A meloxicam composition, preparation method and application thereof

Abstract

The present application belongs to the field of pharmaceutical preparations, and relates to a meloxicam composition, preparation and preparation method and application. One aspect of the present application provides a meloxicam composition, which comprises meloxicam and a latent solvent, wherein the latent solvent is a mixed solvent comprising water and an organic solvent. Another aspect of the present application provides another composition, which comprises meloxicam, a solvent and a pH regulator, wherein the pH regulator at least comprises citric acid. The pharmaceutical composition of the present application can significantly improve the solubility of meloxicam in liquid preparation, and has excellent stability. The meloxicam composition provided by the present application can even be directly used for intravenous injection administration, and quickly reaches an effective therapeutic concentration for postoperative analgesia. In addition, the preparation process of the composition is simple, and can be completed by stirring and dispersing at room temperature for a short time, so that the scale-up production is easy to realize.

Description

[0001] This application is a divisional application of the invention patent application filed on May 10, 2019, with application number 201910390430.1 and invention title "A meloxicam composition, preparation and preparation method and application thereof".

[0002] This application also claims priority to the following earlier applications: patent application No. 201810450456.6, filed with the China National Intellectual Property Administration on May 11, 2018, entitled "A meloxicam composition, formulation, preparation method and application thereof"; and patent application No. 201810451076.4, filed with the China National Intellectual Property Administration on May 11, 2018, entitled "A meloxicam composition containing a pH adjuster, preparation method thereof and application thereof". The entire contents of the aforementioned earlier applications are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of pharmaceutical preparations, specifically relating to a meloxicam composition, preparation, preparation method, and application. Background Technology

[0004] Meloxicam (or "MLX") is an enol nonsteroidal anti-inflammatory drug with the molecular formula: C 14 H 13 N3O4S2, molecular weight: 351.40, chemical name: 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. This compound has the following chemical structural formula:

[0005]

[0006] Meloxicam is practically insoluble in water, with a solubility of only 0.003414 mg / mL at 25°C, and is slightly soluble in chloroform, acetone, and ethanol. Therefore, although Bringer Ingelheim, Iroko, Recro Pharm, and others have developed various dosage forms of meloxicam, improving its solubility remains a challenge in the development of intravenous injection formulations.

[0007] For poorly soluble drugs, solubility can usually be improved by altering the drug's physicochemical properties. This can be achieved by preparing the drug as a salt or changing its crystal form. For example, Ochi et al. used Tris, arginine, DEA, and TEA to recrystallize meloxicam into a salt. Alladi Saritha et al. used spherical crystallization technology to transform the meloxicam crystal form into a spherical shape, thereby increasing its dissolution rate. However, both salt formation and crystal form alteration methods have limitations. Salt formation requires separation of the drug and its salt form, and crystal formation is influenced by various factors such as stirring speed, stirring time, temperature, and solvent type, and is limited by the preparation method and the stability of the salt or crystal form.

[0008] In addition, the solubility of poorly soluble drugs can be improved from a formulation perspective, such as by using mixed solvents, employing inclusion complex technology, or through new dosage forms and technologies. Currently, meloxicam has been studied both domestically and internationally using these methods, but all face challenges such as complex formulation processes, excessive use of excipients, and the unsuitability of many excipients and organic solvents for intravenous administration.

[0009] For example, WO2008062274A2 improves meloxicam solubility by using a mixed solvent containing pyrrolidone, ethanol, and water, but pyrrolidone is not suitable for intravenous administration. US2010137292A1 solubilizes meloxicam using an organic base meglumine, N,N-dimethylacetamide, and polyethylene glycol as a mixed solvent, but N,N-dimethylacetamide is also unsuitable for intravenous administration. Furthermore, CN103110575A uses cyclodextrin as a solubilizer and adds stabilizers, pH adjusters, antibacterial agents, and osmotic pressure adjusters to prepare an ophthalmic formulation containing 1 mg / mL of meloxicam. US2017157061A1 also increases meloxicam solubility by mixing it with stabilizers (including polyvinylpyrrolidone, surfactants, etc.) to prepare nanoparticles. US9345665B2 discloses a meloxicam nanoparticle composition containing at least one surfactant and stabilizer to improve the drug loading of meloxicam. Woraphatphadung et al. improved the solubility of meloxicam by preparing chitosan micelles loaded with meloxicam. CN104825396A improved the dissolution characteristics of bioactive substances by grinding meloxicam and a grinding matrix to a particle size greater than 1 μm.

[0010] However, the above methods use too many organic solvents, surfactants, cyclodextrins and other components, which can easily cause safety problems when administered intravenously. Furthermore, the preparation processes of new dosage forms and technologies such as nanoparticles are relatively complex, with high quality control risks, and commercial production is quite difficult.

[0011] Neelam Seedher et al. found that meloxicam's solubility in pure PEG400 is 3.763 mg / mL. To achieve a meloxicam solubility of 1.5 mg / mL, the solvent must be ethanol, propylene glycol, PEG400, or a PEG400 / ethanol mixture (PEG400 ≥ 40%), and the solution pH must be ≥ 9.58. For a solubility of 3.75 mg / mL, the solvent must be ethanol, propylene glycol, PEG400, or a PEG400 / ethanol mixture (PEG400 ≥ 80%), and the pH must be ≥ 9.85. Zaira J. Cárdenas et al. found that the solubility of meloxicam in PEG400 aqueous solution increases with increasing PEG400 concentration, with a maximum solubility of 9.2 mg / mL in pure PEG400. Dattatray T. Modhave et al. reported that the meloxicam molecule contains amide bonds, which may lead to hydrolysis. The formulation reported in patent CN1236774C contains organic bases, various co-solvents and surfactants. Due to safety restrictions on excipients, it can only be used for intramuscular injection, and it must be prepared at 90°C, which increases the risk of increased degradation products and imposes harsh production conditions.

[0012] In summary, there is an urgent need to develop intravenous meloxicam formulations with improved safety and stability, and simple formulation processes.

[0013] On the other hand, it is well known that safety must be considered when preparing meloxicam liquid formulations, especially injectable formulations, such as improving formulation stability and impurity content. These are often technical problems that are difficult for engineers to solve. Furthermore, meloxicam is practically insoluble in water, with a solubility of only 0.003414 mg / mL at 25°C, and is slightly soluble in chloroform, acetone, and ethanol. Such solubility properties are generally considered detrimental to improving the stability of liquid formulations. Therefore, while improving stability and impurity content, further improving the solubility of meloxicam liquid formulations would be beneficial for expanding the application methods of meloxicam, improving patient compliance, and enhancing its safety and efficacy.

[0014] However, for meloxicam injections, mixed solvents or inclusion complex techniques are typically used to improve the solubility of poorly soluble drugs. Currently, both domestic and international researchers have studied meloxicam using these methods, but all face challenges such as complex formulation processes, poor stability, and potential safety issues during intravenous injection, severely impacting the quality control and safety of the injection.

[0015] Therefore, there is an urgent need to develop meloxicam liquid compositions with improved safety, stability, and impurity content, or even further improved solubility, and with simple formulation processes. Summary of the Invention

[0016] To improve the above-mentioned technical problems, according to one aspect of the present invention, the following technical solution is provided: a meloxicam composition, the composition comprising meloxicam and a co-solvent, wherein the co-solvent is a mixed solvent comprising water and an organic solvent.

[0017] According to embodiments of the present invention, the volume concentration of the organic solvent in the co-solvent is 1% to 80%, preferably 5% to 80%, for example 10% to 60%, such as 15% to 50%, such as 20% to 40%, and examples may be 15%, 18%, 19%, 20%, 25% or 30%.

[0018] According to the present invention, the organic solvent is selected from one, two or more of ethanol, propylene glycol, butanediol, isopropanol, tetrahydrofurfuryl alcohol, tetrahydrofuran polyethylene glycol ether, glycerol, dimethylacetamide, and polyethylene glycol (also known as PEG, such as polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600); preferably one, two or more of ethanol, propylene glycol, butanediol, tetrahydrofurfuryl alcohol, glycerol, polyethylene glycol 300, and polyethylene glycol 400; for example, one, two or more of ethanol, propylene glycol, polyethylene glycol 300, and polyethylene glycol 400; exemplaryly, the organic solvent is selected from polyethylene glycol 300 and / or polyethylene glycol 400.

[0019] According to the present invention, the water in the co-solvent can be pharmaceutically suitable water, such as purified water or water for injection.

[0020] According to the present invention, there is no particular limitation on the pH value of the composition, but the pH value is preferably selected so that the composition can be used as an injection, especially an intravenous injection.

[0021] Preferably, the composition is an injectable preparation, such as meloxicam intravenous injection.

[0022] According to embodiments of the present invention, the pH of the composition can be 3.0 to 10.0, preferably 6.5 to 10.0, for example 6.8 to 9.0, such as 7.2 to 9.0, and in some cases 7.4 to 9.0.

[0023] Alternatively, the composition may further comprise a pH adjuster.

[0024] According to an embodiment of the present invention, the pH adjuster may be selected from alkaline pH adjusters and / or acidic pH adjusters, such as those reagents suitable as pH adjusters for injections or intravenous injections;

[0025] According to an embodiment of the present invention, the alkaline pH adjuster may be selected from one, two or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris (tris(hydroxymethyl)aminomethane), arginine, lysine, histidine, and glycine; preferably, the alkaline pH adjuster is selected from one, two or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, Tris, arginine, lysine, glycine, and triethylamine; more preferably, the alkaline pH adjuster is selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris, or lysine; exemplaryly, the alkaline pH adjuster is selected from sodium hydroxide or lysine.

[0026] According to an embodiment of the present invention, the acidic pH adjuster may be selected from one, two or more of vitamin C (also known as ascorbic acid), lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid; preferably, the acidic pH adjuster is selected from one, two or more of lactic acid, malic acid, tartaric acid, citric acid, hydrochloric acid, phosphoric acid and acetic acid.

[0027] According to an embodiment of the present invention, the mass-to-volume ratio of meloxicam to the co-solvent can be 5–35 mg / mL, for example 7–32 mg / mL, such as 10–30 mg / mL, 15–30 mg / mL, 20–25 mg / mL, etc.

[0028] According to an embodiment of the present invention, the meloxicam composition comprises meloxicam, a co-solvent, and a pH adjuster;

[0029] The latent solvent is a mixed solvent containing water and an organic solvent, wherein the organic solvent is selected from one, two or more of ethanol, propylene glycol, polyethylene glycol 300, and polyethylene glycol 400, preferably polyethylene glycol 300 and / or polyethylene glycol 400;

[0030] The volume concentration of the organic solvent in the co-solvent is 5% to 80%, for example 10% to 60%, such as 15% to 50%, such as 20% to 40%, and examples can be 15%, 18%, 19%, 20%, 25% or 30%;

[0031] The pH adjuster is selected from alkaline pH adjusters and / or acidic pH adjusters. The alkaline pH adjuster is selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris, or lysine, preferably sodium hydroxide or lysine. The acidic pH adjuster is selected from one, two, or more of lactic acid, malic acid, tartaric acid, citric acid, hydrochloric acid, phosphoric acid, and acetic acid.

[0032] The mass-to-volume ratio of meloxicam to the co-solvent can be 5–35 mg / mL, for example 7–32 mg / mL, such as 10–30 mg / mL, 15–30 mg / mL, 20–25 mg / mL, etc.

[0033] The meloxicam composition provided by this invention does not have any particular limitation on the amount of meloxicam used. For example, it can be as high as 10g or more, 50g or more, 100g or more, 200g or more, or 300g or more. The specific amount can be determined in combination with the production scale.

[0034] In the meloxicam composition provided by the present invention, there is no particular limitation on the amount of co-solvent used. For example, it can be as high as 1L or more, 5L or more, 10L or more, 15L or more, or 20L or more. The specific amount can be determined in combination with the production scale.

[0035] Preferably, the meloxicam is soluble in a co-solvent.

[0036] According to embodiments of the present invention, the meloxicam liquid composition preferably does not contain solubilizers and / or surfactants; preferably, the composition does not contain solubilizers and surfactants. The solubilizers include, but are not limited to, solubilizers used in pharmaceutical formulations, such as those known to be suitable for injection, for example, those selected from cyclodextrins and their derivatives. As an example, the cyclodextrins include α-, β-, or γ-cyclodextrins, and the derivatives include, but are not limited to, one, two, or more of α-, β-, γ-cyclodextrin ether derivatives, ester derivatives, polymers, etc.; for example, the ether derivatives are selected from one, two, or more of glucose derivatives, hydroxypropyl derivatives, methyl derivatives, etc.; exemplary, the derivatives are selected from one, two, or more of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, etc.; the surfactants include, but are not limited to, surfactants known to be suitable for pharmaceutical formulations or compositions, such as surfactants suitable for injection, such as those selected from polysorbate 80, polyoxyethylene castor oil derivatives, poloxamer, polyethylene glycol 15-hydroxystearate, etc., one, two, or more.

[0037] The present invention also provides a method for preparing the meloxicam composition, comprising mixing meloxicam, water, an organic solvent, and a pH adjuster, which may or may not be present, wherein the organic solvent has the definition described above.

[0038] According to some embodiments of the present invention, the preparation method includes mixing meloxicam and a co-solvent, wherein the co-solvent is a mixed solvent containing water and an organic solvent.

[0039] According to the present invention, the preparation method may further include the step of providing the co-solvent, for example, mixing water with the co-solvent.

[0040] When the composition contains a pH adjuster, the preparation method further includes mixing water with a first pH adjuster and then further mixing it with an organic solvent to obtain a mixed solution; or mixing water with an organic solvent and then further mixing it with a pH adjuster to obtain a mixed solution.

[0041] Preferably, the preparation method further includes mixing the mixed solution with meloxicam to obtain a mixed solution containing meloxicam.

[0042] Preferably, the preparation method further includes mixing the meloxicam-containing mixed solution with a second pH adjuster, wherein the first pH adjuster and the second pH adjuster may be the same or different, and are independently selected from the definition of pH adjusters described above. Preferably, the first pH adjuster is an alkaline adjuster, and the second pH adjuster is an acidic adjuster.

[0043] According to other embodiments of the present invention, the preparation method may include mixing an alkaline aqueous solution containing meloxicam with an organic solvent.

[0044] Preferably, the preparation method further includes providing an alkaline aqueous solution containing meloxicam, for example, by first mixing a first pH adjuster with water and then mixing it with meloxicam to obtain an alkaline aqueous solution containing meloxicam.

[0045] Preferably, the preparation method further includes mixing an alkaline aqueous solution containing meloxicam with an organic solvent to obtain a mixed solution containing meloxicam, and then mixing it with a second pH adjuster, wherein the first pH adjuster and the second pH adjuster may be the same or different, and are independently selected from the definition of pH adjusters described above.

[0046] According to an embodiment of the present invention, the preparation method may include the following steps:

[0047] 1) Mix the pH adjuster with water to make the pH of the water ≥ 10.0, for example, pH ≥ 11.0, pH ≥ 12.0, pH ≥ 12.5, pH ≥ 13.0, to obtain an alkaline aqueous solution;

[0048] 2) Mix the organic solvent with the alkaline aqueous solution obtained in step 1) to obtain a mixed solution;

[0049] 3) Add meloxicam to the mixed solution obtained in step 2) to obtain a mixed solution containing meloxicam;

[0050] 4) Adjust the pH value of the solution obtained in step 3) to obtain the meloxicam composition.

[0051] Alternatively, according to an embodiment of the present invention, the preparation method may include the following steps:

[0052] 1) Mix the pH adjuster with water to make the pH of the water ≥ 10.0, for example, pH ≥ 11.0, pH ≥ 12.0, pH ≥ 12.5, pH ≥ 13.0, to obtain an alkaline aqueous solution;

[0053] 2) Mix meloxicam with the alkaline aqueous solution obtained in step 1) to obtain an alkaline aqueous solution containing meloxicam;

[0054] 3) The mixed solution obtained in step 2) is mixed with an organic solvent to obtain a mixed solution containing meloxicam;

[0055] 4) Adjust the pH value of the solution obtained in step 3) to obtain the meloxicam composition.

[0056] Generally, there are no particular limitations on the temperature of the preparation method. For example, the temperature of steps 1), 2), 3), or 4) can be 5°C to 80°C, and these temperatures can be adjusted according to specific circumstances based on the present invention. According to the exemplary preparation method of the present invention, there is no need to wait for the above-mentioned alkaline aqueous solution to cool before adding the organic solvent and stirring. Preferably, the temperature of steps 1), 2), 3), or 4) is 10°C to 60°C, more preferably 20°C to 60°C; as an example, the temperature can be 20°C, 25°C, 30°C, 40°C, 50°C, or 60°C.

[0057] According to embodiments of the present invention, in the above different embodiments, stirring can be performed in each step such as step 1), 2), 3), or 4) to promote mixing, and the stirring time can be more than 10 minutes, for example, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes or more.

[0058] The present invention also provides a liquid formulation, such as an injection, preferably an intravenous injection, wherein the injection comprises the above-described meloxicam composition.

[0059] According to the invention, the injectable may further include a container, such as an ampoule, vial, or multi-dose container, containing the meloxicam composition described above.

[0060] The injectable formulation according to the present invention may include small-volume injectables (less than 20 mL, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mL) and large-volume injectables (more than 50 mL, such as 50, 60, 70, 75, 80, 90, 100, 250, 500 mL, etc.).

[0061] The present invention also provides a method for preparing the injection, comprising placing the meloxicam composition in a container; preferably, the composition is sterilized before or after placement in the container. The sterilization may be moist heat sterilization or filtration sterilization.

[0062] The present invention also provides the use of the above-mentioned meloxicam composition in the treatment of diseases such as postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, and ankylosing spondylitis.

[0063] The present invention also provides the use of the above-described meloxicam composition in the preparation of medicaments, particularly medicaments for the treatment of postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, and ankylosing spondylitis.

[0064] Preferably, the drug is an injectable preparation, particularly an intravenous injection.

[0065] To improve the above-mentioned technical problems, according to a second aspect of the present invention, the following technical solution is also provided: a meloxicam composition, the composition comprising meloxicam, a solvent and a pH adjuster, wherein the pH adjuster comprises at least citric acid.

[0066] According to the present invention, the solvent may be selected from water, organic solvents or latent solvents, wherein the latent solvent is a mixture of water and organic solvents.

[0067] According to embodiments of the present invention, the volume concentration of the organic solvent in the co-solvent is 1-80%, preferably 5%-80%, for example 10%-60%, such as 15%-50%, such as 15%-25% or 20%-40%, and examples can be 15%, 16%, 17%, 18%, 19%, 20%, 25% or 30%.

[0068] According to the present invention, the organic solvent is selected from one, two or more of ethanol, propylene glycol, butanediol, isopropanol, tetrahydrofurfuryl alcohol, tetrahydrofuran polyethylene glycol ether, glycerol, and polyethylene glycol (also known as PEG, such as polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600); preferably one, two or more of ethanol, propylene glycol, butanediol, tetrahydrofurfuryl alcohol, glycerol, polyethylene glycol 300, and polyethylene glycol 400; for example, one, two or more of ethanol, propylene glycol, polyethylene glycol 300, and polyethylene glycol 400; exemplaryly, the organic solvent is selected from polyethylene glycol 300 and / or polyethylene glycol 400.

[0069] According to the present invention, the water in the co-solvent can be pharmaceutically suitable water, such as purified water or water for injection.

[0070] According to the present invention, there is no particular limitation on the pH value of the composition, but the pH value is preferably selected so that the composition can be used as an injection, especially an intravenous injection.

[0071] Preferably, the composition is an injectable preparation, such as meloxicam intravenous injection.

[0072] According to embodiments of the present invention, the pH of the composition can be 3.0 to 10.0, preferably 6.5 to 10.0, for example 6.8 to 9.0, such as 7.2 to 9.0, and examples can be 7.4 to 9.0, such as 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8 or 8.9.

[0073] According to an embodiment of the present invention, the pH adjuster may be selected from acidic pH adjusters or a combination of acidic pH adjusters and alkaline pH adjusters, provided that the acidic pH adjuster contains at least citric acid.

[0074] According to an embodiment of the present invention, the acidic pH adjuster may be selected from citric acid, or a mixture of citric acid and one, two or more acids selected from the following: vitamin C (also known as ascorbic acid), lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid.

[0075] According to an embodiment of the present invention, the alkaline pH adjuster may be selected from one, two or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris (tris(hydroxymethyl)aminomethane), meglumine, arginine, lysine, histidine, and glycine; preferably, the alkaline pH adjuster is selected from one, two or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, Tris, meglumine, arginine, lysine, glycine, and triethylamine; more preferably, the alkaline pH adjuster is selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris, or lysine; exemplaryly, the alkaline pH adjuster is selected from sodium hydroxide or lysine.

[0076] According to an exemplary technical solution of the present invention, the pH adjuster includes sodium hydroxide and / or meglumine, and citric acid; or, the pH adjuster is composed of sodium hydroxide and citric acid, or composed of meglumine and citric acid.

[0077] According to an embodiment of the present invention, the mass-to-volume ratio of meloxicam to solvent can be 5-35 mg / mL, for example 7-32 mg / mL, such as 10-30 mg / mL, 15-30 mg / mL, 20-25 mg / mL, etc.

[0078] Preferably, the meloxicam is soluble in a co-solvent.

[0079] According to embodiments of the present invention, the meloxicam liquid composition preferably does not contain solubilizers and / or surfactants; preferably, the composition does not contain solubilizers and surfactants. The solubilizers include, but are not limited to, solubilizers used in pharmaceutical formulations, such as those known to be suitable for injection, for example, those selected from cyclodextrins and their derivatives. As an example, the cyclodextrins include α-, β-, or γ-cyclodextrins, and the derivatives include, but are not limited to, one, two, or more of α-, β-, γ-cyclodextrin ether derivatives, ester derivatives, polymers, etc.; for example, the ether derivatives are selected from one, two, or more of glucose derivatives, hydroxypropyl derivatives, methyl derivatives, etc.; exemplary, the derivatives are selected from one, two, or more of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, etc.; the surfactants include, but are not limited to, surfactants known to be suitable for pharmaceutical formulations or compositions, such as surfactants suitable for injection, such as those selected from polysorbate 80, polyoxyethylene castor oil derivatives, poloxamer, polyethylene glycol 15-hydroxystearate, etc., one, two, or more.

[0080] The present invention also provides a method for preparing the meloxicam composition, comprising mixing meloxicam, a solvent (such as water and / or an organic solvent) and a pH adjuster, wherein the solvent and the pH adjuster have the definitions described above.

[0081] According to some embodiments of the present invention, the preparation method includes mixing meloxicam and a co-solvent, wherein the co-solvent is a mixed solvent containing water and an organic solvent.

[0082] According to the present invention, the preparation method may further include the step of providing the co-solvent, for example, mixing water with the co-solvent.

[0083] When the composition contains a pH adjuster, the preparation method further includes mixing water with a first pH adjuster and then further mixing it with an organic solvent to obtain a mixed solution; or mixing water with an organic solvent and then further mixing it with a second pH adjuster to obtain a mixed solution.

[0084] Preferably, the preparation method further includes mixing the mixed solution with meloxicam to obtain a mixed solution containing meloxicam.

[0085] Preferably, the preparation method further includes mixing the meloxicam-containing mixed solution with a second pH adjuster.

[0086] According to other embodiments of the present invention, the preparation method may include mixing an alkaline aqueous solution containing meloxicam with an organic solvent.

[0087] Preferably, the preparation method further includes providing an alkaline aqueous solution containing meloxicam, for example, by first mixing a first pH adjuster with water and then mixing it with meloxicam to obtain an alkaline aqueous solution containing meloxicam.

[0088] Preferably, the preparation method further includes mixing an alkaline aqueous solution containing meloxicam with an organic solvent to obtain a mixed solution containing meloxicam, and then mixing it with a second pH adjuster.

[0089] According to the present invention, the first pH adjuster and the second pH adjuster may be the same or different, and are independently selected from the definition of pH adjusters described above, provided that the second adjuster is an acidic adjuster containing citric acid. Preferably, the first pH adjuster is an alkaline adjuster, and the second adjuster is an acidic adjuster containing citric acid.

[0090] According to an embodiment of the present invention, the preparation method may include the following steps:

[0091] 1) Mix the first pH adjuster with water to make the pH of the water ≥ 10.0, for example, pH ≥ 11.0, pH ≥ 12.0, pH ≥ 12.5 or pH ≥ 13.0, to obtain an alkaline aqueous solution;

[0092] 2) Mix the organic solvent with the alkaline aqueous solution obtained in step 1) to obtain a mixed solution;

[0093] 3) Add meloxicam to the mixed solution obtained in step 2) to obtain a mixed solution containing meloxicam;

[0094] 4) Adjust the pH of the solution obtained in step 3) using a second pH adjuster to obtain the meloxicam composition.

[0095] Alternatively, according to an embodiment of the present invention, the preparation method may include the following steps:

[0096] 1) Mix the first pH adjuster with water to make the pH of the water ≥ 10.0, for example, pH ≥ 11.0, pH ≥ 12.0, pH ≥ 12.5, to obtain an alkaline aqueous solution;

[0097] 2) Mix meloxicam with the alkaline aqueous solution obtained in step 1) to obtain an alkaline aqueous solution containing meloxicam;

[0098] 3) The mixed solution obtained in step 2) is mixed with an organic solvent to obtain a mixed solution containing meloxicam;

[0099] 4) Adjust the pH of the solution obtained in step 3) using a second pH adjuster to obtain the meloxicam composition.

[0100] Generally, there are no particular limitations on the temperature of the preparation method. For example, the temperature of steps 1), 2), 3), or 4) can be 5°C to 80°C, and these temperatures can be adjusted according to specific circumstances based on the present invention. According to the exemplary preparation method of the present invention, there is no need to wait for the above-mentioned alkaline aqueous solution to cool before adding the organic solvent and stirring. Preferably, the temperature of steps 1), 2), 3), or 4) is 10°C to 60°C, more preferably 20°C to 60°C; as an example, the temperature can be 20°C, 25°C, 30°C, 40°C, 50°C, or 60°C.

[0101] According to embodiments of the present invention, in the above different embodiments, stirring can be performed in each step such as step 1), 2), 3), or 4) to promote mixing, and the stirring time can be more than 10 minutes, for example, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes or more.

[0102] The present invention also provides a liquid formulation, such as an injection, preferably an intravenous injection, wherein the injection comprises the above-described meloxicam composition.

[0103] According to the invention, the injectable may further include a container, such as an ampoule, vial, or multi-dose container, containing the meloxicam composition described above.

[0104] The injectable formulation according to the present invention may include small-volume injectables (less than 20 mL, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mL) and large-volume injectables (more than 50 mL, such as 50, 60, 70, 75, 80, 90, 100, 250, 500 mL, etc.).

[0105] The present invention also provides a method for preparing the injection, comprising placing the meloxicam composition in a container; preferably, the composition is sterilized before or after placement in the container. The sterilization may be moist heat sterilization or filtration sterilization.

[0106] The present invention also provides the use of the above-mentioned meloxicam composition in the treatment of diseases such as postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, and ankylosing spondylitis.

[0107] The present invention also provides the use of the above-described meloxicam composition in the preparation of medicaments, particularly medicaments for the treatment of postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, and ankylosing spondylitis.

[0108] Preferably, the drug is an injectable preparation, particularly an intravenous injection.

[0109] The beneficial effects of this invention are:

[0110] The present invention has unexpectedly discovered that the pharmaceutical composition provided in the first aspect of the present invention can significantly improve the solubility of meloxicam in liquid formulations. For example, when the pH of the solution system is adjusted to above 12.0 before meloxicam dissolution, and the volume ratio of organic solvent in the co-solvent is ≥5%, the concentration of meloxicam can reach 10 mg / mL or even higher, greatly improving the solubility of the drug.

[0111] Furthermore, this invention unexpectedly reveals that the compositions of this invention possess excellent stability. For example, when the organic solvent used accounts for the same proportion as the cosolvent, using polyethylene glycol (such as PEG300 or PEG400) as one of the cosolvent components significantly improves stability. No precipitation occurs during prolonged storage, effectively reducing the content of degradation products and other impurities, resulting in a stable liquid composition under injection conditions (especially intravenous injection conditions). In other words, the cosolvent selected in this invention significantly improves drug solubility while also markedly enhancing drug stability.

[0112] Because the composition of this invention does not contain solubilizers, surfactants, or other excipients, its irritation is reduced, resulting in better safety. The meloxicam composition provided by this invention can even be administered directly via intravenous bolus injection, rapidly achieving an effective therapeutic concentration for postoperative analgesia.

[0113] In addition, the preparation process of this composition is simple, and it can be completed by stirring and dispersing at room temperature for a short time, making it easy to scale up production.

[0114] The present invention also unexpectedly found that the stability of the composition provided by the second aspect of the present invention is significantly improved, especially by using citric acid as an acidic pH adjuster, which effectively reduces the content of degradation product B, significantly improves the safety of the liquid formulation, and prevents precipitation during long-term storage.

[0115] Meanwhile, the solubility of meloxicam in the composition of the present invention is significantly improved, reaching 10 mg / mL or even higher, which is very beneficial for the application of meloxicam as an injection (especially an intravenous injection).

[0116] In addition, the preparation process of this composition is simple, and it can be completed by stirring and dispersing at room temperature for a short time, making it easy to scale up production. Detailed Implementation

[0117] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. 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.

[0118] Unless otherwise stated, the active pharmaceutical ingredients and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0119] In Examples A1-A15 and Comparative Examples A1-A5, the content of meloxicam raw material was 99.9%, and the total impurities were 0.03%.

[0120] The method for determining the meloxicam content described in the embodiments and comparative examples of this invention refers to the method for determining the meloxicam content in USP40-NF35 Monographs: Meloxicam.

[0121] Example A1: Meloxicam Composition

[0122] prescription:

[0123]

[0124] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir evenly at room temperature, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 7.8 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0125] Example A2: Meloxicam Composition

[0126] prescription:

[0127]

[0128] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add meloxicam, stir at room temperature until dissolved, then add the prescribed amount of PEG400, stir well, and adjust the pH of the solution to 7.4 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature, and no insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0129] Example A3: Meloxicam Composition

[0130] prescription:

[0131]

[0132] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG300, stir well, then add meloxicam, stir at room temperature to dissolve, and adjust the pH of the solution to 8.0 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature, and no insoluble particles / visible foreign matter appeared after 15 days of observation at 2-8℃.

[0133] Example A4: Meloxicam Composition

[0134] prescription:

[0135]

[0136] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir well, then add meloxicam, stir at room temperature to dissolve, and adjust the pH of the solution to 8.2 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature, and no insoluble particles / visible foreign matter appeared after 15 days of observation at 2-8℃.

[0137] Example A5: Meloxicam Composition

[0138] prescription:

[0139]

[0140] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 7.8 with lactic acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0141] Example A6: Meloxicam Composition

[0142] prescription:

[0143]

[0144] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 8.4 with malic acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0145] Example A7: Meloxicam Composition

[0146] prescription:

[0147]

[0148] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 8.2 with tartaric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0149] Example A8: Meloxicam Composition

[0150] prescription:

[0151]

[0152] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of propylene glycol, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 8.4 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. A small amount of insoluble particles appeared after 15 days of observation at 2–8℃.

[0153] Example A9: Meloxicam Composition

[0154] prescription:

[0155]

[0156] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of glycerol, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 8.6 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. A small amount of insoluble particles appeared after 15 days of observation at 2–8℃.

[0157] Example A10: Meloxicam Composition

[0158] prescription:

[0159]

[0160] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of butylene glycol, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 8.2 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. A small amount of insoluble particles appeared after 15 days of observation at 2–8℃.

[0161] Example A11: Meloxicam Composition

[0162] prescription:

[0163]

[0164] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add two prescription amounts of PEG400, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, and 9.0 with citric acid, respectively. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0165] Example A12: Scale-up preparation of the meloxicam composition of the present invention

[0166] Prepare liquid compositions with different formulations in 250 mL volumes according to formulations F1 to F14 shown in the table below. Prepare a sodium hydroxide aqueous solution with pH 13.0, add the prescribed amount of organic solvent, stir until homogeneous, then add meloxicam, stir until dissolved, and adjust the pH of the solution to the appropriate value with phosphoric acid.

[0167] Table A1. Formula for Meloxicam Liquid Composition

[0168]

[0169] Example A13 Stability Study of Meloxicam Composition

[0170] Take the sample solutions F1 to F14 from Example A12, filter them through a 0.22 μm microporous membrane, and take 5 mL of each solution. Place the filtered solution in a 10 mL vial and seal it. Place the vials at room temperature, 2–8 °C in a refrigerator, and 60 °C in a constant temperature and humidity chamber to observe the crystallization and changes in related substances. The results are shown in the table below.

[0171] Table A2 Stability Study of Meloxicam Liquid Compositions

[0172]

[0173] Example A14: Scale-up preparation of the meloxicam composition of the present invention

[0174] Prepare liquid compositions with different formulations according to the formulas shown in the table below. Prepare a sodium hydroxide aqueous solution with pH 13.0, add the prescribed amount of organic solvent, stir well, then add different batches of meloxicam, stir to dissolve, adjust the pH of the solution to the appropriate value with phosphoric acid, sterilize, and the product is ready.

[0175] Table A3 Meloxicam Liquid Composition Formulation

[0176]

[0177] S1 and S2 are samples from the same batch, while S3 is a sample from another batch.

[0178] Example A15 Stability Study of the Meloxicam Composition

[0179] The long-term and accelerated stability of the sample from Example A14 were investigated, and the results are shown in the table below.

[0180] Long-term stability study procedure: In accordance with the provisions of the Guidelines for Stability Testing of Raw Materials and Preparations in Part IV of the 2015 Chinese Pharmacopoeia, long-term stability studies were conducted on samples S1 and S2 in Example A14. The test temperature was 30℃±2℃, and the RH was 65%±5%. The studies were conducted for 3, 6, 9, and 12 months.

[0181] Accelerated stability testing procedure: In accordance with the provisions of the Guidelines for Stability Testing of Raw Materials and Preparations in Part IV of the 2015 Chinese Pharmacopoeia, accelerated stability testing was conducted on samples S1, S2 and S3 in Example A14. The test temperature was 40℃±2℃, and the RH was 75%±5%. The testing was conducted for 1, 2, 3 and 6 months.

[0182] Table A4 Stability Study of Meloxicam Liquid Compositions

[0183]

[0184]

[0185] Note: Data measured on day 0 are values ​​obtained immediately after sample preparation.

[0186] The above experimental results show that the meloxicam composition prepared on a larger scale in Example A14 still maintains a low level of degradation impurities and total impurities during long-term stability and accelerated stability studies, demonstrating excellent stability.

[0187] Comparative Example A1: Meloxicam Liquid Composition

[0188] prescription:

[0189]

[0190] Preparation method: Dissolve lysine and PEG400 in an aqueous solution, stir well, add meloxicam, stir at 40℃ to dissolve, and adjust the pH of the solution to 7.5 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature, and no insoluble particles / visible foreign matter appeared after 15 days of observation at 2-8℃.

[0191] Comparative Example A2: Meloxicam Liquid Composition

[0192] prescription:

[0193]

[0194] Preparation method: Dissolve meglumine and PEG400 in an aqueous solution, stir well, add meloxicam, and stir for a long time at above 40°C until dissolved. Adjust the pH of the solution to 7.5 with phosphoric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days at 2–8°C. Comparative Example A3: Meloxicam liquid composition.

[0195] prescription:

[0196]

[0197] Preparation method: Dissolve arginine and PEG400 in an aqueous solution, stir well, add meloxicam, and stir for a long time at above 40°C until dissolved. Adjust the pH of the solution to 7.5 with phosphoric acid. After 7 days at 2–8°C, a small amount of insoluble particles appeared.

[0198] Comparative Example A4

[0199] The solubility of meloxicam in alkaline or alkaline amino acid solutions (glucamine, Tris, arginine, or lysine) was studied, and the solubility is shown in the table below. The experimental results show that meloxicam can achieve a solubility of over 10 mg / mL in high-concentration organic bases or alkaline amino acids. However, at room temperature, it requires a relatively long preparation time (greater than 6 hours) or a high temperature (40℃) to dissolve, making the preparation process complex. Furthermore, crystals precipitate when left at room temperature overnight, resulting in poor solution stability.

[0200] Table A5 Solubility of meloxicam in different concentrations of organic bases or basic amino acids

[0201]

[0202] Comparative Example A5

[0203] The solubility of meloxicam in aqueous solutions of PEG400 at different ratios was studied, and the solubility results are shown in the table below. The results show that the solubility of meloxicam in pure PEG400 is only 2.27 mg / mL, which is insufficient for intravenous injection.

[0204] Table A6 Solubility of meloxicam in PEG400 aqueous solutions of different proportions

[0205]

[0206] The above experimental results demonstrate that the composition of this invention, using polyethylene glycol such as PEG400 or PEG300 as a co-solvent, unexpectedly and significantly improves the meloxicam content in the prepared composition. This will enable meloxicam liquid formulations, especially intravenous injections, to achieve better application prospects and a wider range of applications, significantly improving medical efficiency and patient compliance. Furthermore, with the same meloxicam content, this effect becomes more pronounced with increasing polyethylene glycol concentration.

[0207] Furthermore, surprisingly, the compositions of the present invention also exhibit excellent stability, not only avoiding precipitation during prolonged storage but also maintaining low levels of degradation products and total impurities. In particular, meloxicam compositions prepared with a co-solvent containing polyethylene glycol, especially PEG400, demonstrate good stability and do not precipitate during extended storage when the ratio of organic solvent to co-solvent is equal.

[0208] In Examples B1-B6 and Comparative Examples B1-B4, the content of meloxicam raw material was 99.2%, and the total impurities were 0.06%.

[0209] The "freeze-thaw" method described below is as follows:

[0210] The sample was placed in a -20℃ freezer for two days, and then taken out and examined under accelerated conditions at 40℃ for two days. Each freeze-thaw experiment was repeated three times, and the result of the last cycle was taken as the final result.

[0211] Example B1: Meloxicam Liquid Composition

[0212] prescription:

[0213]

[0214] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir well, then add the two prescribed amounts of meloxicam, stir until dissolved, and adjust the pH of the solution to 7.8 with phosphoric acid or citric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature, and no insoluble particles / visible foreign matter appeared after 15 days at 2–8℃.

[0215] Example B2: Stability Study of the Meloxicam Liquid Composition

[0216] Each sample solution prepared in Example B1 was filtered through a 0.22 μm microporous membrane, and 5 mL was placed in a 10 mL vial and sealed. The vials were then placed in a 60°C constant temperature and humidity chamber to observe the increase in related substances. The results are shown in Table 1.

[0217] Table B1 Stability Study of Meloxicam Liquid Compositions

[0218]

[0219]

[0220] The above experiments show that, compared with other pH adjusters, using citric acid as an acidic pH adjuster can significantly improve the stability of meloxicam and effectively reduce the formation of degradation product B.

[0221] In addition, replacing PEG400 in Example B1 with organic solvents such as ethanol, propylene glycol, butylene glycol, isopropanol, glycerol, and polyethylene glycol 300 also showed that the composition containing citric acid as a pH adjuster could effectively reduce degradation impurity B and total impurity content.

[0222] Example B3: Meloxicam Liquid Composition

[0223] prescription:

[0224]

[0225] Preparation method: Prepare a sodium hydroxide solution with pH 12.0, add the prescribed amount of PEG400, stir well, then add meloxicam and stir until dissolved. Adjust the pH of the solution to the required level (pH = 8.0, 8.2, 8.4, 8.6, 8.8, 9.0) with citric acid. No insoluble particles / visible foreign matter appeared when placed at room temperature. No insoluble particles / visible foreign matter appeared after 15 days of observation at 2–8℃.

[0226] Example B4: Stability Study of the Meloxicam Liquid Composition

[0227] Each sample solution prepared in Example B3 was filtered through a 0.22 μm microporous membrane, and 5 mL was placed in a 10 mL vial and sealed. The vials were then placed in a 60°C constant temperature and humidity incubator for 10 days to observe the increase in related substances. The results showed that the content of degradation product B remained stably below 0.2%. These results indicate that using citric acid as a pH adjuster, even when the sample pH varies over a wide range, the content of degradation product B can be controlled within a low range, significantly improving the stability and formulation safety of meloxicam in the composition.

[0228] Example B5

[0229] Following the preparation method in Example B1, a meloxicam composition was prepared: PEG400 volume concentration 10%, meloxicam concentration 18.75 mg / ml, and the pH of the composition was adjusted to 8.2 using meglumine (replacing NaOH) and citric acid as pH adjusters. No insoluble particles / visible foreign matter appeared when placed at room temperature. After 15 days of observation at 2–8°C, no insoluble particles / visible foreign matter appeared. Although small particles appeared at the bottom after one freeze-thaw treatment, they dissolved rapidly after shaking.

[0230] In addition, when sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris (tris(hydroxymethyl)aminomethane), arginine, lysine, histidine, or glycine were used as alkaline pH adjusters to replace the above-mentioned meglumine, no insoluble particles / visible foreign matter were found.

[0231] Example B6

[0232] Following the preparation method in Example B1, a meloxicam composition was prepared: PEG400 volume concentration 10%, meloxicam concentration 18.75 mg / ml, and the pH of the composition was adjusted to 8.2 using sodium hydroxide and citric acid as pH adjusters. No insoluble particles / visible foreign matter were observed when placed at room temperature. No insoluble particles / visible foreign matter were observed after 15 days of observation at 2–8°C. The product underwent one freeze-thaw treatment, and no insoluble particles / visible foreign matter were observed.

[0233] Comparative Example B1

[0234] Following the preparation method in Example B1, a meloxicam composition was prepared: PEG400 volume concentration 10%, meloxicam concentration 18.75 mg / ml, and the pH of the composition was adjusted to 8.2 using sodium hydroxide and hydrochloric acid as pH adjusters. After one day of observation at 2–8°C, insoluble particles / visible foreign matter appeared in the composition.

[0235] Comparative Example B2

[0236] Following the preparation method in Example B1, a meloxicam composition was prepared: PEG400 volume concentration 10%, meloxicam concentration 18.75 mg / ml, and the pH of the composition was adjusted to 8.2 using sodium hydroxide and acetic acid as pH adjusters. After one day of observation at 2–8°C, insoluble particles / visible foreign matter appeared in the composition.

[0237] Comparative Example B3

[0238] Following the preparation method in Example B1, a meloxicam composition was prepared: PEG400 volume concentration 10%, meloxicam concentration 18.75 mg / ml, and the pH of the composition was adjusted to 8.2 using sodium hydroxide and phosphoric acid as pH adjusters. After 6 days of observation at 2–8°C, insoluble particles / visible foreign matter appeared in the composition. After one freeze-thaw treatment, crystals still appeared after standing, and the composition was essentially insoluble upon shaking.

[0239] Comparative Example B4

[0240] Following the preparation method of Example B1, a meloxicam composition was prepared: PEG400 volume concentration 10%, meloxicam concentration 18.75 mg / ml, and the pH of the composition was adjusted to 8.2 using meglumine and phosphoric acid as pH adjusters. No insoluble particles / visible foreign matter appeared when placed at room temperature. However, after 10 days at 2–8°C, insoluble particles / visible foreign matter appeared. After one freeze-thaw cycle, a large amount of fine solids precipitated out upon standing, and dissolved quickly upon shaking.

[0241] The above experiments show that, compared with other pH adjusters, using citric acid as an acidic pH adjuster to prepare meloxicam liquid compositions can significantly improve the stability of meloxicam, effectively reduce the formation of impurities, and surprisingly improve the safety and efficacy of the formulation.

[0242] 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. A meloxicam composition comprising meloxicam, a mixture of water and an organic solvent, citric acid, and an alkaline pH adjuster; The organic solvent has a volume concentration of 16% to 40% in the mixture of water and organic solvent; The organic solvent is selected from one, two or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600; The pH of the composition is 6.5~10.0; The composition does not contain other known solubilizers and surfactants used in pharmaceutical formulations.

2. The composition of claim 1, wherein: The solubilizers include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfonyl-β-cyclodextrin; The surfactants include polysorbate 80, poloxamer, and polyethylene glycol 15-hydroxystearate.

3. A meloxicam composition comprising meloxicam, a mixture of water and an organic solvent, citric acid, and an alkaline pH adjuster, wherein: The organic solvent has a volume concentration of 15% to 40% in the mixture of water and organic solvent; The organic solvent is selected from one, two or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600; The pH of the composition is 6.5 to 10.

0.

4. The composition of claim 3, wherein the volume concentration of the organic solvent in the mixture of water and organic solvent is 16% to 40%.

5. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixture of water and organic solvent is 17% to 40%.

6. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixed solvent of water and organic solvent is 18% to 40%.

7. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixture of water and organic solvent is 19% to 40%.

8. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixed solvent of water and organic solvent is 16% to 30%.

9. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixture of water and organic solvent is 17% to 30%.

10. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixed solvent of water and organic solvent is 18% to 30%.

11. The composition according to any one of claims 1-4, wherein the volume concentration of the organic solvent in the mixture of water and organic solvent is 19% to 30%.

12. The composition according to any one of claims 1-4, wherein the pH of the composition is 6.8 to 10.

0.

13. The composition according to any one of claims 1-4, wherein the pH of the composition is 7.2 to 10.

0.

14. The composition according to any one of claims 1-4, wherein the pH of the composition is 7.2 to 9.

0.

15. The composition according to any one of claims 1-4, wherein the pH of the composition is 7.4 to 9.

0.

16. The composition according to any one of claims 1-4, wherein the pH of the composition is 7.4 to 8.

5.

17. The composition according to any one of claims 1-4, wherein the pH of the composition is 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9 or 9.

0.

18. The composition according to any one of claims 1-4, wherein the water is pharmaceutically suitable water.

19. The composition according to any one of claims 1-4, wherein the water is purified water.

20. The composition according to any one of claims 1-4, wherein the water is water for injection.

21. The composition according to any one of claims 1-4, wherein the mass-to-volume ratio of meloxicam to the mixed solvent of water and organic solvent is 10-35 mg / mL.

22. The composition according to any one of claims 1-4, wherein the mass-to-volume ratio of meloxicam to the mixed solvent of water and organic solvent is 15-35 mg / mL.

23. The composition according to any one of claims 1-4, wherein the mass-to-volume ratio of meloxicam to the mixed solvent of water and organic solvent is 15-30 mg / mL.

24. The composition according to any one of claims 1-4, wherein the mass-to-volume ratio of meloxicam to the mixed solvent of water and organic solvent is 20-30 mg / mL.

25. The composition according to any one of claims 1-4, wherein the mass-to-volume ratio of meloxicam to the mixed solvent of water and organic solvent is 25-35 mg / mL.

26. The composition according to any one of claims 1-4, wherein the composition further comprises an acidic pH adjuster selected from a mixture of one, two or more acids selected from the following: ascorbic acid, lactic acid, malic acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid.

27. The composition according to any one of claims 1-4, wherein the alkaline pH adjuster is selected from one, two or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tris(hydroxymethyl)aminomethane, meglumine, arginine, lysine, histidine and glycine.

28. The composition according to any one of claims 1-4, wherein the alkaline pH adjuster is selected from one or both of sodium hydroxide and meglumine.

29. The composition according to any one of claims 1-4, wherein the alkaline pH adjuster is selected from sodium hydroxide.

30. The composition according to any one of claims 1-4, wherein the alkaline pH adjuster is selected from meglumine.

31. The composition according to any one of claims 1-4, wherein the method of preparing the composition comprises adjusting the pH of the solution system to pH ≥ 10.0 before dissolving meloxicam.

32. The composition according to any one of claims 1-4, wherein the method of preparing the composition comprises adjusting the pH of the solution system to pH ≥ 11.0 before dissolving meloxicam.

33. The composition according to any one of claims 1-4, wherein the method of preparing the composition comprises adjusting the pH of the solution system to above 12.0 before dissolving meloxicam.

34. A method for preparing the composition according to any one of claims 1-4, wherein the method comprises mixing meloxicam, water, an organic solvent, citric acid, and an alkaline pH adjuster.

35. A method for preparing the composition according to claim 1 or 2, wherein the preparation method comprises the following steps: 1) Mix the first pH adjuster with water to make the pH of the water ≥ 10.0, thus obtaining an alkaline aqueous solution; 2) Mix meloxicam with the alkaline aqueous solution obtained in step 1) to obtain an alkaline aqueous solution containing meloxicam; 3) Mix the mixed solution obtained in step 2) with an organic solvent to obtain a mixed solution containing meloxicam; 4) Adjust the pH of the solution obtained in step 3) using a second pH adjuster to obtain the meloxicam composition; The first pH adjuster is an alkaline adjuster, and the second pH adjuster is an acidic adjuster containing citric acid.

36. A method for preparing the composition according to claim 3 or 4, wherein the preparation method comprises the following steps: 1) Mix the first pH adjuster with water to make the pH of the water ≥ 10.0, thus obtaining an alkaline aqueous solution; 2) Mix meloxicam with the alkaline aqueous solution obtained in step 1) to obtain an alkaline aqueous solution containing meloxicam; 3) Mix the mixed solution obtained in step 2) with an organic solvent to obtain a mixed solution containing meloxicam; 4) Adjust the pH of the solution obtained in step 3) using a second pH adjuster to obtain the meloxicam composition; The first pH adjuster is an alkaline adjuster, and the second pH adjuster is citric acid.

37. The preparation method according to claim 35 or 36, wherein in step 1), the first pH adjuster is mixed with water to make the pH of the water ≥ 11.

0.

38. The preparation method according to claim 35 or 36, wherein in step 1), the first pH adjuster is mixed with water to make the pH of the water ≥ 12.

0.

39. The preparation method according to claim 35 or 36, wherein in step 1), the first pH adjuster is mixed with water to make the pH of the water ≥ 12.

5.

40. An injectable preparation comprising the composition according to any one of claims 1-33.

41. The injectable preparation of claim 40, wherein the injectable preparation is an intravenous injection preparation.

42. The method for preparing the injectable as described in claim 40 or 41, comprising: Place the composition according to any one of claims 1-33 into a container; as well as, The composition is also sterilized before or after being placed in a container.

43. Use of the composition according to any one of claims 1-33 in the preparation of a medicament, wherein the medicament is used for the treatment of postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, and ankylosing spondylitis.

44. The use as described in claim 43, wherein the drug is a liquid formulation.

45. The use as described in claim 43, wherein the drug is an injectable preparation.

46. ​​The use as described in claim 43, wherein the drug is an intravenous injection.

Images