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 with the application date of May 10, 2019, the application number of 201910390430.1, and the invention name of "A Meloxicam Composition, Preparation, and Preparation Method and Application Thereof".

[0002] This application also claims the priority of the following prior applications: the prior application with the patent application number of 201810450456.6 and the invention name of "A Meloxicam Composition, Preparation, and Preparation Method and Application Thereof", which was filed with the State Intellectual Property Office of China on May 11, 2018; and the prior application with the patent application number of 201810451076.4 and the invention name of "A Meloxicam Composition Containing a pH Regulator, Preparation Method and Application Thereof", which was filed with the State Intellectual Property Office of China on May 11, 2018. The entire contents of the prior applications are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of pharmaceutical preparations, and specifically relates to a meloxicam composition, preparation, and preparation method and application thereof. BACKGROUND

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

[0005]

[0006] Meloxicam is almost insoluble in water, and its solubility in water at 25℃ is only 0.003414 mg / mL, and it is slightly soluble in chloroform, acetone, and ethanol. Therefore, although Bringer Ingelheim, Iroko, Recro Pharm, and the like have developed various dosage forms of meloxicam, the improvement of the solubility of meloxicam is still a difficulty in the development of the intravenous injection of the drug.

[0007] For poorly soluble drugs, the solubility can often be improved by changing the physicochemical properties of the drug. For example, the drug can be prepared into a salt or the crystal form of the drug can be changed. For example, Ochi et al. prepared meloxicam into a salt with Tris, arginine, DEA, TEA, etc. by recrystallization. Alladi Saritha et al. converted the crystal form of meloxicam into a spherical shape to improve the dissolution rate. However, the methods of salt formation or crystal form change have limitations. For example, the salt formation method requires separation of the drug and its salt form, and the formation of the crystal form is affected by many factors, such as stirring speed, stirring time, temperature, and solvent type, which are limited by the preparation method and the stability of the salt or crystal form.

[0008] In addition, the solubility of poorly soluble drugs can also be improved from the perspective of formulation, such as using mixed solvents, using inclusion complex technology, or using new dosage forms and new technologies. At present, meloxicam has been studied by the above methods at home and abroad, but all of them face the problems of complex preparation process, excessive use of excipients, and the fact that many excipients and organic solvents are not suitable for intravenous injection.

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

[0010] However, the use of excessive organic solvents, surfactants, cyclodextrins, etc. in the above methods can cause safety problems in intravenous injection, and the preparation process of new dosage forms such as nanoparticles is relatively complex, the risk of quality control is high, and commercial production is difficult.

[0011] Neelam Seedher et al. found that the solubility of meloxicam in pure PEG400 was 3.763 mg / mL, and if the solubility of meloxicam reached 1.5 mg / mL, the solvent must be ethanol, propylene glycol, PEG400, PEG400 / ethanol mixed solution (PEG400≥40%) and the solution pH≥9.58, and the solubility reached 3.75 mg / mL, and the solvent must be ethanol, propylene glycol, PEG400, PEG400 / ethanol mixed solution (PEG400≥80%) and pH≥9.85. Zaira J. Cardenas et al. found that the solubility of meloxicam in PEG400 aqueous solution increased with the increase of PEG400 concentration, and the solubility in pure PEG400 was the largest, which was 9.2 mg / mL. Dattatray T. Modhave et al. reported that meloxicam molecules contained amide bonds, which might be hydrolyzed. The prescription reported in patent CN1236774C contains organic bases, various potential solvents and surfactants, which can only be used for intramuscular injection due to the safety limitations of excipients, and must be prepared at 90°C, which increases the risk of increasing degradation products and harsh production conditions.

[0012] In summary, there is an urgent need to develop meloxicam intravenous injection with improved safety, stability and simple preparation process.

[0013] On the other hand, it is well known that the safety of meloxicam liquid formulations, especially injections, must be considered, such as improving the stability and impurity content of the formulation, which is usually a technical problem that puzzles technicians and is difficult to solve. In addition, since meloxicam is almost insoluble in water, with a solubility of only 0.003414 mg / mL in water at 25°C, it is slightly soluble in chloroform, acetone, ethanol, and it is generally believed that such solubility properties are not conducive to improving the stability of liquid formulations containing them. Therefore, under the premise of improving stability and impurity content, further improving the solubility of meloxicam liquid formulations will be beneficial to expand the application mode of meloxicam, improve patient compliance, and improve the safety and effectiveness of its preparation.

[0014] However, for meloxicam injections, mixed solvents or inclusion complex technology is usually used to improve the solubility of poorly soluble drugs. At present, meloxicam has been studied by the above-mentioned methods at home and abroad, but all of them face the problems of complex preparation process, poor stability, easy safety problems in intravenous injection, and serious impact on the quality controllability and safety of injections.

[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 simple preparation process. SUMMARY

[0016] To improve the above technical problems, according to one aspect of the present application, there is provided a meloxicam composition comprising meloxicam and a latent solvent, wherein the latent solvent is a mixed solvent comprising water and an organic solvent.

[0017] According to an embodiment of the present application, the volume concentration of the organic solvent in the latent solvent is 1% to 80%, preferably 5% to 80%, for example 10% to 60%, such as 15% to 50%, for example 20% to 40%, and examples thereof can be 15%, 18%, 19%, 20%, 25% or 30%.

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

[0019] According to the present application, the water in the latent solvent can be water suitable for pharmaceutical use, for example purified water, water for injection.

[0020] According to the present application, the pH of the composition is not particularly limited, and the pH is preferably selected so that the composition can be used as an injection, in particular an intravenous injection.

[0021] Preferably, the composition is an injection, for example a meloxicam intravenous injection.

[0022] According to an embodiment of the present application, 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 thereof can be 7.4 to 9.0.

[0023] Alternatively, the composition can further comprise a pH adjusting agent.

[0024] According to an embodiment of the present application, the pH adjusting agent can be selected from basic pH adjusting agents and / or acidic pH adjusting agents, for example those agents suitable as pH adjusting agents for injections or intravenous injections;

[0025] According to embodiments of the present application, the basic pH adjusting agent can 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 basic pH adjusting agent 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 basic pH adjusting agent is selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris or lysine; illustratively, the basic pH adjusting agent is selected from sodium hydroxide or lysine.

[0026] According to embodiments of the present application, the acidic pH adjusting agent can 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 adjusting agent 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 embodiments of the present application, the mass to volume ratio of meloxicam to the cosolvent 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 embodiments of the present application, the meloxicam composition comprises meloxicam, a cosolvent and a pH adjusting agent;

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

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

[0031] The pH adjusting agent is selected from a basic pH adjusting agent selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris or lysine, preferably sodium hydroxide or lysine, and / or an acidic pH adjusting agent 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 volume ratio of the meloxicam to the cosolvent 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 the present application does not have a particular limitation on the amount of meloxicam, which can be up to 10 g or more, 50 g or more, 100 g or more, 200 g or more, 300 g or more, and the specific amount can be determined in combination with the production scale.

[0034] The meloxicam composition provided by the present application does not have a particular limitation on the amount of cosolvent, which can be up to 1 L or more, 5 L or more, 10 L or more, 15 L or more, 20 L or more, and the specific amount can be determined in combination with the production scale.

[0035] Preferably, the meloxicam is dissolved in the cosolvent.

[0036] According to the embodiments of the present application, the meloxicam liquid composition preferably does not contain a solubilizer and / or a surfactant; preferably, the composition does not contain a solubilizer and a surfactant. Among them, the solubilizer includes but is not limited to the solubilizers used in pharmaceutical preparations, for example, selected from the solubilizers known to be used in injections, for example, selected from cyclodextrins and derivatives thereof. As an example, the cyclodextrins include a-, b- or g-cyclodextrins, and the derivatives include but are not limited to one, two or more of a-, b-, g-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.; exemplarily, the derivatives are selected from one, two or more of hydroxyethyl- b-cyclodextrin, hydroxypropyl- b-cyclodextrin, sulfobutyl- b-cyclodextrin, etc.; wherein the surfactant includes but is not limited to the surfactants known to be used in pharmaceutical preparations or compositions, for example, selected from the surfactants that can be used in injections, such as selected from one, two or more of polysorbate 80, polyoxyethylene castor oil derivatives, poloxamer, polyethylene glycol 15-hydroxystearate, etc.

[0037] The present application also provides a preparation method of the meloxicam composition, which comprises mixing meloxicam, water, an organic solvent, and optionally a pH adjuster, wherein the organic solvent has the definition described above.

[0038] According to some embodiments of the present application, the preparation method comprises mixing meloxicam and a cosolvent, wherein the cosolvent is a mixed solvent comprising water and an organic solvent.

[0039] According to the present application, the preparation method can further comprise the step of providing the potential solvent, for example mixing water with the potential solvent.

[0040] When the composition comprises a pH adjusting agent, the preparation method can further comprise mixing water with a first pH adjusting agent first, and then further mixing with the organic solvent to obtain a mixed solution; or mixing water with the organic solvent first, and then further mixing with the pH adjusting agent to obtain a mixed solution.

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

[0042] Preferably, the preparation method can further comprise mixing the mixed solution containing meloxicam with a second pH adjusting agent, wherein the first and second pH adjusting agents are the same or different, and are independently selected from the definition of the pH adjusting agent described above. Preferably, the first pH adjusting agent is a basic adjusting agent, and the second pH adjusting agent is an acidic adjusting agent.

[0043] According to other embodiments of the present application, the preparation method can comprise mixing a basic aqueous solution containing meloxicam with an organic solvent.

[0044] Preferably, the preparation method can further comprise providing a basic aqueous solution containing meloxicam, for example mixing a first pH adjusting agent with water first, and then mixing with meloxicam to obtain a basic aqueous solution containing meloxicam.

[0045] Preferably, the preparation method can further comprise mixing a basic aqueous solution containing meloxicam with an organic solvent to obtain a mixed solution containing meloxicam, and then mixing with a second pH adjusting agent, wherein the first and second pH adjusting agents are the same or different, and are independently selected from the definition of the pH adjusting agent described above.

[0046] According to embodiments of the present application, the preparation method can comprise the following steps:

[0047] 1) mixing a pH adjusting agent 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 a basic aqueous solution;

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

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

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

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

[0052] 1) mixing a 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) mixing meloxicam with the alkaline aqueous solution obtained in step 1) to obtain an alkaline aqueous solution containing meloxicam;

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

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

[0056] Generally, there is no particular limitation on the temperature for the preparation method. For example, the temperature of step 1), 2), 3), or 4) can be 5°C to 80°C, which can be adjusted according to the specific circumstances on the basis of the present application. According to an exemplary preparation method of the present application, the organic solvent can be added and stirred without waiting for the above-mentioned alkaline aqueous solution to cool, and preferably, the temperature of step 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 an embodiment of the present application, the stirring can be performed in each step of the above-mentioned different embodiments, such as step 1), 2), 3), or 4), to facilitate mixing, and the time of the stirring can be 10 minutes or more, for example, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, or more.

[0058] The present application also provides a liquid preparation, such as an injection, preferably an intravenous injection, which comprises the above-mentioned meloxicam composition.

[0059] According to the injection of the present application, the injection can further include a container, such as an ampoule, a vial, or a multi-dose container, which contains the above-mentioned meloxicam composition.

[0060] According to the injection of the present application, it can include a small volume injection (20 mL or less, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mL) and a large volume injection (50 mL or more, such as 50, 60, 70, 75, 80, 90, 100, 250, 500 mL, etc.).

[0061] The present application also provides a method for preparing the injection, which comprises placing the meloxicam composition in a container; and preferably, the composition is sterilized before or after being placed in the container. The sterilization can be moist heat sterilization or filter sterilization.

[0062] The present application also provides the use of the above-mentioned meloxicam composition for treating diseases (such as postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis).

[0063] The present application also provides the use of the above-mentioned meloxicam composition for preparing a medicament, particularly a medicament for treating postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis.

[0064] Preferably, the medicament is an injection, particularly an intravenous injection.

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

[0066] According to the present application, the solvent can be selected from water, an organic solvent or a latent solvent, wherein the latent solvent is a mixed solvent of water and an organic solvent.

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

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

[0069] According to the present application, the water in the latent solvent can be water suitable for pharmaceutical use, such as purified water, water for injection.

[0070] According to the present application, the pH value of the composition is not particularly limited, and the pH value is preferably selected so that the composition can be used as an injection, particularly an intravenous injection.

[0071] Preferably, the composition is an injection, for example, an intravenous injection of meloxicam.

[0072] According to an embodiment of the present application, the pH of the composition can be 3.0-10.0, preferably 6.5-10.0, for example 6.8-9.0, such as 7.2-9.0, which can be exemplified by 7.4-9.0, for example 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 application, the pH adjusting agent can be selected from an acidic pH adjusting agent or a combination of an acidic pH adjusting agent and a basic pH adjusting agent, provided that the acidic pH adjusting agent at least comprises citric acid.

[0074] According to an embodiment of the present application, the acidic pH adjusting agent can be selected from citric acid, or be a mixture of citric acid and one, two or more acids selected from the group consisting 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.

[0075] According to an embodiment of the present application, the basic pH adjusting agent can 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 basic pH adjusting agent 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 basic pH adjusting agent is selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris or lysine; exemplarily, the basic pH adjusting agent is selected from sodium hydroxide or lysine.

[0076] According to an exemplary technical solution of the present application, the pH adjusting agent comprises sodium hydroxide and / or meglumine, and citric acid; or, the pH adjusting agent consists of sodium hydroxide and citric acid, or consists of meglumine and citric acid.

[0077] According to an embodiment of the present application, the mass-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 dissolved in a latent solvent.

[0079] According to embodiments of the present application, the meloxicam liquid composition preferably does not contain a solubilizer and / or a surfactant; preferably, the composition does not contain a solubilizer and a surfactant. Among them, the solubilizer includes but is not limited to the solubilizer used in pharmaceutical formulations, for example, selected from the solubilizer known to be used in injections, for example, selected from cyclodextrin and its derivatives. As an example, the cyclodextrin includes a-, b- or g-cyclodextrin, and the derivative includes but is not limited to one, two or more of a-, b-, g-cyclodextrin ether derivatives, ester derivatives, polymers, etc.; for example, the ether derivative is selected from one, two or more of glucose derivatives, hydroxypropyl derivatives, methyl derivatives, etc.; exemplarily, the derivative is selected from one, two or more of hydroxyethyl- b-cyclodextrin, hydroxypropyl- b-cyclodextrin, sulfobutyl- b-cyclodextrin, etc.; wherein the surfactant includes but is not limited to the surfactant known to be used in pharmaceutical formulations or compositions, for example, selected from the surfactant that can be used in injections, such as selected from one, two or more of polysorbate 80, polyoxyethylene castor oil derivatives, poloxamer, polyethylene glycol 15-hydroxystearate, etc.

[0080] The present application also provides a preparation method of 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 application, the preparation method comprises mixing meloxicam and a latent solvent, wherein the latent solvent is a mixed solvent comprising water and an organic solvent.

[0082] According to the present application, the preparation method can further comprise the step of providing the latent solvent, for example, mixing water with a latent solvent.

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

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

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

[0086] According to other embodiments of the present application, the preparation method can comprise mixing a basic aqueous solution containing meloxicam with an organic solvent.

[0087] Preferably, the method of preparation further comprises providing an aqueous alkaline solution comprising meloxicam, for example by mixing the first pH adjusting agent with water and then with meloxicam to obtain an aqueous alkaline solution comprising meloxicam.

[0088] Preferably, the method of preparation further comprises obtaining a mixed solution comprising meloxicam after mixing the aqueous alkaline solution comprising meloxicam with the organic solvent and then mixing with the second pH adjusting agent.

[0089] According to the present application, the first and second pH adjusting agents are the same or different and are independently of each other selected from the definition of the pH adjusting agents described above, with the proviso that the second adjusting agent is an acidic adjusting agent comprising citric acid. Preferably, the first pH adjusting agent is a basic adjusting agent and the second adjusting agent is an acidic adjusting agent comprising citric acid.

[0090] According to an embodiment of the present application, the method of preparation can comprise the following steps:

[0091] 1) mixing a first pH adjusting agent with water to obtain an aqueous alkaline solution having a pH > 10.0, for example a pH > 11.0, a pH > 12.0, a pH > 12.5 or a pH > 13.0;

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

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

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

[0095] Alternatively, according to an embodiment of the present application, the method of preparation can comprise the following steps:

[0096] 1) mixing a first pH adjusting agent with water to obtain an aqueous alkaline solution having a pH > 10.0, for example a pH > 11.0, a pH > 12.0, a pH > 12.5;

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

[0098] 3) mixing the mixed solution obtained in step 2) with an organic solvent to obtain a mixed solution comprising meloxicam;

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

[0100] Generally, the temperature for the preparation method is not particularly limited. For example, the temperature for step 1), 2), 3), or 4) can be 5°C to 80°C, which can be adjusted according to the specific situation on the basis of the present application. According to the exemplary preparation method of the present application, the organic solvent can be added and stirred without waiting for the cooling of the above-mentioned aqueous alkaline solution, preferably, the temperature for step 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 the embodiments of the present application, the stirring for facilitating the mixing can be performed in each step in the above-mentioned different embodiments, such as step 1), 2), 3), or 4), and the time for the stirring can be 10 minutes or more, for example, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, or more.

[0102] The present application also provides a liquid preparation, such as an injection, preferably an intravenous injection, comprising the above-mentioned meloxicam composition.

[0103] According to the injection of the present application, the injection can further comprise a container, such as an ampoule, a vial, or a multi-dose container, containing the above-mentioned meloxicam composition.

[0104] According to the injection of the present application, the injection can comprise a small volume injection (20 mL or less, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 mL) and a large volume injection (50 mL or more, such as 50, 60, 70, 75, 80, 90, 100, 250, 500 mL, etc.).

[0105] The present application also provides a preparation method of the injection, comprising placing the above-mentioned meloxicam composition in a container; preferably, the composition is subjected to a sterilization treatment before or after being placed in the container. The sterilization can be moist heat sterilization or filtration sterilization.

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

[0107] The present application also provides the use of the above-mentioned meloxicam composition in the preparation of a medicament, particularly for the treatment of postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis.

[0108] Preferably, the medicament is an injection, particularly an intravenous injection.

[0109] The beneficial effects of the present application are:

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

[0111] Meanwhile, the present application also surprisingly finds that the composition of the present application has excellent stability. For example, when the organic solvent used in the same proportion in the potential solvent is used as one of the components of the potential solvent, such as PEG300 or PEG400, etc., the stability is significantly improved, and no precipitation occurs during long-term storage, effectively reducing the content of degradation products and other impurities, and obtaining a stable liquid composition under the conditions of injection (especially intravenous injection). In other words, the selection of the potential solvent of the present application significantly improves the solubility of the drug while significantly improving the stability of the drug.

[0112] Since the composition of the present application does not contain auxiliary ingredients such as solubilizers and surfactants, the irritation of the composition is reduced, and the safety is better. The meloxicam composition provided by the present application can even be directly used for intravenous injection, and the effective therapeutic concentration of postoperative analgesia can be quickly reached.

[0113] In addition, the preparation process of the composition is simple, and stirring and dispersion can be completed at room temperature in a short time, which is easy to realize scale-up production.

[0114] The present application also surprisingly finds that the composition provided in the second aspect of the present application has significantly improved stability, especially when citric acid is used as an acidic pH adjuster, which effectively reduces the content of degradation product B, significantly improves the safety of the liquid preparation, and no precipitation occurs during long-term storage.

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

[0116] In addition, the preparation process of the composition is simple, and stirring and dispersion can be completed at room temperature in a short time, which is easy to realize scale-up production. DETAILED DESCRIPTION

[0117] The technical solutions of the present application will be further described in detail below in combination with specific embodiments. The following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above content of the present application is covered within the scope of protection intended by the present application.

[0118] The starting materials and reagents used in the following examples are commercially available or can be prepared by known methods unless otherwise stated.

[0119] In which, the content of meloxicam raw material in examples A1-A15 and comparative examples A1-A5 is 99.9%, and the total impurities is 0.03%.

[0120] The determination method of the content of meloxicam in the examples and comparative examples of the present application refers to USP40-NF35 Monographs: Meloxicam.

[0121] Example A1 Meloxicam composition

[0122] Prescription: Preparation method: prepare sodium hydroxide solution with pH 12.0, add the prescription amount of PEG400, stir uniformly at room temperature, then add meloxicam, stir to dissolve, adjust the pH of the solution to 7.8 with phosphoric acid, and it is obtained. No insoluble particles / visible foreign matter appears at room temperature, and no insoluble particles / visible foreign matter appears after 15 days of investigation at 2-8°C.

[0123] Example A2 Meloxicam composition

[0124] Prescription:

[0125] Preparation method: prepare sodium hydroxide solution with pH 12.0, add meloxicam, stir to dissolve at room temperature, then add the prescription amount of PEG400, stir uniformly, adjust the pH of the solution to 7.4 with phosphoric acid, and it is obtained. No insoluble particles / visible foreign matter appears at room temperature, and no insoluble particles / visible foreign matter appears after 15 days of investigation at 2-8°C.

[0126] Example A3 Meloxicam composition

[0127] Prescription:

[0128]

[0129] Preparation method: prepare sodium hydroxide solution with pH 12.0, add the prescription amount of PEG300, stir uniformly, then add meloxicam, stir to dissolve at room temperature, adjust the pH of the solution to 8.0 with phosphoric acid, and it is obtained. No insoluble particles / visible foreign matter appears at room temperature, and no insoluble particles / visible foreign matter appears after 15 days of investigation at 2-8°C.

[0130] Example A4 Meloxicam composition

[0131] Formulation:

[0132] Formulation: Sodium hydroxide solution, pH 12.0, was prepared and the prescribed amount of PEG 400 was added. The solution was stirred until uniform, and meloxicam was added. The solution was stirred until the meloxicam dissolved. The pH of the solution was adjusted to 8.2 with phosphoric acid. The solution was complete. No insoluble particulates / visible foreign matter was present when the solution was stored at room temperature. No insoluble particulates / visible foreign matter was present when the solution was stored at 2-8°C for 15 days.

[0133] Example A5 Meloxicam Composition

[0134] Formulation:

[0135] Formulation: Sodium hydroxide solution, pH 12.0, was prepared and the prescribed amount of PEG 400 was added. The solution was stirred until uniform, and meloxicam was added. The solution was stirred until the meloxicam dissolved. The pH of the solution was adjusted to 7.8 with lactic acid. The solution was complete. No insoluble particulates / visible foreign matter was present when the solution was stored at room temperature. No insoluble particulates / visible foreign matter was present when the solution was stored at 2-8°C for 15 days.

[0136] Example A6 Meloxicam Composition

[0137] Formulation:

[0138]

[0139] Formulation: Sodium hydroxide solution, pH 12.0, was prepared and the prescribed amount of PEG 400 was added. The solution was stirred until uniform, and meloxicam was added. The solution was stirred until the meloxicam dissolved. The pH of the solution was adjusted to 8.4 with malic acid. The solution was complete. No insoluble particulates / visible foreign matter was present when the solution was stored at room temperature. No insoluble particulates / visible foreign matter was present when the solution was stored at 2-8°C for 15 days.

[0140] Example A7 Meloxicam Composition

[0141] Formulation:

[0142] Formulation: Sodium hydroxide solution, pH 12.0, was prepared and the prescribed amount of PEG 400 was added. The solution was stirred until uniform, and meloxicam was added. The solution was stirred until the meloxicam dissolved. The pH of the solution was adjusted to 8.2 with tartaric acid. The solution was complete. No insoluble particulates / visible foreign matter was present when the solution was stored at room temperature. No insoluble particulates / visible foreign matter was present when the solution was stored at 2-8°C for 15 days.

[0143] Example A8 Meloxicam Composition

[0144] Formulation:

[0145] Preparation: A solution of sodium hydroxide pH 12.0 was prepared, the prescribed amount of propylene glycol was added, stirred until uniform, meloxicam was added, stirred until dissolved, the solution was adjusted to pH 8.4 with phosphoric acid. No insoluble particulates / visible foreign matter was present at room temperature, a small amount of insoluble particulates was present at 2-8°C over 15 days.

[0146] Example A9 Meloxicam composition

[0147] Formulation:

[0148]

[0149] Preparation: A solution of sodium hydroxide pH 12.0 was prepared, the prescribed amount of glycerin was added, stirred until uniform, meloxicam was added, stirred until dissolved, the solution was adjusted to pH 8.6 with phosphoric acid. No insoluble particulates / visible foreign matter was present at room temperature, a small amount of insoluble particulates was present at 2-8°C over 15 days.

[0150] Example A10 Meloxicam composition

[0151] Formulation:

[0152] Preparation: A solution of sodium hydroxide pH 12.0 was prepared, the prescribed amount of butylene glycol was added, stirred until uniform, meloxicam was added, stirred until dissolved, the solution was adjusted to pH 8.2 with phosphoric acid. No insoluble particulates / visible foreign matter was present at room temperature, a small amount of insoluble particulates was present at 2-8°C over 15 days.

[0153] Example A11 Meloxicam composition

[0154] Formulation:

[0155] Preparation: A solution of sodium hydroxide pH 12.0 was prepared, the prescribed amount of PEG 400 was added, stirred until uniform, meloxicam was added, stirred until dissolved, the solution was adjusted to pH 7.8, 8.0, 8.2, 8.4, 8.6, 8.8 and 9.0 with citric acid. No insoluble particulates / visible foreign matter was present at room temperature, no insoluble particulates / visible foreign matter was present at 2-8°C over 15 days.

[0156] Example A12 Scale-up preparation of the meloxicam composition of the present invention

[0157] Liquid compositions with different formulations were prepared according to the formulations F1-F14 shown in the table below. An aqueous solution of sodium hydroxide with pH 13.0 was prepared, the prescribed amount of organic solvent was added, stirred until uniform, then meloxicam was added, stirred until dissolved, and the pH of the solution was adjusted to the corresponding value with phosphoric acid, and sterilized.

[0158] Table A1 Formulations of meloxicam liquid compositions

[0159]

[0160] Example A13 Stability investigation of meloxicam compositions

[0161] The sample solutions F1-F14 in Example A12 were filtered with 0.22 μm microporous filter membranes, 5 mL of each was taken and sealed in 10 mL Schlenk bottles. The bottles were placed in a room temperature environment, a refrigerator at 2-8°C, and a constant temperature and humidity oven at 60°C, respectively, to investigate the changes in crystallization and related substances, and the results are shown in the table below.

[0162] Table A2 Stability investigation of meloxicam liquid compositions

[0163]

[0164] Example A14 Scale-up preparation of meloxicam compositions of the present application

[0165] Liquid compositions with different formulations were prepared according to the formulations shown in the table below. An aqueous solution of sodium hydroxide with pH 13.0 was prepared, the prescribed amount of organic solvent was added, stirred until uniform, then different batches of meloxicam were added, stirred until dissolved, the pH of the solution was adjusted to the corresponding value with phosphoric acid, and sterilized.

[0166] Table A3 Formulations of meloxicam liquid compositions

[0167]

[0168] Among them, S1 and S2 are samples of the same batch, and S3 is a sample of another batch.

[0169] Example A15 Stability investigation of meloxicam compositions

[0170] The long-term and accelerated stability investigations of the samples in Example A14 were carried out, and the results are shown in the table below.

[0171] Operation of long-term stability investigation: According to the provisions in the Chinese Pharmacopoeia 2015 Edition Volume IV 9001 Guidelines for Stability Testing of Raw Materials and Preparations, long-term stability investigations were carried out on samples S1 and S2 in Example A14, the test temperature was 30°C ± 2°C, RH 65% ± 5%, and the investigations were carried out for 3, 6, 9, and 12 months.

[0172] Operation of accelerated stability study: according to the provisions of the Chinese Pharmacopoeia 2015 edition four 9001 raw materials and preparation stability test guidelines, the samples S1, S2 and S3 in example A14 were subjected to accelerated stability study, test temperature 40℃±2℃, RH75%±5%, 1, 2, 3, 6 months.

[0173] Table A4 Stability study of meloxicam liquid composition

[0174]

[0175]

[0176] Note: 0 day test data is the test value obtained immediately after sample preparation.

[0177] The above experimental results show that the meloxicam composition prepared by example A14 using a larger scale can maintain the content of degradation impurities and total impurities at a low level during long-term stability and accelerated stability study, and has excellent stability.

[0178] Comparative example A1 meloxicam liquid composition

[0179] Prescription:

[0180] Preparation method: dissolve lysine and PEG400 in aqueous solution, stir uniformly, add meloxicam, stir at 40℃ to dissolve, adjust the pH of the solution to 7.5 with phosphoric acid, and obtain. No insoluble particles / visible impurities appear at room temperature, no insoluble particles / visible impurities appear after 15 days of investigation at 2-8℃.

[0181] Comparative example A2 meloxicam liquid composition

[0182] Prescription:

[0183] Preparation method: dissolve meglumine and PEG400 in aqueous solution, stir uniformly, add meloxicam, stir at 40℃ or above for a long time to dissolve, adjust the pH of the solution to 7.5 with phosphoric acid, and obtain. No insoluble particles / visible impurities appear at room temperature, no insoluble particles / visible impurities appear after 15 days of investigation at 2-8℃.

[0184] Prescription:

[0185] Preparation method: dissolve arginine and PEG400 in water, stir until uniform, add meloxicam, stir at 40°C for a long time until dissolved, adjust the pH of the solution to 7.5 with phosphoric acid, and obtain. 2-8℃ for 7 days, a small amount of insoluble particles appear.

[0186] Comparative Example A4

[0187] The solubility of meloxicam in alkali or basic amino acid solution (meglumine, Tris, arginine or lysine) was studied, and the solubility is shown in the table below. According to the experimental results, the solubility of meloxicam in high concentration organic alkali or basic amino acid can reach more than 10 mg / mL, but at room temperature, it can only be prepared for a long time (more than 6 hours) or dissolved at a high temperature (40°C), the preparation process is complex, and the solution stability is poor.

[0188] Table A5 Solubility of meloxicam in different concentrations of organic alkali or basic amino acid

[0189]

[0190] Comparative Example A5

[0191] The solubility of meloxicam in different proportions of PEG400 aqueous solution was studied, and the solubility is shown in the table below. The results show that the solubility of meloxicam in pure PEG400 is only 2.27 mg / mL, which cannot meet the requirements of intravenous injection.

[0192] Table A6 Solubility of meloxicam in different proportions of PEG400 aqueous solution

[0193]

[0194] The above experimental results show that the present application uses a potential solvent containing polyethylene glycol such as PEG400, PEG300 as an organic solvent composition, which surprisingly significantly improves the content of meloxicam in the prepared composition, which will make the liquid preparation of meloxicam, especially intravenous injection, have better application prospect and wider application range, significantly improve the medical efficiency and patient compliance, etc. And in the case of the same content of meloxicam, such effect will become more obvious with the increase of the concentration of polyethylene glycol.

[0195] Surprisingly, the composition of the present application also has excellent stability, not only without precipitation during long-term storage, but also with low levels of degradation products and total impurities. In particular, when the ratio of organic solvent in the latent solvent is the same, the meloxicam composition prepared with the latent solvent containing polyethylene glycol, especially PEG400, has good stability and does not precipitate during long-term storage.

[0196] The meloxicam raw material content in Examples B1-B6 and Comparative Examples B1-B4 was 99.2%, and the total impurities were 0.06%.

[0197] The "freeze-thaw" method described below is:

[0198] The sample was placed in a -20°C refrigerator for two days, then taken out and stored at 40°C for two days, and each freeze-thaw experiment was repeated three times, with the last result at the end of the cycle being taken as the final result.

[0199] Example B1 Meloxicam liquid composition

[0200] Formulation:

[0201] Preparation method: A sodium hydroxide solution with a pH of 12.0 was prepared, the prescribed amount of PEG400 was added and stirred until uniform, then the prescribed amounts of meloxicam were added and stirred until dissolved, and the pH of the solution was adjusted to 7.8 with phosphoric acid or citric acid. No insoluble particles or visible foreign matter appeared during storage at room temperature, and no insoluble particles or visible foreign matter appeared during storage at 2-8°C for 15 days.

[0202] Stability study of the meloxicam liquid composition of Example B2

[0203] The sample solutions prepared in Example B1 were filtered separately using a 0.22 μm microporous filter, and 5 mL was placed in a 10 mL vial and sealed with a cap. The increase in related substances was studied in a constant temperature and humidity chamber at 60°C, and the results are shown in the table below.

[0204] Stability study of the meloxicam liquid composition of Example B1

[0205]

[0206] From the above experiments, it can be seen that compared with other pH adjusters, the use of citric acid as an acidic pH adjuster can significantly improve the stability of meloxicam and effectively reduce the formation of degradation product B.

[0207] In addition, using ethanol, propylene glycol, butylene glycol, isopropyl alcohol, glycerin, polyethylene glycol 300 and other organic solvents, replacing PEG 400 in Example Bl, the results also show that the composition containing citric acid as a pH adjuster can effectively reduce the content of degradation impurities B and total impurities.

[0208] Example B3 Meloxicam liquid composition

[0209] Formulation:

[0210] Formulation method: A sodium hydroxide solution with pH 12.0 was prepared, the prescribed amount of PEG 400 was added, stirred until uniform, then meloxicam was added and stirred until dissolved, and the pH of the solution was adjusted to the desired value (pH = 8.0, 8.2, 8.4, 8.6, 8.8, 9.0) using citric acid. No insoluble particles / visible foreign matter appeared when the product was stored at room temperature, and no insoluble particles / visible foreign matter appeared when the product was stored at 2-8°C for 15 days.

[0211] Example B4 Stability study of meloxicam liquid composition

[0212] The sample solutions prepared in Example B3 were filtered using 0.22 μm microporous filter membranes, and 5 mL of each was placed in a 10 mL vial and sealed. The vials were placed in a constant temperature and humidity oven at 60°C for 10 days, and the increase in related substances was observed. The results showed that the content of degradation product B was stably maintained at less than 0.2%. The results show that when citric acid is used as a pH adjuster, even when the pH of the sample changes within a wide range, the content of degradation product B can be controlled within a low content range, significantly improving the stability of meloxicam in the composition and the safety of the preparation.

[0213] Example B5

[0214] Referring to the formulation method of Example Bl, a meloxicam composition was prepared: PEG 400 concentration 10%, meloxicam concentration 18.75 mg / ml, using meglumine (replacing NaOH) and citric acid as pH adjusters, and adjusting the pH of the composition to 8.2. No insoluble particles / visible foreign matter appeared when the product was stored at room temperature, and no insoluble particles / visible foreign matter appeared when the product was stored at 2-8°C for 15 days. The product was subjected to freeze-thaw treatment once, and although small particles appeared at the bottom, they dissolved quickly after shaking.

[0215] In addition, using 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 and other basic pH adjusters, replacing the above meglumine, no insoluble particles / visible foreign matter appeared.

[0216] Example B6

[0217] A meloxicam composition was prepared according to the procedure of Reference Example Bl: PEG 400 concentration 10% by volume, meloxicam concentration 18.75 mg / ml, sodium hydroxide and citric acid as pH adjusters, pH adjusted to 8.2. No insoluble particulates / visible foreign matter were present on standing at room temperature, and no insoluble particulates / visible foreign matter were present on examination at 2-8°C for 15 days. The product was subjected to one freeze-thaw cycle, and no insoluble particulates / visible foreign matter were present on standing.

[0218] Comparative Example Bl

[0219] A meloxicam composition was prepared according to the procedure of Reference Example Bl: PEG 400 concentration 10% by volume, meloxicam concentration 18.75 mg / ml, sodium hydroxide and citric acid as pH adjusters, pH adjusted to 8.2. No insoluble particulates / visible foreign matter were present on standing at room temperature, and no insoluble particulates / visible foreign matter were present on examination at 2-8°C for 15 days. The product was subjected to one freeze-thaw cycle, and no insoluble particulates / visible foreign matter were present on standing.

[0220] Comparative Example B2

[0221] A meloxicam composition was prepared according to the procedure of Reference Example Bl: PEG 400 concentration 10% by volume, meloxicam concentration 18.75 mg / ml, sodium hydroxide and citric acid as pH adjusters, pH adjusted to 8.2. No insoluble particulates / visible foreign matter were present on standing at room temperature, and no insoluble particulates / visible foreign matter were present on examination at 2-8°C for 15 days. The product was subjected to one freeze-thaw cycle, and no insoluble particulates / visible foreign matter were present on standing.

[0222] Comparative Example B3

[0223] A meloxicam composition was prepared according to the procedure of Reference Example Bl: PEG 400 concentration 10% by volume, meloxicam concentration 18.75 mg / ml, sodium hydroxide and citric acid as pH adjusters, pH adjusted to 8.2. No insoluble particulates / visible foreign matter were present on standing at room temperature, and no insoluble particulates / visible foreign matter were present on examination at 2-8°C for 15 days. The product was subjected to one freeze-thaw cycle, and no insoluble particulates / visible foreign matter were present on standing.

[0224] Comparative Example B4

[0225] A meloxicam composition was prepared according to the procedure of Reference Example Bl: PEG 400 concentration 10% by volume, meloxicam concentration 18.75 mg / ml, sodium hydroxide and citric acid as pH adjusters, pH adjusted to 8.2. No insoluble particulates / visible foreign matter were present on standing at room temperature, and no insoluble particulates / visible foreign matter were present on examination at 2-8°C for 15 days. The product was subjected to one freeze-thaw cycle, and no insoluble particulates / visible foreign matter were present on standing.

[0226] The above experiments show that, compared with other pH adjusting agents, the use of citric acid as an acidic pH adjusting agent for preparing a meloxicam liquid composition can significantly improve the stability of meloxicam, effectively reduce the formation of impurities, and surprisingly improve the safety and effectiveness of the preparation.

[0227] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A meloxicam composition comprising meloxicam, and a mixed solvent of water and an organic solvent; a volume concentration of the organic solvent in the mixed solvent of water and an organic solvent is 15% to 40%; the organic solvent is selected from one, two or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600; a pH of the composition is 6.5 to 10.0; a mass volume ratio of the meloxicam to the mixed solvent of water and an organic solvent is 25 to 35 mg / mL; the composition does not contain other known solubilizers and surfactants for pharmaceutical preparations. 2.The composition of claim 1, wherein a mass volume ratio of the meloxicam to the mixed solvent of water and an organic solvent is 30 to 35 mg / mL. 3.The composition of claim 1, wherein a mass volume ratio of the meloxicam to the mixed solvent of water and an organic solvent is 25 to 30 mg / mL.

4. The composition of claim 1, wherein: a volume concentration of the organic solvent in the mixed solvent of water and an organic solvent is 20% to 40%.

5. The composition of claim 1, wherein: a volume concentration of the organic solvent in the mixed solvent of water and an organic solvent is 15% to 30%.

6. The composition of claim 1, wherein: a volume concentration of the organic solvent in the mixed solvent of water and an organic solvent is 20% to 30%.

7. The composition of claim 1, wherein: a volume concentration of the organic solvent in the mixed solvent of water and an organic solvent is 25% to 30%.

8. The composition of claim 1, wherein: a volume concentration of the organic solvent in the mixed solvent of water and an organic solvent is 15%, 16%, 17%, 18%, 19%, 20%, 25% or 30%.

9. The composition of claim 1, wherein: a pH of the composition is 6.8 to 10.

0.

10. The composition of claim 1, wherein: a pH of the composition is 7.2 to 10.

0.

11. The composition of claim 1, wherein: a pH of the composition is 7.2 to 9.

0.

12. The composition of claim 1, wherein: a pH of the composition is 7.4 to 9.

0.

13. The composition of claim 1, wherein: a pH of the composition is 7.4 to 8.

5.

14. The composition of claim 1, wherein: a 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. 15.The composition of claim 1, wherein the water is water for pharmaceutical use. 16.The composition of claim 15, wherein the water for pharmaceutical use is purified water. 17.The composition of claim 15, wherein the water for pharmaceutical use is water for injection. 18.The composition of claim 1, wherein the composition further comprises a pH adjusting agent. 19.The composition of claim 18, wherein the pH adjusting agent is selected from a basic pH adjusting agent and / or an acidic pH adjusting agent; the basic pH adjusting agent 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; the acidic pH adjusting agent is selected from one, two or more of ascorbic acid, lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid.

20. The composition of claim 18, wherein the pH adjusting agent comprises at least citric acid.

21. The composition of claim 19, wherein the acidic pH adjusting agent is selected from citric acid, or is selected from a mixture of citric acid with one, two or more acids selected from the group consisting of ascorbic acid, lactic acid, malic acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid and acetic acid.

22. The composition of claim 19, wherein the basic pH adjusting agent is selected from one or both of sodium hydroxide and meglumine.

23. The composition of claim 18, wherein the pH adjusting agent consists of sodium hydroxide and citric acid, or consists of meglumine and citric acid.

24. The composition of any one of claims 1 to 23, wherein the method of preparing the composition comprises adjusting the pH of the solution system to above 12.0 prior to dissolving meloxicam.

25. The method of preparing the composition of any one of claims 1 to 23, wherein the method of preparing the composition comprises mixing meloxicam, water, an organic solvent, and, when present, a pH adjusting agent.

26. The method of claim 25, wherein the method of preparing the composition comprises the steps of: 1) mixing a first pH adjusting agent with water to give a basic aqueous solution having a pH of > 10.0; 2) mixing meloxicam with the basic aqueous solution from step 1) to give a basic aqueous solution containing meloxicam; 3) mixing the resulting solution from step 2) with an organic solvent to give a mixed solution containing meloxicam; 4) adjusting the pH of the resulting solution from step 3) using a second pH adjusting agent to give a meloxicam composition.

27. The production method according to claim 26, wherein the first pH adjusting agent is a basic adjusting agent and the second pH adjusting agent is an acidic adjusting agent comprising citric acid.

28. The method of claim 26, wherein in step 1) the first pH adjusting agent is mixed with water to give a basic aqueous solution having a pH of > 11.

0.

29. The method of claim 26, wherein in step 1) the first pH adjusting agent is mixed with water to give a basic aqueous solution having a pH of > 12.

0.

30. The method of claim 26, wherein in step 1) the first pH adjusting agent is mixed with water to give a basic aqueous solution having a pH of > 12.

5.

31. An injection, wherein the injection comprises the composition of any one of claims 1 to 23.

32. The injection of claim 31, wherein the injection is an intravenous injection.

33. The method of preparing the injection of claim 31, comprising: placing the composition of any one of claims 1 to 23 in a container; and, optionally, sterilizing the composition prior to or after being placed in the container.

34. Use of the composition of any one of claims 1 to 23 in the manufacture of a medicament for the treatment of postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis.

35. The use of claim 34, wherein the medicament is a liquid formulation.

36. The use of claim 34, wherein the medicament is an injection. ​ 37. The use of claim 34, wherein the medicament is an intravenous injection.

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