Lyophilized etoricoxib powder for injection and suspension thereof

Abstract

Provided in the present invention is a lyophilized Etoricoxib powder for injection. The lyophilized powder comprises: (A) 10-70% of Etoricoxib; (B) 0.1-10% of a wetting agent; and (C) 30-90% of a lyoprotectant, wherein the wetting agent is selected from at least one of oleic acid, oleate, cholic acid, or cholate. Further provided in the present invention are a method for preparing the lyophilized powder, a suspension containing the lyophilized powder, and use thereof. The lyophilized Etoricoxib powder for injection of the present invention has an appropriate particle size, maintains a stable particle size after reconstitution, and features good long-term storage stability. The prepared suspension can be quickly released to reach an effective therapeutic level after intravenous injection, has a long duration of action, and exhibits a better effect compared with parecoxib sodium, an analgesic injection commonly used in current clinical practice.

Description

A lyophilized powder of etoricoxib for injection and its suspension

[0001] This application claims priority to the following patent applications:

[0002] The prior application, filed on November 22, 2024 with the China National Intellectual Property Administration, has patent application number 202411686754.7 and is entitled "A freeze-dried etopoxi for injection and its suspension". Technical Field

[0003] This invention relates to the field of pharmaceutical preparations, specifically to an injectable etoricoxib lyophilized powder and its suspension. Background Technology

[0004] Etoricoxib (CAS No.: 202409-33-4) is a selective COX-2 (cyclooxygenase-2) inhibitor. It exerts its analgesic effect by inhibiting COX-2 alone, thereby suppressing prostaglandin production. Currently, it is available as tablets in strengths of 30mg, 60mg, 90mg, and 120mg, and is clinically used for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gouty arthritis, primary dysmenorrhea, and acute post-dental postoperative pain.

[0005] Currently, postoperative pain is still mainly treated with drugs. Commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) have a short duration of action (e.g., parecoxib 12h, flurbiprofen ester 8h, ketorolac tromethamine 4-6h, etc.). Postoperative analgesia requires frequent administration. Therefore, the development of long-acting postoperative analgesic injections can greatly solve the clinical needs of postoperative pain patients by reducing the number of administrations.

[0006] However, etoricoxib belongs to BCS Class II and has low solubility. It is difficult to prepare it into an injection using solubilizers or organic solvents. Therefore, how to prepare a stable etoricoxib injection to reduce the number of administrations and improve efficacy is an urgent problem to be solved. Summary of the Invention

[0007] In view of this, the present invention provides an injectable etoricoxib lyophilized powder and its preparation method. By using appropriate raw material formulation and process conditions, an etoricoxib lyophilized powder with suitable particle size and good stability is obtained. It can rapidly release the active pharmaceutical ingredient in vivo, and the efficacy lasts for a long time, allowing patients to take the drug once a day. This can effectively solve the problem of the short duration of efficacy of currently commonly used NSAID injections in clinical practice.

[0008] Unless otherwise specified, "%" in this invention refers to mass percentage.

[0009] In a first aspect, the present invention provides an injectable etoricoxib lyophilized powder, the lyophilized powder comprising:

[0010] (A) Relying on Coxib 10-70%;

[0011] (B) Wetting agent 0.1-10%; and,

[0012] (C) Lyophilization protectant 30-90%;

[0013] The wetting agent is selected from at least one of oleic acid, oleate, cholic acid or cholate.

[0014] Preferably, in the injectable etoricoxib lyophilized powder of the present invention, the lyophilized powder comprises:

[0015] (A) Relying on Coxib 15-50%;

[0016] (B) Wetting agent 0.5-5%; and,

[0017] (C) Lyophilization protectant 45-80%.

[0018] In some embodiments, the etoricoxib lyophilized powder for injection of the present invention contains 10-70%, 15-50%, or 18-40% etoricoxib, for example, 10%, 20%, 30%, 40%, 50%, 60%, or 70%.

[0019] In some embodiments, the content of wetting agent in the injectable etoricoxib lyophilized powder of the present invention is 0.1-10%, 0.5-5%, or 1-3%, for example, it can be 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0020] In some embodiments, the content of the lyophilized protectant in the injectable etoricoxib lyophilized powder of the present invention is 30-90%, 45-80%, or 60-80%, for example, it can be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0021] In some preferred embodiments, in the injectable etoricoxib lyophilized powder of the present invention, the cholic acid in the cholic acid or cholate is selected from at least one of glycocholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, lithocholic acid, porcine deoxycholic acid, mouse cholic acid, or taurocholic acid.

[0022] In some embodiments, the salts of the cholic acid or oleic acid are selected from at least one of sodium or potassium salts.

[0023] In some embodiments, the wetting agent is a bile salt or an oleate.

[0024] In some embodiments, the wetting agent is selected from at least one of sodium deoxycholate, sodium ursodeoxycholate, sodium glycocholate, or potassium glycocholate.

[0025] In some preferred embodiments, the freeze-drying protectant comprises at least one of sugars or polyols.

[0026] In some embodiments, the freeze-drying protectant comprises sugars, which include at least one of monosaccharides, disaccharides, or polysaccharides. The monosaccharides include at least one of glucose or fructose; the disaccharides include at least one of lactose, maltose, trehalose, or sucrose; and the polysaccharides include at least one of plant polysaccharides (such as starch, cellulose, pectin, inulin, gum arabic), animal polysaccharides (such as glycogen, chitin, heparin, hyaluronic acid), microbial polysaccharides (such as xanthan gum, dextran, cyclodextrin), or algal polysaccharides (such as agar, seaweed, carrageenan).

[0027] In some embodiments, the freeze-drying protectant comprises a polyol, which includes at least one of the following polyols that can be used as pharmaceutical excipients: sugar alcohols (such as mannitol, sorbitol, xylitol, maltitol, erythritol, lactitol, isomaltitol) or other polyols (such as propylene glycol, glycerin, polyethylene glycol (PEG400, PEG600 or PEG800, etc.)).

[0028] In some preferred embodiments, the freeze-drying protectant comprises at least one of lactose, maltose, glucose, trehalose, sucrose, mannitol, sorbitol, or polyethylene glycol.

[0029] In some embodiments, the freeze-drying protectant comprises at least one of sucrose, trehalose, glucose, or mannitol.

[0030] In some embodiments, the freeze-drying protectant comprises at least one of sucrose or trehalose.

[0031] In some embodiments, the freeze-drying protectant comprises at least one of sucrose or trehalose, and other optional freeze-drying protectants.

[0032] In some embodiments, the freeze-drying protectant comprises at least one of sucrose or trehalose, and other optional sugars and / or polyol freeze-drying protectants; for example, the freeze-drying protectant is a combination of sucrose and mannitol, a combination of trehalose and mannitol, a combination of trehalose and sucrose, a combination of trehalose and glucose, or a combination of sucrose and glucose.

[0033] In some embodiments, the freeze-drying protectant contains sucrose, and the mass percentage of sucrose in the freeze-drying protectant is not less than 40% (i.e., 40%-100%), preferably not less than 50% (i.e., 50%-100%), more preferably not less than 60% (i.e., 60%-100%), for example, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0034] In some embodiments, the freeze-drying protectant contains trehalose, and the mass percentage of trehalose in the freeze-drying protectant is not less than 40% (i.e., 40%-100%), preferably not less than 50% (i.e., 50%-100%), more preferably not less than 60% (i.e., 60%-100%), for example, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0035] In some preferred embodiments, the lyophilized etoricoxib powder for injection of the present invention has a moisture content of less than 2.5% (i.e., 0-2.5%). In some embodiments, the moisture content of the lyophilized powder of the present invention may be, for example, below 2.0% (i.e., 0-2%), below 1.8% (i.e., 0-1.8%), below 1.5% (i.e., 0-1.5%), below 1.2% (i.e., 0-1.2%), or below 1% (i.e., 0-1%). In some embodiments, the moisture content of the lyophilized powder of the present invention may be 1.0%-2.5%, preferably 1.0%-2.0%, more preferably 1.0%-1.8%, further preferably 1.0%-1.5%, and most preferably 1.2%-1.5%.

[0036] In some preferred embodiments, the injectable etoricoxib lyophilized powder of the present invention further includes: (D) other excipients.

[0037] In some embodiments, the other excipients include at least one of fillers, pH adjusters, antioxidants, chelating agents, acid-base adjusters, stabilizers, suspending agents, or antibacterial agents.

[0038] In some preferred embodiments, the other excipients include at least one of a stabilizer or a pH adjuster.

[0039] In some embodiments, the stabilizer is selected from at least one of polyvinylpyrrolidone (PVP K12, PVP K17, PVPK30), carboxymethyl cellulose and its sodium salt, polyethylene glycols (e.g., polyethylene glycol 4000) or poloxamers (e.g., 188, 407).

[0040] In some embodiments, the stabilizer content in the injectable etoricoxib lyophilized powder of the present invention is 0.1% to 10%, preferably 0.5% to 5%, for example, it can be 0.1%, 0.2%, 0.5%, 0.7%, 1%, 2%, 3%, 4%, 5% or 10%.

[0041] In some embodiments, the pH adjuster is selected from at least one of sodium hydroxide, hydrochloric acid, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium acetate, sodium bicarbonate, citric acid, or acetic acid.

[0042] In some embodiments, the pH adjuster content in the injectable etoricoxib lyophilized powder of the present invention is 0% to 2%, preferably 0% to 1%, for example, it can be 0%, 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 1.5% or 2%.

[0043] Preferably, the injectable etoricoxib lyophilized powder of the present invention has a drug particle size of 100-1000 nm, more preferably 150-800 nm, more preferably 200-600 nm, and even more preferably 200-500 nm. For example, it can be 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, or 1000 nm.

[0044] Preferably, after the injectable etoricoxib lyophilized powder of the present invention is reconstituted with water, the particle size of the etoricoxib drug particles is 100-1000 nm, preferably 150-800 nm, more preferably 200-600 nm, and even more preferably 200-500 nm. For example, it can be 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, or 1000 nm.

[0045] Preferably, after the injectable etoricoxib lyophilized powder of the present invention is reconstituted with water, the concentration of etoricoxib in the solution is 5-400 mg / ml, preferably 10-200 mg / ml, more preferably 20-100 mg / ml, for example, it can be 5 mg / ml, 10 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 200 mg / ml, 300 mg / ml or 400 mg / ml, etc.

[0046] In this invention, "particle size" refers to the average particle size of the microparticles in a sample (lyophilized powder or suspension), which is determined using a particle size analyzer. In the following embodiments: if a Malvern Mastersizer 3000 laser particle size analyzer is used to detect micron-sized particles, the average particle size result is expressed as Dv50, which is the 50% volume average particle size, the diameter of the particle located at 50% of the volume when the measured particles are arranged in ascending order of diameter; if a Malvern ZEN 1690 nanoparticle size analyzer is used to detect nano-sized particles, the average particle size result is expressed as Z-Average, which is the weighted average of the particle diameters.

[0047] In a second aspect, the present invention provides a method for preparing the lyophilized etoposide powder for injection as described in any of the preceding claims, the method comprising the following steps:

[0048] (S1) Dissolve the wetting agent in water to form solution 1;

[0049] (S2) Disperse etoricoxib into solution 1 to form suspension 2;

[0050] (S3) Reduce the particle size of the drug particles in suspension 2 to 100-1000 nm to obtain solution 3; and,

[0051] (S4) Add a freeze-drying protectant or freeze-drying protectant and other excipients to solution 3 and then freeze-dry directly or after dilution with water to obtain the freeze-dried powder.

[0052] Preferably, in the method, the method for reducing the particle size of the drug particles in the suspension 2 in step S3 is selected from at least one of ball milling, high-pressure homogenization, or microfluidics.

[0053] Preferably, in the method, step S4 freeze-drying includes a desorption drying step.

[0054] In some embodiments, the typical steps of the ball milling method include: loading the suspension 2 into a ball mill, adjusting the ball mill parameters for ball milling, detecting the particle size of the suspension sample after a certain period of time, and collecting the ball-milled sample after the target particle size is reached.

[0055] In some embodiments, typical steps of the high-pressure homogenization or microfluidization method include: pouring suspension 2 into a high-pressure homogenizer or microfluidizer, gradually adjusting the pressure, periodically detecting the particle size, and collecting the homogenized or microfluidic sample after the target particle size is reached.

[0056] In some embodiments, the method for reducing the particle size of drug particles in suspension 2 may include a combination of ball milling and high-pressure homogenization or microfluidization. A typical step includes: loading suspension 2 into a ball mill, adjusting the ball mill parameters for ball milling, detecting the particle size of the suspension sample after a certain period of time, and after reaching the target particle size, discharging the ball-milled sample 1, then pouring the ball-milled sample 1 into a high-pressure homogenizer or microfluidizer, adjusting the pressure, detecting the particle size at regular intervals, and discharging the homogenized or microfluidized sample 2 after reaching the target particle size.

[0057] In some embodiments, step S4 includes adding other excipients (stabilizers, pH adjusters, etc.) to the product of step S3, diluting it to a predetermined concentration, stirring and dispersing it evenly, dispensing it, and then freeze-drying it to obtain freeze-dried powder.

[0058] In some embodiments, at the start of the freeze-drying step S4, the etoricoxib concentration is 1%-20%, preferably 1%-10%, more preferably 2%-6%, and even more preferably 2%-3%, for example, it can be 1%, 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%, or 20%.

[0059] In some embodiments, the moisture content in the freeze-dried powder is controlled by the freeze-drying step in step S4.

[0060] In some embodiments, the moisture content in the freeze-dried powder is controlled by the analytical drying step in the freeze-drying step of step S4.

[0061] In some embodiments, the freeze-drying step S4 includes a desorption drying step: the product temperature is raised to 20°C to 40°C and maintained for 4 to 24 hours, preferably 8 to 24 hours, and the preferred heating time is 30 to 90 minutes.

[0062] In some embodiments, the freeze-drying in step S4 may further include pre-freezing and sublimation drying steps before desorption drying.

[0063] A typical freeze-drying step in step S4 includes three stages: pre-freezing, sublimation drying, and desorption drying. Pre-freezing: the product temperature is lowered to -40℃ to -45℃ and maintained for 2 to 4 hours. Sublimation drying: vacuum is applied, the product temperature is raised to -25℃ to -15℃ and maintained for 12 to 24 hours, the product temperature is raised to -10℃ to -5℃ and maintained for 6 to 12 hours, and the product temperature is raised to -5℃ to 5℃ and maintained for 6 to 12 hours. Desorption drying: the product temperature is raised to 20℃ to 40℃ within 30 to 90 minutes (i.e., the set time) and maintained (i.e., the duration) for 4 to 24 hours, preferably 8 to 24 hours.

[0064] Thirdly, the present invention provides an injectable suspension comprising the injectable etoricoxib lyophilized powder as described in any of the preceding claims or the injectable etoricoxib lyophilized powder prepared by any of the preceding claims.

[0065] In some embodiments, the concentration of etoricoxib in the suspension of the present invention is 5-400 mg / ml, preferably 10-200 mg / ml, more preferably 20-100 mg / ml, for example, it can be 5 mg / ml, 10 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 200 mg / ml, 300 mg / ml or 400 mg / ml, etc.

[0066] In some embodiments, the lyophilized powder and water for injection of the present invention are stored separately, and the two parts are mixed by manual shaking to form a suspension before intravenous injection.

[0067] In some embodiments, the lyophilized powder or suspension of the present invention does not contain sustained-release excipients.

[0068] Fourthly, the present invention provides the use of the lyophilized etoricoxib for injection, the lyophilized etoricoxib for injection prepared by any of the foregoing methods, or the lyophilized suspension for injection described in any of the foregoing methods in the preparation of a medicament for treating or improving inflammation or pain and related symptoms.

[0069] In some implementations, the relevant symptoms are selected from gout, fever, swelling, articular cartilage degeneration, or movement disorders.

[0070] In some embodiments, the inflammation includes arthritis (e.g., inflammation of the knee, elbow, hand, wrist, and hip, specifically such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, acute gouty arthritis, etc.), upper respiratory tract inflammation, bronchitis, postpartum, pelvic inflammatory disease, adnexitis, cystitis, prostatitis, anterior segment inflammation, postoperative / traumatic / suture removal inflammation, gingivitis, periodontitis, herpes zoster, etc.

[0071] In some implementations, the pain includes acute pain, postoperative pain (e.g., after dental surgery), chronic musculoskeletal pain, neuropathic pain, dysmenorrhea, and may include, for example, muscle pain, back pain, neck pain, fibromyalgia, myofascial pain, sprains, strains, contusions, burns, etc.

[0072] Fifthly, the present invention provides a method for treating or improving inflammation or pain and related symptoms, the method comprising administering to a patient an effective amount of the aforementioned etoricoxib lyophilized powder for injection, the etoricoxib lyophilized powder for injection prepared by any of the aforementioned methods, or the aforementioned suspension for injection.

[0073] In some implementations, the relevant symptoms are selected from gout, fever, swelling, articular cartilage degeneration, or movement disorders.

[0074] In some embodiments, the inflammation includes arthritis (e.g., inflammation of the knee, elbow, hand, wrist, and hip, specifically such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, acute gouty arthritis, etc.), upper respiratory tract inflammation, bronchitis, postpartum, pelvic inflammatory disease, adnexitis, cystitis, prostatitis, anterior segment inflammation, postoperative / traumatic / suture removal inflammation, gingivitis, periodontitis, herpes zoster, etc.

[0075] In some implementations, the pain includes acute pain, postoperative pain (e.g., after dental surgery), chronic musculoskeletal pain, neuropathic pain, dysmenorrhea, and may include, for example, muscle pain, back pain, neck pain, fibromyalgia, myofascial pain, sprains, strains, contusions, burns, etc. Beneficial effects

[0076] 1. The injectable etoricoxib lyophilized powder of the present invention has a suitable particle size, maintains stable particle size after reconstitution, and has good long-term stability.

[0077] 2. The lyophilized powder suspension of the present invention can be rapidly released and achieve an effective therapeutic level after intravenous injection, with a long duration of effect. Compared with parecoxib sodium, a commonly used analgesic injection in clinical practice, it shows superior pharmacokinetic effects. Attached Figure Description

[0078] Figure 1: Photograph of the solubility of the formulation in plasma in Example 7.

[0079] Figure 2: Schematic diagram of particle size change of the formulation in plasma in Example 7.

[0080] Figure 3: Schematic diagram of blood drug concentration curves for the formulations of Example 4 and Comparative Example 1. Detailed Implementation

[0081] In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention can be practiced without one or more of these details. In other instances, certain technical features well-known in the art have not been described in order to avoid obscuring the invention.

[0082] The present invention will now be described in detail through specific embodiments.

[0083] raw material

[0084] The raw and auxiliary materials used in the embodiments of this invention conform to the standards of the 2020 edition of the Chinese Pharmacopoeia.

[0085] Example 1. Screening of wetting agents for etoricoxib lyophilized powder for injection

[0086] Prepare 150g solutions of excipients containing different wetting agents (see Table 1 for specific wetting agent types and concentrations; the percentage of wetting agent in Table 1 is based on the total mass of the suspension). Add 30g of etoricoxib, stir to disperse evenly, and then add the solution to a ball mill for ball milling. The ball milling parameters are: zircon beads: 0.4mm, filling amount: 70%, rotation speed: 1500rpm, pump speed: 150ml / min, and condensate circulation temperature: 5℃. After ball milling for a period of time, take samples and measure the particle size using a Malvern nanoparticle size analyzer. Once the target nanoscale particle size is reached, collect the ball milling liquid. Weigh 0.05g of polyvinylpyrrolidone K17, 3g of sucrose, and 2g of mannitol, add them to 32.45g of water, stir until completely dissolved, then add 12.5g of the above ball milling liquid and stir evenly to obtain etoricoxib suspension. Fill 10ml vials (2ml per vial) and freeze-dry. After freeze-drying, cap and store at room temperature. The lyophilized sample was reconstituted with 1.8 ml of water, and the particle size of the suspension was measured. The results are shown in Table 1.

[0087] Table 1 Screening of Wetting Agent Types

[0088] As shown in Table 1, when Tween 80, HS15 and poloxamer 188 were used as wetting agents to prepare samples, the particle size of the samples increased significantly to the micrometer level after freeze-drying and reconstitution, making them unusable. The particle size of the samples prepared by using sodium oleate and bile salt surfactants as wetting agents was stable after freeze-drying and reconstitution. Therefore, bile salts or oleates are preferred as wetting agents.

[0089] Example 2. Screening of lyophilization protectants for etoricoxib lyophilized powder for injection

[0090] Prepare a 150g suspension containing 20% ​​etoricoxib and 1.2% sodium glycocholate. After uniform dispersion, add the solution to a ball mill for ball milling. The ball milling parameters are: zircon beads: 0.4mm, filling amount: 70%, rotation speed: 1500rpm, pump speed: 400ml / min, and condensate circulation temperature: 5℃. After ball milling for an appropriate time, take a sample and measure the particle size using a Malvern nanoparticle size analyzer. Weigh 1.0g of polyvinylpyrrolidone K17 and add it to 129.0g of water. Add the different lyophilization protectants listed in Table 2, stir until completely dissolved, and then add 50g of the above ball milling solution. Stir until uniform to obtain the etoricoxib suspension (the percentage of lyophilization protectants in Table 2 is based on the total mass of the suspension). The particle size of the samples after ball milling and after lyophilization and reconstitution was investigated using the same method as in Example 1. The results are shown in Table 2.

[0091] Table 2 Screening of Lyophilization Protectants

[0092] As shown in Table 2, the lyophilization protectant of the present invention can produce lyophilized powder with a good particle size after drug reconstitution. Furthermore, selecting sucrose or trehalose as the lyophilization protectant is a more preferred option, as it results in better particle size stability after reconstitution of the lyophilized product. Adding other lyophilization protectants to sucrose or trehalose can also maintain the particle size stability of the lyophilized product after reconstitution.

[0093] Example 3. Screening of freeze-drying process for etoricoxib lyophilized powder for injection

[0094] This embodiment investigates the relationship between moisture content and particle size stability after freeze-drying. Specific method: 150g of suspension containing 20% ​​etoricoxib and 1.2% sodium glycocholate was prepared and dispersed evenly. The solution was then added to a ball mill for ball milling. The milling parameters were: zircon beads: 0.4mm, filling volume: 70%, rotation speed: 1500rpm, pump speed: 400ml / min, and condensate circulation temperature: 5℃. After 3 hours of ball milling, the milling liquid was sampled, and the particle size was measured using a Malvern nanoparticle size analyzer; the average particle size was 325.5nm. 1.0g of polyvinylpyrrolidone K17, 12g of sucrose, and 8g of mannitol were weighed and added to 129.0g of water. After complete dissolution, 50g of the above milling liquid was added and stirred evenly to obtain the etoricoxib suspension. The suspension was then bottled into 10ml vials (2ml per vial) and freeze-dried. The desorption drying time was adjusted during the freeze-drying process, and the moisture and particle size stability of different samples were investigated. The specific results are shown in Table 3.

[0095] Table 3 Screening of freeze-drying processes

[0096] The results show that the moisture content of the sample after freeze-drying affects its stability during subsequent storage. Therefore, by appropriately adjusting the parameters of the freeze-drying process (such as adjusting the desorption drying temperature and time), the moisture content of the sample can be guaranteed to be less than 2.5%. While maintaining the particle size stability after reconstitution, the particle size stability of the sample during storage can be further improved.

[0097] Example 4. Preparation of etoricoxib lyophilized powder for injection

[0098] Weigh 0.155g of sodium hydroxide, add 117.3g of water, stir and dissolve at room temperature, then add 1.809g of glycocholic acid, stir and dissolve, then add 30g of etoricoxib, and stir for 10 minutes to form a homogeneous suspension. Shear the suspension at 6000 rpm for 10 minutes, then ball mill it using the following parameters: zirconium beads: 0.4mm, filling amount: 70%, rotation speed: 1500 rpm, pump speed: 400ml / min, and cooling water circulation temperature: 5℃. After ball milling for 2.5 hours, sample the milling liquid and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size was 278.5nm. Weigh 0.2g of polyvinylpyrrolidone K17, 12g of sucrose, and 8g of mannitol, add to 129.8g of water, stir and dissolve completely, then add 50g of the above milling liquid and stir until homogeneous to obtain the etoricoxib suspension. The sample was filled into 10ml vials (2ml per vial) and freeze-dried. During freeze-drying, the set temperature was 40℃, the set time was 60min, and the total duration was 480min. After freeze-drying, the moisture content was found to be below 1.8%. The vials were then capped and stored at room temperature. After reconstitution with 1.8ml of water, the average particle size was measured to be 305.6nm.

[0099] Example 5. Preparation of etoricoxib lyophilized powder for injection

[0100] Weigh 1.205g of glycocholic acid and add 5.140g of 2% sodium hydroxide solution. Dissolve the solution by stirring at room temperature to obtain sodium glycocholate solution. Add water to bring the volume to 119.27g. Weigh 30g of etoricoxib and add it to the above solution. Stir for 10 minutes to form a homogeneous suspension. Shear the suspension at 6000rpm for 20 minutes and then ball mill it. The ball milling parameters are: zirconium beads: 0.4mm, filling amount: 70%, rotation speed: 1500rpm, pump speed: 200ml / min, and cooling water circulation temperature: 10℃. After ball milling for 3 hours, take a sample of the ball milling liquid and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size is 359.4nm. Add the above ball milling liquid to a high-pressure homogenizer for homogenization. The homogenization parameters are: 1500bar. After homogenization for 10 minutes, take a sample of the homogenate and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size is 309.8nm. Weigh 0.4g of polyvinylpyrrolidone K30, 10g of sucrose, and 10g of mannitol, add them to 129.6g of water, stir until completely dissolved, add 50g of the above homogenized solution, and stir until homogeneous to obtain etoricoxib suspension. Fill 10ml vials (2ml per vial) and freeze-dry. During freeze-drying, the set temperature is 30℃, the set time is 60min, and the duration is 720min. After freeze-drying, the moisture content is found to be below 1.8%, and the vials are capped and stored at room temperature. Redissolve in 1.8ml of water, and the average particle size is measured to be 324.2nm.

[0101] Example 6. Preparation of etoricoxib lyophilized powder for injection

[0102] Weigh 0.217g of potassium hydroxide and add it to 117.3g of water. After dissolving by stirring at room temperature, add 1.807g of glycocholic acid and stir until dissolved. Add 30g of etoricoxib and stir for 10 minutes to form a homogeneous suspension. Shear the suspension at 6000 rpm for 10 minutes and then ball mill it. The ball milling parameters are: zircon beads: 0.4mm, filling amount: 70%, rotation speed: 2000 rpm, pump speed: 400ml / min, and cooling water circulation temperature: 5℃. After ball milling for 2.5 hours, take a sample of the ball milling liquid and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size is 254.6nm. Weigh 0.4g of polyvinylpyrrolidone K30, 10g of sucrose, and 10g of mannitol and add them to 129.6g of water. Stir until completely dissolved. Add 50g of the above ball milling liquid and stir until homogeneous to obtain the etoricoxib suspension. Fill 10ml vials (2ml per vial) and freeze-dry. During the freeze-drying process, the set temperature was 30℃, the set time was 60 min, and the total duration was 1440 min. After freeze-drying, the moisture content was found to be below 1.8%, and the freeze-dried product was capped and stored at room temperature. After reconstitution with 1.8 ml of water, the average particle size was measured to be 295.2 nm.

[0103] Example 7. Preparation of etoricoxib lyophilized powder for injection

[0104] Weigh 0.378g of sodium hydroxide, add 21.401g of water, dissolve, and place in a 65℃ water bath. Add 3.705g of ursodeoxycholic acid, stir until completely dissolved, and add water to a final volume of 175.103g. Weigh 75g of etoricoxib and add to the above solution, stirring for 20 minutes to form a homogeneous suspension. Shear the suspension at 6000rpm for 30 minutes, then ball mill the solution using the following parameters: zirconium beads: 0.4mm, filling volume: 70%, rotation speed: 1500rpm, pump speed: 200ml / min, and cooling water circulation temperature: 10℃. After 6 hours of ball milling, sample the milling liquid and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size was 309.3nm. Weigh 0.6g of polyvinylpyrrolidone K30 and 15g of sucrose, add to 110g of water, stir until completely dissolved, then add 25g of the above milling liquid and stir until homogeneous to obtain the etoricoxib suspension. The sample was filled into 10ml vials (2ml per vial) and freeze-dried. During freeze-drying, the set temperature was 30℃, the set time was 60min, and the total duration was 1440min. After freeze-drying, the moisture content was found to be below 1.8%. The vials were then capped and stored at room temperature. After reconstitution with 1.8ml of water, the average particle size was determined to be 345.6nm.

[0105] Example 8. Preparation of etoricoxib lyophilized powder for injection

[0106] Weigh 0.198g of sodium hydroxide, add 117.15g of water, dissolve, and place in a 65℃ water bath. Then add 1.869g of deoxycholic acid and stir until completely dissolved. Weigh 30g of etoricoxib and add to the above solution, stirring for 20 minutes to form a homogeneous suspension. Shear the suspension at 6000rpm for 30 minutes, then ball mill it. The ball milling parameters are: zirconium beads: 0.4mm, filling amount: 70%, rotation speed: 1500rpm, pump speed: 200ml / min, and cooling water circulation temperature: 5℃. After ball milling for 3 hours, take a sample of the ball milling liquid and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size is 342.6nm. Weigh 0.2g of polyvinylpyrrolidone K17, 10g of sucrose, and 10g of mannitol and add to 129.8g of water. Stir until completely dissolved, then add 50g of the above ball milling liquid and stir until homogeneous to obtain the etoricoxib suspension. The sample was filled into 10ml vials (2ml per vial) and freeze-dried. During freeze-drying, the set temperature was 30℃, the set time was 60min, and the total duration was 720min. After freeze-drying, the moisture content was found to be below 1.8%. The vials were then capped and stored at room temperature. After reconstitution with 1.8ml of water, the average particle size was measured to be 360.0nm.

[0107] Example 9. Preparation of etoricoxib lyophilized powder for injection

[0108] Weigh 0.155g of sodium hydroxide, add 117.3g of water, stir and dissolve at room temperature, then add 1.809g of glycocholic acid, stir and dissolve, then add 30g of etoricoxib, stir for 10 minutes to form a homogeneous suspension. Shear the suspension at 6000rpm for 10 minutes, then homogenize under high pressure. The homogenization parameters are: initially, the pressure gradually increases from 0 to 500 bar within 30 minutes, then the pressure is set to 1500 bar. After homogenization for 3 hours, a sample of the homogenate is taken, and the particle size is measured using a Malvern nanoparticle size analyzer; the average particle size is 318.6nm. Weigh 0.4g of polyvinylpyrrolidone K17 and 20g of trehalose, add 154.6g of water, stir and dissolve completely, then add 25g of the above homogenate, stir until homogeneous to obtain the etoricoxib suspension. Fill 10ml vials (4ml per vial) and freeze-dry. During the freeze-drying process, the set temperature was 40℃, the set time was 60 min, and the duration was 480 min. After freeze-drying, the moisture content was found to be below 1.8%, and the freeze-dried product was capped and stored at room temperature. After reconstitution with 1.8 ml of water, the average particle size was measured to be 324.8 nm.

[0109] Example 10. Preparation of etoricoxib lyophilized powder for injection

[0110] Weigh 0.210g of sodium hydroxide, add 117.7g of water, dissolve, and place in a 65℃ water bath. Add 2.167g of deoxycholic acid and stir until completely dissolved. Weigh 30g of etoricoxib and add to the above solution, stirring for 20 minutes to form a homogeneous suspension. Shear the suspension at 6000rpm for 20 minutes, then ball mill it using the following parameters: zirconium beads: 0.4mm, filling amount: 70%, rotation speed: 1500rpm, pump speed: 400ml / min, and cooling water circulation temperature: 5℃. After ball milling for 3 hours, sample the milling liquid and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size is 318.5nm. Weigh 0.4g of polyvinylpyrrolidone K12, 12g of sucrose, and 8g of mannitol, add to 129.6g of water, stir until completely dissolved, then add 50g of the above milling liquid and stir until homogeneous to obtain the etoricoxib suspension. The sample was filled into 10ml vials (2ml per vial) and freeze-dried. During freeze-drying, the set temperature was 30℃, the set time was 60min, and the total duration was 720min. After freeze-drying, the moisture content was found to be below 1.8%. The vials were then capped and stored at room temperature. After reconstitution with 1.8ml of water, the average particle size was determined to be 343.8nm.

[0111] Example 11. Preparation of etoricoxib lyophilized powder for injection

[0112] Weigh 0.302 g of sodium hydroxide, add 116.7 g of water, stir and dissolve at room temperature, then add 3.004 g of ursodeoxycholic acid, stir and dissolve, then add 30 g of etoricoxib, and stir for 10 min to form a homogeneous suspension. Shear the suspension at 6000 rpm for 20 min, then ball mill it using the following parameters: zirconium beads: 0.4 mm, filling amount: 70%, rotation speed: 1500 rpm, pump speed: 400 ml / min, and condensate circulation temperature: 5℃. After ball milling for 3 h, sample the milling liquid and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size was 298.4 nm. The milling liquid was then treated in a microfluidic system at 1500 bar for 15 min. Sample the microfluidic liquid and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size was 277.5 nm. Weigh 0.4g of polyvinylpyrrolidone K30, 12g of sucrose, and 8g of mannitol, add them to 129.6g of water, stir until completely dissolved, then add 50g of the above microfluidic solution and stir until homogeneous to obtain etoricoxib suspension. Fill 10ml vials (2ml per vial) and freeze-dry. During freeze-drying, the set temperature is 40℃, the set time is 60min, and the duration is 480min. After freeze-drying, the moisture content is found to be below 1.8%, then capped and stored at room temperature. Redissolve in 1.8ml of water, and the average particle size is measured to be 298.2nm.

[0113] Example 12. Preparation of etoricoxib lyophilized powder for injection

[0114] Weigh 0.155g of sodium hydroxide, add 118.0g of water, stir and dissolve at room temperature, then add 1.801g of glycocholic acid, stir and dissolve, then add 30g of etoricoxib, stir for 10min to form a homogeneous suspension. Shear the suspension at 6000rpm for 20min, then ball mill the suspension. The ball milling parameters are: zirconium beads: 0.3mm, filling amount: 70%, rotation speed: 2000rpm, pump speed: 400ml / min, and cooling water circulation temperature: 5℃. After ball milling for 2.5h, take a sample of the ball milling liquid and measure the particle size using a Malvern nanoparticle size analyzer. The average particle size is 294.6nm. Weigh 0.16g of polyvinylpyrrolidone K17, 9.6g of sucrose, and 6.4g of mannitol, add 123.8g of water, stir and dissolve completely, then add 20g of the above ball milling liquid and stir evenly to obtain the etoricoxib suspension. The sample was filled into 10ml vials (4ml per vial) and freeze-dried. During freeze-drying, the set temperature was 40℃, the set time was 60min, and the total duration was 720min. After freeze-drying, the moisture content was found to be below 1.8%. The vials were then capped and stored at room temperature. After reconstitution with 3.7ml of water, the average particle size was determined to be 306.8nm.

[0115] Example 13. Preparation of etoricoxib lyophilized powder for injection

[0116] Weigh 0.155g of sodium hydroxide, add 118.0g of water, stir and dissolve at room temperature, then add 1.800g of glycocholic acid, stir and dissolve, then add 30g of etoricoxib, and stir for 10 minutes to form a homogeneous suspension. Shear the suspension at 6000 rpm for 10 minutes, then add it to a ball mill for ball milling. The ball milling parameters are: zirconium beads: 0.4mm, filling amount: 70%, rotation speed: 1500 rpm, pump speed: 400ml / min, and condensate circulation temperature: 5℃. After ball milling for 2.5 hours, sample the milling liquid and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size is 328.2nm. Add the above milling liquid to a high-pressure homogenizer for homogenization. The homogenization parameters are: 1500 bar. After homogenization for 20 minutes, sample the homogenate and measure the particle size using a Malvern nanoparticle size analyzer; the average particle size is 285.4nm. Weigh 0.16g of polyvinylpyrrolidone K17 and 16g of sucrose, add them to 123.8g of water, stir until completely dissolved, then add 20g of the homogenized solution and stir until homogeneous to obtain etoricoxib suspension. Fill 10ml vials (4ml per vial) and freeze-dry. During freeze-drying, the set temperature was 40℃, the set time was 60min, and the duration was 720min. After freeze-drying, the moisture content was found to be below 1.8%, and the vials were capped and stored at room temperature. Reconstitute with 3.7ml of water, and the average particle size was found to be 287.8nm.

[0117] Comparative Example 1. Preparation of oral etoricoxib suspension (control formulation)

[0118] Weigh 0.042g of sodium deoxycholate, add 99.26g of water, stir until completely dissolved, then slowly add 0.203g of sodium carboxymethyl cellulose, stirring until completely dissolved. Then add 0.506g of etoricoxib and stir until well mixed.

[0119] Experimental Example 1: In vitro simulation of etoricoxib lyophilized powder for injection in canine plasma release

[0120] The lyophilized etoricoxib powder for injection prepared in Example 7 was reconstituted with 1.8 ml of water and added to canine plasma (canine plasma source: obtained by centrifugation of blood from conventional experimental animals, dogs) in a 37°C water bath. After about 30 seconds, the plasma sample with added etoricoxib nano-suspension could be observed to change from turbid to clear (see Figure 1). Furthermore, the particle size distribution of the added etoricoxib nano-suspension was also found to be invisible after 1 minute using a nanoparticle size analyzer (see Figure 2), indicating that the etoricoxib nano-suspension can dissolve rapidly after being added to the plasma.

[0121] Experimental Example 2. Detection of changes in etoricoxib plasma concentration after intravenous and oral administration of etoricoxib suspension in SD rats.

[0122] Experimental animals: Sixteen male SD rats were randomly divided into four groups (n=4) according to their body weight, denoted as group A, group B, group C and group D.

[0123] Administration methods and dosages: Group A: Control formulation etoricoxib suspension (Comparative Example 1), 30 mg / kg, administered orally by gavage; Group B: Etoricoxib lyophilized powder for injection of Example 4, reconstituted with 1.8 ml of water before administration, dose 3 mg / kg, administered via tail vein injection; Group C: Etoricoxib lyophilized powder for injection of Example 4, reconstituted with 1.8 ml of water before administration, dose 10 mg / kg, administered via tail vein injection; Group D: Etoricoxib lyophilized powder for injection of Example 4, reconstituted with 1.8 ml of water before administration, dose 30 mg / kg, administered via tail vein injection.

[0124] Sampling and Detection: After drug administration, 0.25 ml of blood (EDTA-K2 anticoagulated) was collected from the jugular vein in groups B, C, and D before administration (0 h) and at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 1 d (24 h), and 2 d (48 h), respectively. In group A, 0.25 ml of blood (EDTA-K2 anticoagulated) was collected from the jugular vein before administration (0 h) and at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 1 d (24 h), and 2 d (48 h), respectively. The collected whole blood was temporarily stored on wet ice and centrifuged at 1500 g for 10 min within 1 hour to separate the plasma (4℃). The collected plasma was stored at -80℃ for analysis. After determining the plasma drug concentration, a drug-time curve was fitted, and pharmacokinetic parameters were calculated.

[0125] Figure 3 and Table 4 show the changes in etoricoxib concentration in rat plasma over time. The results show that after intravenous injection of 3, 10, and 30 mg / kg into rats, the concentrations of etoricoxib in rat plasma prepared in Example 4... max (1:3.2:8.7), AUC 0-t (1:4.2:12.6), AUC 0-∞ (1:4.4:13.7) is basically linear with the dose; compared with oral administration, intravenous administration of etoricoxib can release it rapidly, achieve rapid onset of action, and maintain the efficacy for 24 hours by adjusting the dosage, which can greatly improve the treatment compliance of patients with postoperative pain.

[0126] Table 4. Pharmacokinetic parameters of etoricoxib suspension and etoricoxib for injection

[0127] Experimental Example 3. Pharmacological Study in SD Rats

[0128] First, a rat model of foot incision pain was established surgically. The day after modeling, baseline pain sensitivity was tested. The 50% paw withdrawal threshold (50% PWT) of the hind paw on the surgical side was measured using a Von Frey test wire. Animals meeting the baseline requirements were selected for inclusion in the study and randomly divided into three groups of eight animals each, based on their 50% PWT values. A double-blind test was conducted, with a single intravenous administration. The pain threshold (50% PWT) was measured before administration (baseline) and at 0.5h, 2h, 4h, and 8h after administration. A higher PWT value indicated better analgesic effect. The specific administration regimen was as follows: Parecoxib sodium for injection (trade name: Corex) was used as a control formulation to evaluate the analgesic effect of the formulation in Example 4. The results are shown in Table 5.

[0129] Table 5. Grouping of Pharmacological Studies

[0130] Tables 6 and 7 below show the specific data comparing the pain threshold and pain threshold AUC of Example 4 with the solvent control (model group) and the positive control (parecoxib sodium for injection). Experimental studies indicate that, as shown in Tables 6 and 7, the formulation of Example 4 has comparable / slightly better efficacy than parecoxib sodium for injection, and also shows a certain trend towards better efficacy in terms of duration of action.

[0131] Table 6 Pain Threshold Results

[0132] Table 7. AUC results of pain threshold

[0133] The Mann-Whitney U test treats the model group as a control and compares all groups with it. * indicates p ≤ 0.05, and ** indicates p ≤ 0.01.

[0134] All technical solutions described above that fall within the scope of this invention's conceptual framework are protected by this invention. It should be noted that for those skilled in the art, any improvements and modifications made without departing from the principles of this invention should also be considered within the scope of protection of this invention.

Claims

1. A lyophilized etoposide powder for injection, wherein the lyophilized powder comprises: (A) Relying on Coxib 10-70%; (B) Wetting agent 0.1-10%; and, (C) Lyophilization protectant 30-90%; The wetting agent is selected from at least one of oleic acid, oleate, cholic acid or cholate.

2. The lyophilized etoricoxib for injection according to claim 1, wherein the lyophilized powder comprises: (A) Relying on Coxib 15-50%; (B) Wetting agent 0.5-5%; and, (C) Lyophilization protectant 45-80%.

3. The lyophilized etoricoxib for injection according to any one of claims 1-2, wherein the cholic acid in the cholic acid or cholate is selected from at least one of glycocholic acid, deoxycholic acid, ursodeoxycholic acid, or chenodeoxycholic acid; the salt of the cholic acid or oleic acid is selected from at least one of sodium salt or potassium salt; preferably, the wetting agent is a cholate or oleate; preferably, the wetting agent is selected from at least one of sodium deoxycholate, sodium ursodeoxycholate, sodium glycocholate, or potassium glycocholate.

4. The lyophilized etocoxib for injection according to any one of claims 1-2, wherein the lyophilization protectant comprises at least one of sugars or polyols; preferably, the lyophilization protectant comprises at least one of lactose, maltose, glucose, trehalose, sucrose, mannitol, sorbitol, or polyethylene glycol; more preferably, the lyophilization protectant comprises at least one of sucrose, trehalose, glucose, or mannitol; most preferably, the lyophilization protectant comprises at least one of sucrose or trehalose.

5. The lyophilized etoricoxib for injection according to any one of claims 1-2, wherein the moisture content of the lyophilized powder is less than 2.5%; preferably, the moisture content of the lyophilized powder is less than 2%, and most preferably less than 1.8%.

6. The lyophilized etoricoxib for injection according to any one of claims 1-2, wherein the lyophilized powder further comprises: (D) Other excipients; said other excipients include at least one of stabilizers or pH adjusters.

7. The etoricoxib lyophilized powder for injection according to any one of claims 1-2, wherein after the lyophilized powder is reconstituted with water, the particle size of the etoricoxib drug is 100-1000 nm, preferably 150-800 nm, more preferably 200-600 nm, and most preferably 200-500 nm.

8. A method for preparing the lyophilized etoricoxib powder for injection according to any one of claims 1-7, the method comprising the following steps: (S1) Dissolve the wetting agent in water to form solution 1; (S2) Disperse etoricoxib into solution 1 to form suspension 2; (S3) Reduce the particle size of the drug particles in suspension 2 to 100-1000 nm to obtain solution 3; and, (S4) After adding a freeze-drying protectant or other excipients to solution 3, freeze-dry the solution directly or after dilution with water to obtain the freeze-dried powder. Preferably, in the method: the method for reducing the particle size of the drug particles in the suspension 2 in step S3 is selected from at least one of ball milling, high-pressure homogenization or microfluidization; preferably, in the method: the freeze-drying process in step S4 includes a desorption drying step.

9. An injectable suspension comprising the lyophilized etoricoxib for injection as described in any one of claims 1-7 or the lyophilized etoricoxib for injection prepared by the method of claim 8.

10. The use of the lyophilized etoricoxib for injection according to any one of claims 1-7, the lyophilized etoricoxib for injection prepared by the method of claim 8, or the suspension for injection according to claim 9 in the preparation of a medicament for treating or improving inflammation or pain and related symptoms, wherein the related symptoms are selected from gout, fever, swelling, articular cartilage degeneration, or movement disorders; preferably, the specific disease of inflammation or pain is acute pain, postoperative pain, chronic musculoskeletal pain, neuropathic pain, dysmenorrhea, arthritis (e.g., osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or acute gouty arthritis).

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