents can prepare samples with the target particle size during ball milling, the particle size stability of the samples varies significantly during the later storage period: the particle size of samples prepared with Tween 80 and HS15 as wetting agents is unstable, and the particle size increases to the micrometer level after one month of storage at 30℃; the particle size of samples prepared with sodium oleate as a wetting agent increases slightly, but still meets the requirements. The particle size of samples prepared with bile salt surfactants as wetting agents is the most stable, and the samples also have good resuspension properties, and can be mixed within 30 seconds by manual shaking.

[0168] Example 13. Reconstitution stability of lyophilized formulations

[0169] A suspension containing 20% ​​raw material and 2% sodium glycocholate was prepared in batches of 150g. After uniform dispersion, the solution was added to a ball mill for ball milling. The ball milling parameters were: zircon beads: 0.4mm, filling amount: 70%, rotation speed: 1500rpm, pump speed: 200ml / min, and condensate circulation temperature: 10℃. After ball milling for 3 hours, samples were taken and the particle size was measured to be 233.0nm using a Malvern nanoparticle size analyzer. Simultaneously, another excipient solution containing 0.2% PVPK17 and different lyophilization protectants was prepared. The weight percentage content and types of lyophilization protectants in the suspension are shown in Table 3. After ball milling, the samples were added to the above excipient solution and filled into 10ml vials (2ml per vial) for lyophilization. The lyophilization process is shown in Table 2. After lyophilization, the vials were capped and stored at room temperature. The particle size of the lyophilized samples was measured. The results are shown in Table 3.

[0170] Table 2 Freeze-drying process parameters

[0171] Table 3 Results of particle size analysis after reconstitution

[0172] The results in Table 3 show that when 5% glucose or 10% glycine is used as a freeze-drying protectant, the particle size of the samples after freeze-drying and reconstitution increases significantly; when 10% mannitol is used as a freeze-drying protectant, the particle size of the samples after freeze-drying and reconstitution also increases, but still meets the requirements; while the samples obtained by using freeze-drying protectants of formulations 2, 3, 6-8 show little change in particle size after reconstitution and have high stability.

[0173] Example 14. Reconstitution stability of lyophilized formulations

[0174] Weigh 0.1g of polyvinylpyrrolidone K17, 2.5g of sucrose, and 2.5g of mannitol and add them to 32.4g of water. After stirring until completely dissolved, add 12.5g of the ball-milled drug solution as described in Examples 6 to 11 and stir until homogeneous to obtain a suspension. Then fill 10ml vials (2ml per vial) and freeze-dry. The freeze-drying process is shown in Table 2. After freeze-drying, cap and seal the vials and store at room temperature. Test the freeze-dried samples, and the results are shown in Table 4.

[0175] Table 4 Particle size detection of lyophilized formulations

[0176] The results in the table above show that when Tween 80 and HS15 are used as wetting agents to prepare samples, the particle size of the samples increases significantly to the micrometer level after freeze-drying and reconstitution, making them unusable. Samples prepared with sodium oleate and bile salt surfactants as wetting agents show little change in particle size after freeze-drying and reconstitution, and have high stability.

[0177] Example 15. Preparation of freeze-dried powder

[0178] Weigh 0.245g of sodium hydroxide, add 118g of purified water, stir to dissolve, then add 2.4g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.1mm grinding beads, add the drug solution to the ball mill for ball milling, the ball milling parameters are: 1500rpm, pump speed: 200ml / min, condensate circulation temperature: 10℃. After ball milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 200.3nm. Collect the ball milling liquid, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.16g of polyvinylpyrrolidone K17 and 8g of sucrose are added to 51.84g of water, stir to dissolve completely, then add 20g of the ball milling liquid just collected, stir evenly to obtain a suspension, then fill into 10ml vials, 2ml per vial, and freeze-dry. The freeze-drying process is shown in Table 2. After freeze-drying, the particles were capped and stored at room temperature. After rehydration with water, the average particle size Z-Average was 211.9 nm.

[0179] Example 16. Preparation of freeze-dried powder

[0180] Weigh 0.306g of sodium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of ursodeoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.1mm grinding beads, add the solution to a ball mill for ball milling, the ball milling parameters are: 2000rpm, pump speed: 200ml / min, condensate circulation temperature: 10℃. After ball milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 200.5nm. The ball-milled solution is then added to a high-pressure homogenizer for homogenization, the homogenization parameters are: 1500bar, homogenize for 20 minutes, and take a sample again for particle size analysis using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 160.3nm. After collecting the homogenized drug solution, another excipient solution was prepared simultaneously. The specific weighings were as follows: 0.16g of polyvinylpyrrolidone K30 and 8g of trehalose were added to 51.84g of water and stirred until completely dissolved. Then, 20g of the collected ball milling liquid was added and stirred until homogeneous to obtain a suspension. This suspension was then filled into 10ml vials (2ml per vial) and freeze-dried. The freeze-drying process is shown in Table 2. After freeze-drying, the vials were capped and stored at room temperature. After reconstitution with water, the average particle size Z-Average was 185.2nm.

[0181] Example 17. Preparation of freeze-dried powder

[0182] Weigh 0.430g of potassium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.1mm grinding beads, add the drug solution to the ball mill for ball milling, the ball milling parameters are: 2000rpm, pump speed: 150ml / min, condensate circulation temperature: 10℃. After ball milling for 3 hours, take a sample and use a Malvern nanoparticle size analyzer to detect the particle size, the average particle size Z-Average = 203.8nm, collect the ball milling liquid, and at the same time prepare another excipient solution, the specific weighing is as follows: 0.16g of polyvinylpyrrolidone K12, 4g of sucrose, 4g of mannitol are added to 51.84g of water, stir to dissolve completely, then add 20g of the ball milling liquid just collected, stir evenly to obtain a suspension, then fill into 10ml vials, 2ml per vial, and freeze-dry. The freeze-drying process is shown in Table 2. After freeze-drying, the particles were capped and stored at room temperature. After rehydration with water, the average particle size Z-Average = 220.6 nm.

[0183] Example 18. Preparation of freeze-dried powder

[0184] Weigh 0.306g of sodium hydroxide, add 117g of purified water, stir to dissolve, then add 3g of deoxycholic acid, stir until completely dissolved, then add 30g of raw material, stir to disperse evenly; weigh 206g of 0.3mm milling beads, add the solution to a ball mill for milling, the milling parameters are: 2000rpm, pump speed: 150ml / min, condensate circulation temperature: 10℃. After milling for 3 hours, take a sample and measure the particle size using a Malvern nanoparticle size analyzer, the average particle size Z-Average = 207.6nm. The ball milling slurry was collected and stirred evenly. The drug solution was then added to a microfluidic jet for homogenization at 2000 bar for 30 cycles. A sample was taken and the particle size was measured using a Malvern nanoparticle size analyzer. The average particle size (Z-Average) was 162.8 nm. The homogenized drug solution was collected, and simultaneously, another excipient solution was prepared. The specific weighings were as follows: 0.4 g of polyvinylpyrrolidone K30, 4 g of sucrose, and 4 g of mannitol were added to 51.6 g of water and stirred until completely dissolved. Then, 20 g of the collected ball milling slurry was added and stirred evenly to obtain a suspension. This suspension was then filled into 10 ml vials (2 ml per vial) and freeze-dried. The freeze-drying process is shown in Table 2. After freeze-drying, the vials were capped and stored at room temperature. After reconstitution with water, the average particle size (Z-Average) was 187.4 nm.

[0185] The embodiments described above are merely illustrative of several implementation methods of this disclosure, facilitating a detailed understanding of the technical solutions of the present invention, but should not be construed as limiting the scope of protection of the disclosed patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this disclosure, and these all fall within the scope of protection of this disclosure. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this disclosure through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A pharmaceutical composition comprising an active ingredient having the structure of formula (I) below, and pharmaceutically acceptable excipients selected from one or more of wetting agents, stabilizers, pH adjusters, osmotic pressure regulators, and lyophilization protectants: in: X 2a It is N, N + -O - or CR 2a ; X 4a It is N, N + -O - or CR 4a ; X 5a It is N, N + -O - or CR 5a ; X 6a It is N, N + -O - or CR 6a ; Each R is independently H or a C1-C6 alkyl group; R 2a R 4a R 5a and R 6a Each is independently H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; R 4b1 and R 4b2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; R 5b1 and R 5b2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; X 3c Is it N or CR? 3c ; X 4c Is it N or CR? 4c ; X 5c Is it N or CR? 5c ; X 6c Is it N or CR? 6c ; R 2c It is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -L 1 -L 2 -(C3-C6 cycloalkyl), wherein the cycloalkyl group is optionally substituted with 1-2 halogen groups; L 1 It is a key or an 'O'; L 2 It is a bond or a C1-C6 alkylene group; R 3c It is H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; R 4c It is H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; R 5c It is H, a halogroup, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; and R 6c It is H, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group; The constraint is X 2a X 4a X 5a and X 6a No more than two of them are N or N + -O - ;and The constraint is X 3c X 4c X 5c and X 6c No more than one of them is N.

2. The pharmaceutical composition according to claim 1, wherein, The active ingredient is compound A with the following structure or an acceptable pharmaceutical salt thereof:

3. The pharmaceutical composition according to claim 1 or 2, wherein, The pharmaceutical composition is a liquid formulation.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein, The pharmaceutical composition comprises the following components by weight percentage: Active ingredient 2.5%–30%, Wetting agent 0.1% to 5%, and The remainder is water for injection; Preferably, the pharmaceutical composition further comprises 0.1% to 5% by weight of a stabilizer.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein it meets one or more of the following conditions: (1) The pharmaceutical composition further comprises 0-1% of a pH adjuster; (2) The pharmaceutical composition further comprises 0% to 10% of an osmotic pressure regulator; (3) The wetting agent is selected from one or more of the following: bile salts, sodium oleate, polyethylene glycol 15-hydroxystearate, polysorbate, sorbitan fatty acid ester, poloxamer, sodium lauryl sulfate, monoglyceride, polyoxyethylene castor oil, and lecithin. (4) The wetting agent is selected from one or more of cholates and sodium oleate; (5) The wetting agent is selected from one or more of deoxycholic acid, glycocholic acid and ursodeoxycholic acid or sodium oleate. (6) The stabilizer is selected from one or more of the following: povidone, cyclodextrin, sodium carboxymethyl cellulose and its sodium salt, polyethylene glycol, hydroxypropyl methylcellulose, and polyethylene glycol 1000 vitamin E succinate (TPGS); (7) The pH adjuster is selected from one or more of sodium hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium citrate and tartrate. (8) The osmotic pressure regulator is selected from one or more of sucrose, mannitol, glycerol, sodium chloride, and glucose.

6. The pharmaceutical composition according to claim 1 or 2, wherein the composition comprises: 10-60% active ingredients; Wetting agent 0.1-10%; as well as 40-90% freeze-drying protectant; The active ingredient is a compound with the structure shown in formula (I) of claim 1, or an acceptable pharmaceutical salt thereof.

7. The pharmaceutical composition according to claim 6, wherein, The pharmaceutical composition is a lyophilized powder formulation.

8. The pharmaceutical composition according to claim 6 or 7, wherein it meets one or more of the following conditions: (1) The pharmaceutical composition further comprises at least one of a stabilizer or a pH adjuster; (2) The wetting agent is selected from one or more of the following: bile salts, sodium oleate, polysorbate, sorbitan fatty acid ester, poloxamer, sodium lauryl sulfate, monoglyceride glycerides, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate, and lecithin; (3) The freeze-drying protectant is selected from one or more of sucrose, trehalose, mannitol, lactose, maltose, glucose, glycerol, sorbitol and albumin; (4) The stabilizer is selected from one or more of polyvinylpyrrolidone, carboxymethyl cellulose and its sodium salt, polyethylene glycol, and poloxamer; (5) The pH adjuster is selected from at least one of sodium hydroxide, hydrochloric acid, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium acetate, sodium bicarbonate, citric acid and acetic acid.

9. A method for preparing a pharmaceutical composition according to any one of claims 1-5, comprising the following steps: Step 1-1: Dissolve the wetting agent in water to form solution A; Steps 1-2: Disperse the active ingredient into solution A, stir until homogeneous, and form suspension B; Steps 1-3: Obtain sample C or sample D by treating suspension B through ball milling, high-pressure homogenization, or microfluidic jet processing; Steps 1-4: Add the remaining excipients to sample C or sample D, stir until completely dissolved, and then dispense to obtain the drug composition.

10. A method for preparing a pharmaceutical composition according to any one of claims 1, 2, 6 and 7, comprising the following steps: Step 2-1: Dissolve the wetting agent in water to form solution A; Step 2-2: Disperse the active ingredient into solution A to form suspension B; Steps 2-3: Treat suspension B by ball milling, high-pressure homogenization and / or microfluidic jetting; Steps 2-4: Add the remaining excipients to sample D, stir until completely dissolved, dispense into vials, and freeze-dry to obtain the drug composition.

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