Stable meloxicam pharmaceutical composition and preparation method thereof

Abstract

The invention discloses a stable meloxicam pharmaceutical composition and a preparation method thereof, the pharmaceutical composition comprises meloxicam, a charge stabilizer, a surface stabilizer and a sedimentation inhibitor, and the charge stabilizer is combined bile acid and / or salt thereof. The charge stabilizer selected in the pharmaceutical composition solves the problems of insoluble particles, precipitates and degradation in the storage process of the preparation. The method is stable and controllable in process, easy for large-scale preparation and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a stable meloxicam pharmaceutical composition and a preparation method thereof. Background Art

[0002] Meloxicam is an enolic acid NSAID developed by Boehringer Ingelheim in Germany, which has anti-inflammatory, antipyretic and analgesic effects and is mainly used for the treatment of rheumatoid arthritis, painful osteoarthritis and postoperative pain. Meloxicam selectively inhibits cyclooxygenase-2 (COX-2) to prevent the synthesis of pro-inflammatory prostaglandins and the like, and has high anti-inflammatory and analgesic effects with less side effects on the gastrointestinal tract and kidneys.

[0003] The chemical name of meloxicam is 2-methyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, with a molecular weight of 351.41, and the structural formula is as follows:

[0004]

[0005] Meloxicam has stable chemical properties, no hygroscopicity and is insensitive to light. It is almost insoluble in water, and its solubility in water is related to the pH value. Its solubility is the lowest at a pH value of 4 and increases with the increase of the pH value. To obtain a clinical effective concentration of 10-20 mg / mL, the pH value should be at least 8.

[0006] The currently marketed dosage forms of meloxicam include oral preparations such as meloxicam tablets and capsules, meloxicam injection, intramuscular injection, and meloxicam nanocrystal injection. Due to the low solubility of meloxicam, the absorption and onset of action are slow after oral administration, which limits its application in the fields of acute arthritis and pain. Although meloxicam injection and intramuscular injection improve the solubility of the drug, they cannot be used for intravenous injection because the prescription contains excipients such as meglumine, alcohol furfural, polyhydroxy body, and glycine, and the maximum blood drug concentration can only be reached 1 hour after injection, so it can only be used as a supplement to oral administration. Meloxicam nanocrystal injection (trade name: Anjeso) was approved by the FDA for marketing in the United States in February 2020 and is administered intravenously once a day for moderate to severe pain. This nanocrystal injection is the world's first intravenous injection of meloxicam. The Cmax is reached about 5 minutes after administration, which significantly relieves moderate to severe pain. However, meloxicam nanocrystal injection is a nanocrystal dispersion of meloxicam in the form of nanoscale solid particles in an aqueous solution. Due to the large surface free energy of the nanocrystal particles, it belongs to a thermodynamically unstable system, and particle size growth, particle aggregation, and even sedimentation will occur during storage. US9345665 discloses a meloxicam nanoparticle injection, which consists of nanoscale meloxicam particles, a surface stabilizer, and a buffer. However, insoluble particles of 10-20 μm will be generated during the storage of the injection, and the insoluble particles entering the human body through the venous blood vessels can cause hazards such as phlebitis, granuloma, and vascular embolism.

[0007] Therefore, developing a stable, safe, and meloxicam intravenous injection preparation with improved impurity content and solubility still faces great challenges. Summary of the Invention

[0008] During the R & D process, the inventors found that the stability of meloxicam injection containing free bile salt or free bile acid is poor, and precipitation or insoluble particles are more likely to precipitate during storage at room temperature or high temperature. After a large number of experiments, the R & D personnel investigated and analyzed the influencing factors of each excipient in the prescription, and surprisingly found that after replacing the free bile salt or free bile acid, the stability of meloxicam nanoparticles has been significantly improved, especially the problems of insoluble particles and precipitates during storage have been significantly reduced, and the degradation products of meloxicam injection are stable during the stability period.

[0009] Accordingly, the present invention provides a stable meloxicam pharmaceutical composition, which comprises meloxicam, a charge stabilizer, a surface stabilizer, and a sedimentation inhibitor, wherein the charge stabilizer comprises a conjugated bile acid and / or its salt.

[0010] In some embodiments, in the pharmaceutical composition of the present invention, the charge stabilizer comprises a conjugated bile salt.

[0011] Preferably, the conjugated bile acid salt is selected from conjugated sodium cholate, conjugated potassium cholate, and conjugated ammonium cholate.

[0012] Preferably, the conjugated sodium cholate is selected from one or more of sodium glycocholate, sodium taurocholate, sodium glycochenodeoxycholate, sodium taurochenodeoxycholate, sodium glycohyodeoxycholate, sodium glycochenodeoxycholate, and sodium taurohyodeoxycholate.

[0013] In some embodiments, in the pharmaceutical composition of the present invention, when the charge stabilizer contains conjugated bile acid, an alkaline pH regulator is optionally included in the composition.

[0014] In some embodiments, in the pharmaceutical composition of the present invention, when the charge stabilizer is conjugated bile acid, an alkaline pH regulator is included in the composition. The conjugated bile acid reacts with the alkaline pH regulator to form a conjugated bile acid salt.

[0015] In some embodiments, in the pharmaceutical composition of the present invention, when the charge stabilizer contains conjugated bile acid salt and a small amount of conjugated bile acid, if the pH of the pharmaceutical composition meets the requirements, an alkaline pH regulator does not need to be added again.

[0016] Preferably, the alkaline pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, concentrated ammonia solution, sodium bicarbonate, sodium carbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris (tris (hydroxymethyl) aminomethane), and organic amines (such as triethylamine and diethylamine).

[0017] Preferably, the conjugated bile acid is selected from one or more of glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycohyodeoxycholic acid, glycochenodeoxycholic acid, and taurohyodeoxycholic acid.

[0018] In some embodiments, the pH value of the pharmaceutical composition of the present invention is 6.0 - 8.0, more preferably 6.6 - 7.8.

[0019] The charge stabilizer selected in the pharmaceutical composition of the present invention mainly improves the stability of the preparation during storage, prevents the rapid growth of the particle size of meloxicam nanoparticles and aggregation or precipitation, and avoids problems such as the precipitation of insoluble particles at normal temperature or high temperature.

[0020] In some embodiments, in the pharmaceutical composition of the present invention, the surface stabilizer can be a non-ionic surface stabilizer or an ionic surface stabilizer.

[0021] In some embodiments, in the pharmaceutical composition of the present invention, the nonionic surface stabilizer includes, but is not limited to, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, poloxamer, polyhydroxystearic acid, hydroxystearate 15, Tween-80, Tween-20, polyethylene glycol 15-hydroxystearate, etc.

[0022] In some embodiments, in the pharmaceutical composition of the present invention, the ionic surface stabilizer is selected from cationic surfactants, anionic surfactants, and zwitterionic surfactants. Among them, the anionic surface stabilizer includes carboxylates, sulfate esters, sulfonates, and phosphate esters, etc. For example, the anionic surface stabilizer includes sodium dioctyl sulfosuccinate (DOSS), sodium dodecyl sulfonate, sodium dodecyl sulfate (SDS), sodium dioctyl sulfosuccinate, etc. The cationic surface stabilizer includes fatty ammonium salts, alkyl imidazoline salts, alkyl pyridinium salts, hydroxylamines, phosphorus compounds, etc. For example, the cationic surface stabilizer includes, but is not limited to, polymers, biopolymers, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polystyrene, poly(methyl methacrylate) trimethylammonium bromide (PMMTMABr), hexylmethyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethyl sulfate. The zwitterionic surface stabilizer includes, but is not limited to, proteins (such as human serum albumin, bovine serum albumin), phospholipids (such as phosphatidylcholine, lecithin), zwitterionic polymers (such as gelatin, gum arabic, tragacanth gum), etc.

[0023] Preferably, the surface stabilizer of the present invention is selected from one or more of polyvinylpyrrolidone, Tween 80, Tween 20, poloxamer, polyethylene glycol 15-hydroxystearate, lecithin, sodium dodecyl sulfonate, sodium dodecyl sulfate, polyvinyl alcohol, and hydroxypropyl methylcellulose.

[0024] In some embodiments, in the pharmaceutical composition of the present invention, the sedimentation inhibitor is selected from polyols or sugars, sugar alcohols.

[0025] The polyols of the present invention include, but are not limited to, glycerol, propylene glycol, butylene glycol, isopropyl alcohol, tetrahydrofurfuryl alcohol, polyethylene glycol (also known as PEG, such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600), etc.

[0026] The sugars and sugar alcohols described in the present invention include, but are not limited to, sucrose, fructose, lactose, glucose, erythritol, isomaltitol, mannitol, sorbitol, xylitol, maltitol, cyclodextrin and its derivatives, starch and its celluloses, etc. As an example, the cyclodextrin includes α-, β- or γ-cyclodextrin, and the derivatives include, but are not limited to, one or more of α-, β-, γ-cyclodextrin ether derivatives, ester derivatives, polymers, etc.; for example, the ether derivatives are selected from one or more of glucose derivatives, hydroxypropyl derivatives, methyl derivatives, etc.; for example, one or more of hydroxyethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin. The starch and its celluloses are selected from methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxyethyl starch, starch, pregelatinized starch, pregelatinized hydroxypropyl starch, sodium carboxymethyl starch, etc.

[0027] Preferably, the sedimentation inhibitor is selected from one or several of lactose, sucrose, fructose, glucose, erythritol, isomaltitol, mannitol, sorbitol, xylitol, maltitol, glycerol, propylene glycol, butylene glycol, sucrose, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, hydroxyethyl starch, sodium carboxymethylcellulose, hydroxypropyl-β-cyclodextrin.

[0028] More preferably, the sedimentation inhibitor is selected from one or several of lactose, sucrose, fructose, glucose, erythritol, isomaltitol, mannitol, sorbitol, xylitol, maltitol, hydroxypropyl-β-cyclodextrin.

[0029] In some embodiments, for the pharmaceutical composition of the present invention, the mass of meloxicam is 10 - 100 mg; preferably, the mass of meloxicam is 10 - 50 mg.

[0030] In some embodiments, for the pharmaceutical composition of the present invention, the mass ratio of meloxicam to the charge stabilizer is 1:(0.02 - 3); preferably, the mass ratio of meloxicam to the charge stabilizer is 1:(0.05 - 1); preferably, the mass ratio of meloxicam to the charge stabilizer is 1:(0.05 - 0.15).

[0031] In some embodiments, for the pharmaceutical composition of the present invention, the mass ratio of meloxicam to the surface stabilizer is 1:(0.05 - 8); preferably, the mass ratio of meloxicam to the surface stabilizer is 1:(0.1 - 5), preferably, the mass ratio of meloxicam to the surface stabilizer is 1:(0.1 - 1).

[0032] In some embodiments, for the pharmaceutical composition of the present invention, the mass ratio of meloxicam to the sedimentation inhibitor is 1:(0.1 - 50); preferably, the mass ratio of meloxicam to the sedimentation inhibitor is 1:(0.5 - 10); more preferably, the mass ratio of meloxicam to the sedimentation inhibitor is 1:(0.5 - 5).

[0033] In some embodiments, for the pharmaceutical composition of the present invention, the average particle size of the meloxicam particles is less than 1000 nm; preferably, the average particle size of the meloxicam particles is less than 500 nm; preferably, the average particle size of the meloxicam particles is less than 200 nm; preferably, the average particle size of the meloxicam particles is less than 100 nm.

[0034] The second aspect of the present invention provides a meloxicam injection, comprising the above pharmaceutical composition and an injection solvent, wherein the content of meloxicam is 10 - 100 mg / ml; preferably, the content of meloxicam is 10 - 50 mg / ml.

[0035] In some embodiments, the pH value of the meloxicam injection of the present invention is 6.0 - 8.0; it can be selected from 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0. More preferably, the pH value is 6.6 - 7.8.

[0036] In some embodiments, the injection is an intravenous injection.

[0037] In some embodiments, for the meloxicam injection of the present invention, the injection solvent is selected from one or more of water for injection, 0.9% sodium chloride solution, injection oil, ethanol, propylene glycol, ethylene glycol, tert-butanol, and polyethylene glycol. The polyethylene glycol includes polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600.

[0038] In some embodiments, the meloxicam injection of the present invention comprises meloxicam, a charge stabilizer, a surface stabilizer, a sedimentation inhibitor, an injection solvent, and optionally contains a basic pH regulator, wherein the charge stabilizer comprises a conjugated bile acid or its salt, wherein the mass of meloxicam is 10 - 100 mg, and the mass ratio of meloxicam to the charge stabilizer is 1:(0.02 - 3); the mass ratio of meloxicam to the surface stabilizer is 1:(0.05 - 8); the mass ratio of meloxicam to the sedimentation inhibitor is 1:(0.1 - 50).

[0039] In some embodiments, for the meloxicam injection of the present invention, the average particle size of the meloxicam particles is less than 1000 nm.

[0040] In some embodiments, the injectable of the present invention may further include a container for containing the above-mentioned meloxicam pharmaceutical composition, such as an ampoule, a vial or a multi-dose container.

[0041] In some embodiments, the injectable of 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.).

[0042] The present invention also provides the use of the stable pharmaceutical composition or injectable in the preparation of a medicament for treating postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, and ankylosing spondylitis.

[0043] The third aspect of the present invention provides a method for preparing a stable meloxicam pharmaceutical composition or a meloxicam injectable, which includes the following steps: mixing meloxicam, a charge stabilizer, a surface stabilizer, and a sedimentation inhibitor.

[0044] In some embodiments, the method for preparing the pharmaceutical composition includes the following steps:

[0045] Mixing, grinding a charge stabilizer, a surface stabilizer and meloxicam to obtain a dispersion; and then adding a sedimentation inhibitor and mixing.

[0046] In some embodiments, the method for preparing the injectable includes the following steps:

[0047] (1) Stirring and mixing a charge stabilizer, a surface stabilizer and an injection solvent;

[0048] (2) Adding meloxicam and mixing, grinding to obtain a suspension;

[0049] (3) Adding a sedimentation inhibitor and mixing with the above suspension.

[0050] In some embodiments, the method for preparing the injectable of the present invention optionally includes a step of adjusting the pH value. The pH regulator of the present invention may be selected from basic pH regulators and / or acidic pH regulators; for example, those reagents suitable as pH regulators for injectables or intravenous injectables are used to adjust the pH value of the final injectable.

[0051] In some embodiments, the basic pH regulator may be selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and Tris (tris (hydroxymethyl) aminomethane). The acidic pH regulator may be selected from one or more of ascorbic acid, lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, and acetic acid.

[0052] In some embodiments, the mixing in the present invention can adopt diffusion mixing, convective mixing, and shear dispersion mixing, which are well known in the art.

[0053] In some embodiments, the present invention can optionally use a grinding device for grinding treatment, such as a ball mill, a grinder, a vibratory mill, and other dispersion grinders, and a media mill such as a sand mill and a bead mill. These grinding devices are well known in the art.

[0054] In some embodiments, optionally, the steps of the present invention further include sterilization or disinfection, and filling.

[0055] In some embodiments, the sterilization can be moist heat sterilization or filtration sterilization.

[0056] Advantageous effects:

[0057] The present invention unexpectedly finds that the use of conjugated bile acids and / or their salts in the pharmaceutical composition of the present invention improves the stability of the pharmaceutical composition or injection during storage, no precipitation occurs during long-term storage, effectively reduces the content of impurities such as degradation products, and obtains a liquid composition that is stable under injection conditions (especially under intravenous injection conditions).

[0058] The pharmaceutical composition of the present invention has strong stability and has low requirements for storage conditions. For example, it can be stored for a long time at low temperature, normal temperature, or high temperature, and the content changes of impurities such as the maximum single impurity and unknown single impurity are slow or there is no significant difference, especially the content of degradation product B.

[0059] The pH of the injection of the present invention does not exceed 8, it has little vascular irritation during intravenous injection, and at the same time has better safety, and no hemolysis and other phenomena occur. It can be directly used for intravenous administration and quickly reaches the effective therapeutic concentration for postoperative analgesia.

[0060] In addition, the preparation process of the pharmaceutical composition or injection is simple, and it can be completed by stirring and dispersing at room temperature for a short time, and it is easy to achieve large-scale production. Description of the drawings

[0061] Figure 1 Electron micrograph of the particle size of the pharmaceutical composition of Example 2 of the present invention, magnification 36K

[0062] Figure 2 Micrographs of insoluble particles of the pharmaceutical compositions of Example 1 and Control Example 1 after being placed at 60 °C for 30 days, magnification 100 times, where the left figure is Example 1 and the right figure is Control Example 1.

[0063] Figure 3Photos of the 3-hour incubation of each test tube in the in vitro hemolysis experiment of the injection liquid of the present invention

[0064] From left to right, the test tubes are: Tube No. 1: negative control tube; Tube No. 2: positive control tube; Tubes No. 3-7: test article tubes of Example 1; Tube No. 8: test article tube of Example 5; Tubes No. 9-10: control group 1 tubes; Tubes No. 11-12: control group 2 tubes.

[0065] In the description and claims of the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, the definitions and explanations of some related terms are provided below.

[0066] As used in the present invention, for example, "the average particle size is less than 1000 nm" means that, by weight, the average particle size of at least 50% of the active substance particles is less than about 1000 nm.

[0067] The average particle size of the particles described in the present invention can be measured by conventional particle size measurement techniques well-known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, etc.

[0068] As used in the present invention, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally, the steps of the present invention further include a step of adjusting the pH value or include an alkaline pH regulator." means that the step of adjusting the pH value may or may not be present, that is, the cases where the steps of the present invention include the step of adjusting the pH value and the cases where the pH value is not adjusted. Including an alkaline pH regulator means that the pH regulator may or may not be present, that is, the cases where the present invention includes an alkaline pH regulator and the cases where it does not include an alkaline pH regulator. Detailed Description of the Invention

[0069] The following examples will help to understand the present invention, but do not limit the scope of the present invention. Some embodiments of the present invention are disclosed below, and those skilled in the art can implement them by appropriately modifying the process parameters according to the content herein. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate modifications and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0070] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

[0071] Example 1

[0072] Table 1: Prescription composition and dosage

[0073]

[0074]

[0075] Weigh each component according to the above formula.

[0076] Step (1): Add sodium glycochenodeoxycholate and polyvinylpyrrolidone K12 into 200 ml of water. After stirring until dissolved and clarified, prepare an auxiliary material solution.

[0077] Step (2): Add meloxicam into the auxiliary material solution and prepare a suspension through shear dispersion and mixing.

[0078] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 70 nm.

[0079] Step (4): Dissolve sucrose in 100 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. Then, obtain the product through aseptic filtration and filling.

[0080] Example 2

[0081] Table 2: Prescription composition and dosage

[0082] Material Function Material Name Composition per Prescription per Vial Prescription Quantity API Meloxicam 30 mg 30g Surface Stabilizer Polyvinylpyrrolidone K12 9 mg 9g Charge Stabilizer Glycocholic Acid 3 mg 3g Alkaline pH Regulator Sodium Hydroxide Appropriate Quantity Appropriate Quantity Sedimentation Inhibitor Sucrose 60 mg 60g Solvent for Injection Water To 1 ml To 1000 ml

[0083] Weigh each component according to the above formula.

[0084] Step (1): Prepare a 0.1% sodium hydroxide solution for standby.

[0085] Step (2): Add glycochenodeoxycholic acid and polyvinylpyrrolidone K12 into 300 ml of water, adjust the pH value to 6 - 8 with 0.1% sodium hydroxide solution, and stir until dissolved and clarified to prepare an auxiliary material solution.

[0086] Step (3): Add meloxicam into the auxiliary material solution and prepare a suspension through shear dispersion and mixing.

[0087] Step (4): Grind the above suspension to obtain a grinding liquid with an average particle size of 75 nm.

[0088] Step (5): Dissolve sucrose in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. Then, obtain the product through aseptic filtration and filling.

[0089] Example 3

[0090] Table 3: Prescription composition and dosage

[0091]

[0092]

[0093] Weigh each component according to the above formula.

[0094] Step (1): Add sodium taurocholate and polyvinylpyrrolidone K12 to 100 ml of water. After stirring until dissolved and clarified, a vehicle solution is prepared.

[0095] Step (2): Add meloxicam to the vehicle solution, and prepare a suspension through shear dispersion and mixing.

[0096] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm.

[0097] Step (4): Dissolve lactose in 100 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, the product is obtained.

[0098] Example 4

[0099] Table 4: Prescription composition and dosage

[0100]

[0101] Weigh each component according to the above formula.

[0102] Step (1): Add sodium glycicholate and polyvinylpyrrolidone K17 to 300 ml of water. After stirring until dissolved and clarified, a vehicle solution is prepared.

[0103] Step (2): Add meloxicam to the vehicle solution, and prepare a suspension through shear dispersion and mixing.

[0104] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 80 nm.

[0105] Step (4): Dissolve mannitol in 100 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, the product is obtained.

[0106] Example 5

[0107] Table 5: Prescription composition and dosage

[0108]

[0109] Weigh each component according to the above formula.

[0110] Step (1): Add sodium glycicholate and polyvinylpyrrolidone K17 to 200 ml of water. After stirring until dissolved and clarified, a vehicle solution is prepared.

[0111] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion and mixing.

[0112] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 69 nm.

[0113] Step (4): Dissolve lactose in 100 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, the product is obtained.

[0114] Example 6

[0115] Table 6: Prescription composition and dosage

[0116] Material Function Material Name Composition per Prescription per Vial Prescription Quantity API Meloxicam 50 mg 50g Surface Stabilizer Tween 20 15 mg 15g Charge Stabilizer Glycodeoxycholate Sodium 4 mg 4g Sedimentation Inhibitor Polyethylene Glycol 400 100 mg 100g Solvent for Injection Water To 1 ml To 1000 ml

[0117] Weigh each component according to the above formula.

[0118] Step (1): Add sodium glycodeoxycholate and Tween 20 to 100 ml of water, stir until dissolved and clarified to obtain an auxiliary material solution.

[0119] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion and mixing.

[0120] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 71 nm.

[0121] Step (4): Dissolve polyethylene glycol 400 in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, the product is obtained.

[0122] Example 7

[0123] Table 7 Prescription composition and dosage

[0124]

[0125] Weigh each component according to the above formula.

[0126] Step (1): Add sodium glycodeoxycholate and polyvinylpyrrolidone K17 to 100 ml of water, stir until dissolved and clarified to obtain an auxiliary material solution.

[0127] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion and mixing.

[0128] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm.

[0129] Step (4): Dissolve glycerol in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, the product is obtained.

[0130] Example 8

[0131] Table 8 Prescription Composition and Dosage

[0132]

[0133] Weigh each component according to the above formula.

[0134] Step (1): Add sodium taurodeoxycholate and polyvinylpyrrolidone K17 to 200 ml of water. After stirring until dissolved and clarified, prepare an auxiliary material solution.

[0135] Step (2): Add meloxicam to the auxiliary material solution, and prepare a suspension through shear dispersion and mixing.

[0136] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm.

[0137] Step (4): Dissolve sucrose in 100 ml of water, mix it with the above grinding liquid, and make up to the target volume. After sterilization filtration and filling, it is obtained.

[0138] Example 9

[0139] Table 9 Prescription Composition and Dosage

[0140]

[0141] Weigh each component according to the above formula.

[0142] Step (1): Add sodium taurochenodeoxycholate and polyvinylpyrrolidone K17 to 200 ml of water. After stirring until dissolved and clarified, prepare an auxiliary material solution.

[0143] Step (2): Add meloxicam to the auxiliary material solution, and prepare a suspension through shear dispersion and mixing.

[0144] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm.

[0145] Step (4): Dissolve lactose in 100 ml of water, mix it with the above grinding liquid, and make up to the target volume. After sterilization filtration and filling, it is obtained.

[0146] Example 10

[0147] Table 10 Prescription Composition and Dosage

[0148]

[0149] Weigh each component according to the above formula.

[0150] Step (1): Add sodium glycochenodeoxycholate and polyvinylpyrrolidone K17 into 100 ml of water, and stir until dissolved and clarified to obtain an auxiliary material solution.

[0151] Step (2): Add meloxicam to the auxiliary material solution, and shear and disperse to mix to obtain a suspension.

[0152] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm.

[0153] Step (4): Dissolve mannitol in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, it is obtained.

[0154] Example 11

[0155] Table 11 Prescription composition and dosage

[0156]

[0157] Weigh each component according to the above formula.

[0158] Step (1): Add sodium glycochenodeoxycholate and polyvinylpyrrolidone K17 into 100 ml of water, and stir until dissolved and clarified to obtain an auxiliary material solution.

[0159] Step (2): Add meloxicam to the auxiliary material solution, and shear and disperse to mix to obtain a suspension.

[0160] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm.

[0161] Step (4): Dissolve mannitol in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, it is obtained.

[0162] Example 12

[0163] Table 12 Prescription composition and dosage

[0164]

[0165]

[0166] Weigh each component according to the above formula.

[0167] Step (1): Add sodium glycochenodeoxycholate and polyvinylpyrrolidone K17 into 100 ml of water, and stir until dissolved and clarified to obtain an auxiliary material solution.

[0168] Step (2): Add meloxicam to the auxiliary material solution, and shear and disperse to mix to obtain a suspension.

[0169] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm;

[0170] Step (4): Dissolve mannitol in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, it is obtained.

[0171] Example 13

[0172] Table 13 Prescription composition and dosage

[0173]

[0174] Weigh each component according to the above formula.

[0175] Step (1): Add sodium glycochenodeoxycholate and polyvinylpyrrolidone K17 to 100 ml of water, stir until dissolved and clarified to obtain an auxiliary material solution;

[0176] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion mixing;

[0177] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm;

[0178] Step (4): Dissolve sucrose in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, it is obtained.

[0179] Example 14

[0180] Table 14: Prescription composition and dosage

[0181]

[0182]

[0183] Weigh each component according to the above formula.

[0184] Step (1): Add sodium glycocholate and polyvinylpyrrolidone K17 to 200 ml of water, stir until dissolved and clarified to obtain an auxiliary material solution;

[0185] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion mixing;

[0186] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 69 nm;

[0187] Step (4): Dissolve lactose in 100 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilizing filtration and filling, it is obtained.

[0188] Test Example 1: Examine the particle size, pH value, polydispersity index (PDI), insoluble particles, and related substances of the injection

[0189] 1. Experimental samples

[0190] 1.1 Injectable preparations of the present invention: Examples 1-7

[0191] 1.2 Formulations of control examples: See Tables 15 and 16

[0192] Table 15: Composition and dosage of the formulation of Control Example 1

[0193] Material Function Material Name Composition per Prescription per Vial Prescription Quantity API Meloxicam 30 mg 30g Surface Stabilizer Polyvinylpyrrolidone K17 6 mg 6g Charge Stabilizer Deoxycholate Sodium 3 mg 3g Sedimentation Inhibitor Sucrose 60 mg 60g Solvent for Injection Water To 1 ml To 1000 ml

[0194] Weigh each component according to the above formula

[0195] Step (1): Add sodium deoxycholate (free bile salt) and polyvinylpyrrolidone K17 to 150 ml of water, and stir until dissolved to obtain an auxiliary material solution

[0196] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion and mixing

[0197] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 72 nm

[0198] Step (4): Dissolve sucrose in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilization filtration and filling, it is obtained

[0199] Table 16: Composition and dosage of the formulation of Control Example 2

[0200] Material Function Material Name Composition per Prescription per Vial Prescription Quantity API Meloxicam 25 mg 25g Surface Stabilizer Polyvinylpyrrolidone K17 5 mg 5g Charge Stabilizer Deoxycholate Sodium 2.5 mg 2.5g Sedimentation Inhibitor Glycerol 50 mg 50g Solvent for Injection Water To 1 ml To 1000 ml

[0201] Weigh each component according to the above formula

[0202] Step (1): Add sodium deoxycholate (free bile salt) and polyvinylpyrrolidone K17 to 500 ml of water, and stir until dissolved to obtain an auxiliary material solution

[0203] Step (2): Add meloxicam to the auxiliary material solution, and obtain a suspension through shear dispersion and mixing

[0204] Step (3): Grind the above suspension to obtain a grinding liquid with an average particle size of 74 nm

[0205] Step (4): Dissolve glycerol in 200 ml of water, mix it with the above grinding liquid, and make up the volume to the target volume. After sterilization filtration and filling, it is obtained

[0206] 2. Experimental methods

[0207] 2.1 Determination method for particle size and particle size distribution

[0208] Determined according to the method for the determination of particle size and particle size distribution (General Chapter 0982, Method 3, Four General Chapters of Chinese Pharmacopoeia 2020 Edition).

[0209] Detection was carried out using the Nano-ZS nano particle size and zeta potential analyzer from Malvern. An appropriate amount of this product was taken and diluted with water to prepare a dispersion containing about 0.3 mg of meloxicam per 1 ml, and after mixing evenly, the test was carried out. The particle refractive index was 1.72, the particle absorption rate was 0.01, the equilibrium time was 120 seconds, water was used as the dispersion medium, and the equilibrium temperature was 25 °C.

[0210] 2.2 Determination method for related substances

[0211] Determined according to the high performance liquid chromatography method (General Chapter 0512, Four General Chapters of Chinese Pharmacopoeia 2020 Edition).

[0212] Chromatographic conditions and system suitability test: Octadecylsilane chemically bonded silica was used as the filler; 0.2% diammonium hydrogen phosphate solution (pH 7.5) was used as mobile phase A, and a mixed solution of methanol and isopropanol was used as mobile phase B; the column temperature was 40 °C; the elution gradient was: 0 - 10 minutes, 0% B → 50% B, 10 - 25 minutes, 50% B; the flow rate was 0.5 ml / min, and the detection wavelengths were 272 nm and 260 nm.

[0213] The number of theoretical plates calculated based on the meloxicam peak should be not less than 1500, and the resolution between the 5-methyl-2-aminothiazole peak and the meloxicam peak should meet the requirements. For the system suitability requirements, the signal-to-noise ratio of the main component chromatographic peak in the sensitivity solution chromatogram should be not less than 10.

[0214] Test solution: Dilute with the solvent to prepare a solution containing 1 mg of meloxicam per 1 ml as the test solution;

[0215] Reference solution: Separately weigh accurately 10 mg of 5-methyl-2-aminothiazole reference substance and 100 mg of meloxicam reference substance, place them in a 100 ml volumetric flask, add an appropriate amount of the solvent to dissolve and dilute to the scale, shake well, accurately measure 5 ml, place it in a 100 ml volumetric flask, dilute to the scale with the solvent, and shake well as the reference solution.

[0216] Solvent preparation: Take 650 ml of 0.02 mol / L disodium hydrogen phosphate (pH 8.3), add 350 ml of a mixed solution of methanol and isopropanol, mix well to obtain it.

[0217] Determination method: Measure 20 μl each of the test solution and the reference solution, inject them into the liquid chromatograph respectively, detect 5-methyl-2-aminothiazole at the wavelength of 260 nm, detect the remaining known impurities at the wavelength of 272 nm, and record the chromatogram.

[0218] 2.3 Detection method for insoluble particles:

[0219] Take this product and examine it according to the law (the second method in General Principles 0903 of the Fourth Part of Chinese Pharmacopoeia 2020 Edition). It should meet the requirements. In each test sample container, the number of particles with a size of 10 μm or more should not exceed 3000, and the number of particles with a size of 25 μm or more should not exceed 300.

[0220] 3. Experimental results:

[0221] As shown in Table 17 - 18, after the meloxicam injection of Examples 1 - 7 of the present invention was placed at 60°C for 30 days, the average particle size did not increase significantly, the total impurities did not increase significantly, and the insoluble particles did not increase significantly. The detection of insoluble particles in Example 1 is as shown in Figure 2 the left figure. In Control Example 1, a large number of insoluble particles were generated even at 0 day when placed at 60°C, and even needle - like substances were generated as shown in Figure 2 the right figure. The growth rate of insoluble particles in Control Examples 1 and 2 was fast. The amount of insoluble particles generated in Control Example 1 was so large that it was impossible to count, far exceeding the provisions of the Chinese Pharmacopoeia (the number of particles with a size of 10 μm or more should not exceed 3000). The number of insoluble particles ≥10 μm in Control Example 2 reached 2311. The amount of impurities generated in Control Examples 1 and 2 was large, and with the extension of the placement time, the growth rate of the total impurities was fast, and the total impurities reached 0.25% and 0.31% respectively. It can be seen that the samples containing sodium deoxycholate in Control Examples 1 and 2 have weak stability, especially a large amount of impurities and insoluble particles are generated after being placed at high temperature, thus bringing potential safety hazards.

[0222] 4. Experimental conclusion:

[0223] This result shows that using conjugated bile salts or conjugated bile acids as charge stabilizers has a better effect of inhibiting crystal precipitation or sedimentation than their free bile acids. While improving the stability and solubility of the product, it further reduces the generation of degradation impurities of meloxicam sodium in the injection.

[0224] Table 17: Detection results of sample particle size and potential

[0225]

[0226] * A small amount of insoluble substances precipitated at the bottom of the bottle.

[0227] Table 18: Results of pH, insoluble particles and related substances

[0228]

[0229] * The number of particles was too many to be accurately counted, and needle - like substances were observed under the microscope.

[0230] Test Example 2: Sample properties of different conjugated bile salt injections after being placed at 60°C for 10 days

[0231] 1. Experimental method:

[0232] Detect the particle size of the sample on day 0 and the change in properties after being placed at 60°C for 10 days.

[0233] 2. Experimental results:

[0234] As shown in Table 19, the experiment shows that the injections containing other conjugated bile salts in Examples 8 - 13 have the same stability as the injection containing glycocholate in Example 1. After being placed at high temperature for 10 days, there is no change in properties, and no precipitation or particulates are precipitated.

[0235] Table 19 Properties of samples of different conjugated bile salt injections after being placed at 60°C for 10 days

[0236]

[0237] Test Example III Investigation Test of Sedimentation Inhibitor

[0238] 1. Experimental samples: As shown in Table 20, the preparation process is the same as that in Example 1.

[0239] 2. Experimental method: Detect the particle size of the sample on day 0 and the properties of the sample after being placed at 60°C under high temperature and exposed to light for 10 days.

[0240] 3. Experimental results: As shown in Table 20, through the screening of sedimentation inhibitors, it is found that choosing sulfobutyl - β - cyclodextrin, carbomer, sodium hyaluronate, and histidine as the precipitation inhibitors of the present invention, the injections prepared therefrom show precipitation, whitening, or flocculation phenomena after standing overnight and being placed at 60°C for 10 days. It can be seen that using this series of sedimentation inhibitors cannot effectively inhibit the generation of precipitation.

[0241] Table 20 Prescription, pH value, particle size, and property detection form

[0242]

[0243]

[0244] Test Example IV Long - term Stability Test

[0245] 1. Experimental method: Place the injection solutions obtained in Examples 2 and 4 under the conditions of (25°C ± 2°C, RH60 ± 5%) for 6 months, and test the stability of the samples.

[0246] Test results: As shown in Table 21, when this product is placed at room temperature for 6 months, there are no obvious changes in properties, pH, particle size, impurity content, etc., and the stability is good.

[0247] Table 21 - 1: Stability data for long - term test (25 ± 2°C, RH60 ± 5%):

[0248]

[0249] Table 21-2: Stability data of long-term test (25±2°C, RH60±5%):

[0250]

[0251] Test Example Five: Safety Experiment

[0252] 1. Concentration of test article

[0253] Concentration of test article: 30 mg / mL. Examples 1 and 5 were taken as the test articles.

[0254] This product is intended for intravenous administration clinically, and the clinically proposed maximum concentration is 30 mg / mL. Therefore, the concentration of the test article in this test was set at 30 mg / mL.

[0255] Positive control: 2.5 mL of sodium chloride injection

[0256] Negative control: 2.5 mL of sterile water for injection

[0257] 2. Experimental procedure

[0258] Preparation of 2% red blood cell suspension: Approximately 10 mL of blood was collected from the rabbit's heart and placed in a triangular flask containing glass beads. It was shaken for about 10 minutes to remove fibrinogen, making it defibrinated blood. 1 mL of defibrinated blood was transferred into a centrifuge tube, and then 9 mL of sodium chloride injection was added to this centrifuge tube, and a total of 4 tubes were prepared. After shaking well, it was centrifuged at 1500 rpm for 15 minutes at 4°C, and the supernatant was removed. The precipitated red blood cells were washed once more with sodium chloride injection according to the above method until the supernatant was not red. 1 mL of red blood cells was added to 49 mL of sodium chloride injection to prepare a 2% red blood cell suspension.

[0259] Sample addition and observation: Take 12 clean test tubes and number them from 1 to 12 from left to right. Tube 1 is the negative control tube, tube 2 is the positive control tube, tubes 3-8 are the test article tubes, and tubes 9-12 are the control tubes. Add 2% red blood cell suspension, sodium chloride injection or sterile water for injection, and the drug successively according to Table 22 below. After mixing, immediately place it in an electrothermal constant temperature water bath at 37 (±0.5)°C for incubation. The temperature at the start of incubation was 37.2°C. The solutions in each test tube were observed visually at 15, 30, 45 min and 1, 2, 3 h after the start of incubation, and the test tubes at the 3 h incubation time point were photographed.

[0260] 3. Experimental results:

[0261] Photos of each test tube after 3 h of incubation in the in vitro hemolysis experiment of the injection liquid of the present invention are shown in the appendix Figure 3As shown, no hemolytic reaction was observed in each group of the test articles. Hemolytic reactions were caused by Control Group 1 and 2, but reactions such as red blood cell aggregation were not caused. The above experiments indicate that compared with other charge stabilizers, using conjugated bile acids or their salts to prepare meloxicam injection can significantly improve the stability of meloxicam nanoparticles, effectively reduce the formation of insoluble particles, and surprisingly improve the safety and effectiveness of the preparation.

[0262] Table 22: Sample Numbers and Administrations

[0263]

[0264]

[0265] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A stable meloxicam pharmaceutical composition, characterized in that: the pharmaceutical composition comprises meloxicam, a charge stabilizer, a surface stabilizer and a sedimentation inhibitor, wherein the charge stabilizer comprises conjugated bile acid and / or its salt.

2. The pharmaceutical composition according to claim 1, characterized in that: the charge stabilizer comprises conjugated bile acid salt; preferably, the conjugated bile acid salt is selected from sodium conjugated bile acid salt, potassium conjugated bile acid salt, ammonium conjugated bile acid salt; preferably, the sodium conjugated bile acid salt is selected from one or more of sodium glycocholate, sodium taurocholate, sodium glycochenodeoxycholate, sodium taurochenodeoxycholate, sodium glycohyodeoxycholate, sodium glycohyodeoxycholate, sodium taurohyodeoxycholate; or preferably, when the charge stabilizer comprises conjugated bile acid, the pharmaceutical composition optionally comprises a basic pH regulator; preferably, the basic pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, concentrated ammonia solution, sodium bicarbonate, sodium carbonate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tris(hydroxymethyl)aminomethane and organic amines; preferably, the conjugated bile acid is selected from one or more of glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, glycohyodeoxycholic acid, glycohyodeoxycholic acid, taurohyodeoxycholic acid; preferably, the pH value of the pharmaceutical composition is 6.0 - 8.0, more preferably 6.6 - 7.

8.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that: the surface stabilizer is selected from one or more of polyvinylpyrrolidone, Tween 80, Tween 20, poloxamer, polyethylene glycol 15 - hydroxystearate, lecithin, sodium dodecylsulfonate, sodium dodecylsulfate, polyvinyl alcohol, hydroxypropylmethylcellulose.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that: the sedimentation inhibitor is selected from polyols, sugars and sugar alcohols; preferably, the sedimentation inhibitor is selected from one or several of lactose, fructose, glucose, erythritol, isomaltitol, mannitol, sorbitol, xylitol, maltitol, glycerol, propylene glycol, sucrose, polyethylene glycol, butylene glycol, hydroxyethyl starch, albumin, sodium carboxymethylcellulose, hydroxypropyl - β - cyclodextrin; preferably, the sedimentation inhibitor is selected from one or several of lactose, sucrose, fructose, glucose, erythritol, isomaltitol, mannitol, sorbitol, xylitol, maltitol, hydroxypropyl - β - cyclodextrin.

5. The pharmaceutical composition according to any one of claims 1 - 4, characterized in that: the mass of meloxicam is 10 - 100 mg; preferably, the mass of meloxicam is 10 - 50 mg.

6. The pharmaceutical composition according to any one of claims 1 - 4, characterized in that: the mass ratio of meloxicam to the charge stabilizer is 1:(0.02 - 3); preferably, the mass ratio of meloxicam to the charge stabilizer is 1:(0.05 - 1); preferably, the mass ratio of meloxicam to the charge stabilizer is 1:(0.05 - 0.15); and / or The mass ratio of the meloxicam to the surface stabilizer is 1∶(0.05 - 8); Preferably, the mass ratio of the meloxicam to the surface stabilizer is 1∶(0.1 - 5); Preferably, the mass ratio of the meloxicam to the surface stabilizer is 1∶(0.1 - 1); and / or The mass ratio of the meloxicam to the sedimentation inhibitor is 1∶(0.1 - 50); Preferably, the mass ratio of the meloxicam to the sedimentation inhibitor is 1∶(0.5 - 10); Preferably, the mass ratio of the meloxicam to the sedimentation inhibitor is 1∶(0.5 - 5).

7. The pharmaceutical composition according to any one of claims 1 - 6, wherein, the average particle size of the meloxicam particles is less than 1000 nm; Preferably, the average particle size of the meloxicam particles is less than 500 nm; Preferably, the average particle size of the meloxicam particles is less than 200 nm; Preferably, the average particle size of the meloxicam particles is less than 100 nm.

8. A meloxicam injection, characterized in that: the injection contains the pharmaceutical composition according to any one of claims 1 - 7 and an injection solvent, wherein the content of meloxicam is 10 - 100 mg / ml; Preferably, the content of the meloxicam is 10 - 50 mg / ml; Preferably, the injection solvent is selected from one or more of water for injection, 0.9% sodium chloride solution, injection oil, ethanol, propylene glycol, tert - butanol and polyethylene glycol; Preferably, the pH value of the injection is 6.0 - 8.0, more preferably 6.6 - 7.8; Preferably, the injection is an intravenous injection; Optionally, the injection further contains a pH value regulator.

9. A preparation method of the pharmaceutical composition according to any one of claims 1 - 7 or the injection according to claim 8, characterized in that , comprising the following steps: mixing meloxicam, a charge stabilizer, a surface stabilizer and a sedimentation inhibitor; Preferably, the preparation method of the pharmaceutical composition comprises the following steps: mixing the charge stabilizer, the surface stabilizer and meloxicam, grinding to obtain a dispersion; then adding the sedimentation inhibitor and mixing; or Preferably, the preparation method of the injection comprises the following steps: (1) stirring and mixing the charge stabilizer, the surface stabilizer and the injection solvent; (2) adding meloxicam and mixing, grinding to obtain a suspension; (3) adding the sedimentation inhibitor and mixing with the above suspension; Optionally, adjusting the pH value is further included in the steps; Optionally, sterilization or disinfection and filling are further included in the steps.

10. Use of the pharmaceutical composition according to claims 1 - 7 or the injection according to claim 8 in the preparation of a drug for treating postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis.

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