Celecoxib nanocrystal injection, preparation method therefor, and use thereof

Abstract

Provided are a celecoxib nanocrystal injection, a preparation method therefor, and use thereof, belonging to the field of pharmaceutical formulations. The provided celecoxib nanocrystal injection comprises celecoxib nanocrystals, a wetting agent, a stabilizer, and an osmotic pressure regulator. Moreover, the average particle diameter of the celecoxib nanocrystals is 100-500 nm. Optionally, the celecoxib nanocrystal injection further comprises a pH regulator and / or a lyoprotectant. After intravenous injection, the provided celecoxib nanocrystal injection can be rapidly dissolved in plasma, so that the application expectation of rapid onset of action in clinical acute pain management can be met. The celecoxib nanocrystal injection is prepared by adopting a combined technique of ball milling method and high-pressure homogenization. The ball milling method can process the micron-sized raw materials to the nanoscale, which can be further processed to a target particle diameter by high-pressure homogenization.

Description

Celecoxib nanocrystal injection and its preparation method and application

[0001] Citation of Related Applications

[0002] This disclosure claims priority to the invention patent application filed with the Patent Office of China on November 24, 2023, with application number 202311597305.0 and invention name “A celecoxib nanocrystal injection, its preparation method and application”, and incorporates its entire contents into this disclosure by reference. Technical Field

[0003] The present disclosure belongs to the field of pharmaceutical preparations, and specifically relates to a celecoxib nanocrystal injection, a preparation method, and applications thereof, and more specifically relates to a rapidly soluble and stable celecoxib nanocrystal injection, a preparation method, and applications thereof. Background Art

[0004] Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor that exerts analgesic effects by inhibiting the production of prostaglandins, the main substances that cause inflammation and pain. It has weaker gastrointestinal adverse reactions than non-selective nonsteroidal antiinflammatory drugs (NSAIDs).

[0005] Celecoxib is only available in oral capsule dosage form on the market at present, and indication includes rheumatoid arthritis, ankylosing spondylitis, acute pain etc. However, because celecoxib is almost insoluble in water, it belongs to biopharmaceutics classification system class II (BCS II) medicine, causes its gastrointestinal absorption to be limited, and bioavailability is lower (22~40%). In addition, for acute pain management, such as postoperative analgesia, expectation can be fast-acting during clinical application, and some patients have phenomena such as being unable to eat or dysphagia, and the clinical application of oral preparations is subject to certain restrictions. Therefore, the celecoxib new dosage form that develops parenteral administration route has important clinical application value.

[0006] Among the many published studies on new dosage forms of celecoxib, they can be roughly divided into two categories: carrier-based and non-carrier-based preparations. Representative types of carrier-based preparations include emulsions (such as disclosed in CN108472253A), microspheres (such as disclosed in CN112933050B), inclusion compounds (such as disclosed in CN113336874B), etc. On the one hand, such preparations are restricted by the carrier type and have a low drug loading capacity. On the other hand, the preparation process is relatively complex and industrial production is difficult. In comparison, the biggest advantage of non-carrier-based preparations represented by nanocrystals is that they do not require carrier materials and get rid of the drug loading constraint factor; secondly, the nanocrystal preparation process is relatively simple and has great industrial application and development potential.

[0007] The preparation methods of nanocrystal preparations can be divided into two categories: bottom-up method and top-down method. To avoid the use of organic solvents, which increases solvent residue and clinical application safety risks, celecoxib nanocrystal preparations are mostly prepared using the top-down method. For example:

[0008] CN103263385B discloses a method for preparing celecoxib nano-long-acting injection by combining airflow milling and high-pressure homogenization. The average particle size of the drug particles is 200-3000 nm; the prescription includes a surface stabilizer, a suspending agent (preferably PEG), and a pH regulator; the average particle size of the airflow milling is less than 200 μm, and the homogenization pressure is 50-2000 bar; the drug efficacy can be maintained for 3 days or more through intramuscular or subcutaneous injection.

[0009] CN105147607A discloses a celecoxib nanosuspension prepared by a high-speed shearing combined with a high-pressure homogenization method. The average particle size of celecoxib is 50 to 500 nm. The formulation includes a stabilizer, and a lyoprotectant is added during freeze-drying. During the preparation process, the mass volume concentration of celecoxib is 0.1 to 5%. The high-pressure homogenization conditions are 200 to 300 bar, and 8 to 15 cycles are performed at 500 to 1000 bar. The suspension can effectively increase the solubility and dissolution rate of the drug, and significantly improve the in vivo bioavailability.

[0010] CN108542886A discloses a celecoxib nanocrystal preparation using a ball milling method, resulting in a finished product with an average particle size of approximately 150 to 400 nm and a celecoxib content of 2 to 5 wt% during ball milling. This method also significantly improves celecoxib dissolution and bioavailability. CN114917188A also uses ball milling to prepare a celecoxib long-acting nanosuspension with a finished product particle size of 50 to 600 nm and a celecoxib mass-volume concentration of 1 to 30% during ball milling. This method achieves an analgesic effect of up to 10 days via intramuscular injection.

[0011] From the perspective of clinical application, these published researches mainly provide solutions for improving the bioavailability of celecoxib and prolonging the analgesic time, do not pay attention to the problem that acute pains such as postoperative pain, trauma need to be alleviated immediately, and do not clearly reach the clinical application expectation of rapid onset. From the perspective of preparation technology, published research shows that the concentration of celecoxib suspension should not be too high during high-pressure homogenization, otherwise the suspension viscosity is too high to reduce the homogenization efficiency, so in the disclosed scheme of CN103263385B and CN105147607A, celecoxib concentration is up to 5% during high-pressure homogenization. Lower suspension concentration limits product preparation efficiency, is unfavorable for industrialization transfer.

[0012] Summary of the Invention

[0013] Problems to be solved by the invention

[0014] At present, the prior art has studied celecoxib nanocrystal preparations, but it is still not sufficient. For example, in terms of application, the prior art does not pay attention to the problem of immediate relief for acute pain such as postoperative pain and trauma, and does not clearly reach the clinical application expectation of rapid onset; in terms of research, the prior art does not investigate product quality stability. Moreover, in the schemes disclosed in CN103263385B and CN105147607A, the celecoxib concentration is up to 5% during high-pressure homogenization, and the lower suspension concentration limits the preparation efficiency of the product, which is unfavorable for industrialization transfer. CN108542886A and CN114917188A both only adopt ball milling to prepare celecoxib nanocrystals. Although the celecoxib particle size can reach nanometer level, it is in the shape of a long rod. Based on the self-developed data of the inventors of the present disclosure, the particle size stability of the preparation is not good under this form; more seriously, if used for intravenous injection, it will increase the risk of vascular occlusion.

[0015] To this end, the present disclosure aims to provide a rapidly soluble and stable celecoxib nanocrystal injection and a preparation method thereof, so as to improve the drug dissolution rate and stability, provide an effective solution for clinical acute pain management, and improve product preparation efficiency through systematic process prescription optimization, which is more conducive to commercial production.

[0016] Solutions for solving problems

[0017] The first aspect of the present disclosure provides a celecoxib nanocrystal injection, which comprises celecoxib nanocrystals, a wetting agent, a stabilizer and an osmotic pressure regulator; and the average particle size of the celecoxib nanocrystals is 100 to 500 nm; optionally, the celecoxib nanocrystal injection further comprises a pH regulator and / or a lyoprotectant.

[0018] In some specific embodiments, the celecoxib nanocrystal injection comprises celecoxib nanocrystals, a wetting agent, a stabilizer, and an osmotic pressure regulator.

[0019] In some specific embodiments, the celecoxib nanocrystal injection comprises celecoxib nanocrystals, a wetting agent, a stabilizer, an osmotic pressure regulator, and a pH regulator.

[0020] In some specific embodiments, the celecoxib nanocrystal injection comprises celecoxib nanocrystals, a wetting agent, a stabilizer, an osmotic pressure regulator, and a lyoprotectant.

[0021] In some specific embodiments, the celecoxib nanocrystal injection comprises celecoxib nanocrystals, a wetting agent, a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant.

[0022] In some embodiments, the wetting agent is an ionic surfactant; preferably, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholic acid salt, deoxycholic acid, deoxycholic acid salt, cholic acid, cholic acid salt, oleic acid salt, lauryl sulfate, glycocholic acid, glycocholic acid salt, taurocholic acid and taurocholic acid salt; more preferably, the wetting agent is selected from any one or more of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate, sodium oleate and glycocholic acid.

[0023] In some specific embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholate, deoxycholic acid, deoxycholate, cholic acid, cholate, oleate and lauryl sulfate.

[0024] In some specific embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate and sodium oleate.

[0025] In some specific embodiments, the wetting agent is any one of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate and sodium oleate.

[0026] In some specific embodiments, the wetting agent is any one or more of glycocholic acid, glycocholate, taurocholic acid and taurocholate.

[0027] In some specific embodiments, the wetting agent is any one of glycocholic acid, sodium glycocholate, taurocholic acid and sodium taurocholate.

[0028] In some specific embodiments, the wetting agent is glycocholic acid.

[0029] In some embodiments, in the celecoxib nanocrystal injection, the mass ratio of the wetting agent to the celecoxib is (0.25-2.5):(5-15).

[0030] In some embodiments, the stabilizer is povidone; preferably, the stabilizer is selected from any one or more of PVP K12, PVP K15, PVP K17, PVP K25 and PVP K30.

[0031] In some specific embodiments, the stabilizer is any one of PVP K12, PVP K15, PVP K17, PVP K25 and PVP K30.

[0032] In some embodiments, in the celecoxib nanocrystal injection, the mass ratio of the stabilizer to the celecoxib is (0.05-1.5):(5-15).

[0033] In some embodiments, the osmotic pressure regulator is selected from any one or more of sodium chloride, sucrose, and glucose.

[0034] In some specific embodiments, the osmotic pressure regulator is any one of sodium chloride, sucrose and glucose.

[0035] In some embodiments, in the celecoxib nanocrystal injection, the mass ratio of the osmotic pressure regulator to the celecoxib is (1.5-30):(5-15).

[0036] In some embodiments, the pH adjuster is selected from any one or more of sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium bicarbonate.

[0037] In some embodiments, in the celecoxib nanocrystal injection, if present, the mass ratio of the pH adjuster to the celecoxib is (0.02-0.5):(5-15);

[0038] In some embodiments, the lyoprotectant is selected from any one or more of mannitol, sorbitol, trehalose, and lactose.

[0039] In some embodiments, in the celecoxib nanocrystal injection, if present, the mass ratio of the lyoprotectant to the celecoxib is (1-30):(5-15).

[0040] In some embodiments, the preparation method of the celecoxib nanocrystal injection comprises the steps of wet ball milling and high-pressure homogenization.

[0041] The second aspect of the present disclosure provides a method for preparing the celecoxib nanocrystal injection, comprising the following steps (a) to (d):

[0042] (a) preparing a suspension containing celecoxib and a wetting agent; wherein, by weight percentage, the content of celecoxib in the suspension is 10% to 30%, and the content of the wetting agent in the suspension is 0.5% to 5%; optionally, the suspension further comprises any one or more of a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant; if present, wherein, by weight percentage, the content of the stabilizer in the suspension is 0.1% to 3%, and / or the content of the osmotic pressure regulator in the suspension is 3% to 60%, and / or the content of the pH regulator in the suspension is 0.04% to 1%, and / or the content of the lyoprotectant in the suspension is 2% to 60%;

[0043] (b) wet ball milling the suspension to obtain a first-stage particle size-controlled product;

[0044] (c) performing high-pressure homogenization on the particle size-controlled product of the first stage to obtain a particle size-controlled product of the second stage;

[0045] (d) diluting the particle size controlled product of the second stage with a diluent to a target concentration; wherein the diluent comprises water and any one or more of the following optional substances: a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant;

[0046] Optionally, when the celecoxib used in step (a) is a non-sterile raw material, the method further comprises, before step (a), a step of recrystallizing the celecoxib to obtain sterile-grade celecoxib;

[0047] Optionally, when the celecoxib used in step (a) is a non-sterile raw material, the method further comprises a step of sterilizing the suspension before step (b);

[0048] Preferably, the method further comprises a freeze-drying step after step (d).

[0049] In some specific embodiments, the method comprises the following steps (a1) to (d1):

[0050] (a1) preparing a suspension consisting of celecoxib, a wetting agent, and water; wherein, by weight, the content of celecoxib in the suspension is 10% to 30%, and the content of the wetting agent in the suspension is 0.5% to 5%;

[0051] (b1) wet ball milling the suspension to obtain a first-stage particle size-controlled product;

[0052] (c1) performing high-pressure homogenization on the particle size-controlled product of the first stage to obtain a particle size-controlled product of the second stage;

[0053] (d1) diluting the second-stage particle size controlled product with a diluent until the target concentration is reached; wherein the diluent comprises water, a stabilizer, an osmotic pressure regulator, an optional pH regulator, and an optional lyoprotectant.

[0054] In some specific embodiments, the method comprises the following steps (a2) to (d2):

[0055] (a2) preparing a suspension consisting of water, celecoxib, a wetting agent, a stabilizer, an osmotic pressure regulator, an optional pH regulator, and an optional lyoprotectant; wherein, by weight, the content of celecoxib in the suspension is 10% to 30%, the content of the wetting agent in the suspension is 0.5% to 5%, the content of the stabilizer in the suspension is 0.1% to 3%, the content of the osmotic pressure regulator in the suspension is 3% to 60%, and if present, the content of the pH regulator in the suspension is 0.04% to 1%, and the content of the lyoprotectant in the suspension is 2% to 60%;

[0056] (b2) wet ball milling the suspension to obtain a first-stage particle size-controlled product;

[0057] (c2) performing high-pressure homogenization on the particle size-controlled product of the first stage to obtain a particle size-controlled product of the second stage;

[0058] (d2) diluting the second-stage particle size control product with water to a target concentration.

[0059] In some embodiments, the wet ball milling conditions include: medium size: 0.1 to 0.5 mm; medium filling amount: 50% to 80%; linear speed: 4 to 8 m / s; the ball milling system is cooled using a refrigerant at -10 to 20° C. during the ball milling process;

[0060] Preferably, the endpoint of the wet ball milling is that the average particle size of the particle size-controlled product in the first stage is 200 to 600 nm.

[0061] In some embodiments, the conditions for high-pressure homogenization include: homogenization pressure: 800 to 2000 bar; using a refrigerant at -10 to 10° C. to cool the homogenization system during the homogenization process;

[0062] Preferably, the endpoint of the high-pressure homogenization is that the average particle size of the particle size-controlled product in the second stage is 100 to 500 nm.

[0063] The third aspect of the present disclosure provides a celecoxib nanocrystal injection, which is prepared by the preparation method described in the second aspect of the present disclosure.

[0064] The fourth aspect of the present disclosure provides a celecoxib product, comprising the celecoxib nanocrystal injection according to the first aspect or the third aspect of the present disclosure and a container for filling the celecoxib nanocrystal injection;

[0065] Preferably, the container comprises any one of a vial, an ampoule and a syringe.

[0066] The fifth aspect of the present disclosure provides use of the celecoxib nanocrystal injection described in the first aspect or the third aspect of the present disclosure and / or the celecoxib product described in the fourth aspect of the present disclosure in the preparation of a medicament for relieving pain.

[0067] Effects of the Invention

[0068] Through the implementation of the above technical solutions, the present disclosure achieves the following beneficial technical effects:

[0069] First, the present disclosure provides a celecoxib nanocrystal injection, which enables celecoxib to be administered via small-volume intravenous injection. After intravenous injection, celecoxib can be rapidly dissolved in plasma, meeting the application expectations of rapid onset of clinical acute pain management (including but not limited to postoperative pain, traumatic pain, advanced cancer pain, and acute neuralgia). In addition, the celecoxib nanocrystal injection prepared by the present disclosure has good stability, with a particle size growth rate of no more than 5% when placed at 30°C or 40°C for one month. Furthermore, the present disclosure also provides a filled product containing the celecoxib nanocrystal injection, which facilitates the storage, transportation, and clinical application of the injection.

[0070] Secondly, the present disclosure provides a method for preparing the celecoxib nanocrystal injection, which utilizes a combined ball milling and high-pressure homogenization process. The ball milling process can process micron-scale raw materials to the nanoscale, and the high-pressure homogenization process can further reduce the target particle size. In the celecoxib nanocrystal injection provided by the present disclosure, the average particle size of the celecoxib nanocrystals is 100 to 500 nm, the aspect ratio is less than 5, and the particle length does not exceed 1 μm, which ensures that celecoxib has good safety during clinical use such as intravenous injection. In addition, during the preparation process, the drug solution concentration can reach 10% to 30% (w / w) during high-pressure homogenization, which is 2 to 6 times that of previously published technical solutions, significantly improving product preparation efficiency and being more conducive to commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1: Investigation results of celecoxib crystal forms in Example 6; wherein, from top to bottom in the figure are the XRD patterns of celecoxib raw material, C-013-3-after sterilization, C-013-3-after ball milling, C-013-3-after homogenization, and C-013-3.

[0072] FIG2A : TEM characterization results of sample C-023-Mill in Example 7; wherein, magnification: 2K, scale: 5 μm.

[0073] FIG2B : TEM characterization results of sample C-023 in Example 7; wherein, magnification: 12K, scale: 1 μm.

[0074] Figure 3: Dissolution curve of celecoxib nanocrystal injection in 5% (v / v) albumin solution in Example 8.

[0075] Figure 4: PK curve of celecoxib nanocrystal injection in SD rats in Example 8. DETAILED DESCRIPTION

[0076] The following describes the embodiments of the present disclosure, but the present disclosure is not limited thereto. The present disclosure is not limited to the various structures described below, and various modifications can be made within the scope of the protection claimed in the present disclosure. The embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present disclosure.

[0077] In the present disclosure, a numerical range expressed using "a value A to a value B" or "a value A - a value B" means a range including the endpoints A and B.

[0078] In the present disclosure, the use of “may” includes both the meanings of performing a certain process and the meaning of not performing a certain process.

[0079] In this disclosure, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0080] In the present disclosure, the term “a” or “an” or “the” may mean “one”, and may also mean “one or more”, “at least one” and “one or more than one”.

[0081] In this disclosure, the term "about" may mean that a value includes the standard error or standard deviation of the device or method used to determine the value. The numerical ranges and parameters used to define the present disclosure are all approximate values, and the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations caused by the aforementioned testing devices or methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within ±5%, ±3%, ±1% or ±0.5% of a particular value or range.

[0082] In the present disclosure, the “water” includes any feasible water that can be used in the art, such as deionized water, distilled water, ion-exchanged water, double-distilled water, high-purity water, purified water, and water for injection.

[0083] In the present disclosure, the "normal temperature" refers to 25±2°C.

[0084] In the present disclosure, the “normal pressure” refers to one standard atmospheric pressure.

[0085] Furthermore, unless otherwise defined, other technical and scientific terms used in the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0086] The technical solution of the present disclosure is further described below:

[0087] <Celecoxib Nanocrystal Injection>

[0088] The present disclosure provides a celecoxib nanocrystal injection, which comprises celecoxib, a wetting agent, a stabilizer and an osmotic pressure regulator; optionally, the celecoxib nanocrystal injection further comprises a pH regulator and / or a lyoprotectant.

[0089] In some embodiments, the celecoxib nanocrystal injection is a white or off-white suspension, that is, the celecoxib nanocrystal injection is a celecoxib nanocrystal injection. In other embodiments, the celecoxib nanocrystal injection is a white or off-white freeze-dried block, that is, the celecoxib nanocrystal injection is a celecoxib nanocrystal injection freeze-dried preparation. For the celecoxib nanocrystal injection freeze-dried preparation, a solvent (e.g., sterile water for injection) can be added before use and vigorously shaken for 30 to 60 seconds to form a white or off-white suspension, thereby forming an injection.

[0090] The celecoxib nanocrystal injection prepared in this disclosure rapidly dissolves in plasma (dissolution rate ≥98% in simulated plasma within 1 minute) and is primarily administered intravenously for the management of clinical acute pain, including but not limited to postoperative pain, traumatic pain, advanced cancer pain, and acute neuralgia. For clinical administration, a 26G (0.45×25mm) or higher needle can be used for injection, with an initial force of less than 15N and a sliding force of less than 10N.

[0091] [Celecoxib]

[0092] Celecoxib described in the present disclosure is a selective cyclooxygenase-2 inhibitor having the following structure:

[0093] In some embodiments, when the celecoxib nanocrystal injection is a liquid preparation, the content of celecoxib in the celecoxib nanocrystal injection is 5% to 15% by mass, for example, it can be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%, etc.; preferably, it is 7% to 13%, more preferably, it is 8% to 12%, even more preferably, it is 9% to 11%, and further preferably, it is 10%.

[0094] In some embodiments, in the celecoxib nanocrystal injection, the average particle size of the celecoxib nanocrystals is 100 to 500 nm, the aspect ratio is less than or equal to 5, preferably less than or equal to 3, and the maximum particle length does not exceed 1 μm.

[0095] [Wetting agent]

[0096] The main purpose of the wetting agent disclosed in the present invention is to reduce the surface energy of celecoxib particles so that they can form a uniform suspension in water.

[0097] In some embodiments, the wetting agent is an ionic surfactant. The present disclosure found that the ionic wetting agent is substantially unaffected by changes in celecoxib particle size and can be well adapted to the preparation process of the celecoxib nanocrystal injection provided by the present disclosure.

[0098] In some specific embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholate, deoxycholic acid, deoxycholate, cholic acid, cholate, oleate, lauryl sulfate and glycocholic acid, glycocholate, taurocholic acid and taurocholate.

[0099] In some specific embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholate, deoxycholic acid, deoxycholate, cholic acid, cholate, oleate and lauryl sulfate.

[0100] In some preferred embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholate, deoxycholic acid, deoxycholate, cholic acid, cholate, oleate, glycocholic acid, glycocholate, taurocholic acid and taurocholate.

[0101] In some preferred embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholate, deoxycholic acid, deoxycholate, cholic acid, cholate and oleate.

[0102] In some preferred embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, sodium ursodeoxycholate, deoxycholic acid, sodium deoxycholate, cholic acid, sodium cholate, sodium oleate and glycocholic acid.

[0103] In some preferred embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, sodium ursodeoxycholate, deoxycholic acid, sodium deoxycholate, cholic acid, sodium cholate and sodium oleate.

[0104] In some more preferred embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate, sodium oleate and glycocholic acid.

[0105] In some more preferred embodiments, the wetting agent is selected from any one or more of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate and sodium oleate.

[0106] In some more preferred embodiments, the wetting agent is selected from glycocholic acid.

[0107] In some embodiments, in the celecoxib nanocrystal injection, the mass ratio of the wetting agent to the celecoxib is (0.25-2.5):(5-15), preferably (0.3-2):(5-15), more preferably (0.3-2):10, for example, it can be 0.25:15, 0.2:10, 0.25:10, 0.3:10, 0.4:10, 0.5:10, 0.6:10, 0.7:10, 0.8:10, 0.9:10, 1:10, 1.1:10, 1.2:10, 1.3:10, 1.4:10, 1.5:10, 1.6:10, 1.7:10, 1.8:10, 1.9:10 or 2:10, etc.

[0108] In some embodiments, when the celecoxib nanocrystal injection is a liquid preparation, the content of the wetting agent in the celecoxib nanocrystal injection is 0.25% to 2.5% by mass, for example, it can be 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25% or 2.5%, etc.; preferably, it is 0.3% to 2%.

[0109] [Stabilizer]

[0110] The main purpose of the stabilizer disclosed in the present invention is to prevent the celecoxib nanocrystals from agglomerating during storage, thereby stabilizing the particle size of the celecoxib nanocrystals.

[0111] In some embodiments, the stabilizer is a povidone-type substance. Povidone has a good stabilizing effect on celecoxib nanocrystal injection.

[0112] In some specific embodiments, the stabilizer is selected from any one or more of PVP K12, PVP K15, PVP K17, PVP K25 and PVP K30.

[0113] In some embodiments, in the celecoxib nanocrystal injection, the mass ratio of the stabilizer to the celecoxib is (0.05-1.5):(5-15), preferably (0.1-0.9):(5-15), more preferably (0.1-0.9):10, for example, it can be 0.05:15, 0.05:10, 0.06:10, 0.07:10, 0.08:10, 0.09:10, 0.1:10, 0.2:10, 0.3:10, 0.4:10, 0.5:10, 0.6:10, 0.7:10, 0.8:10 or 0.9:10, etc.

[0114] In some embodiments, when the celecoxib nanocrystal injection is a liquid preparation, the content of the stabilizer in the celecoxib nanocrystal injection is 0.05% to 1.5% by mass, for example, it can be 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25% or 1.5%, etc.; preferably, it is 0.1% to 0.9%.

[0115] [Osmotic pressure regulator]

[0116] The main purpose of the osmotic pressure regulator described in this application is to adjust the osmotic pressure of the celecoxib nanocrystal injection to within the physiological range.

[0117] In some embodiments, the osmotic pressure regulator is selected from any one or more of sodium chloride, sucrose, and glucose.

[0118] In some embodiments, in the celecoxib nanocrystal injection, the mass ratio of the osmotic pressure regulator to the celecoxib is (1.5-30):(5-15), preferably (5-10):(5-15), more preferably (5-10):10, for example, it can be 1.5:15, 1.5:10, 2:10, 2.5:10, 3.0:10, 3.5:10, 4.0:10, 4.5:10, 5.0:10, 5.5:10, 6:10, 6.5:10, 7:10, 7.5:10, 8:10, 8.5:10, 9:10 or 10:10, etc.

[0119] In some embodiments, when the celecoxib nanocrystal injection is a liquid preparation, the content of the osmotic pressure regulator in the celecoxib nanocrystal injection is 1.5% to 30% by mass, for example, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%, etc., preferably 5% to 10%.

[0120] [pH adjuster]

[0121] The main purpose of the pH regulator described in this application is to adjust the pH value of the celecoxib nanocrystal injection to within the physiological range. In some embodiments, the pH regulator can also help dissolve some of the poorly soluble wetting agents.

[0122] In some embodiments, the pH adjuster is selected from any one or more of sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium bicarbonate.

[0123] In some embodiments, in the celecoxib nanocrystal injection, if the pH regulator is present, the mass ratio of the pH regulator to the celecoxib is (0.02-0.5):(5-15), preferably (0.11-0.22):(5-15), more preferably (0.11-0.22):10, for example, it can be 0.02:15, 0.02:10, 0.03:10, 0.04:10, 0.05:10, 0.06:10, 0.07:10, 0.08:10, 0.09:10, 0.1:10, 0.11:10, 0.12:10, 0.13:10, 0.14:10, 0.15:10, 0.16:10, 0.17:10, 0.18:10, 0.19:10, 0.2:10, 0.22:10, 0.26:10, 0.28:10, 0.3:10, 0.31:10, 0.33:10, 0.35:10, 0.37:10, 0.39:10, 0.4:10, 0.42:10, 0.44:10, 0.46:10, 0.48:10 or 0.5:10, etc.

[0124] In some embodiments, when the celecoxib nanocrystal injection is a liquid preparation, the content of the pH regulator in the celecoxib nanocrystal injection is 0.02% to 0.5% by mass, for example, it can be 0.02%, 0.04%, 0.06%, 0.08%, 0.1%, 0.11%, 0.13%, 0.15%, 0.17%, 0.19%, 0.2%, 0.22%, 0.26%, 0.28%, 0.3%, 0.31%, 0.33%, 0.35%, 0.37%, 0.39%, 0.4%, 0.42%, 0.44%, 0.46%, 0.48% or 0.5%, etc., preferably 0.11% to 0.22%.

[0125] [Lyophilization protectant]

[0126] The main purpose of the lyoprotectant disclosed in the present invention is to maintain the stability of the properties of the celecoxib nanocrystal injection during the freeze-drying process.

[0127] In some embodiments, the lyoprotectant is selected from any one or more of mannitol, sorbitol, trehalose, and lactose.

[0128] In some embodiments, in the celecoxib nanocrystal injection, if the lyoprotectant is present, the mass ratio of the lyoprotectant to the celecoxib is (1-30):(5-15), for example, it can be 1:10, 2:10, 3:10, 4:10, 5:10, 6:10, 7:10, 8:10, 9:10, 10:10, 11:10, 12:10, 13:10, 14:10, 15:10, 16:10, 17:10, 18:10, 19:10, 20:10, 21:10, 22:10, 23:10, 24:10, 25:10, 26:10, 27:10, 28:10, 29:10 or 30:10, etc.

[0129] In some embodiments, when the celecoxib nanocrystal injection is a liquid preparation, the content of the lyoprotectant in the celecoxib nanocrystal injection is 1% to 30% by mass, for example, it can be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%, etc.

[0130] <Preparation Method of Celecoxib Nanocrystal Injection>

[0131] The present disclosure provides a method for preparing the above-mentioned celecoxib nanocrystal injection, which comprises the following steps:

[0132] (a) preparing a suspension containing celecoxib and a wetting agent; wherein, by weight percentage, the content of celecoxib in the suspension is 10% to 30%, and the content of the wetting agent in the suspension is 0.5% to 5%; optionally, the suspension further comprises any one or more of a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant; if present, wherein, by weight percentage, the content of the stabilizer in the suspension is 0.1% to 3%, and / or the content of the osmotic pressure regulator in the suspension is 3% to 60%, and / or the content of the pH regulator in the suspension is 0.04% to 1%, and / or the content of the lyoprotectant in the suspension is 2% to 60%;

[0133] (b) wet ball milling the suspension to obtain a first-stage particle size-controlled product;

[0134] (c) performing high-pressure homogenization on the particle size-controlled product of the first stage to obtain a particle size-controlled product of the second stage;

[0135] (d) diluting the particle size controlled product of the second stage with a diluent to a target concentration; wherein the diluent comprises any one or more of water, a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant.

[0136] The preparation method of the celecoxib nanocrystal injection provided by the present disclosure comprises the combined use of ball milling and high-pressure homogenization. Ball milling can process micron-sized raw materials to the nanoscale, and then high-pressure homogenization can be performed to the target particle size. For the excipients mentioned in the preparation method, such as wetting agents, stabilizers, osmotic pressure regulators, pH regulators, and lyoprotectants, their specific optional materials are as described in the above-mentioned "Celecoxib Nanocrystal Injection" section.

[0137] [Preparation of sterile grade celecoxib]

[0138] When the raw material drug celecoxib is not sterile, sterile grade celecoxib can be obtained by recrystallization.

[0139] In some embodiments, the recrystallization method includes the following steps: dissolving, sterilizing filtration, crystallization, filtration and washing; optionally, the filtration and washing steps include a suspension step; optionally, the filtration and washing steps include a drying step; optionally, the drying steps include a crushing and screening step.

[0140] In some embodiments, the solvent in the dissolving step is selected from alcohols or ketones, such as ethanol, propanol, and acetone.

[0141] In some embodiments, the mass of the solvent in the dissolving step is 2-10 times the mass of celecoxib, for example, it can be 5-10 times, 7-10 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times or 10 times, etc.

[0142] In some embodiments, heating may be performed during the dissolving step, and the heating temperature is no higher than the boiling point of the solvent, for example, the heating temperature may be half the boiling point of the solvent.

[0143] In some embodiments, the sterilization filtration step is to pass the dissolved celecoxib solution through at least one 0.22 μm sterilization grade filter.

[0144] In some embodiments, the sterilization filtration step is to first pass the dissolved celecoxib solution through at least one pre-filtration filter selected from 0.65 μm or 0.45 μm, and then pass it through at least one 0.22 μm sterilization grade filter.

[0145] In some embodiments, the sterilization filtration step is to pass the dissolved celecoxib solution through 0.45 μm, 0.22 μm, and 0.22 μm sterilization-grade filter cartridges in sequence, or through 0.65 μm, 0.22 μm, and 0.22 μm sterilization-grade filter cartridges in sequence.

[0146] In some embodiments, the filter element in the sterilization filtration step is made of polyvinylidene fluoride (PVDF) or polytetrafluoroethylene (PTFE).

[0147] In some embodiments, the crystallization step is to mix the sterile filtered celecoxib solution with a crystallization solvent, wherein the crystallization solvent is selected from water or a mixed solvent of water and an organic solvent; preferably, the crystallization solvent is water.

[0148] In some embodiments, the crystallization step is to add the sterile filtered celecoxib solution to the crystallization solvent, or to add the crystallization solvent to the sterile filtered celecoxib solution.

[0149] In some embodiments, the mass of the crystallization solvent in the crystallization step is 5-20 times the mass of celecoxib, for example, 10-20 times or 10-15 times.

[0150] In some embodiments, the crystallization temperature in the crystallization step is controlled to be 0-30°C, for example, 10-25°C or 20-25°C.

[0151] In some embodiments, after the crystallization is completed in the crystallization step, the incubation is continued for 0.5-4 hours.

[0152] In some embodiments, the crystallization solvent in the crystallization step passes through at least one 0.22 μm sterilizing grade filter.

[0153] In some embodiments, the filtration and washing is to separate the precipitated celecoxib crystals from the liquid and wash them with a washing solvent, wherein the washing solvent is selected from water or a mixed solvent of water and an organic solvent; preferably, the washing solvent is water.

[0154] In some embodiments, the mass of the washing solvent in the filtration and washing is 0.5-5 times the mass of celecoxib, for example, it can be 1-5 times, 1.5-5 times, or 1.5-4 times, etc.

[0155] In some embodiments, the wash solvent in the filter wash passes through at least one 0.22 μm sterilizing grade filter element.

[0156] In some embodiments, after filtering and washing, the filter cake is re-suspended with a solution containing at least a wetting agent so that the resulting suspension has the same composition as the suspension prepared in step (a), and subsequent steps such as ball milling and high-pressure homogenization are continued.

[0157] In some embodiments, after filtration and washing, the sterile-grade celecoxib solid powder is obtained after drying, and a suspension is prepared according to step (a), and subsequent steps such as ball milling and high-pressure homogenization are performed. Alternatively, after obtaining the sterile-grade celecoxib solid powder, it is first crushed and sieved, and then a suspension is prepared according to step (a), and subsequent steps such as ball milling and high-pressure homogenization are performed. The sterile-grade celecoxib solid powder has a Dv90 of no greater than 50 μm (Dv90 represents the particle size corresponding to 90% of the particles in the volume distribution).

[0158] [Step (a)]

[0159] In order to carry out ball milling process to celecoxib, need first be formulated into suspension.In some embodiments, in suspension, comprise celecoxib and wetting agent, by mass percentage, the content of described celecoxib in described suspension is 10%~30%, for example, can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% etc., the content of described wetting agent in described suspension is 0.5%~5%, for example, can be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% etc. The present invention can effectively stabilize the fluidity of the suspension during the ball milling process by selecting a reasonable wetting agent and controlling its concentration, so that the suspension can be ball milled and homogenized under high pressure at a high concentration of celecoxib, thereby greatly improving the preparation efficiency.

[0160] In order to promote the dissolution of the excipients, in some specific embodiments, the suspension may be heated during preparation, for example, to 65±10°C.

[0161] In some embodiments, the suspension further comprises any one or more of a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant.

[0162] In some embodiments, the suspension further comprises the stabilizer, and the content of the stabilizer in the suspension is 0.1% to 3% by mass, for example, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5% or 3%, etc.

[0163] In some embodiments, the suspension further comprises the osmotic pressure regulator, and the content of the osmotic pressure regulator in the suspension is 3% to 60% by mass, for example, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%. , 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60%, etc.

[0164] In some embodiments, the suspension further comprises the pH regulator, and the content of the pH regulator in the suspension is 0.04% to 1% by mass, for example, 0.04%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95% or 1%, etc.

[0165] In some embodiments, the suspension further comprises the lyoprotectant, and the content of the lyoprotectant in the suspension is 2% to 60% by mass, for example, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%. %, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60%, etc.

[0166] In order to provide a more stable, safe and easy-to-use celecoxib nanocrystal injection, in some embodiments, when the raw material drug celecoxib used in step (a) is not sterile, the suspension prepared can be sterilized, preferably using an excessive sterilization method with F0 ≥ 12 to carry out in situ sterilization of the suspension. When taking this scheme, optionally, only celecoxib, wetting agent and water are included in the suspension, and other components are added during the subsequent dilution step. Further, after sterilization, shearing treatment can be carried out, linear speed: 7~15m / s, shearing time: 3~10min, so that the suspension particle size is restored to a considerable level before sterilization.

[0167] [Step (b)]

[0168] The present disclosure utilizes a ball milling method to perform first-stage particle size control on the suspension.

[0169] In order to achieve a good ball milling effect and obtain the first stage particle size controlled product of the target particle size, the ball milling parameters can be appropriately controlled. In some embodiments, the ball milling conditions include: medium size: 0.1-0.5 mm, for example, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm or 0.5 mm; medium filling amount: 50%-80%, for example, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80%; Linear speed: 4-8 m / s, for example, 4 m / s, 5 m / s, 6 m / s, 7 m / s or 8 m / s; The ball milling system is cooled using a refrigerant at -10 to 20°C during the ball milling process, for example, a refrigerant at -10°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C or 20°C can be used to cool the ball milling system.

[0170] In some embodiments, the flow rate of the ball mill is 20% to 60% of the maximum flow rate of the peristaltic pump, and the flow rate is preferably gradually increased to the target value, for example, it can be gradually increased to 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% or 60% of the maximum flow rate of the peristaltic pump. Those skilled in the art can select a specific peristaltic pump and its flow rate according to actual needs.

[0171] In some embodiments, the endpoint of the ball milling is that the average particle size of the particle size controlled product in the first stage is 200-600 nm.

[0172] In addition, the ball milling described in this disclosure refers to a technical processing process, which can achieve the desired goal through a ball mill or equipment with similar working principles.

[0173] During ball milling, celecoxib exhibits a dominant fractured crystal plane, resulting in rod-shaped particles of varying lengths. The maximum aspect ratio is approximately 8-10, and the maximum particle length can reach approximately 3-5 μm. Based on the experimental data disclosed herein, sample stability is poor at this stage, and there is a risk of capillary clogging during clinical use, necessitating a second stage of particle size control.

[0174] Furthermore, in some embodiments, in order to facilitate the subsequent second-stage particle size control and improve the preparation efficiency, the concentration of the first-stage particle size control product can be appropriately adjusted.

[0175] [Step (c)]

[0176] The present disclosure utilizes high-pressure homogenization to perform second-stage particle size control on the suspension that has undergone first-stage particle size control.

[0177] The present disclosure discovered that based on the optimized suspension formulation, it breaks through the concentration limit of the drug solution and can successfully complete high-pressure homogenization processing under the condition of a higher concentration of celecoxib (10% to 30%, w / w), which is 2 to 6 times that of the existing technical solutions, significantly improving the processing efficiency.

[0178] In order to achieve a good homogenization effect and obtain the second stage particle size control product of the target particle size, the high pressure homogenization parameters can be appropriately controlled. In some embodiments, the conditions of the high pressure homogenization include: homogenization pressure: 800 to 2000 bar, for example, it can be 800 bar, 900 bar, 1000 bar, 1100 bar, 1200 bar, 1300 bar, 1400 bar, 1500 bar, 1600 bar, 1700 bar, 1800 bar, 1900 bar or 2000 bar; the homogenization process uses a refrigerant of -10 to 10°C to cool the homogenization system, for example, a refrigerant of -10°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C or 10°C can be used to cool the homogenization system.

[0179] In some embodiments, the flow rate of the high-pressure homogenization is 10 to 200 L / h, for example, it can be 10 L / h, 11 L / h, 12 L / h, 13 L / h, 14 L / h, 15 L / h, 16 L / h, 17 L / h, 18 L / h, 19 L / h, 20 L / h, 30 L / h, 40 L / h, 50 L / h, 60 L / h, 70 L / h, 80 L / h, 90 L / h, 100 L / h, 150 L / h or 200 L / h, etc.

[0180] In some embodiments, the endpoint of the high-pressure homogenization is that the average particle size of the particle size-controlled product in the second stage is 100 to 500 nm.

[0181] The present disclosure found that compared with the product after ball milling, the long rod-shaped particles after high-pressure homogenization are significantly reduced, and the particles are short rod-shaped or block-shaped, with an aspect ratio of less than or equal to 5, preferably less than or equal to 3, and the maximum particle length does not exceed 1 μm. The sample stability is significantly improved (after being placed at 40°C for 1 month, the average particle size (Z-Average) growth rate is no more than 5%), and it has improved clinical application safety.

[0182] In addition, the high-pressure homogenization described in the present disclosure refers to a technical processing process, which can achieve the desired goal through a high-pressure homogenizer, micro jet or equipment with similar working principles.

[0183] [Step (d)]

[0184] In some embodiments, the second-stage particle size controlled product may be diluted with a diluent to a target concentration.

[0185] In some specific embodiments, the diluent comprises water and any one or more of the following optional substances: a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyoprotectant. The present disclosure does not particularly limit the specific contents of the diluent, as long as the diluent is mixed with the second-stage particle size control product to meet the requirements of the various components in the celecoxib nanocrystal injection.

[0186] In some embodiments, the water in the diluent is preferably water for injection.

[0187] The present disclosure does not impose any particular limitation on the concentration of each component of the diluent, as long as the concentration of each component in the celecoxib nanocrystal injection is achieved after mixing with the particle size controlled product of the second stage.

[0188] In some embodiments, the diluent can be sterilized for mixing with the sterile second-stage particle size control product to produce a sterile preparation. Sterilization of the diluent can be achieved, for example, by using a redundant filtration system consisting of two 0.45 and 0.22 μm filter elements in series. Furthermore, the diluted drug solution can be filtered through a 1-10 μm filter, using, but not limited to, single-layer / multi-layer mesh stainless steel filter elements, stainless steel sintered filter elements, and titanium filter elements, to remove any mechanical debris or large foreign matter, further enhancing the quality assurance of the finished product.

[0189] [Other steps]

[0190] In order to provide a more stable, safe and convenient celecoxib nanocrystal injection, the preparation method provided in the present disclosure may further include other processing steps acceptable in the art.

[0191] In some embodiments, the preparation method further includes step (e): filling the diluted product with packaging materials acceptable in the art. Optional filling materials include but are not limited to vials, ampoules, and prefilled syringes for medium / high borosilicate injections.

[0192] In some embodiments, in order to facilitate the long-term storage and transportation of celecoxib nanocrystal injection, the filled liquid can be freeze-dried. In some specific embodiments, the freeze-drying process includes the following stages: pre-freezing stage: the oil temperature is cooled to about -40°C within 2 hours and maintained for about 2 to 3 hours; the oil temperature is raised to about -20°C within 1 hour and maintained for about 2 hours; the oil temperature is lowered to about -40°C within 1 hour and maintained for about 2 to 3 hours; sublimation and desorption drying stage: vacuum degree 15 to 25 Pa, from about -40°C to about -20°C within 3 hours, maintained for about 12 to 24 hours; from about -20°C to -5°C within 2 hours, maintained for about 12 to 24 hours; the temperature is raised to 10°C within 1 hour and maintained for 0.5 to 1 hour; nitrogen or compressed air is filled and unpacked.

[0193] <Celecoxib Products>

[0194] The present disclosure provides a celecoxib product, which comprises the celecoxib nanocrystal injection and a container for filling the celecoxib nanocrystal injection.

[0195] In some embodiments, the container is a liquid medicine packaging material acceptable in the art, including but not limited to vials, ampoules and syringes for medium / high borosilicate injections.

[0196] In some specific embodiments, when the celecoxib nanocrystal injection is a lyophilized preparation, a double-chamber prefilled syringe can be selected as the packaging material, with one chamber storing the lyophilized block and the other chamber storing the solvent to facilitate storage, transportation and clinical application of the preparation.

[0197] <Medical Use>

[0198] In some embodiments, the celecoxib nanocrystal injection and / or the celecoxib product described in the present disclosure can be used to prepare a drug for relieving pain; preferably, the pain includes acute pain.

[0199] In some embodiments, the celecoxib nanocrystal injection and / or the celecoxib product described in the present disclosure can be used to relieve pain; preferably, the pain includes acute pain.

[0200] In some embodiments, the present disclosure provides a method for relieving pain, which may comprise administering an effective amount of the celecoxib nanocrystal injection and / or the celecoxib product to an individual in need thereof; preferably, the pain comprises acute pain.

[0201] Example

[0202] To more clearly illustrate the technical solutions of the present disclosure, the following examples are provided for further explanation. However, these examples are not intended to limit the present disclosure and are merely partial examples. Unless otherwise specified, the instruments, reagents, materials, and experimental animals used in the present disclosure were all commercially available. Where specific conditions are not specified in the examples, conventional conditions or those recommended by the manufacturer were used.

[0203] Preparation Example 1: Preparation of sterile grade celecoxib

[0204] 12 kg of standard pharmaceutical-grade celecoxib was dissolved in 94 kg of anhydrous ethanol (heated to 40°C) and filtered through three-stage PVDF filter cartridges (0.45 μm, 0.22 μm, and 0.22 μm). The celecoxib solution was obtained. 142 kg of water for injection was filtered through two-stage PES filter cartridges (0.22 μm and 0.22 μm). The temperature was controlled at 20-25°C, and the celecoxib solution was added dropwise after stirring. The temperature was maintained for 2 hours after the addition was complete. After filtration, the filter cake was rinsed with 18 kg of sterile-filtered water for injection. The filter cake was stirred and dried under vacuum at -0.08 MPa and 48-53°C, then pulverized and sieved to obtain sterile-grade celecoxib (yield 90%). The particle size was measured by laser particle size analyzer dry method, Dv90: 13 μm.

[0205] Example 1: Wetting agent screening and optimization

[0206] Sample preparation: Based on the type and dosage of the wetting agent to be investigated, a suspension was prepared (batch size: 300 g, the suspension consisted of celecoxib, the wetting agent to be investigated, an optional pH adjuster and water). The celecoxib content in the suspension was 25% (w / w). The suspension state was observed, and the first stage of particle size control was completed by ball milling. The ball milling conditions were: ball milling medium size: 0.3 mm, medium filling amount: 75%, linear speed: 5 m / s, flow rate: gradually adjusted to 20% of the maximum flow rate of the peristaltic pump, and the drug solution was cooled using a refrigerant (15°C) during the ball milling process. After ball milling, the drug solution was directly processed by a high-pressure homogenizer to complete the second stage of particle size control. The homogenization pressure was 1500 bar, the flow rate was 13.5 L / h, and the drug solution was cooled using a -10°C refrigerant during the homogenization process. The homogenized liquid was diluted with a diluent to a celecoxib content of 10% (w / w), the diluent consisting of povidone K17, sucrose and water, and the diluted liquid contained 0.3% (w / w) povidone K17 and 5% (w / w) sucrose.

[0207] Quality inspection: Measure the Zeta potential of the diluted samples and inspect their particle size stability at 30°C or 40°C.

[0208] Particle size detection: Malvern nanoparticle size analyzer (ZEN1690).

[0209] The survey results are shown in Table 1-1 and Table 1-2.

[0210] Table 1-1 Wetting agent screening results

[0211] Table 1-2 Wetting agent screening results

[0212] According to the investigation results, all the wetting agents investigated can make celecoxib form a uniform suspension in water. However, in the ball milling stage (i.e., the first stage of particle size control), as the particle size decreases from micrometer level to nanometer level, the wetting effect of non-ionic wetting agents (such as polyethylene glycol (15)-hydroxystearate (HS15) and Tween 80) is significantly weakened, the fluidity of the drug solution deteriorates, and the second stage of particle size control cannot be continued. During the experiment, it was unexpectedly discovered that the ionic wetting agent was basically unaffected by the change in the size of the celecoxib particles, so that the drug solution at a high concentration (celecoxib content of 25% (w / w) in this embodiment) was able to successfully complete the second stage of particle size control. Therefore, the wetting agent is preferably an ionic wetting agent represented by sodium oleate, ursodeoxycholic acid (UDCA), deoxycholic acid (DOCA), sodium deoxycholate (DOCA-Na) or glycocholic acid (GCA). The particle size of the drug solution after dilution is also relatively stable (after optimizing its dosage, the particle size growth rate is no more than 5% after being placed at 30°C or 40°C for one month).

[0213] Example 2: Stabilizer screening and optimization

[0214] Sample preparation: A suspension (batch size of 300 g) was prepared using ursodeoxycholic acid as a wetting agent. The suspension contained 25% (w / w) celecoxib, 5% (w / w) UDCA, and 0.55% (w / w) NaOH, with the remainder being water. The first stage of particle size control was achieved by ball milling. Ball milling conditions included: ball milling media size: 0.3 mm, media fill: 75%, linear velocity: 5 m / s, and flow rate: gradually adjusted to 20% of the maximum flow rate of the peristaltic pump. The drug solution was cooled with refrigerant (15°C) during the ball milling process, and the particle size change was monitored. After ball milling, the drug solution was directly processed in a high-pressure homogenizer to achieve the second stage of particle size control. The homogenization pressure was 1500 bar and the flow rate was 13.5 L / h. The drug solution was cooled with a -10°C refrigerant during the homogenization process. The homogenized liquid was diluted with a diluent to a celecoxib content of 10% (w / w). The diluent consisted of the stabilizer to be investigated, sucrose and water. The diluted liquid contained 2% (w / w) UDCA, 0.22% (w / w) NaOH and 5% (w / w) sucrose.

[0215] Particle size detection: same as in Example 1.

[0216] The results of the investigation are shown in Table 2.

[0217] Table 2 Stabilizer screening results

[0218] According to the investigation results, polyvidone (PVP) stabilizers are significantly better than polyethylene glycol (PEG 4000) and cellulose derivatives (sodium carboxymethylcellulose (CMC-Na)). Specifically, PVP K12 and PVP K17 have a good stabilizing effect on celecoxib nanocrystal injection (after their dosage is optimized, the particle size growth rate is no more than 5% after being placed at 40°C for one month).

[0219] Example 3: Investigation of sterilization conditions

[0220] The celecoxib nanocrystal injection prepared by the present disclosure proposes route of administration as intravenous injection, and when sterile grade celecoxib raw material can not be satisfied, the requirement of sterile injection can be reached by carrying out in situ sterilization to suspension.Using UDCA as wetting agent, suspension (300g in batches) is prepared, and in suspension, celecoxib content 25% (w / w), UDCA content 5% (w / w), NaOH content 0.55% (w / w), PVP K17 content 0.75% (w / w), sucrose content 7.5% (w / w), all the other are water.The suspension prepared is sterilized under 121 ℃ × 12min, 121 ℃ × 30min and 124 ℃ × 12min conditions respectively, contrast suspension properties, particle diameter, pH, content, related substances change situation before and after sterilization, and confirm sterilizing effect, investigation result is as shown in table 3.

[0221] Particle size detection: same as in Example 1.

[0222] Table 3 Sterilization conditions investigation results

[0223] After the suspension was sterilized under the three sterilization conditions, no significant differences were observed in any of the test parameters, indicating sterile growth in all samples. The particle size of the samples increased slightly, but recovered to a similar level before sterilization after shearing. The suspension was sterile when sterilized at 121°C for 12 minutes, ensuring overkill. The suspension also withstood temperature fluctuations during the sterilization process (124°C) and extreme conditions in actual production where the cumulative F0 exceeded 12 (12 ≤ F0 ≤ 30).

[0224] Example 4: Investigation of ball milling process parameters

[0225] During the ball milling process, the main influencing factors include ball milling medium size, filling amount, linear velocity, flow rate (expressed as a percentage of the maximum flow rate of the peristaltic pump), and liquid concentration. These main influencing factors were investigated.

[0226] Suspensions containing celecoxib at varying concentrations (batch size: 300 g) were prepared using sodium deoxycholate (DOCA-Na) as a wetting agent. The DOCA-Na content in the suspension was 1 / 5 of the celecoxib content, with the remainder being water. The prepared suspensions were ball-milled under the desired conditions. The milling process was cooled using a refrigerant (15°C). The milling process and particle size changes were monitored.

[0227] Particle size detection method: same as Example 1.

[0228] The results of the investigation are shown in Table 4.

[0229] Table 4 Results of ball milling process parameters

[0230] The results show that smaller ball milling media and higher linear speeds result in smaller particle sizes after milling, consistent with the principles of wet ball milling. Furthermore, it was found that directly using small ball milling media (0.1 mm) can produce even smaller particle sizes, but this results in lower initial milling efficiency. This suggests that initial particle size control can be split into two steps, initially using larger ball milling media (e.g., 0.5 mm, 0.3 mm) for a period of time before switching to smaller ball milling media (e.g., 0.1 mm) for further milling.

[0231] Example 5: Investigation of high pressure homogenization process parameters

[0232] In this embodiment, a high-pressure homogenizer is used for high-pressure homogenization.

[0233] The main factors influencing the high-pressure homogenization process include drug concentration, feed particle size, homogenization pressure, and drug temperature. Celecoxib suspensions (batch size: 300 g) were prepared using UDCA as a wetting agent. The UDCA content in the suspension was 1 / 10 of the celecoxib content, the NaOH content was 1 / 10 of the UDCA content, and the remainder was water. The prepared suspensions were sterilized at 121°C for 12 min, sheared for 5 min (9.4 m / s), and ball milled for the first stage of particle size control. The ball milling conditions included: ball milling media size: 0.3 mm, media fill: 75%, linear velocity: 5 m / s, and flow rate: gradually adjusted to 20% of the maximum flow rate of the peristaltic pump. The drug solution was cooled using a refrigerant (15°C) during the ball milling process, and particle size changes were monitored. The endpoint particle size of the ball milling was the feed particle size during the high-pressure homogenization process. The ball-milled liquid was subjected to high-pressure homogenization under the conditions to be investigated, with a flow rate of 13.5 L / h. During the homogenization process, the liquid was cooled with a -10°C refrigerant.

[0234] Particle size detection method: same as Example 1.

[0235] The survey results are shown in Table 5.

[0236] Table 5 Results of investigation on high pressure homogenization process parameters

[0237] According to the investigation result, the medicinal liquid concentration can smoothly complete the high pressure homogenization process when it is up to 30% (w / w), and the medicinal liquid has good fluidity during the homogenization process. When the medicinal liquid concentration reduces the situation (such as 10%~30%, w / w), high pressure homogenization can also be smoothly completed. In the embodiment, the situation that celecoxib content is 25% (w / w) during high pressure homogenization is in the majority. The feed particle size is positively correlated with the medicinal liquid particle size after homogenization, and the larger the feed particle size is, the larger the particle size of the medicinal liquid after homogenization is; less homogenization pressure, if reaching the appropriate particle size effect of high pressure homogenization, needs to significantly increase the homogenization number of times. During the homogenization process, the medicinal liquid temperature has no obvious effect on the preparation process within the range of about 5~30 ℃.

[0238] Example 6: Investigation of Celecoxib Crystal Forms during Preparation

[0239] During the sample preparation process, overkill sterilization, ball milling and high-pressure homogenization processes will input a large amount of energy (such as thermal energy and mechanical energy) into the drug solution, which may trigger celecoxib crystal transformation.

[0240] Investigation method: Take part of the suspension of C-013-3-after sterilization (Example 3) and perform the first stage particle size control by ball milling. The ball milling conditions are as follows: ball milling medium size: 0.3 mm, medium filling amount: 75%, linear speed: 5 m / s, flow rate: gradually adjusted to 20% of the maximum flow rate of the peristaltic pump, and the liquid was cooled by refrigerant (15 ° C) during the ball milling process. After the particle size (Z-Average) is 235.1 nm (sample number : C-013-3-after ball milling), and then subjected to second-stage particle size control by high-pressure homogenization (pressure: 1500 bar, flow rate: 13.5 L / h, refrigerant temperature: -10°C). The particle size (Z-Average) after 45 homogenization times was 203.9 nm (sample number: C-013-3-after homogenization); after homogenization, the celecoxib content was 10% (w / w) after the liquid was diluted with water (sample number: C-013-3). Parts of C-013-3-after sterilization, C-013-3-after ball milling, C-013-3-after homogenization, and C-013-3 were filtered through a 0.22 μm filter membrane, and the filter cake was rinsed with water and dried. The dried filter cake and celecoxib raw material were subjected to XRD characterization together, and the test results are shown in Figure 1.

[0241] According to XRD testing result, after sterilization, ball milling, homogenization treatment, crystal formation does not change in medicinal liquid, and medicinal liquid stability is good. There is advantage fracture crystal face in celecoxib in ball milling process, and drug granules are rod-shaped (seeing embodiment 7) of different lengths after ball milling, so the XRD pattern of celecoxib after ball milling is slightly different from celecoxib raw material; Long rod-shaped particles obviously reduce after homogenization, and are short rod-shaped or bulk (seeing embodiment 7), and the XRD pattern of celecoxib after homogenization is consistent with celecoxib raw material.

[0242] Example 7: Preparation of samples and investigation of celecoxib morphology and stability during the process

[0243] Sample preparation: Ursodeoxycholic acid was used as a wetting agent to prepare a suspension (batch size 300 g), containing celecoxib 25% (w / w), UDCA 2.5% (w / w), NaOH 0.285% (w / w), the rest is water. After sterilization (121℃×12min), the first stage of particle size control is completed by ball milling. The ball milling conditions are as follows: ball milling medium size: 0.3mm, medium filling amount: 75%, linear speed: 5m / s, flow rate: gradually adjusted to 20%. The drug solution is cooled by refrigerant (15℃) during the ball milling process and ground to 375.2nm (Z-Average, sample number: C-023-after grinding); after ball milling, the drug solution is directly processed by a high-pressure homogenizer to complete the second stage of particle size control. The homogenization pressure is 1500bar and the flow rate is 13.5L / h. The drug solution is cooled by -10℃ refrigerant during the homogenization process. The particle size after 45 homogenization is 271.4nm (Z-Average). The homogenized solution was diluted to 10% (w / w) celecoxib using a diluent consisting of PVP K17, sucrose, and water. The resulting particle size was 262.8 nm (Z-Average, Sample No.: C-023). A separate portion of the C-023-milled sample was diluted with the same diluent to create the same composition as C-023 (Sample No.: C-023-Mill).

[0244] C-023-Mill and C-023 were sent for transmission electron microscopy (TEM) for morphological characterization, and their particle size stability was investigated at 40°C.

[0245] The results of the investigation are shown in Figure 2A, Figure 2B and Table 6.

[0246] Table 6 Investigation on the stability of sample particle size

[0247] The results of the investigation revealed that celecoxib exhibited a dominant fracture plane during the ball milling process, resulting in rod-shaped, variably sized particles with a maximum aspect ratio of approximately 8 to 10 and a maximum particle length of approximately 3 to 5 μm. The presence of this dominant plane was reflected in the differences in the XRD pattern after ball milling compared to the celecoxib raw material (Example 6). The particle size stability of the milled particles was significantly poor, with the particle size increasing by approximately 100% after being stored at 40°C for one month.

[0248] After high-pressure homogenization treatment, the long rod-shaped particles are significantly reduced and become short rods or blocks. The maximum aspect ratio is about 3 to 5, the particle length does not exceed 1 μm, and the particle size stability is significantly improved. After being placed at 40°C for one month, the particle size growth rate is less than 5%.

[0249] Example 8: Performance evaluation of prefilled syringe packaging materials

[0250] A portion of C-023 was filled into a COP prefilled syringe. After stoppering, the syringe was installed with a push rod and 26G (0.45×15mm), 23G (0.6×25mm), and 22G (0.7×30mm) needles, respectively. The starting force and sliding force were tested on a universal testing machine (AGS-X, Shimadzu). The test results are shown in Table 7.

[0251] Table 7 Performance test of prefilled syringes

[0252] According to the test results, when the minimum specification needle (0.45×15mm) is installed, the starting force is <15N and the sliding force is <10N, indicating that the preparation can be injected with a needle of 0.45×15mm or above in clinical application.

[0253] Example 9: Investigation of Rapid Solubility of Celecoxib Nanocrystal Injection

[0254] ① Turbidimetric method investigation

[0255] Using a 5% (v / v) albumin solution to simulate plasma, 15 mL of the 5% (v / v) albumin solution was measured for turbidity as a baseline value (the celecoxib dissolution rate was considered 100%). C-023 was then added to a celecoxib concentration of 0.1 mg / mL (human plasma volume was calculated as 2.4 L, the maximum oral daily dose was 600 mg, and the bioavailability was calculated as 40%). The solution was immediately shaken and dispersed, and the turbidity was measured (the celecoxib dissolution rate was considered 0%). The solution was then placed in a 37°C water bath and shaken for 1 minute before the turbidity was measured again. The celecoxib dissolution rate was estimated based on the turbidity values. The results of the investigation are shown in Table 8.

[0256] Table 8 Turbidimetric method for measuring the dissolution rate of celecoxib

[0257] ② Theoretical calculation method to predict the dissolution time of celecoxib granules

[0258] Using a 5% (v / v) albumin solution to simulate plasma, the following steps were used to predict the time required for complete dissolution of celecoxib particles of varying sizes (reference: 1,3-Dicyclohexyl urea nanosuspension for intravenous steady-state delivery in rats, Journal of Experimental Nanoscience, Vol. 2, No. 3, September 2007, 239–250).

[0259] i) Solubility test

[0260] About 10 mL of 5% (v / v) albumin solution was taken, and about 0.1 g of celecoxib raw material was added. The solution was placed in a constant temperature oscillator and shaken for 24 h (37). After filtration with a 0.45 μm filter membrane, the content was detected, and the solubility was measured to be 0.33 mg / mL.

[0261] ii) Dissolution rate test

[0262] 50 mg celecoxib tablets (15 kg × 3 times, 2 min / time, diameter 4 mm) were taken and the drug-loaded mold was immersed in 600 mL of 5% albumin solution at 37 ° C and 50 rpm. Samples were taken at 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8 h, filtered through a 0.45 μm filter membrane, and sent for content analysis. The dissolution rate was obtained based on the concentration-time linear relationship (Figure 3 and Table 9). The dissolution rate was 3×10 -5 μg / mL / s;

[0263] Table 9 Concentration-time linear relationship

[0264] iii) Diffusion coefficient calculation:

[0265] The diffusion coefficient was calculated according to the Noyes and Whitney equation:

[0266] Where dC / dt: dissolution rate; D: diffusion coefficient; V: volume of dissolution medium; h d : diffusion layer thickness (assuming that the diffusion layer thickness is consistent with the average particle size of the sample); S: solute area; Cs: saturated solubility; C t (t): drug concentration at time t.

[0267] iv) Calculate the theoretical dissolution time:

[0268] The dissolution time of products with different particle sizes was calculated according to the Hixson–Crowell equation:

[0269] Where Γ is the estimated time for complete dissolution; ρ is the density of the medium, expressed as 1 g / ml; r0 is the radius of the particle; D is the diffusion coefficient; and Cs is the saturation solubility.

[0270] The diffusion coefficient and theoretical dissolution time of celecoxib particles in the particle size range of 100 to 500 nm were calculated based on the experimental data. The results are shown in Table 10. Theoretically, all particles can be completely dissolved within 1 minute.

[0271] Table 10 Theoretical dissolution time of celecoxib particles in the range of 100-500 nm

[0272] ③In vivo PK behavior investigation

[0273] i) Oral sample preparation: Celecoxib was ultrasonically dispersed in a dispersant consisting of methylcellulose (0.5%, w / w) and Tween 80 (0.1%, w / w). The celecoxib content was 0.5% (w / w). Sample number: C-024.

[0274] ii) Intravenous injection sample: C-023.

[0275] iii) Dosage Regimen: Male SD rats were randomly divided into two groups, 5 rats per group, and administered 20 mg / kg intravenously and orally, respectively. Plasma concentrations were measured at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours, and 48 hours. The resulting plasma concentration-time curves are shown in Figure 4. Compared with oral administration, intravenous injection resulted in an instantaneous peak in plasma concentration, while oral administration reached peak concentration approximately 3 hours later. It is expected that the onset of action after intravenous injection will be significantly faster than that of the oral formulation.

[0276] Based on the above experimental results, it can be seen that the dissolution rate of celecoxib nanocrystal injection in simulated plasma is ≥98% in 1 minute; the theoretical complete dissolution time in the particle size range of 100 to 500 nm is all <1 minute; the PK results of SD rats show that the peak time after intravenous injection is significantly earlier than that of the oral route. All these indicate that the celecoxib nanocrystal injection prepared by the present invention can be rapidly dissolved in plasma after intravenous injection, and can meet the application expectations of rapid onset of clinical acute pain management.

Claims

1. A celecoxib nanocrystal injection, characterized in that, The celecoxib nanocrystal injection comprises celecoxib nanocrystals, a wetting agent, a stabilizer and an osmotic pressure regulator; and the average particle size of the celecoxib nanocrystals is 100 to 500 nm; optionally, the celecoxib nanocrystal injection further comprises a pH regulator and / or a lyophilization protectant.

2. The celecoxib nanocrystal injection according to claim 1, characterized in that The wetting agent is an ionic surfactant; preferably, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, deoxycholic acid, bile acid, bile acid salt, oleate and dodecyl sulfate; or, preferably, the wetting agent is selected from any one or more of ursodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, deoxycholic acid, bile acid, bile acid salt, oleate, dodecyl sulfate, glycocholic acid, glycocholic acid, taurocholic acid and taurocholic acid; more preferably, the wetting agent is selected from any one or more of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate and sodium oleate; or, more preferably, the wetting agent is selected from any one or more of ursodeoxycholic acid, deoxycholic acid, sodium deoxycholate, sodium oleate and glycocholic acid; and / or, in the celecoxib nanocrystal injection, the mass ratio of the wetting agent to the celecoxib is (0.25-2.5):(5-15); and / or, The stabilizer is povidone; preferably, the stabilizer is selected from any one or more of PVP K12, PVP K15, PVP K17, PVP K25 and PVP K30; and / or, in the celecoxib nanocrystal injection, the mass ratio of the stabilizer to the celecoxib is (0.05-1.5):(5-15); and / or, The osmotic pressure regulator is selected from any one or more of sodium chloride, sucrose and glucose; and / or, in the celecoxib nanocrystal injection, the mass ratio of the osmotic pressure regulator to the celecoxib is (1.5-30):(5-15).

3. The celecoxib nanocrystal injection according to claim 1 or 2, characterized in that, The pH regulator is selected from any one or more of sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium bicarbonate; and / or, in the celecoxib nanocrystal injection, if present, the mass ratio of the pH regulator to the celecoxib is (0.02-0.5):(5-15); and / or, The lyoprotectant is selected from any one or more of mannitol, sorbitol, trehalose and lactose; and / or, in the celecoxib nanocrystal injection, if present, the mass ratio of the lyoprotectant to the celecoxib is (1-30):(5-15).

4. The celecoxib nanocrystal injection according to any one of claims 1 to 3, characterized in that: The preparation method of the celecoxib nanocrystal injection comprises the steps of wet ball milling and high-pressure homogenization.

5. The method for preparing the celecoxib nanocrystal injection according to any one of claims 1 to 4, characterized in that: The method comprises the following steps (a) to (d): (a) preparing a suspension containing celecoxib and a wetting agent; wherein, by weight percentage, the content of celecoxib in the suspension is 10% to 30%, and the content of the wetting agent in the suspension is 0.5% to 5%; optionally, the suspension further comprises any one or more of a stabilizer, an osmotic pressure regulator, a pH regulator and a lyophilization protectant; if present, wherein, by weight percentage, the content of the stabilizer in the suspension is 0.1% to 3%, and / or, the content of the osmotic pressure regulator in the suspension is 3% to 60%, and / or, the content of the pH regulator in the suspension is 0.04% to 1%, and / or, the content of the lyophilization protectant in the suspension is 2% to 60%; (b) subjecting the suspension to wet ball milling to obtain a first-stage particle size controlled product; (c) performing high pressure homogenization on the particle size controlled product of the first stage to obtain a particle size controlled product of the second stage; (d) diluting the particle size controlled product of the second stage with a diluent to a target concentration; wherein the diluent comprises water and any one or more of the following optional substances: a stabilizer, an osmotic pressure regulator, a pH regulator, and a lyophilization protectant; Optionally, when the celecoxib used in step (a) is a non-sterile raw material, the method further comprises a step of recrystallizing the celecoxib to obtain sterile grade celecoxib before step (a); Optionally, when the celecoxib used in step (a) is a non-sterile raw material, the method further comprises a step of sterilizing the suspension before step (b); Preferably, the method further comprises a freeze-drying step after step (d).

6. The preparation method according to claim 5, characterized in that: The conditions of the wet ball milling include: medium size: 0.1-0.5 mm; medium filling amount: 50%-80%; linear speed: 4-8 m / s; the ball milling system is cooled by a refrigerant at -10-20° C. during the ball milling process; Preferably, the endpoint of the wet ball milling is that the average particle size of the particle size controlled product in the first stage is 200 to 600 nm.

7. The preparation method according to claim 5 or 6, characterized in that: The conditions of the high-pressure homogenization include: homogenization pressure: 800 to 2000 bar; during the homogenization process, a refrigerant at -10 to 10°C is used to cool the homogenization system; Preferably, the endpoint of the high-pressure homogenization is that the average particle size of the particle size controlled product in the second stage is 100 to 500 nm.

8. A celecoxib nanocrystal injection, characterized in that: The celecoxib nanocrystal injection is prepared by the preparation method according to any one of claims 5 to 7.

9. A celecoxib product, characterized in that: The celecoxib product comprises the celecoxib nanocrystal injection according to any one of claims 1 to 4 or claim 8 and a container for filling the celecoxib nanocrystal injection; Preferably, the container comprises any one of a vial, an ampoule and a syringe.

10. Use of the celecoxib nanocrystal injection according to any one of claims 1 to 4 or claim 8 and / or the celecoxib product according to claim 9 in the preparation of a medicament for relieving pain.

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