Composition of non-steroidal Anti-inflammatory drug

Abstract

The present invention relates to a non-steroidal anti-inflammatory drug injection formulation and belongs to the field of pharmaceutical formulations. The formulation comprises a non-steroidal anti-inflammatory drug, a suspending agent, a stabilizer, and the like. The formulation may be a ready-to-use liquid injection. The formulation has a significant slow-release effect after being injected and can prolong the drug action time, thereby reducing the administration frequency, enhancing patient compliance, and improving bioavailability. Meanwhile, the present invention further provides a method for preparing the non-steroidal anti-inflammatory drug injection formulation. The method is simple and economical and thus is suitable for industrial production.

Description

A composition of nonsteroidal anti-inflammatory drugs Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a composition of non-steroidal anti-inflammatory drugs and a preparation method thereof. Background Art

[0002] Acute pain is one of the common clinical symptoms. It is a physiological response and experience to harmful stimuli, usually with sudden onset, including postoperative pain, acute back pain, renal colic, musculoskeletal pain and pain related to other diseases. The duration of pain generally does not exceed 7 days. For example, postoperative pain usually lasts for 3-7 days. Non-steroidal anti-inflammatory drugs (NSAIDs) achieve antipyretic and analgesic effects by inhibiting cyclooxygenase and reducing the production of prostaglandins. They are commonly used clinically to control and relieve acute pain. However, existing NSAIDs drugs usually have a slow onset of action in oral preparations, while the duration of action of injections is generally several hours (less than 1 day). It is difficult for a single dose to meet the long-term analgesic requirements, and frequent administration is required. There are problems such as poor drug management and patient compliance.

[0003] Given the sudden onset and duration of acute pain, it is necessary to develop a long-acting injection of non-steroidal anti-inflammatory drugs (NSAIDs) that can take effect quickly and maintain blood drug concentrations for a long time.

[0004] The following nonsteroidal anti-inflammatory drugs or their salts can be prepared into long-acting injections: celecoxib, parecoxib, etoricoxib, meloxicam, ketorolac tromethamine, flurbiprofen axetil, lornoxicam or ibuprofen.

[0005] Celecoxib (English name celecoxib), chemical name is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1-hydrogen-1-pyrazol-1-yl]benzenesulfonamide, and its chemical structure is shown in formula (A):

[0006] The chemical name of celecoxib propionyl sodium is N-[[4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1-hydrogen-1-pyrazol-1-yl]phenyl)sulfonyl)-sodium salt, and the chemical structure is shown in formula (B):

[0007] Parecoxib (English name: Parecoxib), chemical name: N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide, chemical structure is shown in formula (C): Summary of the Invention

[0008] SUMMARY OF THE INVENTION

[0009] In a first aspect, the present invention provides an injection whose active ingredient is a non-steroidal anti-inflammatory drug. The injection can be administered once a day or longer, can take effect quickly and maintain effective blood drug concentration for a long time. Compared with oral administration, it can improve bioavailability, reduce the number of doses, avoid peak-to-valley fluctuations, and thus improve patient treatment compliance and safety.

[0010] In a second aspect, the present invention provides an injection comprising a combination of a nonsteroidal anti-inflammatory drug and a salt thereof as an active ingredient. The injection can be administered once daily or longer, exhibiting rapid onset of action and sustained effective blood drug concentrations over a long period of time. The weight ratio of the nonsteroidal anti-inflammatory drug to its salt in the formulation significantly influences the onset of action and the duration of steady-state blood drug concentration.

[0011] The injection provided by the present invention has a high concentration of active ingredients, a high drug loading, and a controllable particle size. It can obtain a higher dosage within a limited injection volume, and achieve a long-lasting drug release effect by controlling the particle size distribution. It is well known to those skilled in the art that the more types of excipients added to the injection, the greater the risk introduced. The injection provided by the present invention has a simple prescription and only requires the addition of fewer types of excipients, which can reduce the risks brought by the excipients. The injection provided by the present invention is a ready-to-use injection and can be used directly. The injection provided by the present invention has good storage stability.

[0012] The third aspect of the present invention provides a method for preparing the injection, which is simple and easy to implement, has good stability, high safety, and is suitable for industrial production.

[0013] The fourth aspect of the present invention provides use of the injection in preparing a drug for treating acute pain or postoperative analgesia.

[0014] Definition of terms

[0015] The present invention is intended to encompass all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0016] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0017] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0018] The term "include" or "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0019] In the present invention, "optionally" or "optionally" means that it may or may not be present, such as "optionally containing a buffer" means that a buffer may or may not be contained.

[0020] In the context of the present invention, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may vary by less than 10% or by a reasonable difference considered by those skilled in the art, such as 1%, 2%, 3%, 4% or 5%.

[0021] The term "D10" refers to the particle size corresponding to when the cumulative particle size volume distribution percentage of a sample reaches 10%, the term "D50" refers to the particle size corresponding to when the cumulative particle size volume distribution percentage of a sample reaches 50%, and the term "D90" refers to the particle size corresponding to when the cumulative particle size volume distribution percentage of a sample reaches 90%.

[0022] "qs" specifies the capacity.

[0023] LC-MS / MS refers to triple tandem liquid chromatography-mass spectrometry.

[0024] “Sustained release” means that the blood concentration of celecoxib or other nonsteroidal anti-inflammatory drugs can be detected based on the detection limit of the LC-MS / MS analytical instrument when testing the sample.

[0025] CMC refers to carboxymethyl cellulose, CMC-Na refers to sodium carboxymethyl cellulose, PVP refers to crospovidone, PEG refers to polyethylene glycol, HPMC refers to hypromellose, and HPC refers to hydroxypropyl cellulose;

[0026] TPGS refers to polyethylene glycol 1000 vitamin E succinate, RH40 refers to polyoxyethylene hydrogenated castor oil, HS15 refers to polyethylene glycol 15-hydroxystearate, and EL35 refers to polyoxyethylene castor oil.

[0027] Concentration "mg / mL" or "mg / ml" refers to milligrams per milliliter and is expressed as weight per volume, where the volume is the volume of the suspension. The concentration range of each component in the injection is calculated based on the ratio of the component weight to the total volume of the injection.

[0028] W / V refers to weight / volume, μm refers to micrometer, μL refers to microliter, L refers to liter, mm refers to millimeter, mL refers to milliliter, nm refers to nanogram, ng refers to nanogram, kg refers to kilogram, min refers to minute, d refers to day, Hz refers to hertz, g refers to gram, qs refers to metric tons, mbar refers to millibar, V refers to volt, and °C refers to degree Celsius.

[0029] Detailed Description of the Invention

[0030] Based on the deficiencies of the prior art, the present invention, after in-depth investigation and research, provides an injection containing a nonsteroidal anti-inflammatory drug, or a combination of a nonsteroidal anti-inflammatory drug and a salt thereof. The preparation can be a suspension for direct use and can be injected intramuscularly or subcutaneously. Compared with the oral preparation of celecoxib, the advantages of the present invention include:

[0031] (1) After injection, the suspension can first take effect quickly and then slowly release the drug, which can significantly reduce the number of dosing times and avoid peak-valley fluctuations, thereby improving patient treatment compliance and safety;

[0032] (2) The drug loading capacity of this preparation is high, and sustained release for at least 1 day or longer can be achieved;

[0033] (3) The celecoxib particles in the suspension are small and evenly distributed, which has good injectability and is conducive to improving its bioavailability.

[0034] The injection provided by the present invention has good stability and is convenient for storage and transportation.

[0035] The present invention provides an injection, the active ingredient of which is a nonsteroidal anti-inflammatory drug or a combination of a nonsteroidal anti-inflammatory drug and a salt thereof; after injection, the injection continuously releases the nonsteroidal anti-inflammatory drug for at least one day.

[0036] The injection of the present invention continuously releases nonsteroidal anti-inflammatory drugs over a period of at least 1 day, up to 2 days, or longer, for example, up to 3 days. The nonsteroidal anti-inflammatory drugs of the present invention include at least one of celecoxib, parecoxib, etrecoxib, meloxicam, ketorolac tromethamine, flurbiprofen axetil, lornoxicam, and ibuprofen. In some embodiments, the nonsteroidal anti-inflammatory drug is celecoxib, parecoxib, etrecoxib, meloxicam, ketorolac tromethamine, flurbiprofen axetil, lornoxicam, or ibuprofen. In some embodiments, the salt of the nonsteroidal anti-inflammatory drug includes acyl salts, carbonate salts, phosphate salts, amino acid salts, iminoester salts, etc. In certain embodiments, the nonsteroidal anti-inflammatory drug is celecoxib, and its salt is celecoxib propionyl sodium. In certain embodiments, the nonsteroidal anti-inflammatory drug is celecoxib, and its salt is celecoxib sulfonamide sodium. In some embodiments, the nonsteroidal anti-inflammatory drug is celecoxib, and its salt is o-hydroxyphenylpropionyl celecoxib sulfonamide sodium.

[0037] In some embodiments, the active ingredient of the injection is celecoxib.

[0038] In some embodiments, the active ingredient of the injection is parecoxib.

[0039] In some embodiments, the active ingredient of the injection is a combination of celecoxib and celecoxib propionyl sodium.

[0040] In some embodiments, the particle size D50 of the active ingredient in the injection is 0.2 μm-15 μm, preferably 0.5 μm-10 μm, more preferably 0.5 μm-8 μm. In some embodiments, the particle size D50 of the active ingredient in the injection is 0.5 μm-3 μm. In some embodiments, the particle size D50 of the active ingredient in the injection is 1 μm-12 μm. In some embodiments, the particle size D50 of the active ingredient in the injection is 2 μm-10 μm. In some embodiments, the particle size D50 of the active ingredient in the injection is 3 μm-8 μm. In some embodiments, the particle size D50 of the active ingredient in the injection is about 0.3 μm, 0.5 μm, 0.8 μm, 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm, 8.5 μm, 9.0 μm, 9.5 μm, 10.0 μm, 11.0 μm, 12.0 μm, 13.0 μm, 14.0 μm or 15.0 μm. The above particle size range is beneficial to the physical stability of the injection; too small a particle size will affect the long-term release of the injection, and too large a particle size will result in poor stability of the injection.

[0041] In some embodiments, the concentration of the active ingredient in the injection is 5 mg / mL-500 mg / mL (W / V) calculated as the ratio of the weight of the active ingredient to the total volume of the injection. The concentration of the active ingredient in the injection is 50 mg / mL-400 mg / mL calculated as the ratio of the weight of the active ingredient to the total volume of the injection. In some embodiments, the concentration of the active ingredient in the injection is 50 mg / mL-300 mg / mL; in some embodiments, the concentration of the active ingredient in the injection is 100 mg / mL-300 mg / mL. In some embodiments, the concentration of the active ingredient in the injection is 200 mg / mL-300 mg / mL. In some embodiments, the concentration of the active ingredient in the injection is about 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 350 mg / mL, 400 mg / mL or 500 mg / mL.

[0042] In some embodiments, the active ingredient of the injection is a combination of a nonsteroidal anti-inflammatory drug and a salt thereof, and the weight ratio of the nonsteroidal anti-inflammatory drug and the salt thereof is 1:10-10:1. In some embodiments, the weight ratio of the nonsteroidal anti-inflammatory drug and the salt thereof is 1:1-8:1. In some embodiments, the weight ratio of the nonsteroidal anti-inflammatory drug and the salt thereof is 1:1-5:1. In some embodiments, the weight ratio of the nonsteroidal anti-inflammatory drug and the salt thereof is 2:1-4:1. In some embodiments, the weight ratio of the nonsteroidal anti-inflammatory drug and the salt thereof is about 1:5, 1:1, 4:3, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 9:1. In some embodiments, the combination of the nonsteroidal anti-inflammatory drug and the salt thereof is a combination of celecoxib and celecoxib propionyl sodium.

[0043] In some embodiments, the injection further comprises a suspending agent; the suspending agent comprises at least one selected from CMC, CMC-Na, PVP, PEG, HPMC, glycerol, propylene glycol, and HPC. In some embodiments, the suspending agent comprises CMC. In some embodiments, the suspending agent comprises CMC-Na. In some embodiments, the suspending agent comprises PVP. In some embodiments, the suspending agent comprises PEG. In some embodiments, the suspending agent is CMC-Na.

[0044] In some embodiments, the suspending agent is preferably PEG with a molecular weight of 400-12000. In some embodiments, the suspending agent is selected from at least one of PEG4000, PEG8000, PEG3350 and PEG8000. In some embodiments, the suspending agent is PEG4000.

[0045] In some embodiments, the suspending agent PVP is selected from at least one of PVPK17, PVPK30, and PVPK29 / 32.

[0046] In some embodiments, the concentration of the suspending agent is 0.1 mg / ml-120 mg / ml (W / V) calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is 20 mg / ml-80 mg / ml calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is 40 mg / ml-75 mg / ml calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is 1 mg / ml-80 mg / ml calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is 1 mg / ml-50 mg / ml calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is 1 mg / ml-30 mg / ml calculated according to the ratio of the weight of the suspending agent to the total volume of the injection. In some embodiments, the concentration of the suspending agent is calculated based on the ratio of the weight of the suspending agent to the total volume of the injection, and is 1 mg / ml to 20 mg / ml. In some embodiments, the concentration of the suspending agent is calculated based on the ratio of the weight of the suspending agent to the total volume of the injection, and is 0.1 mg / ml to 10 mg / ml. In some embodiments, the concentration of the suspending agent is calculated based on the ratio of the weight of the suspending agent to the total volume of the injection, and is 0.5 mg / ml to 5 mg / ml. In some embodiments, the concentration of the suspending agent is calculated based on the ratio of the weight of the suspending agent to the total volume of the injection, and is 1 mg / ml to 4 mg / ml. In some embodiments, the concentration of the suspending agent is about 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml or 120 mg / ml, calculated as the ratio of the weight of the suspending agent to the total volume of the injection.

[0047] In some embodiments, the injection further comprises a stabilizer; the stabilizer comprises at least one selected from poloxamer 188, poloxamer 338, poloxamer 407, Tween-20, Tween-80, TPGS, EL35, RH40, and HS15. In some embodiments, the stabilizer comprises poloxamer 338. In some embodiments, the stabilizer comprises poloxamer 188. In some embodiments, the stabilizer comprises poloxamer 407. In some embodiments, the stabilizer comprises Tween-20. In some embodiments, the stabilizer comprises Tween-80. In some embodiments, the stabilizer is poloxamer 407. In some embodiments, the stabilizer is poloxamer 338. In some embodiments, the stabilizer is Tween-80.

[0048] In some embodiments, the concentration of the stabilizer is 0.1 mg / ml-50 mg / ml (W / V) calculated as the ratio of the weight of the stabilizer to the total volume of the injection. In some embodiments, the concentration of the stabilizer is 10 mg / ml-30 mg / ml calculated as the ratio of the weight of the stabilizer to the total volume of the injection. In some embodiments, the concentration of the stabilizer is 15 mg / ml-25 mg / ml calculated as the ratio of the weight of the stabilizer to the total volume of the injection. In some embodiments, the concentration of the stabilizer is 0.1 mg / ml-40 mg / ml. In some embodiments, the concentration of the stabilizer is 1 mg / ml-20 mg / ml calculated as the ratio of the weight of the stabilizer to the total volume of the injection. In some embodiments, the concentration of the stabilizer is 5 mg / ml-20 mg / ml calculated as the ratio of the weight of the stabilizer to the total volume of the injection. In some embodiments, the concentration of the stabilizer, calculated as the ratio of the weight of the stabilizer to the total volume of the injection, is about 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml or 50 mg / ml.

[0049] The injection of the present invention may further include a pH adjuster. The pH adjuster includes a phosphate or a hydrate thereof, a citrate or a hydrate thereof. In some embodiments, the pH adjuster includes at least one of citric acid, sodium citrate, anhydrous disodium hydrogen phosphate, anhydrous sodium dihydrogen phosphate, anhydrous dipotassium hydrogen phosphate, citric acid monohydrate, sodium hydroxide, and hydrochloric acid. In some embodiments, the pH adjuster is sodium hydroxide.

[0050] In some embodiments, the concentration of the pH regulator is 0.1 mg / mL-10 mg / mL (W / V) calculated as the ratio of the weight of the pH regulator to the total volume of the injection. In some embodiments, the concentration of the pH regulator is 1 mg / mL-5 mg / mL calculated as the ratio of the weight of the pH regulator to the total volume of the injection. In some embodiments, the concentration of the pH regulator is about 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml or 10 mg / ml calculated as the ratio of the weight of the pH regulator to the total volume of the injection.

[0051] The injection of the present invention may further include an osmotic pressure regulator. In some embodiments, the osmotic pressure regulator includes at least one of sodium chloride, glucose, mannitol, and sorbitol. In some embodiments, the osmotic pressure regulator is mannitol. In some embodiments, the osmotic pressure regulator is sodium chloride. In some embodiments, the osmotic pressure regulator is glucose.

[0052] In some embodiments, the concentration of the osmotic pressure regulator is 0.1 mg / mL-10 mg / mL (W / V) calculated as the ratio of the weight of the osmotic pressure regulator to the total volume of the injection. In some embodiments, the concentration of the osmotic pressure regulator is 1 mg / mL-5 mg / mL calculated as the ratio of the weight of the osmotic pressure regulator to the total volume of the injection. In some embodiments, the concentration of the osmotic pressure regulator is about 0.1 mg / ml, 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml or 10 mg / ml, calculated as the ratio of the weight of the osmotic pressure regulator to the total volume of the injection.

[0053] The injection of the present invention may further include a buffer. In some embodiments, the buffer comprises a phosphate or a hydrate thereof, or a citrate or a hydrate thereof. In some embodiments, the buffer is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, citric acid monohydrate, acetic acid, sodium acetate, lactic acid, tartaric acid, sodium tartrate, sodium bicarbonate, and sodium carbonate. In some embodiments, the buffer is a combination of sodium dihydrogen phosphate monohydrate and anhydrous disodium hydrogen phosphate; in some embodiments, the buffer is a combination of citric acid monohydrate and anhydrous disodium hydrogen phosphate; in some embodiments, the buffer is a combination of acetic acid and sodium acetate; in some embodiments, the buffer is a combination of citric acid monohydrate and sodium citrate; in some embodiments, the buffer is a combination of tartaric acid and sodium tartrate; in some embodiments, the buffer is a combination of sodium bicarbonate and sodium carbonate. In some embodiments, the buffer is a combination of citric acid and sodium citrate; in some embodiments, the buffer is a combination of citric acid and disodium hydrogen phosphate; in some embodiments, the buffer is a combination of citric acid and sodium dihydrogen phosphate; in some embodiments, the buffer is a combination of sodium citrate and disodium hydrogen phosphate; in some embodiments, the buffer is a combination of sodium citrate and sodium dihydrogen phosphate; in some embodiments, the buffer is a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0054] In some embodiments, the concentration of the buffer is 5.0 mg / mL-30.0 mg / mL (W / V), preferably 8.0 mg / mL-15.0 mg / mL, calculated based on the weight of the buffer to the total volume of the injection. In some embodiments, the concentration of the buffer is 8 mg / mL-20 mg / mL, calculated based on the weight of the buffer to the total volume of the injection. In some embodiments, the concentration of the buffer is about 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml or 19 mg / ml, calculated based on the weight of the buffer to the total volume of the injection.

[0055] In some embodiments, the injection of the present invention is a ready-to-use suspension. In certain embodiments, the nonsteroidal anti-inflammatory drug ready-to-use suspension is administered intramuscularly or subcutaneously. In certain embodiments, the celecoxib ready-to-use suspension is administered intramuscularly or subcutaneously. In certain embodiments, the parecoxib ready-to-use suspension is administered intramuscularly or subcutaneously.

[0056] The injection of the present invention is in the form of a suspension, the D50 of the nonsteroidal anti-inflammatory drug present in the suspension is in the range of 0.2 μm-15 μm, and the preparation continuously releases the nonsteroidal anti-inflammatory drug for at least 1 day, up to 2 days or longer, for example, up to 3 days. In some embodiments, the injection of the present invention is in the form of a suspension, the D50 of celecoxib present in the suspension is in the range of 0.5 μm-10 μm, and the preparation continuously releases celecoxib for at least 1 day, up to 2 days or longer, for example, up to 3 days. In some embodiments, the injection of the present invention is in the form of a suspension, the D50 of parecoxib present in the suspension is in the range of 0.5 μm-10 μm, and the preparation continuously releases parecoxib for at least 1 day, up to 2 days or longer, for example, up to 3 days.

[0057] The injection of the present invention is in the form of a suspension, the concentration of the nonsteroidal anti-inflammatory drug present in the suspension is in the range of 5 mg / mL-500 mg / mL, and the preparation continuously releases the nonsteroidal anti-inflammatory drug for at least 1 day, up to 2 days, or longer, for example, up to 3 days. In some embodiments, the injection of the present invention is in the form of a suspension, the concentration of celecoxib present in the suspension is in the range of 50 mg / mL-350 mg / mL, and the preparation continuously releases celecoxib for at least 1 day, up to 2 days, or longer, for example, up to 3 days. In some embodiments, the injection of the present invention is in the form of a suspension, the concentration of parecoxib present in the suspension is in the range of 50 mg / mL-350 mg / mL, and the preparation continuously releases parecoxib for at least 1 day, up to 2 days, or longer, for example, up to 3 days.

[0058] The injection of the present invention has a pH of 6.0-11.0, preferably 6.0-8.0, more preferably 6.5-7.5. In some embodiments, the pH of the injection is 6.8-7.2. In some embodiments, the pH of the injection is 6.5-9.0. In some embodiments, the pH of the injection is about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.5, 9.0, 9.5, 10.0 or 10.5.

[0059] In some embodiments, an injection comprises:

[0060] (a) celecoxib, wherein the concentration of celecoxib in the injection is in the range of 50 mg / mL to 500 mg / mL (W / V), calculated based on the ratio of celecoxib weight to the total volume of the injection; and

[0061] (b) a suspending agent, whose concentration range is 0.1 mg / mL-100 mg / mL (W / V) calculated based on the ratio of its weight to the total volume of the injection. In some embodiments, an injection comprises:

[0062] (a) celecoxib and celecoxib propionyl sodium, in a concentration range of 50 mg / mL to 500 mg / mL, calculated based on the ratio of celecoxib weight to the total volume of the injection; and

[0063] (b) a suspending agent having a concentration ranging from 0.1 mg / mL to 50 mg / mL calculated based on the ratio of its weight to the total volume of the injection; and optionally comprising

[0064] (c) Stabilizer.

[0065] In some embodiments, an injection comprises:

[0066] (a) celecoxib at a concentration ranging from 100 mg / mL to 400 mg / mL; and

[0067] (b) Sodium carboxymethyl cellulose, concentration range 1 mg / mL-50 mg / mL.

[0068] In some embodiments, an injection comprises:

[0069] (a) celecoxib at a concentration ranging from 50 mg / mL to 350 mg / mL; and

[0070] (b) a stabilizer, with a concentration range of 0.1 mg / mL to 50 mg / mL, wherein the stabilizer is selected from at least one of poloxamer 188, poloxamer 338, poloxamer 407, and Tween-20.

[0071] In some embodiments, an injection comprises:

[0072] (a) celecoxib at a concentration ranging from 50 mg / mL to 350 mg / mL; and

[0073] (b) a suspending agent having a concentration range of 0.1 mg / mL to 100 mg / mL, wherein the suspending agent is selected from at least one of sodium carboxymethylcellulose, PVPK17, PEG4000, and PEG3350.

[0074] In some embodiments, an injection comprises:

[0075] (a) celecoxib at a concentration ranging from 100 mg / mL to 300 mg / mL; and

[0076] (b) a stabilizer, with a concentration ranging from 10 mg / mL to 30 mg / mL, wherein the stabilizer is selected from poloxamer 338 or poloxamer 407; and

[0077] (c) suspending agent, with a concentration range of 30 mg / mL-80 mg / mL, wherein the suspending agent is sodium carboxymethyl cellulose or PEG4000.

[0078] In some embodiments, an injection comprises:

[0079] (a) celecoxib at a concentration ranging from 200 mg / mL to 300 mg / mL; and

[0080] (b) a stabilizer, with a concentration ranging from 15 mg / mL to 25 mg / mL, wherein the stabilizer is selected from poloxamer 338 or poloxamer 188; and

[0081] (c) a suspending agent, with a concentration range of 40 mg / mL to 75 mg / mL, wherein the suspending agent is PEG3350 or PEG4000.

[0082] In some embodiments, an injection comprises:

[0083] (a) celecoxib at a concentration of 200 mg / mL, 250 mg / mL, or 300 mg / mL; and

[0084] (b) poloxamer 338 or poloxamer 407 at a concentration of about 20 mg / mL or 25 mg / mL; and

[0085] (c) PEG3350 or PEG4000 at a concentration of about 40 mg / mL, 60 mg / mL, or 75 mg / mL; and

[0086] (d) optionally, at least one of citric acid, sodium citrate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, in a concentration range of 8 mg / mL to 15 mg / mL; and

[0087] (e) Optionally, sodium hydroxide or hydrochloric acid.

[0088] In some embodiments, an injection comprises:

[0089] (a) celecoxib and celecoxib propionyl sodium, in a concentration range of 100 mg / mL to 400 mg / mL, calculated based on the ratio of celecoxib weight to the total volume of the injection; and

[0090] (b) sodium carboxymethylcellulose at a concentration ranging from 1 mg / mL to 50 mg / mL; and optionally

[0091] (c) Poloxamer 407, or Poloxamer 188, or Poloxamer 338, with a concentration range of 1 mg / mL to 40 mg / mL.

[0092] In some embodiments, an injection comprises:

[0093] (a) Celecoxib, at a concentration of 100 mg / mL to 300 mg / mL;

[0094] (b) a stabilizer, which is poloxamer 188, poloxamer 338, or poloxamer 407, at a concentration of 1 mg / mL to 30 mg / mL; and

[0095] (c) a suspending agent, which is sodium carboxymethylcellulose, carboxymethylcellulose, hypromellose or cross-linked polyvinylpyrrolidone.

[0096] In some embodiments, an injection comprises:

[0097] (a) celecoxib and celecoxib propionyl sodium, at a concentration of 100 mg / mL to 300 mg / mL, calculated based on the ratio of celecoxib weight to the total volume of the injection; and

[0098] (b) a stabilizer, which is poloxamer 188, poloxamer 338, or poloxamer 407, at a concentration ranging from 1 mg / mL to 20 mg / mL; and

[0099] (c) a suspending agent, which is sodium carboxymethylcellulose, carboxymethylcellulose, hypromellose or cross-linked polyvinylpyrrolidone, with a concentration range of 1 mg / mL to 20 mg / mL.

[0100] In another aspect, the present invention provides a method for preparing any of the above-mentioned injections. A method for preparing the injection comprises the following steps:

[0101] (1) adding a suspending agent and any other auxiliary materials into water and dissolving them completely, then adding the active ingredient and stirring to disperse them uniformly to obtain a celecoxib mixture;

[0102] (2) Grinding the mixture obtained in (1) to obtain a celecoxib suspension.

[0103] In some embodiments, a method for preparing an injection comprises the following steps:

[0104] (1) adding a stabilizer and any other auxiliary materials into water and dissolving them completely, then adding the active ingredient and stirring to disperse them uniformly to obtain a celecoxib mixture;

[0105] (2) Grinding the mixture obtained in (1) to obtain a celecoxib suspension.

[0106] In some embodiments, a method for preparing an injection comprises the following steps:

[0107] (1) adding at least one of poloxamer 338, poloxamer 407, poloxamer 188, Tween-20, and Tween-80 into water and dissolving the mixture completely, then adding celecoxib and stirring to uniformly disperse the mixture to obtain a celecoxib mixture;

[0108] (2) Grinding the mixture obtained in (1) to obtain a celecoxib suspension.

[0109] The celecoxib suspension of the present invention can be further prepared into a lyophilized powder.

[0110] The present invention also provides use of the aforementioned celecoxib injection in preparing a medicine for treating acute pain.

[0111] A use of celecoxib injection in preparing a medicine for treating acute pain. The medicine can be injected intramuscularly or subcutaneously. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] FIG1 depicts a graph showing the relationship between the mean plasma concentration of celecoxib and time after injection of samples of Formulations 7-1, 7-2, 7-3 and 7-4 of Example 7 of the present invention into dogs.

[0113] FIG2 depicts the relationship between the average plasma concentration of celecoxib and time in 6 groups of rats after injection of the sample of Prescription 8-1 in Example 8 of the present invention.

[0114] FIG3 depicts the relationship between the average plasma concentration of celecoxib and time after injection of samples 12-1, 12-2, and 12-3 of Example 12 of the present invention and oral gavage of sample 12-4 of Example 12 of the present invention in rats.

[0115] FIG4 depicts the relationship between the average plasma concentration of celecoxib and time after injection of samples of formulations 13-1, 13-2, 13-3, 13-4, and 13-5 of Example 13 of the present invention into dogs. DETAILED DESCRIPTION

[0116] Example general method:

[0117] 1. Particle size determination method for active ingredients in injections

[0118] Instrument: Malvern Laser Particle Size Analyzer, Model: MS3000

[0119] Procedure: Rinse the dispersion unit twice with purified water, then add approximately 100 mL of purified water to the dispersion unit and slowly adjust the speed to 2000 rpm. Set the instrument parameters to a dispersant refractive index of 1.33. Click "Start" to measure the background. After the instrument has measured the background, add the sample to a light-blocking value of 10%-20%. Allow it to stabilize for approximately 10 seconds before testing the sample. If the light-blocking value does not meet the requirements, drain the sample and retest. Measure each sample in triplicate and take the average value.

[0120] In all example tables, “ / ” indicates that there is no data at the corresponding position.

[0121] Example 1 Investigation of different specifications of active ingredients-1

[0122] Table 1-1 Prescription table

[0123] Preparation process:

[0124] 1. Dissolve Poloxamer 407, CMC-Na, and propylene glycol in water for injection and stir until a clear, transparent, and colorless solution is obtained.

[0125] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0126] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 8 hours;

[0127] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0128] 5. Add zirconium beads (75 g each, 2.0 mm diameter and 0.3 mm diameter) to an agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, detect the particle size, and record the results. Finally, examine the nanocrystal suspension with the smallest particle size.

[0129] According to the above method, the particle size was measured and its appearance and microscopic properties were judged. The results are shown in Table 1-2.

[0130] Table 1-2

[0131] The results showed that among the three formulations, only formulation 1-1 met all the requirements and warranted further stability assessment. To improve the specifications of the active ingredient, it is necessary to first screen for suitable surfactants, suspending agents, and ionic surfactants, otherwise the product will easily become a paste.

[0132] Example 2 Investigation of different types of stabilizers

[0133] Table 2-1 Prescription table

[0134] Preparation process:

[0135] 1. Dissolve poloxamer 188 (or poloxamer 338, or poloxamer 407, or Tween-20, or Tween-80, or TPGS, or RH40) in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0136] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0137] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 6 hours;

[0138] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0139] 5. Add zirconium beads (2.0 mm diameter zirconium beads and 0.3 mm diameter zirconium beads, both 75 g) to the agate cup; place the prepared suspension in the agate cup, set the equipment parameters to 30 Hz for ball milling, observe the properties of the suspension during the ball milling process, detect the particle size and record the results.

[0140] According to the above method, the particle size was measured and its appearance and microscopic properties were judged. The results are shown in Table 2-2.

[0141] Table 2-2

[0142] The results showed that the preferred surfactants screened out from the 7 prescriptions included poloxamer 338, poloxamer 407, Tween-20, and TPGS.

[0143] Table 2-3 Prescription table

[0144] Preparation process:

[0145] 1. Dissolve poloxamer P188 (or poloxamer P338, or poloxamer P407), CMC-Na, and celecoxib propionyl sodium in water for injection and stir until a completely clear, transparent, and colorless solution is obtained.

[0146] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0147] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 6 hours;

[0148] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0149] 5. Add zirconium beads (150 g of 2.0 mm diameter zirconium beads) to the agate cups respectively; place the prepared suspension in the agate cups, set the equipment parameters to 20 Hz for ball milling, observe the properties of the suspension during the ball milling process, detect the particle size and record the results; finally, obtain a nanocrystal suspension with the target particle size.

[0150] The stability of several formulations in Table 2-3 was investigated at 5°C for 20 days. The test items were the particle size D50 and ζ potential of the active ingredient in the suspension. The results are shown in Table 2-4.

[0151] Table 2-4

[0152] The results showed that the suspension had good stability when poloxamer 188, poloxamer 407 or poloxamer 338 was used as the stabilizer.

[0153] Example 3 Investigation of different types of suspending agents and their dosage-1

[0154] Table 3-1 Prescription table (different dosages of suspending agents)

[0155] Preparation process:

[0156] 1. Dissolve poloxamer 407 and PEG 4000 in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0157] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0158] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 6 hours;

[0159] 4. Add water for injection to make up to 350 ml and continue stirring for 1 hour;

[0160] 5. Using a NETZSCH ball mill, add 140 ml of 0.3 mm diameter zirconium beads and mill using a 150 µm mesh. Set the flow rate to 50-200 rpm and the rotation speed to 1500-2000 rpm.

[0161] The particle size of the suspension was monitored during the ball milling process until it was around 0.3 μm, and the particle size stability of the suspension was investigated.

[0162] The target samples were prepared according to the above method, and the particle size, diameter distance, pH, viscosity, ζ potential and density were tested. The results are shown in Table 3-2, and the storage stability results are shown in Table 3-3.

[0163] Table 3-2 0-day quality measurement

[0164] The results showed that prescriptions 3-1 to 3-3 were all capable of initially preparing injections (nanocrystalline suspensions) with good quality on day 0.

[0165] Table 3-3 Storage stability results

[0166] The results showed that the particle size stability of the formulation with a dosage of 40-100 mg / ml of PEG4000 was good after being placed at 5°C for 57 days.

[0167] Table 3-4 Prescription table (different types of suspending agents-1)

[0168] Preparation process:

[0169] 1. Dissolve poloxamer 338 and PEG 4000 (or PEG 3350, or CMC Na) separately in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0170] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0171] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 6 hours;

[0172] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0173] 5. Add zirconium beads (2.0 mm diameter and 0.3 mm diameter, 75 g each) to an agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, detect the particle size, and record the results. Finally, obtain a nanocrystal suspension with the target particle size.

[0174] The target samples were prepared according to the above method, and the particle size, diameter distance, pH, viscosity, ζ potential and density were tested. The results are shown in Table 3-5, and the storage stability results are shown in Table 3-6.

[0175] Table 3-5 0-day quality measurement

[0176] The results showed that prescriptions 3-4 to 3-10 were all capable of initially preparing injections (nanocrystalline suspensions) with good quality on day 0.

[0177] Table 3-6 Storage stability results

[0178] The results showed that the particle size stability of prescriptions 3-6 was good when placed at 5°C for 30 days; no suspending agent was added to prescription 3-4, and the particle size stability was poor; the particle size of other prescriptions increased slightly and needed further optimization.

[0179] Table 3-7 Prescription table (different types of suspending agents-2)

[0180] Preparation process:

[0181] 1. Dissolve CMC-Na (or CMC, or PEG4000, or PVPK17, or HPMC) and celecoxib propionyl sodium in water for injection and stir until a completely clear, transparent and colorless solution is obtained;

[0182] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0183] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 8 hours;

[0184] 4. Add water for injection to make up to 50 ml and continue stirring for 1.5 hours;

[0185] 5. Add zirconium beads to the agate cup (add 2.0 mm diameter zirconium beads and 0.3 mm diameter zirconium beads, both 75 g, to prescriptions 3-11 to 3-14; add 2.0 mm diameter zirconium beads, 150 g, to prescriptions 3-15 to 3-19); place the prepared suspension in the agate cup, set the equipment parameters to 30 Hz for ball milling, observe the properties of the suspension during the ball milling process, detect the particle size and record the results; finally, obtain a nanocrystal suspension with the target particle size.

[0186] The stability of several formulations listed in Table 3-7 was investigated at 5°C for 20 days. The test items were the particle size D50 and ζ potential of the active ingredient in the suspension. The results are shown in Table 3-8.

[0187] Table 3-8

[0188] The results showed that the suspensions with CMC-Na, PEG4000, CMC, PVPK17 and HPMC as suspending agents had good stability.

[0189] Table 4-1 Prescription table (active ingredient is celecoxib)

[0190] Preparation process:

[0191] 1. Dissolve Poloxamer 407, CMC-Na, and propylene glycol in water for injection and stir until a completely clear, transparent, and colorless solution is obtained.

[0192] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0193] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 1 hour;

[0194] 4. Add water for injection to make up to 350 ml and continue stirring for 1 hour;

[0195] 5. Using a NETZSCH ball mill, add 140 ml of 0.3 mm diameter zirconium beads and mill using a 150 μm mesh. Set the flow rate to 50-200 rpm and the rotation speed to 1500-2000 rpm. Observe the properties of the suspension during the milling process. Samples are taken at different time points to measure particle size, zeta potential, and pH. The particle size stability of the suspension is also investigated.

[0196] Table 4-2

[0197] The results showed that by adjusting the ball milling time, a high-quality celecoxib nanocrystal suspension with an active ingredient particle size D50 of about 0.1-7.3 μm could be prepared.

[0198] The formulations with different particle sizes in Table 4-2 were subjected to stability studies at 5°C for 18 days and 90 days. The particle size D50 of the active ingredient in the suspension is shown in Table 4-3.

[0199] Table 4-3 Storage stability results

[0200] The results showed that the samples with the particle size D50 of the active ingredient in the suspension of about 1.0-7.3um had good particle size stability after being placed at 5°C for 90 days; the samples with D50 of about 0.1um and 0.5um had poor particle size stability and needed further optimization.

[0201] Table 4-4 Prescription table (active ingredients are celecoxib + celecoxib propionyl sodium)

[0202] Preparation process:

[0203] 1. Dissolve poloxamer P407, CMC-Na, and celecoxib propionyl sodium in water for injection and stir until a completely clear, transparent, and colorless solution is obtained;

[0204] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0205] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 10 hours;

[0206] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0207] 5. Add zirconium beads to the agate cup (2.0 mm diameter zirconium beads and 0.3 mm diameter zirconium beads were added to the recipe 4-2, 4-3 and 4-4, respectively, 75 g each; 150 g of 2.0 mm diameter zirconium beads were added to the recipe 4-5 and 4-6 respectively); the prepared suspension was placed in the agate cup, and the equipment parameters were set to 30 Hz / 30 Hz / 30 Hz / 20 Hz for ball milling. The ball milling time for recipe 4-2 and recipe 4-3 was 5 h, the ball milling time for recipe 4-4 was 10 min, and the ball milling time for recipe 4-5 and recipe 4-6 was 8 min;

[0208] 6. During the ball milling process, observe the properties of the suspension, detect the particle size and record the results; ultimately, obtain a nanocrystal suspension with the target particle size.

[0209] The stability of the formulations with different particle sizes in Table 4-4 was investigated. The investigation conditions were 20 days at 5°C. The test item was the particle size D50 of the active ingredient in the suspension. The results are shown in Table 4-5.

[0210] Table 4-5

[0211] The results showed that for samples with celecoxib particle sizes D50 of about 1.5 μm, 5 μm, 8 μm and 10 μm in the suspension, there was no significant change in the particle size D50 of the active ingredient after being placed at 5°C for 20 days, indicating good stability.

[0212] Example 5 Investigation of Celecoxib Suspensions with Different Particle Sizes and Different pH

[0213] Table 5-1 Prescription Table

[0214] Preparation process:

[0215] 1. Dissolve poloxamer 338, citric acid, and sodium dihydrogen phosphate in water for injection and stir until a completely clear, transparent, and colorless solution is obtained.

[0216] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0217] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 10 hours;

[0218] 4. Add sodium hydroxide to adjust the pH of the suspension to 6.0, 7.2, and 11.0 respectively;

[0219] 5. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0220] 6. Add zirconium beads (2.0 mm diameter and 0.3 mm diameter, 75 g each) to an agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, detect the particle size, and record the results. Finally, obtain a nanocrystal suspension with the target particle size.

[0221] 7. After ball milling, add PEG4000 (concentration of 40 mg / ml) in proportion;

[0222] 8. Determine the particle size, zeta potential, viscosity and pH, and investigate the particle size stability of the suspension.

[0223] The 9 prescriptions in Table 5-1 were subjected to quality measurement on day 0. The measurement results are shown in Table 5-2.

[0224] Table 5-2 0-day quality measurement results

[0225] The results showed that by adjusting the pH range of the suspension to about 6.0-11.0, a celecoxib nanocrystal suspension with good appearance and controllable particle size could be prepared.

[0226] The stability of the different formulations in Table 5-1 was investigated at 5°C for 41 days. The particle size D50 of the active ingredient in the suspension is shown in Table 5-3.

[0227] Table 5-3 Storage stability results

[0228] The results showed that the celecoxib suspension with a pH range of about 6.0-11.0 had good particle size stability after being stored at 5°C for 41 days.

[0229] Example 6 Investigation of different types and amounts of buffer salts

[0230] Table 6-1 Prescription table

[0231] Preparation process:

[0232] 1. Dissolve poloxamer 338, citric acid, sodium citrate, sodium dihydrogen phosphate, and disodium hydrogen phosphate (add specific types according to the prescription in Table 6-1) in water for injection and stir until a completely clear, transparent, and colorless solution is obtained;

[0233] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0234] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 10 hours;

[0235] 4. The pH of the suspension of formula 6-1, 6-2, 6-5, and 6-6 was adjusted to about 7.2;

[0236] 5. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0237] 6. Add zirconium beads (75 g each, 2.0 mm diameter and 0.3 mm diameter) to an agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, measure the particle size, and record the results. Finally, obtain a nanocrystal suspension with the target particle size.

[0238] 7. Add PEG4000 in proportion after ball milling;

[0239] 8. Determine the particle size, zeta potential, viscosity and pH, and investigate the particle size stability of the suspension.

[0240] The 9 prescriptions in Table 6-1 were subjected to quality tests on day 0. The test results are shown in Table 6-2.

[0241] Table 6-2 0-day quality measurement results

[0242] The results showed that the sample of Formulation 6-3 formed a paste after ball milling. This may be due to the excessive proportion of a certain buffer salt component and the high ionic strength, which destroyed the thickness of the double layer of the suspended particles that repel each other, causing the suspended particles to aggregate and not disperse evenly. Formulation 6-4 formed a paste when ball milled to a smaller particle size.

[0243] The stability of the different formulations in Table 6-1 was investigated at 5°C for 30 days, 34 days, 41 days, or 93 days. The particle size D50 of the active ingredient in the suspension is shown in Table 6-3.

[0244] Table 6-3 Storage stability results

[0245] The results showed that, except for prescription 6-3, the celecoxib suspensions of other prescriptions had good particle size stability when stored at 5°C for 30-93 days.

[0246] Example 7 Pharmacokinetic Study in Dogs-1

[0247] Table 7-1 Prescription table

[0248] Preparation process:

[0249] 1. Dissolve poloxamer 407 and PEG 4000 in water for injection and stir until a clear, transparent, colorless solution is obtained;

[0250] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0251] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 6 hours;

[0252] 4. Add water for injection to make up to 350 ml and continue stirring for 1 hour;

[0253] 5. Using a NETZSCH ball mill, add 140 ml of 0.3 mm diameter zirconium beads and mill using a 150 µm mesh. Set the flow rate to 50-200 rpm and the rotation speed to 1500-2000 rpm.

[0254] 6. After ball milling to the target particle size, sample and continue ball milling to the next particle size. A total of 3 particle sizes are collected, with D50 of 0.3, 1.0, and 3.0 μm respectively.

[0255] Animal testing process:

[0256] Samples from each group were administered to male beagle dogs via intramuscular thigh injection at the corresponding dose. The IV1 group (intravenous injection) consisted of 3 animals, and the Im1, Im2, and Im3 groups (intramuscular injection) consisted of 6 animals each. Whole blood was collected at 0.25, 1, 2, 4, 8, 24, 30, 36, 48, 60, 72, 96, 120, 144, 168, 216, and 264 hours after administration. Plasma was separated and frozen for analysis until LC / MS / MS analysis was performed.

[0257] Determination method:

[0258] Take 15 μL of sample and add it to 130 μL of IS working solution. Vortex for 5 minutes. Centrifuge at 4000 rpm for 5 minutes. Take 100 μL of supernatant and add it to 150 μL of water. After vortexing for 5 minutes, take a 1 μL aliquot and inject it into the LC-MS / MS system. Take 30 μL of sample and add it to 120 μL of IS working solution. Vortex for 2 minutes. Add 1 mL of MTBE to the mixture. After vortexing, transfer 0.7 mL of the upper layer. Dry under a stream of nitrogen. Reconstitute the results with 120 μL of MeoH:H2O (1:1, v / v).

[0259] The pharmacokinetic results in beagle dogs are shown in Table 7-2, and the concentration-time curve is shown in Figure 1.

[0260] Table 7-2:

[0261] The results showed that the half-life of celecoxib suspension formulations 7-2, 7-3 and 7-4 was significantly shorter than that of intravenous celecoxib solution formulation 7-1. 1 / 2 The duration of action is significantly prolonged, reaching a long-term effect of 1-3 days; among them, the bioavailability of prescriptions 7-3 and 7-4 is about 100%, and the bioavailability of prescription 7-2 reaches 120%.

[0262] Example 8 Pharmacokinetic Study in Rats-1

[0263] Table 8-1: Prescription table

[0264] Preparation process:

[0265] 1. Dissolve poloxamer 338, citric acid, and disodium hydrogen phosphate in water for injection and stir until a completely clear, transparent, and colorless solution is obtained.

[0266] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0267] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 10 hours;

[0268] 4. Add sodium hydroxide to adjust the pH of the suspension to about 7.2;

[0269] 5. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0270] 6. Add zirconium beads (75 g each of 2.0 mm diameter and 0.3 mm diameter) to an agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, measure the particle size, and record the results. Finally, obtain a nanocrystal suspension with a target particle size of 1.5 μm.

[0271] 7. Add PEG4000 in proportion after ball milling;

[0272] Table 8-2: Quality measurement results

[0273] Animal testing process:

[0274] Samples from each group were administered via intramuscular thigh injection into SD rats at the corresponding dose. Three male and three female SD rats were included in each group. Whole blood was collected at 0.25, 1, 2, 4, 8, 24, 30, 36, 48, 60, 72, 96, 120, 144, and 168 hours after administration. Plasma was separated and frozen for analysis until LC / MS / MS analysis.

[0275] Determination method:

[0276] Take 10 μL of sample and add it to 120 μL of IS working solution. Vortex for 5 minutes. Centrifuge at 12,000 rpm for 2 minutes. Take 150 μL of supernatant and add it to 100 μL of water. After vortexing for 5 minutes, take a 1 μL aliquot and inject it into the LC-MS / MS system. Take 30 μL of sample and add it to 120 μL of IS working solution. Vortex for 2 minutes. Add 1 mL of MTBE to the mixture. After vortexing, transfer 0.7 mL of the upper layer. Dry under a stream of nitrogen. Reconstitute the results with 120 μL of MeoH:H2O (1:1, v / v).

[0277] The pharmacokinetic results in rats are shown in Table 8-3, and the concentration-time curve is shown in Figure 2.

[0278] Table 8-3

[0279] The results showed that the sample of prescription 8-1 had good pharmacokinetic properties, and its half-life was stable at around 30 hours under different dosage conditions, meeting the long-term effect of 3 days.

[0280] Example 9: Investigation of Parecoxib Long-Acting Injection

[0281] Table 9-1: Prescription table

[0282] Preparation process:

[0283] 1. Dissolve poloxamer 338, PVPK17, and disodium hydrogen phosphate in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0284] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0285] 3. Add parecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 8 hours;

[0286] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0287] 5. Add zirconium beads (2.0mm diameter and 0.8mm diameter, 75g each) to the agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30Hz for ball milling. Observe the properties of the suspension during the ball milling process, detect the particle size and record the results. Discharge the material when the ball milling reaches about 1um.

[0288] 6. Fill into 3ml glass bottles with a filling volume of 2ml and use freeze-drying rubber stoppers for half-stoppering.

[0289] The samples were freeze-dried and the freeze-drying program was set as follows:

[0290] Table 9-2 Freeze-drying process

[0291] After freeze-drying, the quality is confirmed by testing the freeze-dried appearance, reconstitution time, pH, microscopic observation, and particle size.

[0292] Table 9-3 Quality measurement results

[0293] The results showed that all test items were qualified.

[0294] Table 9-4 Particle size stability results

[0295] The results showed that the freeze-dried preparation of parecoxib suspension had good particle size stability when stored at 25°C for 7 days.

[0296] Example 10 Investigation of the Weight Ratio of Celecoxib and Celecoxib Propionyl Sodium

[0297] Table 10-1 Prescription Table

[0298] Preparation process:

[0299] 1. Dissolve celecoxib propionyl sodium in water for injection and stir until a clear, transparent, colorless solution is obtained;

[0300] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0301] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 6 hours;

[0302] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0303] 5. Add zirconium beads (75 g each, 2.0 mm diameter and 0.3 mm diameter) to an agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, detect the particle size, and record the results. Finally, obtain a nanocrystal suspension with the target particle size.

[0304] The target samples were prepared according to the above method, and the particle size, diameter distance, pH, viscosity, zeta potential and density were tested. The results are shown in Table 10-2.

[0305] Table 10-2

[0306] The results showed that prescriptions 10-1 to 10-5 were all capable of initially preparing injections (nanocrystalline suspensions) of good quality.

[0307] Table 10-3 Storage stability results

[0308] The results showed that the particle size stability of the five prescriptions was good after being placed at 5°C for 13 days.

[0309] Example 11 Investigation of skin irritation in rats

[0310] Table 11-1 Prescription Table

[0311] Animal Experimental Procedure: Celecoxib sodium propionyl injection (prescriptions 11-1, 11-2, and 11-3), along with a control group, was injected intramuscularly into the thighs of male Sprague-Dawley rats. Five animals were injected into each group, each at a dose of 150 mg / kg. Skin at the injection site was observed for any abnormalities within three days of administration. The results are shown in Table 11-2.

[0312] Table 11-2

[0313] The results showed that the long-acting injection of nanocrystals of celecoxib and celecoxib propionyl sodium combination had good tolerance to local irritation in rats.

[0314] Example 12 Pharmacokinetic Study in Rats-2

[0315] Table 12-1 Prescription Table

[0316] Preparation process:

[0317] 1. Dissolve poloxamer P407, CMC-Na, and celecoxib propionyl sodium in water for injection and stir until a completely clear, transparent, and colorless solution is obtained;

[0318] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0319] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 8 hours;

[0320] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0321] 5. Add 75g of zirconium beads (0.5mm diameter and 0.3mm diameter) to an agate cup. Place the prepared suspension in the agate cup and ball mill at 30Hz. Mill for 4 hours for recipe 9-1 and 10 minutes for recipes 9-2 and 9-3. Observe the suspension properties during the milling process, measure the particle size, and record the results. A nanocrystal suspension with the target particle size will be obtained.

[0322] Celecoxib oral suspension for rats (prescription 12-4, group Ig1): Weigh approximately 60% of the total amount of water for injection, add 100 mg of Tween 80 and 50 mg of methylcellulose, stir until dissolved, then add 6 g of celecoxib, continue stirring until completely dispersed to obtain a 60 mg / ml prescription solution, fill and set aside.

[0323] Animal Experimental Procedure: Samples from each group were administered intramuscularly to the thigh muscles of male Sprague-Dawley rats at the corresponding dose. Five male Sprague-Dawley rats were included in each group. Whole blood was collected at 0.25, 1, 2, 4, 8, 24, 30, 36, 48, 60, 72, 96, 120, 144, and 168 hours after administration. Plasma was separated and frozen for analysis until LC / MS / MS analysis was performed.

[0324] Assay method: Add 15 μL of sample to 130 μL of IS working solution and vortex for 5 minutes. Centrifuge at 4000 rpm for 5 minutes. Add 100 μL of supernatant to 150 μL of water. After vortexing for 5 minutes, a 1 μL aliquot is injected into the LC-MS / MS system. Add 30 μL of sample to 120 μL of IS working solution and vortex for 2 minutes. Add 1 mL of MTBE to the mixture. After vortexing, transfer 0.7 mL of the upper layer. Dry under a stream of nitrogen. Reconstitute the results with 120 μL of MeOH:H2O (1:1, v / v).

[0325] The pharmacokinetic results in rats are shown in Table 12-2, and the concentration-time curve is shown in Figure 3.

[0326] Table 12-2

[0327] The results showed that the samples of prescriptions 12-1, 12-2, and 12-3 had good pharmacokinetic properties. Compared with the oral gavage sample group of prescription 12-4, the Tmax was significantly shortened, achieving a rapid onset of effect.

[0328] Example 13 Pharmacokinetic Study in Dogs-2

[0329] Table 13-1 Prescription Table

[0330] Preparation process:

[0331] (1) For Prescription 13-1 and Prescription 13-2, the solute is directly dissolved in the solvent until it is completely dissolved.

[0332] (2) The preparation process of Prescription 13-3, Prescription 13-4, and Prescription 13-5 is as follows:

[0333] 1. Dissolve poloxamer P407, PEG4000, and celecoxib propionyl sodium in water for injection and stir until a completely clear, transparent, and colorless solution is obtained.

[0334] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm + 0.22μm for filtration;

[0335] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 8 hours;

[0336] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0337] 5. Add zirconium beads (75g each of 2mm diameter and 0.3mm diameter zirconium beads for Recipe 13-3; 150g of 0.8mm diameter zirconium beads for Recipes 13-4 and 13-5) to an agate cup. Place the prepared suspension in the agate cup and ball mill at 30Hz. For Recipe 13-3, mill for 4 hours, and for Recipes 13-4 and 13-5, mill for 10 minutes. Observe the suspension properties during the milling process, measure the particle size, and record the results. Finally, obtain a nanocrystal suspension with the target particle size.

[0338] Animal testing process:

[0339] Samples from each group were administered via intramuscular thigh injection into male beagle dogs at the corresponding dose. The IV group consisted of three dogs, and the remaining groups consisted of five male beagle dogs. Whole blood was collected at 0.25, 1, 2, 4, 8, 24, 30, 36, 48, 60, 72, 96, 120, 144, and 168 hours after administration. Plasma was separated, frozen, and stored until analysis by LC / MS / MS.

[0340] Determination method:

[0341] Take 15 μL of sample and add it to 130 μL of IS working solution. Vortex for 5 minutes. Centrifuge at 4000 rpm for 5 minutes. Take 100 μL of supernatant and add it to 150 μL of water. After vortexing for 5 minutes, take a 1 μL aliquot and inject it into the LC-MS / MS system. Take 30 μL of sample and add it to 120 μL of IS working solution. Vortex for 2 minutes. Add 1 mL of MTBE to the mixture. After vortexing, transfer 0.7 mL of the upper layer.

[0342] The solution was dried under a stream of nitrogen and reconstituted with 120 μL of MeoH:H2O (1:1, v / v).

[0343] The pharmacokinetic results in beagle dogs are shown in Table 13-2, and the concentration-time curve is shown in Figure 4.

[0344] Table 13-2

[0345] The results showed that the suspension prescription 13-3, prescription 13-4, and prescription 13-5 samples had good pharmacokinetic properties. Compared with the intravenous injection of celecoxib prescription 13-1 and the intramuscular injection of celecoxib sodium propionyl prescription 13-2 sample groups, T1 / 2 was significantly prolonged, achieving a long-term effect of 3 days.

[0346] Example 14 Investigation of different specifications of active ingredients-2

[0347] Table 14-1 Prescription Table

[0348] Preparation process of Prescription 14-1 and Prescription 14-2:

[0349] 1. Dissolve poloxamer 338, citric acid, disodium hydrogen phosphate, and sodium hydroxide in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0350] 2. Use polyethersulfone PES filter membrane with pore size of 0.45μm+0.22μm for filtration;

[0351] 3. Add celecoxib in proportion to the actual recovery amount, stir and disperse evenly, and stir for 8 hours;

[0352] 4. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0353] 5. Add zirconium beads (2.0 mm diameter and 0.3 mm diameter, 75 g each) to the agate cup. Place the prepared suspension in the agate cup and set the equipment parameters to 30 Hz for ball milling. Observe the properties of the suspension during the ball milling process, detect the particle size, and record the results.

[0354] 6. After ball milling, add PEG4000 in proportion.

[0355] Prescription 14-3 Preparation process:

[0356] 1. Dissolve poloxamer 338, citric acid, disodium hydrogen phosphate, and sodium hydroxide in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0357] 2. Add celecoxib and stir until evenly dispersed. Stir for 8 hours;

[0358] 3. Add water for injection to make up to 100 ml and continue stirring for 1 hour;

[0359] 4. Use a high-pressure homogenizer for homogenization. The reference range of high-pressure homogenization process parameters is: 200-1400 bar, the reference range of plunger pump power is 25-40 Hz, and the reference range of homogenization time is 30-120 minutes;

[0360] 5. When the particle size reaches the target particle size, sample and divide into sub-batches, and add the prescribed amount of PEG4000 according to the actual weight of the sample.

[0361] According to the above method, the particle size was measured and its appearance and microscopic properties were judged. The results are shown in Table 14-2.

[0362] Table 14-2

[0363] The results showed that after formulation optimization, all three formulations met the requirements of the initial properties of the suspension and could be further investigated for stability.

[0364] Table 14-3 Storage stability results

[0365] The results showed that after prescription optimization, the three prescriptions had good initial stability.

[0366] Example 15 Investigation of different amounts of stabilizer

[0367] Table 15-1 Prescription Table

[0368] Preparation process:

[0369] 1. Dissolve poloxamer 338, citric acid, disodium hydrogen phosphate, and sodium hydroxide in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0370] 2. Add celecoxib and stir until evenly dispersed. Stir for 8 hours;

[0371] 3. Add water for injection to make up to 50 ml and continue stirring for 1 hour;

[0372] 4. Add zirconium beads (2.0 mm diameter zirconium beads and 0.3 mm diameter zirconium beads, both 75 g) to the agate cup; place the prepared suspension in the agate cup, set the equipment parameters to 30 Hz for ball milling, observe the properties of the suspension during the ball milling process, detect the particle size and record the results.

[0373] 6. After the ball milling is completed, add PEG4000 according to the proportion.

[0374] According to the above method, the particle size was measured and its appearance and microscopic properties were judged. The results are shown in Table 15-2.

[0375] Table 15-2

[0376] The results showed that Poloxamer 338 significantly affected the viscosity of the suspension system, which further affected ball milling. The suspension appearance was acceptable when the dosage of Poloxamer 338 was 20-35 mg / ml.

[0377] Table 15-3 Storage stability results

[0378] The results showed that after prescription optimization, prescriptions 15-1, 15-2, and 15-3 had good initial stability.

[0379] Example 16 Investigation of different dosages of suspending agents-2

[0380] Table 16-1 Prescription Table

[0381] Preparation process:

[0382] 1. Dissolve poloxamer 338, citric acid, disodium hydrogen phosphate, and sodium hydroxide in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0383] 2. Add celecoxib and stir until evenly dispersed. Stir for 8 hours;

[0384] 3. Add water for injection to make up to 350 ml and continue stirring for 1 hour;

[0385] 4. Use a high-pressure homogenizer for homogenization. The reference range of high-pressure homogenization process parameters is: 200-1400 bar, the reference range of plunger pump power is 25-40 Hz, and the reference range of homogenization time is 10-120 minutes;

[0386] 5. When the particle size reaches the target particle size, sample and divide into sub-batches, and add the prescribed amount of PEG4000 according to the actual weight of the sample.

[0387] Table 16-2

[0388] The results showed that PEG4000 significantly affected the viscosity of the suspension system, which in turn affected its injectability. The appearance of the suspension was acceptable when the PEG4000 dosage was 40-120 mg / ml.

[0389] Table 16-3 Storage stability results

[0390] The results showed that after formulation optimization, the initial stability of PEG4000 at a dosage of 40-120 mg / ml was good.

[0391] Example 17 Investigation of the particle size D50 of the active ingredient in the suspension-2

[0392] Table 17-1 Prescription Table

[0393] Preparation process:

[0394] 1. Dissolve poloxamer 338, citric acid, disodium hydrogen phosphate, and sodium hydroxide in water for injection and stir until a clear, transparent, colorless solution is obtained.

[0395] 2. Add celecoxib and stir until evenly dispersed. Stir for 8 hours;

[0396] 3. Add water for injection to make up to 100 ml and continue stirring for 1 hour;

[0397] 4. Use a high-pressure homogenizer for homogenization. The reference range of high-pressure homogenization process parameters is: 200-1400 bar, the reference range of plunger pump power is 25-40 Hz, and the reference range of homogenization time is 10-180 minutes;

[0398] 5. When the particle size reaches the target particle size, sample and divide into sub-batches, and add the prescribed amount of PEG4000 according to the actual weight of the sample.

[0399] Table 17-2

[0400] The results showed that the suspension properties of different particle sizes were good, with uniform microdispersion and no aggregation. The viscosity of different particle sizes showed a certain trend, but had no effect on injectability.

[0401] Table 17-3 Storage stability results

[0402] The results showed that after the formulation was optimized, the suspension with a particle size D50 of the active ingredient of about 0.8-2.1 μm was stable at room temperature for 11 days.

[0403] In the description of the present specification, the reference terms "some embodiments", "some implementation methods", "a specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples, unless they are contradictory.

[0404] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. An injection, the active ingredient of which is a non-steroidal anti-inflammatory drug or a combination of a non-steroidal anti-inflammatory drug and its salt; after injection, the injection continuously releases the non-steroidal anti-inflammatory drug during a period of at least 1 day.

2. The injection according to claim 1, wherein the non-steroidal anti-inflammatory drug comprises at least one of celecoxib, parecoxib, ericoxib, meloxicam, ketorolac tromethamine, flurbiprofen axetil, lornoxicam and ibuprofen.

3. The injection according to claim 1 or 2, wherein the particle size D50 of the active ingredient in the injection is 0.2 μm - 15 μm, preferably 0.5 μm - 10 μm.

4. The injection according to any one of claims 1 - 3, wherein calculated by the ratio of the weight of the active ingredient to the total volume of the injection, the concentration of the active ingredient in the injection is 5 mg / mL - 500 mg / mL.

5. The injection according to any one of claims 1 - 4, wherein the active ingredient is a combination of a non-steroidal anti-inflammatory drug and its salt, and the weight ratio of the non-steroidal anti-inflammatory drug to its salt is 1:10 - 10:

1.

6. The injection according to any one of claims 1 - 5, which further comprises a stabilizer; optionally, the stabilizer is selected from at least one of poloxamer 188, poloxamer 338, poloxamer 407, tween-20, tween-80, TPGS, EL35, RH40 and HS15.

7. The injection according to claim 6, wherein calculated by the ratio of the weight of the stabilizer to the total volume of the injection, the concentration of the stabilizer is 0.1 mg / ml - 50 mg / ml.

8. The injection according to any one of claims 1 - 7, which further comprises a suspending agent; optionally, the suspending agent is selected from at least one of carboxymethyl cellulose, sodium carboxymethyl cellulose, PVP, PEG, HPMC, glycerol, propylene glycol and HPC.

9. The injection according to claim 8, wherein calculated by the ratio of the weight of the suspending agent to the total volume of the injection, the concentration of the suspending agent is 0.1 mg / ml - 120 mg / ml.

10. The injection according to any one of claims 1 - 9, which further comprises a buffer; optionally, the buffer is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, citric acid monohydrate, acetic acid, sodium acetate, lactic acid, tartaric acid, sodium tartrate, sodium bicarbonate and sodium carbonate.

11. The injection according to claim 10, wherein calculated by the ratio of the weight of the buffer to the total volume of the injection, the concentration of the buffer is 5.0 mg / ml - 30.0 mg / ml.

12. The injection according to any one of claims 1 - 11, which further comprises a pH regulator; optionally, the pH regulator is selected from at least one of sodium hydroxide, hydrochloric acid, phosphate or its hydrate, citrate or its hydrate.

13. The injection according to any one of claims 1 - 12, wherein the injection is a ready-to-use suspension.

14. The injection according to any one of claims 1 - 13, wherein the pH of the injection is 6.0 - 11.0, preferably 6.0 - 8.

0.

15. The injection according to any one of claims 1 - 4, comprising: (a) Celecoxib, with a concentration range of 50 mg / mL - 350 mg / mL; and (b) A stabilizer, with a concentration range of 0.1 mg / mL - 50 mg / mL, and the stabilizer is selected from at least one of poloxamer 188, poloxamer 338, poloxamer 407, and Tween - 20.

16. The injection according to any one of claims 1 - 4, comprising: (a) Celecoxib, with a concentration range of 50 mg / mL - 350 mg / mL; and (b) A suspending agent, with a concentration range of 0.1 mg / mL - 100 mg / mL, and the suspending agent is selected from at least one of sodium carboxymethyl cellulose, PVPK17, PEG4000, and PEG3350.

17. The injection according to any one of claims 1 - 4, comprising: (a) Celecoxib, with a concentration range of 100 mg / mL - 300 mg / mL; and (b) A stabilizer, with a concentration range of 10 mg / mL - 30 mg / mL, and the stabilizer is selected from poloxamer 338 or poloxamer 407; and (c) A suspending agent, with a concentration range of 30 mg / mL - 80 mg / mL, and the suspending agent is sodium carboxymethyl cellulose or PEG4000.

18. The injection according to any one of claims 1 - 4, comprising: (a) Celecoxib, with a concentration range of 200 mg / mL - 300 mg / mL; and (b) A stabilizer, with a concentration range of 15 mg / mL - 25 mg / mL, and the stabilizer is selected from poloxamer 338 or poloxamer 188; and (c) A suspending agent, with a concentration range of 40 mg / mL - 75 mg / mL, and the suspending agent is PEG3350 or PEG4000.

19. The injection according to any one of claims 1 - 5, comprising: (a) A combination of celecoxib and sodium celecoxib propionate, with a concentration range of the combination being 100 mg / mL - 400 mg / mL; and (b) Sodium carboxymethyl cellulose, with a concentration range of 1 mg / mL - 50 mg / mL; and optionally comprising (c) Poloxamer 407, or poloxamer 188, or poloxamer 338, with a concentration range of 1 mg / mL - 40 mg / mL.

20. A method for preparing the injection according to any one of claims 1 - 19, comprising the following steps: (1) Adding the stabilizer and optional other excipients to water, completely dissolving, and then adding the active ingredient, and stirring and dispersing evenly to obtain a mixed solution; and (2) Grinding the mixed solution in (1) to obtain a suspension.

21. Use of an injection according to any one of claims 1 - 19 in the preparation of a medicament for treating acute pain.

22. The injection according to any one of claims 1 - 4, 6 - 14, wherein the active ingredient is celecoxib or parecoxib.

23. The injectable preparation according to any one of claims 1-14, wherein the active ingredient is a combination of celecoxib and sodium celecoxib propionate, and the weight ratio of celecoxib to sodium celecoxib propionate is 1:1 to 4:

1.

24. The injectable preparation according to claim 22, wherein the concentration of celecoxib or parecoxib in the injectable preparation is 100 mg / mL to 300 mg / mL calculated according to the ratio of the weight of celecoxib or parecoxib to the total volume of the injectable preparation.

25. The injectable preparation according to claim 23, wherein the concentration of celecoxib in the injectable preparation is 50 mg / mL to 500 mg / mL calculated according to the ratio of the weight of celecoxib to the total volume of the injectable preparation.

26. The injectable preparation according to any one of claims 22-25, wherein the particle size D50 of celecoxib in the injectable preparation is 0.5 μm to 12 μm.

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