Etoricoxib injection and preparation method thereof

Abstract

The invention relates to an injectable etoricoxib injection true solution or injection etoricoxib for postoperative analgesia and a composition thereof. The composition comprises an active component etoricoxib, water for injection, an injectable acid, an injectable alkali and sulfobutyl beta-cyclodextrin sodium.

Description

[0001] This application requests the following:

[0002] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on June 17, 2024, with patent application number 202410777857.8 and title "An Etocoxib Injection and a Method for Preparing the Same".

[0003] The full text of the prior application is incorporated herein by reference. Technical Field

[0004] This invention belongs to the field of pharmaceutical preparations, specifically relating to an etoricoxib injection and its preparation method. Background Technology

[0005] Etoricoxib is a selective COX-2 inhibitor with anti-inflammatory, analgesic, and antipyretic effects. It is indicated for the treatment of symptoms and signs in both acute and chronic phases of osteoarthritis, and can also be used to treat acute gouty arthritis. Etoricoxib is recommended by the American College of Rheumatology guidelines for the treatment of gout. The Chinese guidelines for the diagnosis and treatment of osteoarthritis and the expert opinions on orthopedic pain management from the Chinese Orthopaedic Association recommend etoricoxib as a selective COX-2 inhibitor for patients with gastrointestinal risks.

[0006] The relationship between the indications and dosage of etoricoxib is as follows: (1) Acute gouty arthritis: The recommended dose during the acute phase is 120 mg once daily; during the uric acid-lowering period, a small dose of 60 mg once daily can be taken for 3-6 months to significantly reduce the frequency of gout attacks; (2) Osteoarthritis: The recommended dose is 30 mg once daily; for patients whose symptoms cannot be relieved, the dose can be increased to 60 mg once daily; (3) Ankylosing spondylitis: The recommended dose is 60-120 mg once daily; (4) Rheumatoid arthritis (5) Chronic low back pain: Recommended dose is 60mg once a day; (7) Primary dysmenorrhea: Recommended dose is 120mg once a day; (8) Perioperative analgesia: Postoperative pain (mild): Oral administration after surgery, recommended dose is 120mg once a day; Postoperative pain (moderate to severe): Oral administration of etoricoxib 120mg 90min before surgery; Postoperative use of PCA pump, oral administration of etoricoxib 120mg once a day after 6h fasting period, for 7-14 days.

[0007] Currently, etoricoxib is only available in oral formulations. Patent CN105343002A discloses the preparation of an oral etoricoxib emulsion, but the emulsion has a low drug loading capacity, less than 1 mg / mL, making it difficult to meet clinical requirements. In clinical settings, patients, especially during general anesthesia, often struggle to maintain consciousness, and oral analgesics are difficult to administer due to factors such as fasting during surgery. Therefore, the development of an injectable formulation of etoricoxib is of significant clinical importance. However, etoricoxib has extremely poor water solubility, being almost insoluble in water, making the development of an injectable formulation quite challenging. Therefore, there is an urgent need for an etoricoxib injection solution with high solubility, high drug loading capacity, and good stability. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides an etoricoxib injection and its preparation method.

[0009] This invention provides an etoricoxib injection solution, which comprises the following components:

[0010] Etocoxib or its pharmaceutically acceptable salts and solubilizers.

[0011] According to embodiments of the present invention, the pharmaceutically acceptable salt of etoricoxib is selected from oxalate, succinate, fumarate, benzenesulfonate, hydrobromide, glutamate, aminosulfonate, benzoate, cinnamate, salicylate or toluenesulfonate of etoricoxib.

[0012] According to an embodiment of the present invention, the solubilizer is selected from one, two or more of polyethylene glycol or its derivatives, polyethylene glycol (15)-hydroxystearate or its derivatives, and cyclodextrin or its derivatives.

[0013] According to an embodiment of the present invention, the cyclodextrin or its derivative is selected from α-cyclodextrin, beta-cyclodextrin, γ-cyclodextrin, hydroxypropyl beta-cyclodextrin, sodium sulfobutyl beta-cyclodextrin, and preferably sodium sulfobutyl beta-cyclodextrin.

[0014] According to an embodiment of the present invention, the etoricoxib injection comprises the following components:

[0015] Etocoxib or its pharmaceutically acceptable salts, sodium sulfobutylbetacyclodextrin.

[0016] According to an embodiment of the present invention, the mass ratio of etoricoxib to the solubilizer is 1:0.1-100, preferably 1:1-50, more preferably 1:5-40, 1:10-25, for example 1:10, 1:12, 1:12.5, 1:13, 1:15, 1:16.7, 1:18, 1:20, 1:20.8, 1:22, 1:25.

[0017] According to an embodiment of the present invention, the mass ratio of etoricoxib to sodium sulfobutylbetacyclodextrin is 1:0.1-100, preferably 1:1-50, more preferably 1:5-40, 1:10-25, for example 1:10, 1:12, 1:12.5, 1:13, 1:15, 1:16.7, 1:18, 1:20, 1:20.8, 1:22, 1:25.

[0018] According to embodiments of the present invention, the concentration of the solubilizer is 30 mg / mL-100 mg / mL, 100 mg / mL-300 mg / mL, preferably 40 mg / mL-90 mg / mL, 100 mg / mL-280 mg / mL, for example 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 66.6 mg / mL, 70 mg / mL, 73.3 mg / mL, 75 mg / mL, 80 mg / mL, 83.3 mg / mL, 85 mg / mL. / mL, 90mg / mL, 100mg / mL, 110mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 140mg / mL, 150mg / mL, 160mg / mL, 166.7mg / mL, 170mg / mL, 180mg / mL, 190mg / mL, 200mg / mL, 210mg / mL, 220mg / mL, 230mg / mL, 240mg / mL, 250mg / mL, 260mg / mL, 270mg / mL, 280mg / mL.

[0019] According to embodiments of the present invention, the concentration of sodium sulfobutylbetacyclodextrin is 30 mg / mL-100 mg / mL, 100 mg / mL-300 mg / mL, preferably 40 mg / mL-90 mg / mL, 100 mg / mL-280 mg / mL, or 60 mg / mL-250 mg / mL, for example 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 62.5 mg / mL, 65 mg / mL, 66.6 mg / mL, 70 mg / mL, 73.3 mg / mL, 75 mg / mL, 80 mg / mL, or 83.3 mg / mL. mg / mL, 85mg / mL, 90mg / mL, 100mg / mL, 110mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 140mg / mL, 150mg / mL, 160mg / mL, 166.7mg / mL, 1 70mg / mL, 180mg / mL, 190mg / mL, 200mg / mL, 210mg / mL, 220mg / mL, 230mg / mL, 240mg / mL, 250mg / mL, 260mg / mL, 270mg / mL, 280mg / mL.

[0020] According to an embodiment of the present invention, the injection solution is a true injection solution.

[0021] According to an embodiment of the present invention, the injection solution optionally further comprises an acid for injection; preferably, the acid for injection is selected from one, two or more of hydrochloric acid, sulfuric acid, lactic acid, acetic acid, phosphoric acid, citric acid, malic acid, and tartaric acid.

[0022] According to an embodiment of the present invention, in the injection solution, the mass ratio of etoricoxib to injectable acid is 1:1-20, preferably 1:2-18, for example 1:2.5, 1:3.3, 1:5, 1:8, 1:8.3, 1:10, 1:12.5, 1:15.

[0023] According to an embodiment of the present invention, the concentration of the injectable acid is 0.005 g / mL to 0.01 g / mL, preferably 0.01 g / mL to 0.04 g / mL, for example 0.008 g / mL, 0.01 g / mL, 0.013 g / mL, 0.017 g / mL, 0.02 g / mL, 0.027 g / mL, 0.03 g / mL, 0.033 g / mL, 0.04 g / mL, 0.05 g / mL, 0.06 g / mL, 0.07 g / mL, 0.08 g / mL, or 0.09 g / mL.

[0024] According to an embodiment of the present invention, the injection solution optionally further comprises an injection base; preferably, the injection base is selected from one, two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium phosphate, meglumine, and arginine.

[0025] According to an embodiment of the present invention, the pH value of the injection solution is less than 4.4, preferably less than or equal to 4.3, and more preferably 2.5-4.2, for example 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5.

[0026] According to an embodiment of the invention, the injection solution optionally further comprises a solvent; preferably, the solvent is selected from water; for example, water for injection.

[0027] According to an embodiment of the present invention, the concentration of etoricoxib in the injection solution is less than 30 mg / mL, preferably 1 mg / mL to 30 mg / mL, for example 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, 12 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, or 30 mg / mL.

[0028] According to an embodiment of the present invention, the etoricoxib injection comprises the following components:

[0029] Etocoxib or its pharmaceutically acceptable salts, solubilizers (e.g., sodium sulfobutylbetacyclodextrin), acids for injection (e.g., hydrochloric acid, citric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, or tartaric acid), bases for injection (e.g., disodium hydrogen phosphate, sodium hydroxide, trisodium hydrogen phosphate, dipotassium hydrogen phosphate, meglumine, arginine, sodium carbonate, or sodium bicarbonate), and solvents (e.g., water);

[0030] Preferably, the solubilizer is selected from sodium sulfobutylbetacyclodextrin;

[0031] Preferably, the pH value of the injection solution is less than or equal to 4.1 (e.g., 3.5-4.1);

[0032] Preferably, the mass ratio of etoricoxib to solubilizer (e.g., sodium sulfobutyl betacyclodextrin) is 1:12.5-25;

[0033] Preferably, the concentration of the solubilizer (e.g., sodium sulfobutyl betacyclodextrin) is 50 mg / mL-100 mg / mL or 100 mg / mL-250 mg / mL;

[0034] Preferably, the concentration of etoricoxib in the injection solution is less than 30 mg / mL (e.g., 2 mg / mL-20 mg / mL).

[0035] According to an embodiment of the present invention, the injection solution has a therapeutically effective amount of etoricoxib in a single-dose formulation, wherein the therapeutically effective amount is selected from 10 mg to 200 mg, for example 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg, and 200 mg.

[0036] According to an embodiment of the present invention, the volume of the injection solution is selected from 5mL to 80mL, for example 5mL, 10mL, 15mL, 20mL, 25mL, 30mL, 35mL, 40mL, 50mL, and 60mL.

[0037] According to an embodiment of the present invention, the osmotic pressure of the injection solution is 280mOsm / kg-300mOsm / kg, for example 280mOsm / kg, 281mOsm / kg, 282mOsm / kg, 283mOsm / kg, 284mOsm / kg, 285mOsm / kg, 286mOsm / kg, 288mOsm / kg, 290mOsm / kg, 295mOsm / kg, and 300mOsm / kg.

[0038] According to an embodiment of the invention, the injection is administered as part of a combination therapy with at least one other therapeutic agent.

[0039] According to an embodiment of the present invention, the injection solution does not contain antioxidants. The stability of the injection solution system can be maintained without the addition of antioxidants.

[0040] According to an embodiment of the invention, the injection solution is diluted with a diluent before administration.

[0041] According to an embodiment of the present invention, the diluent is selected from sodium chloride aqueous solution (concentration, for example, 0.9%) and glucose aqueous solution (concentration, for example, 5%).

[0042] According to an embodiment of the present invention, the volume ratio of the injection solution to the diluent is 1:1 to 1:20, for example 1:3, 1:5, 1:8, 1:10, 1:12, 1:15, or 1:18.

[0043] The present invention also provides a solution composition comprising the above-described injection solution and a diluent.

[0044] According to an embodiment of the present invention, the diluent is selected from sodium chloride aqueous solution (concentration, for example, 0.9%) and glucose aqueous solution (concentration, for example, 5%).

[0045] According to an embodiment of the present invention, the volume ratio of the injection solution to the diluent is 1:1 to 1:20, for example 1:3, 1:5, 1:8, 1:10, 1:12, 1:15, or 1:18.

[0046] The present invention also provides a method for preparing the above-mentioned injection solution, the method comprising the following steps:

[0047] The injection solution is obtained by mixing etoricoxib or its pharmaceutically acceptable salt, solubilizer, and optionally an injectable acid, base, and solvent.

[0048] According to an embodiment of the present invention, the preparation method includes the following steps:

[0049] (1) Weigh out etoricoxib or its pharmaceutically acceptable salt, injectable acid and solvent, and mix them thoroughly;

[0050] (2) Add the solubilizer and mix well;

[0051] (3) Add alkali for injection to adjust the pH of the injection solution to obtain the injection solution.

[0052] The present invention also provides a method for preparing the above-mentioned solution composition, the method comprising the following steps:

[0053] The injection solution is diluted with a diluent to obtain the solution composition.

[0054] The present invention also provides lyophilized formulations of the above-described injection or solution compositions.

[0055] According to an embodiment of the present invention, the lyophilized formulation is a lyophilized powder injection.

[0056] This invention also provides a method for preparing the above-mentioned lyophilized formulation, the method comprising the following steps:

[0057] The above-mentioned injection or solution composition is freeze-dried to obtain the freeze-dried preparation.

[0058] The present invention also provides the use of the above-mentioned injection solution, solution composition or lyophilized preparation in the preparation of medicaments for treating pain, fever and inflammation.

[0059] According to embodiments of the present invention, the inflammation includes osteoarthritis, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, such as the acute phase and chronic phase of osteoarthritis.

[0060] According to an embodiment of the present invention, the pain includes orthopedic pain and postoperative pain (perioperative analgesia; including mild postoperative pain, moderate postoperative pain, and severe postoperative pain).

[0061] According to embodiments of the present invention, the above-mentioned injection, solution composition, or lyophilized preparation can be used to relieve pain symptoms, including but not limited to nociceptive pain, neuropathic pain, postoperative pain (mild, moderate, severe), lower back pain, cluster headache, herpetic neuralgia, phantom limb pain, central pain, toothache, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during childbirth and delivery, pain caused by burns (including sunburn), postpartum pain, migraine and genitourinary pain (including cystitis), chronic low back pain, and primary dysmenorrhea.

[0062] According to embodiments of the present invention, the above-mentioned injection, solution composition, or lyophilized preparation can be used to reduce fever, including but not limited to fever caused by infection, drug reaction, allergic reaction, transfusion reaction, stroke, surgery, heatstroke, rheumatic disease, cancer, or fever of unknown cause.

[0063] According to embodiments of the present invention, the above-mentioned injection, solution composition, or lyophilized preparation is administered once every 0.5 to 2 days, for example, once daily.

[0064] The present invention also provides a method for treating pain, fever, or inflammation in a subject, the method comprising administering a therapeutically effective amount of the above-mentioned injectable solution, solution composition, or lyophilized preparation to the subject parenterally. Preferably, it is administered to the subject intravenously.

[0065] According to embodiments of the present invention, the inflammation includes osteoarthritis, acute gouty arthritis, such as the acute phase of osteoarthritis and the chronic phase of osteoarthritis.

[0066] According to an embodiment of the present invention, the pain includes orthopedic pain and postoperative pain (perioperative analgesia; including mild postoperative pain, moderate postoperative pain, and severe postoperative pain).

[0067] According to embodiments of the present invention, the above-mentioned injection, solution composition, or lyophilized preparation can be used to relieve pain symptoms, including but not limited to nociceptive pain, neuropathic pain, postoperative pain, lower back pain, cluster headache, herpetic neuralgia, phantom limb pain, central pain, toothache, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during childbirth and delivery, pain caused by burns (including sunburn), postpartum pain, migraine, and genitourinary pain (including cystitis).

[0068] According to embodiments of the present invention, the above-mentioned injection, solution composition, or lyophilized preparation can be used to reduce fever, including but not limited to fever caused by infection, drug reaction, allergic reaction, transfusion reaction, stroke, surgery, heatstroke, rheumatic disease, cancer, or fever of unknown cause.

[0069] According to embodiments of the present invention, the above-mentioned injection, solution composition, or lyophilized preparation is administered once every 0.5 to 2 days, for example, once daily.

[0070] Beneficial effects

[0071] This invention provides an etoricoxib injection solution whose concentration, osmotic pressure, and pH value all meet clinical drug requirements. The injection solution can be administered directly via intravenous bolus injection or diluted with 0.9% sodium chloride or 5% glucose injection for intravenous drip administration, and exhibits high freeze-thaw safety. The etoricoxib injection solution provided by this invention has significant advantages in terms of dosage (60-120 mg), dosing frequency (once daily), and adverse reactions, and is highly safe, non-sensitizing, and non-hemolytic. Furthermore, the etoricoxib injection solution provided by this invention achieves a half-life comparable to commercially available oral etoricoxib formulations, thus enabling once-daily injection administration and resulting in good patient compliance.

[0072] The etoricoxib injection provided by this invention has the following advantages compared with marketed nonsteroidal anti-inflammatory drug injections for analgesia (especially postoperative analgesia): 1) its safety is not inferior to flurbiprofen ester injection, but the frequency of administration is better than flurbiprofen ester injection; 2) its safety is superior to lornoxicam (17% incidence of gastrointestinal adverse reactions), parecoxib sodium (severe skin adverse reactions and >10% nausea) and ketocyochromate tromethamine (gastrointestinal adverse reactions >15%, and continuous use should not exceed 3 days).

[0073] Terminology Definition

[0074] As used herein, “treatment” includes relieving, reducing or improving symptoms of a disease or condition, preventing additional symptoms, delaying or preventing the underlying metabolic cause of symptoms, inhibiting a disease or condition, preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, relieving symptoms caused by a disease or condition, or stopping the symptoms of a disease or condition, and is intended to include prevention.

[0075] As used herein, “effective amount” refers to any amount necessary or sufficient to achieve or promote a desired outcome. In some cases, effective amount is therapeutically effective. Therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. Effective amount for any particular application can vary depending on factors such as the disease or condition being treated, the specific drug administered, the subject’s body size, or the severity of the disease or condition.

[0076] As used herein, “application” refers to a method for enabling a pharmaceutical composition to be delivered to the target site of biological action.

[0077] As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or a mammal species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including but not limited to non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and undomesticated animals. As used herein, the term "patient" refers to a human or animal. As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates such as monkeys, chimpanzees, baboons, or rhesus monkeys. In one embodiment, the mammal is a human. Attached Figure Description

[0078] Figure 1 The pharmacokinetic curve of formulation 36 in SD rat plasma is shown. Detailed Implementation

[0079] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0080] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0081] Example 1

[0082] Table 1 contains single-dose formulations containing etoricoxib and solubilizer.

[0083]

[0084]

[0085] Note: 2-Hydroxypropyl-β-cyclodextrin is no longer used in injectable formulations due to its high risk of nephrotoxicity.

[0086] According to the formulation in Table 1 of Example 1, etoricoxib and a commonly used solubilizer were weighed out in proportion, and purified water was added and stirred to ensure complete dissolution of etoricoxib and the solubilizer. The solution state was observed after stirring for 24 hours. The results showed that etoricoxib in all formulations was suspended and could not be dissolved. This indicates that the above-mentioned solubilizer cannot be used directly to prepare a true aqueous solution of etoricoxib.

[0087] Example 2

[0088] Table 2 contains single-dose formulations containing etoricoxib, hydrochloric acid, and solubilizer.

[0089]

[0090] According to the formulations in Table 2 of Example 2, etoricoxib, hydrochloric acid, and commonly used solubilizers were weighed out in proportion, and purified water was added and stirred to ensure complete dissolution of etoricoxib and the solubilizer. The results showed that after stirring for 24 hours, etoricoxib in all formulations was completely dissolved, except for formulation 10, which remained in a suspension state. This indicates that adding an acid (e.g., hydrochloric acid) to the formulation can significantly improve the solubilizing ability of etoricoxib. However, the pH values ​​of all formulation solutions were below 2.5, which is too low to meet the basic requirements for clinical preparations.

[0091] Example 3

[0092] Table 3 contains single-dose formulations of etoricoxib, hydrochloric acid, disodium hydrogen phosphate, and solubilizer.

[0093]

[0094] According to the prescription in Table 3 of Example 3, purified water, etoricoxib, and hydrochloric acid were weighed out in proportion to completely dissolve etoricoxib. A common solubilizer was then added, and the pH was adjusted to 3.1 with an appropriate amount of disodium hydrogen phosphate. After standing for 24 hours, the appearance of the solution was observed. The results showed that only the solution with sodium sulfobutyl betacyclodextrin as the solubilizer (Prescription 20) was a true solution; all others showed obvious crystal precipitation, indicating that sodium sulfobutyl betacyclodextrin also has a stabilizing effect on the etoricoxib solution.

[0095] Example 4

[0096] Table 4 Single-dose prescriptions for different pH values

[0097]

[0098] According to the prescription in Table 4 of Example 4, purified water, etoricoxib, and hydrochloric acid were weighed out in proportion to completely dissolve the etoricoxib. Then, sodium sulfobutylbetacyclodextrin was added and stirred until dissolved. The pH was adjusted to different values ​​using an appropriate amount of disodium hydrogen phosphate. After standing for 24 hours, the appearance of the solution was observed. The results showed that solutions below pH 4.1 were in a true solution state, while solutions above pH 4.1 showed obvious yellow crystal precipitation, indicating that the pH value of the solution is crucial to its stability.

[0099] Example 5

[0100] Table 5 Single-dose formulations with different solubilization amounts

[0101]

[0102] According to the formulation in Table 5 of Example 5, purified water, etoricoxib, and hydrochloric acid were weighed out in proportion to completely dissolve the etoricoxib. Different amounts of sodium sulfobutyl betacyclodextrin were then added and stirred until dissolved. The target pH was adjusted to 3.80 using an appropriate amount of disodium hydrogen phosphate. After standing for 24 hours, the appearance of each formulation was observed. The results showed that the amount of sodium sulfobutyl betacyclodextrin used as a stabilizer had a positive effect on the stability of the solution.

[0103] Example 6

[0104] Table 6 Single-dose prescriptions at different concentrations

[0105]

[0106] According to the formulations in Table 6 of Example 6, different amounts of purified water, etoricoxib, and hydrochloric acid were weighed out in proportion to completely dissolve the etoricoxib. Then, sodium sulfobutylbetacyclodextrin was added and stirred until dissolved. The target pH was adjusted to 3.80 using an appropriate amount of disodium hydrogen phosphate. After standing for 24 hours, the appearance of each formulation was observed. The results showed that a small amount of crystals precipitated at a concentration of 30 mg / ml (formulation 33), while no abnormalities were observed in the others, indicating that concentration also affects the stability of the solution.

[0107] Example 7

[0108] Table 7 Single-dose prescriptions for different acids and bases

[0109]

[0110]

[0111] According to the formulation in Table 7 of Example 7, purified water, etoricoxib, and injectable acid were weighed out in proportion to completely dissolve the etoricoxib. Then, sodium sulfobutylbetacyclodextrin was added, and the pH was adjusted to 3.80 using an appropriate amount of injectable alkali. After standing for 24 hours, the solution state was observed. The results showed that all formulations were in a pale yellow true solution state.

[0112] Example 8

[0113] Table 8 Single-dose formulations for lyophilized reconstitution

[0114]

[0115] According to the formulation in Table 8 of Example 8, purified water, etoricoxib, and phosphoric acid or hydrochloric acid were weighed out in proportion to completely dissolve etoricoxib. Then, sodium sulfobutylbetacyclodextrin was added and stirred until dissolved. The target pH was adjusted to 3.80 using an appropriate amount of disodium hydrogen phosphate before freeze-drying. The results showed that the freeze-dried formulation could be completely reconstituted with purified water, and its appearance and pH were consistent with the state before freeze-drying.

[0116] Example 9: Formulation Stability Study

[0117] (1) Appearance

[0118] The prescription solution was placed at different temperatures (25℃, 2-8℃, 40℃), and its appearance was observed at 0 days, 1 month, 2 months, 3 months, 6 months, and 12 months. The results are shown in Table 9-11.

[0119] Table 9. Changes in the prescription solution at 25℃

[0120]

[0121] Table 10 Changes in the prescription solution at 2-8℃

[0122]

[0123]

[0124] Table 11 Changes in the appearance of the prescription at 40℃

[0125]

[0126] Among them, prescriptions 38 and 40 are freeze-dried finished products.

[0127] (2) Related substances

[0128] The active pharmaceutical ingredient and the prescription solution were subjected to moist heat sterilization, and the changes in impurities before and after moist heat sterilization were observed. The results are shown in Table 12. Simultaneously, the prescription solution was placed at 40℃, and the changes in impurities were observed at 0 days, 1 month, 2 months, 3 months, and 6 months, respectively. The results are shown in Table 13. The results indicate that the prescription has good stability.

[0129] Method for determining impurities: Take 1 ml of sample and dilute to 50 ml in a volumetric flask with 50% acetonitrile to prepare the test solution; transfer 1 ml of the test solution and dilute to 50 ml in a volumetric flask with 50% acetonitrile to prepare the reference solution.

[0130] Chromatographic conditions: Column: Waters Symmetry C 18 The packing material size was 3.5 μm, the column size was 4.6*150 mm, the column temperature was 40℃, the flow rate was 1.2 mL / min, the detection wavelength was 235 nm, the injection volume was 10 μL, and the mobile phase was 0.02 M phosphate buffer: acetonitrile. The detection was performed under certain gradient conditions.

[0131] Table 12 Changes in impurities of raw materials and formulations before and after moist heat sterilization

[0132]

[0133]

[0134] Table 13 shows the changes in impurities in the formulation at 40℃.

[0135]

[0136] (3) Compatibility stability

[0137] 10 ml of sample 34 from prescription was taken and mixed with 100 ml of sodium chloride (0.9%) and 100 ml of glucose (5%), respectively. The compatibility stability was tested at room temperature, and the results are shown in Tables 14-15. The results show that the prescription has good compatibility stability.

[0138] Table 14. Changes in the compatibility stability of the prescription with 0.9% sodium chloride.

[0139]

[0140] Table 15. Changes in the compatibility and stability of the prescription with 5% glucose.

[0141]

[0142] (4) Freeze-thaw stability

[0143] Thirty-four samples of the prescription were stored at -20℃ and 40℃ respectively, and the freeze-thaw stability, appearance and impurity changes were examined by repeated cycles three times. The results are shown in Table 16. The results show that the prescription has good freeze-thaw stability.

[0144] Table 16 Freeze-thaw stability of the prescription

[0145]

[0146] (5) Reconstitution effect of lyophilized samples

[0147] The lyophilized sample of prescription 39 was reconstituted with 0.9% sodium chloride and 5% glucose, respectively, and the compatibility stability after reconstitution was investigated. The results are shown in Tables 17-18. The results show that the lyophilized prescription has good compatibility stability after reconstitution.

[0148] Table 17. Stability changes of lyophilized formulations when combined with 0.9% sodium chloride.

[0149]

[0150] Table 18. Changes in the compatibility and stability of freeze-dried formulations with 5% glucose.

[0151]

[0152] Example 10: Pharmacokinetic Study of Intravenous Administration in SD Rats

[0153] Three male rats were administered etoricoxib 36 via a single tail vein injection at a dose of 12.4 mg / kg. Blood samples were collected before administration and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration. Plasma etoricoxib levels were measured, and pharmacokinetic parameters were calculated. The experimental results are shown in Table 19, and the pharmacokinetic curves are shown in [Table data missing]. Figure 1 .

[0154] Table 19 Pharmacokinetic parameters of SD rats after intravenous administration (iv).

[0155] Pharmacokinetic parameters unit M-Rat 1 M-Rat 2 M-Rat 3 average value SD <![CDATA[t 1 / 2 ]]> h 1.85 3.15 2.48 2.49 0.65 <![CDATA[T max ]]> h 0.083 0.083 0.083 0.083 0.00 <![CDATA[C max ]]> ng / mL 10685.20 9942.70 11364.29 10664.06 711.03 <![CDATA[AUC 0-t ]]> h*ng / mL 23800.34 32460.59 39228.31 31829.75 7733.30 <![CDATA[AUC 0-∞ ]]> h*ng / mL 24307.35 32550.13 39266.73 32041.40 7492.65 Cl mL / h / kg 510.13 380.95 315.79 402.29 98.91 <![CDATA[MRT 0-∞ ]]> h 2.35 3.37 3.48 3.07 0.62 <![CDATA[V ss ]]> mL / kg 1198.97 1283.68 1098.91 1193.86 92.49

[0156] t 1 / 2 Drug half-life; T max Peak time; C max Peak concentration; AUC 0-t AUC0-∞: Area under the curve from the start of administration to the last time point; Cl: Clearance after intravenous injection; MRT 0-∞ V: The average drug residence time from the start of drug administration to theoretical infinity; ss Apparent volume of distribution after intravenous injection.

[0157] Example 11: Pharmacokinetic Study of a Single Intravenous Administerment of Formula 36 in Beagle Dogs

[0158] This study used 24 Beagle dogs, which were randomly divided into 4 groups of 6 each, with half males and half females. Animals in groups 1-3 received a single intravenous (IV) injection (15 min) of prescription 36 at doses of 4, 8, and 20 mg / kg, respectively, without fasting. Animals in group 4 received a single oral (PO) gavage of one tablet (120 mg) of etoricoxib (manufacturer: Rovi Pharma Industrial Services SA). Blood samples were collected before administration and at 0.083 h, 0.25 h, 0.5 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0159] Table 20 summarizes the main pharmacokinetic parameters of etoricoxib in plasma after a single intravenous injection of prescription 36 in Beagle dogs.

[0160] The experimental results show that:

[0161] (1) Within the dosage range of 4 to 20 mg / kg, after a single intravenous injection (15 min) of prescription 36 in male and female Beagle dogs that had not fasted, the systemic exposure of etoricoxib in plasma increased with increasing dosage, and the increase in exposure was approximately or slightly higher than the increase in dosage.

[0162] (2) Within the dosage range of 4–20 mg / kg, after a single intravenous injection (15 min) of Prescription 36 in male and female Beagle dogs that had not fasted, there was no difference in the systemic exposure of etoricoxib in plasma between sexes;

[0163] (3) After a single intravenous injection (15 min) of Prescription 36 to Beagle dogs, the plasma exposure of the test group animals was 4.09 to 5.09 times that of the marketed control group (oral administration of etoricoxib tablets) after dose correction.

[0164] In the above experiments, the half-life of 120 mg etoricoxib tablets orally administered to beagle dogs was 1.55 h, while the half-life of 20 mg / kg of the injection solution of this invention in beagle dogs was 1.64 h. This suggests that the half-lives of intravenous and oral administration are comparable, and also indicates that etoricoxib is metabolized much faster in beagle dogs than in humans (the oral half-life of etoricoxib in humans is approximately 22 h). Therefore, it can be inferred that the elimination half-life of the etoricoxib injection solution of this invention, administered intravenously in humans, is comparable to that of commercially available oral formulations, allowing for once-daily dosing.

[0165]

[0166]

[0167] Example 12 Toxicity Assessment of a 14-Day Repeated-Dosing Study in Beagle Dogs

[0168] Beagle dogs were given Prescription 36 once daily for 14 consecutive days via intravenous injection (15 min), at doses of 0 mg / kg (solvent), 5 mg / kg, 15 mg / kg, and 30 mg / kg. Detailed clinical observation, administration site irritation observation, monitoring of body weight, food intake, ophthalmological examination, body temperature, electrocardiogram, blood pressure, hematology, serum biochemistry, coagulation, urinalysis, gross anatomical observation, organ weight and organ coefficients, and histopathological examination revealed no drug-related toxicities. The NOAEL (No Observed Adverse Effect Level) for Prescription 36 was 30 mg / kg. Repeat-dose toxicity studies included administration site irritation, and the product showed no irritation. Formulation safety studies indicated that the product was non-sensitizing and non-hemolytic.

[0169] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An etoricoxib injection solution, wherein the etoricoxib injection solution comprises the following components: Etoricoxib or its pharmaceutically acceptable salts, solubilizers, and injectable acids; The solubilizer is selected from sodium sulfobutyl betacyclodextrin.

2. The etoricoxib injection according to claim 1, characterized in that, The mass ratio of etoricoxib to sodium sulfobutylbetacyclodextrin is 1:0.1-100, preferably 1:1-50; Preferably, the concentration of sodium sulfobutyl betacyclodextrin is 30 mg / mL-100 mg / mL, 100 mg / mL-300 mg / mL, and more preferably 40 mg / mL-90 mg / mL, 100 mg / mL-280 mg / mL.

3. The etoricoxib injection solution according to claim 1 or 2, characterized in that, The acid for injection is selected from one, two or more of the following: hydrochloric acid, sulfuric acid, lactic acid, acetic acid, phosphoric acid, citric acid, malic acid, and tartaric acid. Preferably, in the injection solution, the mass ratio of etoricoxib to injectable acid is 1:1-20, more preferably 1:2-18; Preferably, the concentration of the acid for injection is 0.005 g / mL to 0.01 g / mL, and more preferably 0.01 g / mL to 0.04 g / mL; Preferably, the injection solution optionally further comprises an injection base; preferably, the injection base is selected from one, two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium phosphate, meglumine, and arginine. Preferably, the pH value of the injection solution is less than 4.4, and more preferably less than or equal to 4.3; Preferably, the injection solution optionally further comprises a solvent; preferably, the solvent is selected from water; Preferably, the concentration of etoricoxib in the injection solution is less than 30 mg / mL, and more preferably 1 mg / mL to 30 mg / mL; Preferably, the etoricoxib injection comprises the following components: etoricoxib or a pharmaceutically acceptable salt thereof, sodium sulfobutylbetacyclodextrin, an acid for injection, a base for injection, and a solvent; preferably, the pH of the injection is less than or equal to 4.1 (e.g., 3.5-4.1); preferably, the mass ratio of etoricoxib to sodium sulfobutylbetacyclodextrin is 1:12.5-25; preferably, the concentration of sodium sulfobutylbetacyclodextrin is 50 mg / mL-100 mg / mL or 100 mg / mL-250 mg / mL; preferably, the concentration of etoricoxib in the injection is less than 30 mg / mL (e.g., 2 mg / mL-20 mg / mL).

4. The etoricoxib injection according to any one of claims 1-3, characterized in that, The injection solution contains a therapeutically effective amount of etoricoxib in a single-dose formulation, wherein the therapeutically effective amount is selected from 10 mg to 200 mg. Preferably, the volume of the injection solution is selected from 5 mL to 80 mL; Preferably, the osmotic pressure of the injection solution is 280 mOsm / kg-300 mOsm / kg; Preferably, the injection is administered as part of a combination therapy with at least one other therapeutic agent; Preferably, the injection solution is diluted with a diluent before administration; preferably, the diluent is selected from sodium chloride aqueous solution or glucose aqueous solution; preferably, the volume ratio of the injection solution to the diluent is 1:1 to 1:

20.

5. A solution composition comprising the injection solution according to any one of claims 1-4 and a diluent; Preferably, the diluent is selected from sodium chloride aqueous solution and glucose aqueous solution; preferably, according to an embodiment of the present invention, the volume ratio of the injection solution to the diluent is 1:1 to 1:

20.

6. A method for preparing the injection solution according to any one of claims 1-4, the method comprising the following steps: The injection solution is obtained by mixing etoricoxib or its pharmaceutically acceptable salt, solubilizer, and optionally an injectable acid, base, and solvent.

7. A method for preparing the solution composition according to claim 5, the method comprising the following steps: The injection solution is diluted with a diluent to obtain the solution composition.

8. A lyophilized formulation of the injectable solution according to any one of claims 1-4 or the solution composition according to claim 5; Preferably, the lyophilized formulation is a lyophilized powder injection.

9. A method for preparing the lyophilized formulation according to claim 8, wherein the preparation method comprises the following steps: The lyophilized formulation is obtained by freeze-drying the injection solution according to any one of claims 1-4 or the solution composition according to claim 5.

10. The use of the injection solution according to any one of claims 1-4, the solution composition according to claim 5, or the lyophilized preparation according to claim 8 in the preparation of a medicament for treating pain, fever, and inflammation; Preferably, the inflammation includes osteoarthritis, acute gouty arthritis, ankylosing spondylitis, rheumatoid arthritis, such as the acute phase and chronic phase of osteoarthritis; Preferably, the pain includes orthopedic pain and postoperative pain.

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