WO2024198768A1 - Composition de méloxicam, son procédé de préparation et son utilisation - Google Patents

Composition de méloxicam, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024198768A1
WO2024198768A1 PCT/CN2024/077688 CN2024077688W WO2024198768A1 WO 2024198768 A1 WO2024198768 A1 WO 2024198768A1 CN 2024077688 W CN2024077688 W CN 2024077688W WO 2024198768 A1 WO2024198768 A1 WO 2024198768A1
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Prior art keywords
meloxicam
solution
clear
composition
hours
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Chinese (zh)
Inventor
孙群
彭国维
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Zhuhai Beihai Biotech Co Ltd
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Zhuhai Beihai Biotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the technical field of pharmaceutical preparations, and in particular to a meloxicam composition and a preparation method and application thereof.
  • Meloxicam is a nonsteroidal anti-inflammatory drug used to treat rheumatoid arthritis, osteoarthritis and postoperative pain. Its mechanism of action is to selectively inhibit the activity of cyclooxygenase-2 (COX-2) and prevent the synthesis of inflammatory prostaglandins (PGs), thereby achieving antipyretic, analgesic and anti-inflammatory effects.
  • COX-2 cyclooxygenase-2
  • PGs inflammatory prostaglandins
  • Its molecular formula is C 14 H 13 N 3 O 4 S 2 , its molecular weight is 351.42, and its chemical name is 2-methyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
  • the chemical structure of meloxicam is shown below:
  • Meloxicam is almost insoluble in water (solubility is 0.154 mg/mL), has high solubility in strong acid and strong base, and is soluble in dimethyl sulfoxide.
  • the relevant dosage forms currently on the market include oral dosage forms such as meloxicam tablets and meloxicam capsules, and intramuscular injection of meloxicam.
  • oral dosage forms such as meloxicam tablets and meloxicam capsules
  • intramuscular injection of meloxicam due to the low solubility of meloxicam, its drug absorption in oral dosage forms and intramuscular injections is slow, making it unusable for the treatment of acute rheumatism, arthritis and pain. Therefore, improving solubility is the focus and difficulty of the development of meloxicam intravenous injection.
  • ANJESO TM a meloxicam intravenous injection, for the treatment of moderate and severe pain.
  • ANJESO TM is a complex dosage form of meloxicam nanocrystals, but because it takes 1-2 hours to take effect in clinical use, the FDA restricted ANJESO TM in its instructions to the treatment of acute pain, which limits the clinical use of ANJESO TM .
  • Patent CN110464846A provides a meloxicam composition, which comprises meloxicam and a latent solvent.
  • the latent solvent organic solvent
  • the latent solvent can increase the solubility of meloxicam, but the toxicity problem of the latent solvent (such as hemolysis, allergic reaction, etc.) has not been solved.
  • Patent CN103054872B provides a meloxicam pharmaceutical composition and a preparation method thereof.
  • the composition increases the solubility of meloxicam by using auxiliary materials such as solubilizers, but does not solve the toxic side effects caused by the solubilizers and cannot be used for injections.
  • one of the objects of the present invention is to provide a meloxicam composition, which has high solubility, rapid onset of action, and better safety and stability.
  • a meloxicam composition comprises meloxicam and human serum albumin, wherein the meloxicam and human serum albumin have a weight ratio of 1:0.1 to 1:100.
  • the weight ratio of meloxicam to human albumin in the composition is about 1:0.2 to about 1:90, about 1:0.5 to about 1:80, about 1:1 to about 1:60, about 1:1.5 to about 1:50, about 1:2 to about 1:40, about 1:2 to about 1:30, about 1:2.5 to about 1:20, about 1:3 to about 1:20, about 1:3 to about 1:10.
  • the weight ratio of meloxicam to human albumin in the composition is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:5, about 1:30, about 1:40, about 1:50, about 1:60, about 1:80.
  • the meloxicam is selected from one or more of meloxicam, meloxicam in pharmaceutically acceptable salt form, meloxicam solvate, and meloxicam deuterated.
  • the human albumin is natural human serum albumin. In some embodiments, the human albumin is recombinant human serum albumin. In some embodiments, the human albumin is substantially free of fatty acids.
  • human albumin is a human serum albumin solution for infusion that has been approved for clinical use.
  • the concentration of human albumin in the human serum albumin solution is 20% (w/v), 25% (w/v), or 5% (w/v).
  • human albumin refers to recombinant human serum albumin.
  • the pH of the composition is 6.0 to 10.0.
  • the pH of the composition is 6.0 to 9.0. In some embodiments, the pH of the composition is 6.5 to 9.5. In some embodiments, the pH of the composition is 7.0 to 9.0. In some embodiments, the pH of the composition is 7.5 to 9.0. In some embodiments, the pH of the composition is 7.5 to 8.5. In some embodiments, the pH of the composition is 8.0 to 8.5.
  • the composition further contains a pH adjuster; the pH adjuster is an alkaline pH adjuster and/or an acidic pH adjuster.
  • the alkaline pH regulator is selected from one or a mixture of any two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris, arginine, lysine, histidine, glycine or meglumine;
  • the acidic pH regulator is selected from one or a mixture of any two or more of ascorbic acid, lactic acid, malic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid or acetic acid.
  • the concentration of meloxicam in the composition is 0.1-30 mg/ml.
  • the concentration of meloxicam in the composition is 1.5 to 20 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 2 to 10 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 3 to 10 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 3.5 to 8 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 4 to 6 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 4 to 5 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 25 mg/ml.
  • the concentration of meloxicam in the composition is 0.1 to 20 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 15 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 10 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 9.5 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 9 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 8.5 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 8 mg/ml.
  • the concentration of meloxicam in the composition is 0.1 to 7.5 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 0.1 to 7 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 1 to 7 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 2 to 7 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 3 to 7 mg/ml. In some embodiments, the concentration of meloxicam in the composition is 4 to 7 mg/ml.
  • the composition is an aqueous preparation, which substantially does not contain any solvent other than water and does not contain any surfactant.
  • the aqueous preparation is a clear aqueous solution.
  • the clear state of the clear aqueous solution remains for at least 1 hour. In some embodiments, the clear state of the clear aqueous solution remains for at least 2 hours. In some embodiments, the clear state of the clear aqueous solution remains for at least 3 hours. In some embodiments, the clear state of the clear aqueous solution remains for at least 4 hours. In some embodiments, the clear state of the clear aqueous solution remains for at least 6 hours. In some embodiments, the clear state of the clear aqueous solution remains for at least 8 hours. In some embodiments, the clear state of the clear aqueous solution remains for at least 12 hours. In some embodiments, the clear state of the clear aqueous solution remains for at least 24 hours.
  • the clear state of the clear aqueous solution is maintained for at least 1 hour at a temperature of about 0°C to about 25°C. In some embodiments, the clear state of the clear aqueous solution is maintained for at least 2 hours at a temperature of about 0°C to about 25°C. In some embodiments, the clear state of the clear aqueous solution is maintained for at least 3 hours at a temperature of about 0°C to about 25°C. In some embodiments, the clear state of the clear aqueous solution is maintained for at least 4 hours at a temperature of about 0°C to about 25°C.
  • the clear state of the clear aqueous solution is maintained for at least 6 hours at a temperature of about 0°C to about 25°C. In some embodiments, the clear state of the clear aqueous solution is maintained for at least 8 hours at a temperature of about 0°C to about 25°C. In some embodiments, the clear state of the clear aqueous solution is maintained for at least 12 hours at a temperature of about 0°C to about 25°C. In some embodiments, the clear state of the clear aqueous solution is maintained for at least 24 hours at a temperature of about 0°C to about 25°C.
  • the clear state of the clear aqueous solution remains for at least 1 hour. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 2 hours. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 3 hours. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 4 hours. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 6 hours. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 8 hours. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 12 hours. In some embodiments, at room temperature, the clear state of the clear aqueous solution remains for at least 24 hours.
  • the composition further comprises an excipient, and the excipient is selected from one or more of mannitol, sorbitol, inositol, dextran, maltodextrin, ⁇ -cyclodextrin, polyethylene glycol-4000, polyoxyethylene pyrrolidone, sucrose, maltose, lactose, glucose, trehalose, sodium chloride, potassium chloride, calcium chloride, sodium dihydrogen phosphate, hydrolyzed gelatin, glycine, histidine, lysine, alanine, proline, arginine, aspartic acid, asparagine and sodium glutamate, preferably mannitol.
  • the excipient is selected from one or more of mannitol, sorbitol, inositol, dextran, maltodextrin, ⁇ -cyclodextrin, polyethylene glycol-4000, polyoxyethylene pyrrolidone, sucrose, maltose, lac
  • a meloxicam composition comprises meloxicam and human serum albumin, wherein the pH of the composition is 7-9.5, and the weight ratio of the meloxicam to the human serum albumin is about 1:2.2-70.
  • a meloxicam composition comprises meloxicam and human serum albumin, wherein the pH of the composition is 6-6.5, and the weight ratio of the meloxicam to the human serum albumin is about 1:10-35.
  • the second object of the present invention is to provide a method for preparing the meloxicam composition as described above, which comprises the following steps:
  • Meloxicam, excipients and human albumin are dissolved in 0.001-0.1 mol/L sodium hydroxide solution, and then a proper amount of pH adjuster is added to adjust the pH of the solution to 6.0-10.0, and water is added to make the total preparation amount, and sterile filtration is performed to obtain a meloxicam composition.
  • the preparation method comprises the following steps:
  • Meloxicam is dissolved in 0.001-0.1 mol/L sodium hydroxide solution, excipients and human albumin are added, and after stirring to dissolve, a proper amount of pH adjuster is added to adjust the pH of the solution to 6.0-10.0, water is added to make the total preparation amount, and sterilization and filtration are performed to obtain a meloxicam composition.
  • Meloxicam is first dispersed in an excipient to form a mixture, the mixture is dissolved in a 0.001-0.1 mol/L sodium hydroxide solution, human albumin is added, and after stirring and dissolving, a proper amount of a pH adjuster is added to adjust the pH of the solution to 6.0-10.0, water is added to make the total preparation amount, and sterilization and filtration are performed to obtain a meloxicam composition.
  • the third object of the present invention is to provide a meloxicam lyophilized powder, which is prepared by lyophilizing the meloxicam composition as described above.
  • the meloxicam lyophilized powder is a slightly yellow lyophilized cake or powder. In some embodiments, the meloxicam lyophilized powder is a light yellow lyophilized cake or powder. In some embodiments, the meloxicam lyophilized powder is a yellow lyophilized cake or powder. In some embodiments, the meloxicam lyophilized powder is a slightly green to light yellowish green lyophilized cake or powder. In some embodiments, the meloxicam lyophilized powder is a yellowish green lyophilized cake or powder.
  • the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 6.0-10.0. In some embodiments, the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 6.5-9.5. In some embodiments, the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 7.0-9.0. In some embodiments, the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 6.5-8.5. In some embodiments, the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 7.0-8.5.
  • the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 7.5-8.5. In some embodiments, the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 8.0-8.5. In some embodiments, the pH value of the liquid medicine after reconstitution of the meloxicam lyophilized powder is 7.5-8.0.
  • the meloxicam lyophilized powder is a clear aqueous solution after reconstitution.
  • the clear aqueous solution after reconstitution remains clear for at least 1 hour. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 2 hours. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 3 hours. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 4 hours. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 6 hours. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 8 hours. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 12 hours. In some embodiments, the clear aqueous solution after reconstitution remains clear for at least 24 hours.
  • the reconstituted clear aqueous solution remains clear for at least 1 hour at a temperature of about 0°C to about 25°C. In some embodiments, the reconstituted clear aqueous solution remains clear for at least 2 hours at a temperature of about 0°C to about 25°C. In some embodiments, the reconstituted clear aqueous solution remains clear for at least 3 hours at a temperature of about 0°C to about 25°C. In some embodiments, the reconstituted clear aqueous solution remains clear for at least 4 hours at a temperature of about 0°C to about 25°C. In some embodiments, the reconstituted clear aqueous solution remains clear for at least 6 hours at a temperature of about 0°C to about 25°C.
  • the reconstituted clear aqueous solution remains clear for at least 8 hours at a temperature of about 0°C to about 25°C. In some embodiments, the reconstituted clear aqueous solution remains clear for at least 12 hours at a temperature of about 0°C to about 25°C. In some embodiments, the reconstituted clear aqueous solution remains clear for at least 24 hours at a temperature of about 0°C to about 25°C.
  • the clear aqueous solution after the reconstitution remains clear for at least 1 hour. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 2 hours. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 3 hours. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 4 hours. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 6 hours. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 8 hours. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 12 hours. In some embodiments, at room temperature, the clear aqueous solution after the reconstitution remains clear for at least 24 hours.
  • a fourth object of the present invention is to provide the use of the meloxicam composition as described above in the preparation of a drug, wherein the prepared drug is a drug for treating postoperative analgesia, cancer pain, rheumatoid arthritis, and painful osteoarthritis.
  • a fifth object of the present invention is to provide a method for treating postoperative analgesia, cancer pain, rheumatoid arthritis or painful osteoarthritis, wherein the method comprises administering the meloxicam composition as described above to a patient.
  • the present invention has the following beneficial effects:
  • the meloxicam composition provided by the present invention significantly improves the solubility of meloxicam in water (the improvement can reach about 40 times or more) and has good stability (clarifies within 2 hours, or even within 8 hours), can be administered as an injection, and has the characteristics of rapid onset;
  • the meloxicam composition provided by the present invention uses human albumin as a solubilizer, and the auxiliary materials do not contain surfactants, organic solvents and cyclodextrins, so that the product has better safety;
  • the preparation method provided by the present invention has simple production process and good product stability
  • composition of the present invention still has high solubility and good stability after freeze-drying and reconstitution.
  • Figure 1 is a state diagram of meloxicam lyophilized powder in Example 24 of the present invention being reconstituted with 5 ml of normal saline for 8 hours.
  • a meloxicam composition comprises meloxicam and human serum albumin, wherein the meloxicam and human serum albumin have a weight ratio of 1:0.1 to 1:100.
  • the weight ratio of meloxicam to human albumin in the composition is preferably 1:0.2 to 1:90, more preferably 1:2 to 1:30, and most preferably 1:3 to 1:15.
  • the pH of the composition is 6.0-10.0, preferably 6.5-9.5, more preferably 7.0-9.0, such as 7.5-9.0, such as 7.5-8.6, such as 7.8-8.5.
  • the composition further contains a pH adjuster;
  • the pH adjuster is an alkaline pH adjuster and/or an acidic pH adjuster, for example, a pH adjuster for injection or intravenous injection.
  • the alkaline pH regulator is selected from one or a mixture of any two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris (trishydroxymethylaminomethane), arginine, lysine, histidine, glycine or meglumine.
  • the alkaline pH regulator is selected from one or a mixture of any two or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, Tris, arginine, lysine and triethylamine. More preferably, the alkaline pH regulator is selected from sodium hydroxide, sodium carbonate, sodium phosphate, Tris or lysine; illustratively, the alkaline pH regulator is selected from sodium hydroxide.
  • the acidic pH regulator is selected from one or a mixture of any two or more of ascorbic acid (vitamin C), lactic acid, malic acid, sorbic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid or acetic acid.
  • the acidic pH regulator is selected from one or a mixture of any two or more of lactic acid, malic acid, tartaric acid, citric acid, hydrochloric acid, phosphoric acid or acetic acid.
  • the acidic pH regulator is selected from hydrochloric acid, phosphoric acid and citric acid.
  • the meloxicam is selected from one or more of meloxicam, meloxicam in salt form, meloxicam solvate, and meloxicam deuterated form.
  • a meloxicam composition comprises meloxicam and human serum albumin, wherein the pH of the composition is 7-9.5, and the weight ratio of the meloxicam to the human serum albumin is about 1:2.2-70.
  • a meloxicam composition comprises meloxicam and human serum albumin, wherein the pH of the composition is 6-6.5, and the weight ratio of the meloxicam to the human serum albumin is about 1:10-35.
  • human albumin refers to natural or recombinant human serum albumin.
  • human albumin is a human serum albumin solution for infusion that has been approved for clinical use.
  • the concentration of human albumin in the human serum albumin solution is 20% (w/v), 25% (w/v), or 5% (w/v).
  • human albumin refers to recombinant human serum albumin.
  • the concentration of meloxicam in the composition is 0.1-30 mg/ml, for example 1-20 mg/ml, such as 2-20 mg/ml, 3-20 mg/ml, 5-15 mg/ml, 3-10 mg/ml, 5-10 mg/ml, etc.
  • the composition is an aqueous preparation, and the aqueous preparation is a clear aqueous solution.
  • the aqueous preparation is substantially free of solvents other than water, and does not contain a surfactant.
  • the surfactant includes but is not limited to surfactants known to be used in pharmaceutical preparations or compositions such as injections, such as polysorbate 80, polyoxyethylene castor oil derivatives, poloxamer, polyethylene glycol 15-hydroxystearate, etc.
  • the clear aqueous solution of the meloxicam composition has good stability.
  • the clear aqueous solution of the meloxicam composition can remain clear for 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or 24 hours.
  • composition of the present invention further comprises an excipient, and the excipient can be selected from lactose or mannitol, preferably mannitol.
  • the preparation method of the above-mentioned meloxicam composition comprises the following steps:
  • Meloxicam, excipients and human albumin are dissolved in 0.001-0.1 mol/L sodium hydroxide solution, and then a proper amount of pH adjuster is added to adjust the pH of the solution to 6.0-10.0, and water is added to make the total preparation amount, and sterile filtration is performed to obtain a meloxicam composition.
  • the preparation method comprises the following steps:
  • Meloxicam is dissolved in 0.001-0.1 mol/L sodium hydroxide solution, excipients and human albumin are added, and after stirring to dissolve, a proper amount of pH adjuster is added to adjust the pH of the solution to 6.0-10.0, water is added to make the total preparation amount, and sterilization and filtration are performed to obtain a meloxicam composition.
  • Meloxicam is first dispersed in an excipient to form a mixture, the mixture is dissolved in a 0.001-0.1 mol/L sodium hydroxide solution, human serum albumin is added, and after stirring and dissolving, a proper amount of a pH adjuster is added to adjust the pH of the solution to 6.0-10.0, water is added to make the total weight, and sterilization and filtration are performed to obtain a meloxicam composition.
  • the present invention also provides a meloxicam lyophilized powder, which is prepared by lyophilizing the meloxicam composition as described above.
  • the meloxicam lyophilized powder is a clear aqueous solution after being reconstituted (for example, reconstituted with water or physiological saline).
  • the pH of the aqueous solution obtained after reconstitution of the meloxicam lyophilized powder is 6.0-10.0, preferably 6.5-9.5, more preferably 7.0-9.0, such as 7.5-9.0, such as 7.5-8.6, such as 7.8-8.5.
  • the aqueous solution obtained after reconstitution of the meloxicam lyophilized powder can remain clear for 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or 24 hours.
  • the above-mentioned meloxicam composition or meloxicam lyophilized powder can be used in the preparation of medicines, and the prepared medicines are medicines for treating postoperative analgesia, cancer pain, rheumatoid arthritis, and painful osteoarthritis.
  • the present invention also provides a method for treating postoperative analgesia, cancer pain, rheumatoid arthritis or painful osteoarthritis, which comprises administering the meloxicam composition as described above to a patient.
  • the human serum albumin solution (20%) described herein means that the concentration of human serum albumin is 0.2 g/ml.
  • the temperature is room temperature.
  • a meloxicam liquid composition the preparation process of which is as follows:
  • Preparation of samples 1-7 Take 8 ml of the above solution into 7 vials respectively, then add 0.5 ml of human serum albumin solution (20%) to each vial, mix well, and adjust the pH to 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5 respectively with 20 mg/mL citric acid solution or 0.017 mol/L NaOH solution.
  • Preparation of samples 8-14 Take 8 ml of the above solution into 7 vials respectively, then add 1 ml of human serum albumin solution (20%) to each vial, mix well, and adjust the pH to 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5 respectively with 20 mg/mL citric acid solution or 0.017 mol/L NaOH solution.
  • Preparation of samples 1-6 Take 10 ml of the above solution into 6 vials, add 0.5 ml of human serum albumin solution (20%) to each vial, mix well, and then adjust the pH to 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5 with 20 mg/mL citric acid solution and 0.017 mol/L NaOH solution, respectively.
  • Preparation of samples 7-12 Take 10 ml of the above solution in 6 vials, and adjust the pH of each vial to 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5 with 20 mg/mL citric acid solution.
  • Preparation of samples 1-5 Take 8 ml of the above solution into 5 vials, add 0.5 ml of human serum albumin solution (20%) to each vial, mix well, and adjust the pH to 7.0, 7.5, 8.26, 8.5, and 9.0 with 20 mg/mL citric acid solution and 0.008 mol/L NaOH solution, respectively.
  • Preparation of samples 6-10 Take 10 ml of the above solution into 5 vials, add 0.5 ml of human serum albumin solution (20%) into each vial, mix well, and adjust the pH to 7.0, 7.5, 8.0, 8.62, and 9.0 respectively with 20 mg/mL citric acid solution.
  • sample 1 Take 6 ml of the above solution, add 1 ml of human serum albumin solution (20%) to each vial and mix well.
  • the pH value is 7.37.
  • sample 2 Take 6 ml of the above solution, add 2 ml of human serum albumin solution (20%) to each vial and mix well. Measure the pH to be 7.10.
  • sample 3 Take 6 ml of the above solution, add 3 ml of human serum albumin solution (20%) to each vial and mix well.
  • the pH value is 7.02.
  • sample 4 Take 6 ml of the above solution, add 4 ml of human serum albumin solution (20%) to each vial and mix well. Measure the pH to be 7.0.
  • samples 1-3 Take 6 ml of the above solution into 3 vials respectively, add 2 ml of human serum albumin solution (20%) into each vial and mix well. Adjust the pH to 5.5, 6.0 and 6.5 respectively with saturated citric acid solution.
  • samples 1-4 Take 5 ml of the above solution into 4 vials respectively, add 0.5 ml of human serum albumin solution (20%) into each vial and mix well. Adjust the pH to 5.5, 5.8, 6.0, and 6.5 respectively with saturated citric acid solution.
  • samples 1-4 Take 7.5 ml of the above solution, add 0.5 ml of human serum albumin solution (20%) to each vial and mix well. Adjust the pH to 5.5, 5.8, 6.0, and 6.5 with saturated citric acid solution.
  • samples 5-8 Take 4 ml of the above solution, add 2 ml of human serum albumin solution (20%) to each vial and mix well. Adjust the pH to 5.5, 5.8, 6.0, and 6.5 with saturated citric acid solution.
  • Preparation of samples 9-12 Take 5 ml of the above solution, add 0.5 ml of human serum albumin solution (20%) to each vial and mix well. Adjust the pH to 5.5, 5.8, 6.0, and 6.5 with saturated citric acid solution.
  • Preparation of samples 13-16 Take 6 ml of the above solution, add 1 ml of human serum albumin solution (20%) to each vial and mix well. Adjust the pH to 5.5, 5.8, 6.0, and 6.5 with saturated citric acid solution.
  • Preparation of samples 1-6 Take 10 ml of the above solution in 6 vials, and adjust the pH of each vial to 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5 respectively with 5 mg/mL citric acid solution.
  • Preparation of samples 7-9 Take 8 ml of the above solution into 3 vials, add 0.5 ml of human serum albumin solution (20%) into each vial and mix well, and adjust the pH to 7.0, 7.5, and 8.0 respectively with 5 mg/mL citric acid solution.
  • sample 10 Preparation of sample 10: Weigh 0.20 g of meloxicam, add 100 ml of 0.008 mol/L NaOH solution, dissolve at 60°C to obtain a clear yellow-green solution, and filter with a 0.22 ⁇ m PES filter membrane. Take 20 ml of the above solution, add 1 ml of human serum albumin solution (20%) to each vial, and adjust the pH to 7.0 with 5 mg/mL citric acid solution.
  • sample 11 Take 20 ml of the above solution, add 1 ml of human serum albumin solution (20%) into each vial, and adjust the pH to 7.5 with 5 mg/mL citric acid solution.
  • sample 12 Take 20 ml of the above solution, add 1 ml of human serum albumin solution (20%) into each vial, and adjust the pH to 8.5 with 5 mg/mL citric acid solution.
  • human serum albumin can increase the stability of meloxicam.
  • pH value is in the range of 7-9.5, the greater the proportion of human serum albumin, the better the stability of the product.
  • Preparation of samples 1-6 Take 8 ml of the above solution into 6 vials, add 0.5 ml of human serum albumin solution (20%) into each vial and mix well. Use 20 mg/mL citric acid solution to adjust the pH to 6.0, 6.5, 7.0, 7.5, 8.0, and 8.5 respectively.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 640 mg of meloxicam, add it to a beaker containing 304 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 17.78 ml of human serum albumin solution (20%) and 6756 mg of mannitol at room temperature and stir and mix well (temperature is room temperature), then adjust the pH to 8.34 with an appropriate amount of 0.008 mol/L NaOH solution, and finally add purified water to weigh to 341.97 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, and fill 8.48 ml in 20 ml vials, a total of 40 vials. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 800 mg of meloxicam, add it to a beaker containing 360 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 25 ml of human serum albumin solution (20%) and 8.5 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.24 with an appropriate amount of 0.008 mol/L NaOH solution, and finally add purified water to weigh to 429.25 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 8.08 ml in 20 ml vials, a total of 50 vials. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 240 mg of meloxicam, add it to a beaker containing 108 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 7.5 ml of human serum albumin solution (20%) and 2.55 g of lactose and stir to mix (temperature is room temperature), then adjust the pH to 8.27 with an appropriate amount of 0.008 mol/L NaOH solution, and finally add purified water to weigh to 128.775 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, and fill 8.08 ml in 20 ml vials, a total of 15 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 320 mg of meloxicam, add it to a beaker containing 144 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 10 ml of human serum albumin solution (20%) and 3.42 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.23 with an appropriate amount of 0.008 mol/L NaOH solution, and finally add purified water to weigh to 171.76 g. Take 10 ml of the solution to measure the intermediate density, which is 1.01 mg/ml. Filter the solution with a 0.22 ⁇ m PES filter membrane and fill 8.08 ml in 20 ml vials, a total of 19 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows: Meloxicam 320mg Human serum albumin solution (20%) 10ml Water: add to 171.76g
  • Preparation method Weigh 320 mg of meloxicam, add it to a beaker containing 144 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 10 ml of human serum albumin solution (20%) and stir to mix (temperature is room temperature), then adjust the pH to 8.25 with an appropriate amount of 0.008 mol/L NaOH solution, and finally add purified water to weigh to 171.76 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, and fill 8.06 ml in 20 ml vials, a total of 19 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 192 mg of meloxicam and add it into a beaker containing 96 ml of NaOH (0.008 mol/L) solution at 60°C. Stir and dissolve completely, cool and set aside. Add 6 ml human serum albumin solution (20%) and 2.04 g mannitol and stir to mix (temperature is room temperature), then adjust pH to 8.07 with appropriate amount of 0.008 mol/L NaOH solution, and finally add purified water to 102 ml. Filter the solution with a 0.22 ⁇ m PES filter membrane, fill 7.98 ml into 20 ml vials, a total of 12 vials. After freeze drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows: Meloxicam 240mg Human serum albumin solution (20%) 8ml Water add to 128ml
  • Preparation method Weigh 240 mg of meloxicam, add it to a beaker containing 120 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 8 ml of human serum albumin solution (20%) and stir to mix (temperature is room temperature), measure the pH to 8.15, and finally add purified water to quantify to 128 ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 8.07 ml in 20 ml vials, a total of 14 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 240 mg of meloxicam, add it to a beaker containing 120 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 8 ml of human serum albumin solution (20%) and 2.56 g of mannitol and stir to mix (temperature is room temperature), measure the pH to 8.28, and finally add purified water to 128 ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 8.07 ml in 20 ml vials, a total of 14 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 240 mg of meloxicam, add it to a beaker containing 120 ml of NaOH (0.008 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 8 ml of human serum albumin solution (20%) and 2.56 g of lactose and stir and mix them evenly (temperature is room temperature), measure the pH to 8.27, and finally add purified water to quantify to 128 ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 8.07 ml in 20 ml vials, a total of 14 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 960 mg of meloxicam, add it to a beaker containing 209.1 ml of NaOH (0.015 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Take 88.2 ml of the above-obtained liquid in a beaker, add 5 ml of human serum albumin solution (20%) and 1.9 g of mannitol, stir and mix (temperature is room temperature), then adjust the pH to 8.35 with an appropriate amount of 0.015 mol/L NaOH solution, and finally add purified water to quantify to 95 ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 7.04 ml in a 20 ml vial, a total of 13 bottles. After freeze-drying for 27 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 960 mg of meloxicam, add it to a beaker containing 209.1 ml of NaOH (0.015 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Take 78.4 ml of the above-obtained liquid in a beaker, add 5 ml of human serum albumin solution (20%) and 1.7 g of mannitol, stir and mix (temperature is room temperature), then adjust the pH to 8.38 with an appropriate amount of 0.1 mol/L NaOH solution, and finally add purified water to quantify to 85 ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 7.08 ml in 20 ml vials, a total of 14 bottles. After freeze-drying for 27 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 360 mg of meloxicam, add it to a beaker containing 88.2 ml of NaOH (0.015 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 5 ml of human serum albumin solution (20%) and 1.9 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.26 with 0.5 ml of 20 mg/mL citric acid solution, and finally add purified water to 95 ml. Filter the solution with a 0.22 ⁇ m PES filter membrane, fill 7.92 ml in 20 ml vials, a total of 11 bottles. After freeze-drying for 27.5 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 1000 mg of meloxicam, add it to a beaker containing 185 ml of NaOH (0.017 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 11.1 ml of human serum albumin solution (20%) and 3.166 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.29 with an appropriate amount of 0.017 mol/L NaOH solution, and finally add purified water to quantify to 211.1 ml. Take 10 ml of the liquid and measure the density, which is 1.01 mg/ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane and fill 6.46 ml in a 20 ml vial, a total of 28 bottles. After freeze-drying for 23.5 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 1000 mg of meloxicam, add it to a beaker containing 186 ml of NaOH (0.017 mol/L) solution, stir and dissolve completely at 60°C, and cool for use. Add 11.1 ml of human serum albumin solution (20%) and stir to mix (temperature is room temperature), then measure the pH to 8.21, and finally add purified water to quantify to 211.1 ml. Take 100 ml of the above solution into a beaker, add 1.0 g of mannitol and stir to dissolve. Filter the solution with a 0.22 ⁇ m PES filter membrane, and fill 6.34 ml in 20 ml vials, a total of 15 bottles. After freeze-drying for 24.5 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 1.575g of meloxicam, add it to a beaker containing 292.95ml NaOH (0.017mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 17.5ml human serum albumin solution (20%) and 4.9875g mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.30 with an appropriate amount of 0.017mol/L NaOH solution, and finally add purified water to weigh to 335.82g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 6.74ml in 20ml vials, a total of 47 bottles. After freeze-drying for 26 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 3.15g of meloxicam, add it to a beaker containing 585.9ml NaOH (0.017mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 35ml human serum albumin solution (20%) and 9.975g mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.33 with an appropriate amount of 0.017mol/L NaOH solution, and finally add purified water to weigh to 671.65g. Take 10ml of the liquid to measure the density, which is 1.096mg/ml. Filter the liquid with a 0.22 ⁇ m PES filter membrane, and fill 6.68ml in a 20ml vial, a total of 96 bottles. After freeze-drying for 27 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 250 mg of meloxicam, add it to a beaker containing 47 ml of NaOH (0.017 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 2.78 ml of human serum albumin solution (20%) and 0.95 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 9.0 with an appropriate amount of 0.017 mol/L NaOH solution, and finally add purified water to weigh to 53.30 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, and fill 5.28 ml in 20 ml vials, a total of 9 bottles. After freeze-drying for 16.5 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 250 mg of meloxicam, add it to a beaker containing 47 ml of NaOH (0.017 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 2.78 ml of human serum albumin solution (20%) and 0.95 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 9.5 with an appropriate amount of 0.017 mol/L NaOH solution, and finally add purified water to weigh to 53.30 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 5.28 ml in 20 ml vials, a total of 9 bottles. After freeze-drying for 16.5 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 500 mg of meloxicam, add it to a beaker containing 94 ml of NaOH (0.019 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 5.56 ml of human serum albumin solution (20%) and 2.005 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.8 with an appropriate amount of 0.1 mol/L NaOH solution, and finally add purified water to weigh to 106.61 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, fill 6.42 ml in 50 ml vials, a total of 14 bottles. After freeze-drying for 16.16 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 508 mg of meloxicam, add it to a beaker containing 94 ml of NaOH (0.021 mol/L) solution, stir and dissolve it completely at 60°C, and cool it for use. Add 5.56 ml of human serum albumin solution (20%) and 2.005 g of mannitol and stir to mix (temperature is room temperature), then adjust the pH to 8.67 with an appropriate amount of 1 mol/L HCL solution, and finally add purified water to weigh to 106.61 g. Filter the liquid with a 0.22 ⁇ m PES filter membrane, and fill 6.38 ml in 20 ml vials, a total of 10 bottles. After freeze-drying for 16 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 1575mg of meloxicam, add it to 6300mg of mannitol, mix thoroughly and add it to a beaker of 210ml NaOH (0.03mol/L) solution, stir and dissolve completely at 60°C, cool and set aside. Add 17.5ml human albumin solution (20%) and stir and mix (temperature is room temperature), then adjust the pH to 8.5 with an appropriate amount of 0.2mol/L HCl solution, and finally add water for injection to weigh to 334g. Filter the liquid with a 0.22um PES filter membrane, clarify it for 8h, and fill 6.63ml in a 20ml vial, a total of 50 bottles. After freeze-drying for 25 hours, a light yellow solid freeze-dried powder is obtained.
  • a meloxicam lyophilized powder the prescription of which is as follows:
  • Preparation method Weigh 1575mg of meloxicam, add it to 6300mg of mannitol, mix thoroughly and add it to a beaker of 210ml NaOH (0.03mol/L) solution, stir and dissolve completely at 60°C, cool and set aside. Add 30ml human albumin solution (20%) and stir and mix (temperature is room temperature), then adjust the pH to 8.0 with an appropriate amount of 0.2mol/L HCl solution, and finally add water for injection to weigh to 334g. Filter the liquid with a 0.22um PES filter membrane and clarify it for 8h. Fill 6.81ml into 20ml vials, a total of 48 bottles. After freeze-drying for 30 hours, a light yellow solid freeze-dried powder is obtained.

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Abstract

L'invention concerne une composition de méloxicam, son procédé de préparation et son utilisation, et se rapporte au domaine technique des préparations pharmaceutiques. La composition de méloxicam comprend du méloxicam et de l'albumine humaine dans un rapport pondéral de 1:0,1 à 1:100, et comprend en outre un régulateur de pH. La composition de méloxicam est une préparation aqueuse claire, sensiblement exempte de solvants autres que l'eau et de tensioactifs. Le pH de la composition est compris entre 6,0 et 10,0. Le méloxicam contenu dans la composition présente une bonne solubilité et agit plus rapidement. Le produit est sûr et stable, et son processus de production et de préparation est simple.
PCT/CN2024/077688 2023-03-24 2024-02-20 Composition de méloxicam, son procédé de préparation et son utilisation Ceased WO2024198768A1 (fr)

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