CN118267350A

CN118267350A - Preparation of meloxicam with low concentration

Info

Publication number: CN118267350A
Application number: CN202311824460.1A
Authority: CN
Inventors: 王青松; 武曲; 李玲
Original assignee: Nanjing Delova Biotech Co ltd
Current assignee: Nanjing Delova Biotech Co ltd
Priority date: 2022-12-29
Filing date: 2023-12-28
Publication date: 2024-07-02

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a preparation of meloxicam with low concentration, more specifically, the preparation comprises meloxicam solution, the meloxicam concentration is 0.001mg/ml-3mg/ml, the preparation has pH of 6.5-10.0, and the preparation comprises: a. meloxicam as active component; b. a pharmaceutically acceptable basic stabilizer; c. pharmaceutically acceptable acidic stabilizers, the preparation does not contain polyethylene glycol, cyclodextrin, amino acid, more preferably, the preparation can still keep good stability under the condition that the preparation does not contain antioxidants such as ascorbic acid, cysteine hydrochloride and the like; the invention also includes lyophilizing the solution.

Description

Preparation of meloxicam with low concentration

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to a preparation of meloxicam with low concentration.

Background

1. Marketed formulation of meloxicam and development progress

Meloxicam is a selective cyclooxygenase-2 (COX-2) inhibitor with antiinflammatory, analgesic and antipyretic effects, and has little adverse reaction to digestive system. The preparations which are currently marketed include tablets, capsules, injection (intramuscular injection) and the like, and are mainly used for treating diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and the like. QP001 injection (trade name) developed by Baudax Bio company in month 2 of 2020) In the united states, the treatment of moderate to severe pain in adults is available for postoperative analgesia.Nanocrystal technology is employed to increase the concentration of meloxicam in aqueous media. However, the nanocrystal production process is complex, and the aseptic production or the aseptic filtration process is adopted, so that the safety risk is easily introduced, and the aseptic guarantee level is low. Meanwhile, the nanocrystals belong to a thermodynamically unstable system,The auxiliary materials of povidone and sodium deoxycholate are used for maintaining the stability of the system, but the safety risk of povidone used in injection is high.

Patent CN103110575B discloses a meloxicam eye drop, a preparation method and application thereof, which comprises meloxicam or pharmaceutically acceptable salt thereof as an active ingredient, a solubilizer, a stabilizer, a pH regulator, a bacteriostatic agent and an osmotic pressure regulator; the solubilizer is one or a mixture of hydroxypropyl beta cyclodextrin, sulfobutyl beta cyclodextrin and beta cyclodextrin; the stabilizer is one or a mixture of high molecular polymer povidone, sodium hyaluronate and hypromellose, wherein the meloxicam concentration is 1mg/mL.

The application CN 112823787A discloses a meloxicam injection, which consists of meloxicam, arginine and water, wherein the mass ratio of meloxicam to arginine is 4:1-1:10, and the injection also comprises a surfactant Solutal HS or poloxamer, wherein the meloxicam concentration is 5mg/mL.

Patent application CN110464846a discloses a meloxicam composition comprising meloxicam and a latent solvent which is a mixed solvent of water and an organic solvent, wherein the meloxicam concentration is 5-35 mg/mL, and the organic solvent is preferably one, two or more of polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, etc.

2. Technical problems to be solved by meloxicam transfusion

Meloxicam contains phenolic hydroxyl and amide groups in the structure, which can undergo hydrolysis and oxidation reactions, and document Successful characterization of degradation products of drugs using LC-MS tools:Application to piroxicam and meloxicam describes the degradation process of meloxicam. Wherein meloxicam oxidized impurities are complex and various, and high temperature and illumination are carried out

The conditions are such that oxidation reactions are catalysed. Generally, the lower the concentration of the general drug, the worse the stability, and the applicant adopts the prescription composition in the prior patent technology to prepare a low-concentration meloxicam preparation, which is easy to generate higher impurities under the conditions of high temperature and illumination.

Furthermore, the meloxicam compositions disclosed in the prior art contain organic solvents or surfactants, which may present safety risks if used for intravenous infusion, and thus there is a need to develop a new meloxicam Kang Jingmai infusion product, which at the same time has good stability.

Disclosure of Invention

In one aspect, the invention provides a formulation of meloxicam at low concentrations, including a solution of meloxicam, having a concentration of meloxicam of from 0.001mg/mL to 3mg/mL, the formulation having a pH of from 6.5 to 10.0.

Preferably, the solution of meloxicam has a pH of 6.8 to 10.0; more preferably, has a pH of 7.0 to 9.0; further preferably, the pH is 7.0 to 8.0; more specifically, has a pH of 6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10.0.

Preferably, the concentration of meloxicam in the formulation is from 0.06mg/ml to 1mg/ml, more particularly 0.001、0.003、0.006、0.010、0.012、0.014、0.016、0.018、0.020、0.022、0.024、0.026、0.028、0.030、0.032、0.034、0.036、0.038、0.040、0.042、0.044、0.046、0.048、0.050、0.052、0.054、0.056、0.058、0.060、0.062、0.064、0.066、0.068、0.070、0.072、0.074、0.076、0.078、0.080、0.082、0.084、0.084、0.086、0.088、0.090、0.092、0.094、0.096、0.098、0.1、0.15、0.2、0.25、0.3、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1、1.5、2、2.5、3mg/ml.

According to one aspect of the present application, the pH may be adjusted with a pH buffer, preferably, the pH buffer includes, but is not limited to, one or more of citric acid and citrate, acetic acid and acetate, phosphoric acid and phosphate, ascorbic acid and ascorbate, tartaric acid and tartrate, maleic acid and maleate, lactic acid and lactate, carbonic acid and carbonate, succinic acid and succinate, benzoic acid and benzoate, phthalic acid and phthalate. The salt is preferably sodium salt, potassium salt or calcium salt, etc.

In some embodiments, the formulation further comprises:

a. Meloxicam as active component;

b. a pharmaceutically acceptable basic stabilizer;

c. pharmaceutically acceptable acidic stabilizers.

In another aspect, the present invention provides a formulation of meloxicam at low concentrations, including a solution of meloxicam, at a concentration of between 0.001mg/ml and 3mg/ml, having a pH of between 6.5 and 10.0, which formulation is free of polyethylene glycol, cyclodextrin, amino acids, further which formulation is free of ascorbic acid, cysteine hydrochloride, more preferably which formulation is free of one or more of organic solvents, surfactants, amino acids, antioxidants, yet has good stability.

In any one of the preceding embodiments, the formulation further comprises:

a. Meloxicam as active component;

b. a pharmaceutically acceptable basic stabilizer;

c. pharmaceutically acceptable acidic stabilizers.

The pharmaceutically acceptable alkaline stabilizer can be selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, diethanolamine, arginine, lysine and histidine; preferably one or more of meglumine, tromethamine and sodium hydroxide.

In some embodiments, the molar ratio of meloxicam to basic stabilizer is from 1:1 to 1:90, preferably from 1:5 to 1:90, preferably from 1:9 to 1:60, preferably from 1:9 to 1:50, more preferably from 1:9 to 1:30; more specifically, the molar ratio of meloxicam to the basic stabilizer is 1:1、1:1.8、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、1:24、1:25、1:26、1:27、1:28、1:29、1:30、1:31、1:32、1:33、1:34、1:35、1:36、1:37、1:38、1:39、1:40、1:41、1:42、1:43、1:44、1:45、1:46、1:47、1:48、1:49、1:50、1:51、1:52、1:53、1:54、1:55、1:56、1:57、1:58、1:59、1:60、1:61、1:62、1:63、1:64、1:65、1:66、1:67、1:68、1:69、1:70、1:71、1:72、1:73、1:74、1:75、1:76、1:77、1:78、1:79、1:80、1:81、1:82、1:83、1:84、1:85、1:86、1:87、1:88、1:89、1:90.

Preferably, the alkaline stabilizer is meglumine, and the molar ratio of meloxicam to meglumine is 1:5-1:50.

Preferably, the alkaline stabilizer is tromethamine, and the molar ratio of meloxicam to tromethamine is 1:15-1:60.

Preferably, the alkaline stabilizer is sodium hydroxide, and the molar ratio of meloxicam to sodium hydroxide is 1:1.8-1:60, preferably 1:5-1:60.

According to another aspect of the invention, the pH is adjusted with an acidic stabilizer.

The pharmaceutically acceptable acid stabilizer is one or more selected from citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate and potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid and malic acid.

According to another aspect of the invention, the formulation may further comprise d. an osmolality adjusting agent.

Osmolality adjusting agents include, but are not limited to, one or more of sodium chloride, mannitol, lactose, glucose, sorbitol and glycerin, preferably one or more of sodium chloride, glucose, sorbitol, mannitol.

In any of the foregoing embodiments, the solution of meloxicam is treated under at least one sterilization technique. In some embodiments, the treatment is performed using a wet heat sterilization technique; in some embodiments, irradiation sterilization techniques are employed; in some embodiments, the treatment is performed using a filter sterilization technique.

According to another aspect of the invention, the solution of meloxicam is provided in a) a vial having a septum; b) A syringe, infusion bag or sealable bottle; or c) in a container, wherein the container comprises indicia indicating that the pharmaceutical formulation has been autoclaved.

In some embodiments, the solution of meloxicam is provided in an ampoule.

According to another aspect of the invention, the use of a formulation according to any of the preceding claims for the manufacture of a medicament for the treatment of postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis, preferably the formulation is a liquid formulation, such as an injection, in particular an intravenous injection.

According to another aspect of the invention there is provided a method of producing a formulation according to any one of the preceding claims.

In some embodiments, the method of producing the formulation of any one of the preceding claims, further comprising lyophilizing the solution.

In some embodiments, the method of producing the formulation of any one of the preceding claims, the formulation further comprises a lyoprotectant.

The lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol and polyvinylpyrrolidone, preferably one or more of mannitol, lactose, trehalose, sucrose and polyvinylpyrrolidone.

According to a further aspect of the present invention there is provided a pharmaceutical formulation prepared by the method of any one of the preceding claims.

According to another aspect of the present invention there is provided a product comprising a lyophilized formulation of meloxicam prepared from a solution of a pharmaceutical formulation according to any one of the preceding claims.

According to another aspect of the present invention there is provided a kit comprising package insert instructions comprising a sealed container containing a pharmaceutical formulation according to any one of the preceding claims.

In some embodiments, a kit comprises package instructions comprising a sealed container comprising a product comprising a lyophilized formulation of meloxicam as described in any of the preceding claims.

In some embodiments, a kit further comprises a diluent container comprising a pharmaceutically acceptable diluent, wherein: a) The diluent is glucose injection, sodium chloride injection, ringer's lactate solution or water for injection; b) The diluent is contained in a sealable bottle or infusion bag; and/or c) the kit further comprises instructions for mixing the formulation and the diluent; preferably, the glucose injection is 5% glucose injection, preferably, the sodium chloride injection is 0.9% sodium chloride injection.

In one aspect, the meloxicam formulation provided herein may be present in a therapeutically effective amount, such as 30mg to 120mg, preferably 30mg, 60mg, 90mg or 120mg in total, and the volume of the solution or diluted solution may be an injectable effective amount, such as 10ml to 1000ml, preferably 10ml, 25ml, 50ml, 100ml, 250ml, 500ml, 1000ml, 2000ml, 3000ml; preferably, meloxicam is present in the solution or diluted solution in a low concentration of 0.001mg/ml to 3mg/ml, preferably 0.06mg/ml to 1mg/ml.

The invention aims to develop a stable low-concentration meloxicam transfusion composition, but the lower the drug concentration is, the more chemical reaction is easy to occur, and the stability is worse.

The meloxicam injection composition of the prior published patent mainly comprises an organic solvent system, a cyclodextrin system, a basic amino acid system and a surfactant system. The surfactant is used for intravenous transfusion, has safety risk, and the applicant discovers that meloxicam, meglumine, sodium chloride, sodium hydroxide, polyethylene glycol 400 and citric acid low-concentration meloxicam injection has good physical stability after long-term placement in the development process of an organic solvent system, a cyclodextrin system and a basic amino acid system, but the impurities are obviously increased under the conditions of illumination and high temperature. The meloxicam injection with low concentration of meloxicam, meglumine, sodium hydroxide, sodium chloride, hydroxypropyl beta cyclodextrin and citric acid has excellent physical stability even if being placed for a long time, but the meloxicam injection is also obviously increased under the illumination condition. Whereas meloxicam has poor solubility in arginine and histidine, there is a risk of insoluble particles/visible foreign matter occurring over long periods of time.

The present invention provides a novel low-concentration formulation of meloxicam, comprising a solution of meloxicam, having a meloxicam concentration of 0.001mg/ml to 3mg/ml, which formulation has a pH of 6.5 to 10.0.

Preferably, the solution of meloxicam has a pH of 6.8 to 10.0; more preferably, has a pH of 7.0 to 9.0; further preferably, the pH is 7.0 to 8.0.

Preferably, the concentration of meloxicam in the formulation is from 0.001mg/ml to 3mg/ml, more preferably from 0.06mg/ml to 1mg/ml.

Applicants have surprisingly found that a stable solution formulation of meloxicam comprises:

a. Meloxicam as active component;

b. a pharmaceutically acceptable basic stabilizer;

c. pharmaceutically acceptable acidic stabilizers.

The novel low-concentration meloxicam preparation has good long-term storage stability at room temperature and good chemical stability under the conditions of illumination and high temperature.

Furthermore, the meloxicam formulation may be free of polyethylene glycol, cyclodextrin, amino acids, and further, the formulation may be free of ascorbic acid, cysteine hydrochloride, or have good stability without one or more of organic solvents, surfactants, amino acids, antioxidants.

According to the meloxicam preparation, the pharmaceutically acceptable alkaline stabilizer is added, so that on one hand, the alkaline stabilizer can be used as a cosolvent, and the dissolution rate of meloxicam is effectively accelerated; on the other hand, the increase of meloxicam impurities can be effectively inhibited by controlling the mol ratio of meloxicam to the alkaline stabilizer.

In the invention, several alkaline compounds such as arginine, histidine, lysine, meglumine, tromethamine, sodium hydroxide and the like are selected, and experiments show that partial alkaline amino acid can accelerate the dissolution of meloxicam but can cause the increase of meloxicam impurities, and preferably, the pharmaceutically acceptable alkaline stabilizer is one or more of meglumine, tromethamine and sodium hydroxide.

In further studies, applicants have unexpectedly found that meloxicam and alkaline stabilizer are effective in inhibiting the growth of impurities only within a specific ratio range, increasing product stability, in some embodiments the molar ratio of meloxicam to alkaline stabilizer is from 1:1 to 1:90, preferably from 1:5 to 1:90, preferably from 1:9 to 1:60, preferably from 1:9 to 1:50, more preferably from 1:9 to 1:30, and in some specific embodiments the molar ratio of meloxicam to alkaline stabilizer is from 1:1 to 1:90 1:1、1:1.8、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、1:24、1:25、1:26、1:27、1:28、1:29、1:30、1:31、1:32、1:33、1:34、1:35、1:36、1:37、1:38、1:39、1:40、1:41、1:42、1:43、1:44、1:45、1:46、1:47、1:48、1:49、1:50、1:51、1:52、1:53、1:54、1:55、1:56、1:57、1:58、1:59、1:60、1:61、1:62、1:63、1:64、1:65、1:66、1:67、1:68、1:69、1:70、1:71、1:72、1:73、1:74、1:75、1:76、1:77、1:78、1:79、1:80、1:81、1:82、1:83、1:84、1:85、1:86、1:87、1:88、1:89、1:90.

When the basic stabilizer is meglumine, the molar ratio of meloxicam to meglumine is preferably 1:5 to 1:50.

When the alkaline stabilizer is tromethamine, the molar ratio of meloxicam to tromethamine is preferably 1:15-1:60.

When the alkaline stabilizer is sodium hydroxide, the molar ratio of meloxicam to sodium hydroxide is 1:1.8-1:60, preferably 1:5-1:60.

In the research process, the applicant tries to add different types of acids for adjusting pH, such as inorganic acid hydrochloric acid and phosphoric acid, monobasic acid lactic acid and acetic acid, and the like, and polybasic acid citric acid, tartaric acid, and the like, and experiments find that the citric acid, the tartaric acid, the maleic acid and the malic acid can improve the stability of the composition, and effectively inhibit the growth of meloxicam impurities.

The formulation of the invention may also include d. an osmolality adjusting agent.

The applicant also considers that antioxidants are useful according to the invention, antioxidants which can inhibit oxidation by scavenging free radicals in solution are substances well known to the person skilled in the art, including substances such as ascorbic acid, ascorbic acid derivatives (e.g. ascorbyl palmitate, ascorbyl stearate, sodium ascorbate, calcium ascorbate, etc.), butylated hydroxyanisole, butylated hydroxytoluene, alkyl gallates, sodium metabisulfite, sodium bisulphite, sodium dithionite, sodium thioglycolate, sodium formaldehyde sulfoxylate, tocopherols and their derivatives (d-alpha tocopherol, d-alpha tocopheryl acetate, dl-alpha tocopheryl acetate, d-alpha tocopheryl succinate, beta-tocopherol, delta-tocopherol, gamma-tocopherol and d-alpha tocopheryl polyethylene oxide 1000 succinate), disodium edetate, cysteine hydrochloride, methionine, thioglycerol and sodium sulfite, which are generally added in amounts of 0.01-0.5%, preferably 0.05% -0.2%.

However, the addition of an antioxidant does not bring about an unexpected effect of improving the stability of the formulation, but when the antioxidant is ascorbic acid or cysteine hydrochloride, the stability effect is rather inferior to that of a formulation without the addition of an antioxidant.

Further, the solution of meloxicam according to the present invention is treated under at least one sterilization technique. In some embodiments, the treatment is performed using a wet heat sterilization technique. In some embodiments, irradiation sterilization techniques are employed; in some embodiments, the treatment is performed using a filter sterilization technique.

It will be appreciated that the pharmaceutical formulations of the present invention are typically stored in bottles, vials, ampoules, infusion bags and the like, any of which may be sparged to remove oxygen or purged with nitrogen. In some embodiments, the bottles, vials, and ampoules are opaque, such as when amber. Such spraying and cleaning rules are well known to those of ordinary skill in the art and should help maintain the stability of the pharmaceutical formulation. In certain embodiments, it is also desirable for the pharmaceutical formulation to be contained within a syringe.

The invention also discloses a method for producing the preparation of any one of the preceding.

Preferably, the method further comprises freeze-drying the solution.

In some embodiments, the method of producing the formulation of any one of the preceding claims, the formulation further comprises a lyoprotectant. Protecting meloxicam from the adverse effects of freezing. Such agents can also prevent caking and peeling, which can be problematic in reconstitution solutions and preparation processes. Important lyoprotectants are one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol and polyvinylpyrrolidone. Most preferred is one or more of mannitol, lactose, sucrose and polyvinylpyrrolidone.

The solution is treated with at least one sterilization technique either before or after final packaging of the solution in a sealed container to form a stable pharmaceutical formulation.

Meloxicam is present in the formulation in an amount sufficient to treat, ameliorate, and even prevent postoperative analgesia, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis.

The dosage may be appropriately adjusted to achieve the desired level of drug locally or globally. The pharmaceutical formulations of the present invention, when used alone or in combination, are administered in a therapeutically effective amount. Typically, the daily injection dose of the active compound is 30mg per day. It is desirable that the IV dose is effective in the range of 30mg to 120mg, preferably 30mg to 90mg, preferably 30mg to 60 mg. In cases where the patient is not adequately responsive at that dose, an even higher dose that the patient can tolerate (or an effective higher dose can be used in a different, more localized delivery route) can be employed. Continuous IV administration over, for example, 24 hours or multiple doses per day are also contemplated to achieve suitable systemic levels of the compound.

According to another aspect of the invention, a kit is also provided. The kit includes a pharmaceutical formulation vial and a pharmaceutical dilution vial, and the kit further includes instructions for diluting the pharmaceutical formulation with the pharmaceutical diluent. Instructions may include instructions for treating a patient with an effective amount of meloxicam. It will also be appreciated that the container containing the pharmaceutical formulation, whether the container is a bottle, a vial with a septum, an ampoule with a septum, an infusion bag, or other similar container, may contain indicia such as conventional indicia that change color after the pharmaceutical formulation has been autoclaved or otherwise sterilized.

In some embodiments, the kit further comprises a diluent container comprising a pharmaceutically acceptable diluent, wherein: a) The diluent is glucose injection, sodium chloride injection, ringer's lactate solution or water for injection; b) The diluent is contained in a sealable bottle or infusion bag; and/or c) the kit further comprises instructions for mixing the formulation and the diluent; preferably, the glucose injection is 5% glucose injection, preferably, the sodium chloride injection is 0.9% sodium chloride injection. Preferably, the water for injection can be used for deoxidizing, so that the oxidation of oxygen in the water for injection is effectively avoided.

Unless otherwise indicated, all numbers expressing quantities, concentrations, proportions, weights, percentages, technical effects, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about" or "approximately". "about" represents a range of + -10% of the value to which it modifies.

Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations. Unless otherwise indicated, terms used herein have the ordinary understood meaning to those skilled in the art. It will be appreciated by those skilled in the art that each numerical parameter should be construed in light of the number of significant digits and conventional rounding techniques, or in a manner well understood by those skilled in the art, depending upon the desired properties and effects sought to be obtained by the present disclosure.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

Unless otherwise indicated, the definitions of excipients recited in the description and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific excipients in the examples, and the like, may be arbitrarily combined and combined with each other. Such combinations and combined excipients should fall within the scope of the present description.

Polyethylene glycols include, but are not limited to, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600.

Cyclodextrins include, but are not limited to, dimethyl-beta-cyclodextrin, 2-hydroxyethyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 3-hydroxypropyl-beta-cyclodextrin, and trimethyl-beta-cyclodextrin.

Amino acids include, but are not limited to, histidine, arginine, lysine, valine, threonine, serine, or proline.

Both mg/mL and w/v% are mass volume concentrations, with 1mg/mL being equivalent to 0.1 w/v%.

Damp heat sterilization refers to a method of sterilization with saturated steam, boiling water, or circulating steam. The method can be divided into: autoclaving, flow steam sterilization, and batch steam sterilization.

Radiation sterilization refers to an effective method of killing microorganisms on most substances using electromagnetic waves generated by ionizing radiation. Examples of the radiation used for sterilization include electron beam, X-ray, and gamma ray.

Filter sterilization refers to the removal of bacteria from a liquid by physical retention to achieve sterility. The device used was a bacterial filter with a small pore size. Typical bacterial filters include thin film bacterial filters (0.45 μm and 0.22 μm pore size), ceramic bacterial filters, asbestos bacterial filters, sintered glass bacterial filters, and the like.

Advantageous effects

(1) The invention provides a preparation of meloxicam with low concentration, which does not contain organic solvent, surfactant and cyclodextrin, and fundamentally avoids irritation and toxicity caused by the organic solvent, the surfactant or the cyclodextrin and the like.

(2) The invention discovers that the increase of meloxicam impurities can be effectively inhibited by adding a specific alkaline stabilizer into the system and controlling the proportion of meloxicam to the alkaline stabilizer.

(3) The invention discovers that the increase of meloxicam impurities can be effectively inhibited by selecting specific acid as an acidic stabilizer.

(4) The invention discovers that other impurities can be introduced into the composition by adding the conventional antioxidant, and the composition can still maintain good stability under the condition of no antioxidant.

(5) The composition of the invention has safe components, can be used for intravenous infusion, and the medicine in the novel composition is not easy to be adsorbed in the infusion bag.

(6) The composition has small irritation and good medication safety and tolerance.

Drawings

FIG. 1 is a graph showing the total impurity growth amplitude of the different acid species compositions of example 4 at 60℃for 15 days

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.

Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.

EXAMPLE 1 solubility study of meloxicam

The solution pH for intravenous infusion is typically 4.0-9.0, so the solubility of meloxicam in solutions of different pH is examined. Phosphate (sodium salt) buffer solution with pH of 2.0-10.0 is prepared in a penicillin bottle, excessive meloxicam is sequentially added, and after shaking for 24 hours, the supernatant is taken to detect the drug concentration, and the results are shown in the table 1-1.

Table 1-1: solubility of meloxicam in phosphate solutions of different pH

Medium (D)	Solubility (mg/mL)
		pH2.0	0.0004
pH5.0	0.0018
		pH6.0	0.0150
pH7.0	0.1400
		pH8.0	1.1067
pH9.0	2.2000
		pH10.0	3.2800

When the pH value of the solution is above 6, the concentration requirement of the invention can be met.

Example 2

Investigation of alkaline stabilizers

(1) Dissolution of meloxicam in different alkaline stabilizers

As can be seen from the results of example 1, the solubility of meloxicam was pH dependent, so that several basic compounds commonly used in injections were selected, an alkaline environment was formed first for accelerating the dissolution of meloxicam, an aqueous solution of 0.01mol/L of alkaline stabilizer was prepared, and the dissolution of meloxicam in various alkaline stabilizers was examined, and the results are shown in Table 2-1.

TABLE 2-1 dissolution of meloxicam in various alkaline stabilizers

Species of type	0.01Mol/L alkaline stabilizer	Meloxicam addition	Dissolution conditions
				Sodium hydroxide	7mL	10mg	Solution cleaner
Meglumine (meglumine)	7mL	10mg	Solution cleaner
				Tromethamine	7mL	10mg	Solution cleaner
Lysine	7mL	10mg	Solution cleaner
				Arginine (Arg)	7mL	10mg	Can not be dissolved and cleared
Histidine	7mL	10mg	Can not be dissolved and cleared

Experiments show that arginine and histidine have poor dissolution assisting capability.

(2) Effect of alkaline stabilizers on stability of compositions

According to the dissolution of meloxicam in different alkaline stabilizers, sodium hydroxide, meglumine, tromethamine and lysine were selected for research, compositions were prepared according to the composition of table 2-1, the pH was adjusted to 8.0 with an appropriate amount of citric acid, and the wet heat sterilization was performed at 121 ℃ for 15min, and the differences between the pH and the related substances after sterilization were compared, and the results are shown in tables 2-2 and 2-3.

Table 2-1 compositions containing different alkaline stabilizers

TABLE 2 comparison of pH after sterilization

Composition and method for producing the same	PH before sterilization	PH after sterilization
			1001	8.03	7.53
1002	8.01	7.97
			1003	8.03	7.99
1004	7.96	7.98

TABLE 2-3 comparison of substances after sterilization

Composition and method for producing the same	Impurity 1%	Impurity 2%	Impurity 3%	Impurity 4%	Impurity 5%	Total impurity%
							1001	0.23	Not detected	Not detected	0.07	Not detected	0.42
1002	0.22	Not detected	Not detected	0.09	Not detected	0.36
							1003	0.28	Not detected	Not detected	0.07	Not detected	0.51
1004	0.30	0.17	0.28	0.03	0.07	4.43

Experiments show that the pH fluctuation of the composition 1001 after sterilization is large, the pH fluctuation can cause precipitation of active ingredients, and risks exist; while basic amino acid compositions such as 1004, while accelerating the dissolution of meloxicam, cause a dramatic increase in the total impurities of meloxicam.

Example 3

Study of the ratio of meloxicam to alkaline stabilizer

(1) Composition of meloxicam/meglumine with different molar ratios

Based on the results of example 2, meglumine was selected as an alkaline stabilizer, formulations containing meloxicam/meglumine in different molar ratios were prepared according to table 3-1, pH was adjusted to 7.5-8.0 with an appropriate amount of citric acid, heat sterilization was performed at 121 ℃ for 15min, and the compositions were left at 60 ℃ for 15 days, and the results are shown in table 3-2.

TABLE 3-1 Meloxicam/meglumine compositions with different molar ratios

TABLE 3-2 composition related substance results

Experiments show that the increase of impurities can be effectively inhibited when the molar ratio of meloxicam to meglumine is 1:5-1:50.

(2) Composition of meloxicam/tromethamine with different molar ratio

According to the results of example 2, tromethamine was selected as an alkaline stabilizer, formulations containing meloxicam/tromethamine in different molar ratios were prepared according to tables 3-3, pH was adjusted to 7.5-8.0 with an appropriate amount of citric acid, heat-wet sterilization was performed at 121℃for 15min, and the compositions were left at 60℃for 15 days, and the results are shown in tables 3-4.

Tables 3-3 different mole ratios meloxicam/tromethamine compositions

Tables 3 to 4 composition-related substance results

Experiments show that the increase of impurities can be effectively inhibited when the molar ratio of meloxicam to tromethamine is 1:15-1:60.

(3) Meloxicam/sodium hydroxide compositions of varying molar ratios

Based on the results of example 2, sodium hydroxide was selected as an alkaline stabilizer, formulations containing meloxicam/sodium hydroxide in different molar ratios were prepared according to tables 3 to 5, pH was adjusted to 7.5 to 8.0 with an appropriate amount of citric acid, and the formulations were subjected to wet heat sterilization at 121℃for 15 minutes and left at 60℃for 15 days, and the results are shown in tables 3 to 6, comparing the growth of the related substances of each composition.

Tables 3-5 meloxicam/sodium hydroxide compositions with different molar ratios

Tables 3 to 6 composition-related substance changes

Experiments show that the composition has better stability when the molar ratio of meloxicam to sodium hydroxide is 1:5-1:60.

Example 4

Investigation of acid stabilizers

The applicant screens the acid stabilizers to examine the effect of the acid stabilizers on the stability of the composition.

(1) Effect of acidic amino acids on stability of compositions

The formulations were prepared as in Table 4-1, pH was adjusted to 7.5 with an appropriate amount of acidic amino acid, and the compositions were subjected to heat-moisture sterilization at 121℃for 15 minutes, and the appearance and the related substances after sterilization were compared, and the results are shown in tables 4-2 and 4-3.

TABLE 4-1 compositions containing different acidic amino acids

TABLE 4-2 composition appearance Change

TABLE 4-3 composition related substance changes

Composition and method for producing the same	Sampling point	Impurity 1%	Impurity 2%	Impurity 3%	Impurity 4%	Total impurity%
							1023	Day 0	0.14	Not detected	Not detected	0.09	0.63
1024	Day 0	0.20	Not detected	Not detected	0.11	0.68
							1025	Day 0	0.23	Not detected	Not detected	0.10	0.66

Experiments show that after the composition adopting the acidic amino acid is sterilized, opalescence occurs in part, and impurities are obviously increased. (2) Effect of other acids on stability of compositions

The formulations were prepared as shown in tables 4 to 4, pH was adjusted to 7.5 to 8.0 with an appropriate amount of acid, heat-wet sterilized at 121℃for 15min, and left at 60℃for 15 days, and the appearance of each composition and the results of the appearance and the related substances are shown in tables 4 to 5 and 4 to 6, and the increase of the related substances is shown in tables 4 to 7 and FIG. 1.

Tables 4-4 compositions containing different acids

Tables 4-5 composition appearance changes

Tables 4 to 6 composition-related substance results

Tables 4-7 Total impurity increase amplitude of compositions

Composition and method for producing the same	Acid species	Total impurity increase%
			1002	Citric acid	0.24
1028	Acetic acid	0.52
			1029	Phosphoric acid	1.09
1030	Hydrochloric acid	0.44
			1031	Tartaric acid	0.25
1033	Maleic acid	0.24
			1034	Malic acid	0.31
1035	Succinic acid	0.48

The invention surprisingly found that citric acid, tartaric acid, maleic acid and malic acid can improve the stability of the composition by effectively inhibiting the increase of impurities.

Example 5

Meloxicam compositions of varying concentrations

Compositions containing meloxicam at various concentrations were prepared as shown in Table 5-1, pH was adjusted to 7.5-8.0 with an appropriate amount of citric acid, heat-wet sterilized at 121℃for 15min, and left at 25℃for 15 days at 40℃for detection of the relevant substances, and the results are shown in Table 5-2.

TABLE 5-1 meloxicam compositions of varying concentrations

TABLE 5-2 results on substances

Example 6

Meloxicam compositions of different pH

The preparation samples were prepared as in Table 6-1, pH was adjusted to 6.5, 7.0, 7.5, 8.0 with an appropriate amount of citric acid, heat-wet sterilized at 121℃for 15min, and left at 25℃for 15 days at 40℃and 60℃for detection of the relevant substances, and the results are shown in Table 6-2.

Table 6-1 meloxicam compositions of different pH

TABLE 6-2 results on substances

Example 7

Comparative study with the disclosed System

The meloxicam injection composition of the prior published patent mainly comprises an organic solvent system, a cyclodextrin system, an arginine system and a surfactant system. The use of surfactants for intravenous infusion presents a safety risk, and example 2 compares the dissolution of meloxicam in different basic amino acids, wherein the dissolution properties of arginine and histidine are poor, so the applicant has chosen the first two systems for comparison studies.

(1) Comparative studies with compositions containing organic solvents

The common organic solvents in the published patent are ethanol, polyethylene glycol 400 and polyethylene glycol 300, and the polyethylene glycol 400 is selected as the organic solvent for preparing samples by referring to patent CN110464846A as a comparative example. Samples were prepared according to the formulation of Table 7-1, wherein the comparative examples were diluted to 0.06mg/mL, 0.6mg/mL, and 1mg/mL with a 0.9% sodium chloride solution, respectively, and examined as comparative example 1, comparative example 2, and comparative example 3, and the compositions of the present application and comparative examples 1 to 3 were sterilized at 121℃for 15 minutes, and left in the light condition, and the changes of the related substances were examined, and the results are shown in Table 7-2.

TABLE 7-1 composition

TABLE 7-2 related substance changes

The results show that the total impurity growth of the composition containing polyethylene glycol 400 is significantly higher than that of the composition of the application.

Prior patent CN110464846a discloses stability data of meloxicam compositions, when meloxicam concentration is 7.5mg/mL and polyethylene glycol 400 ratio is 10% v/v and 30% v/v (F1 and F3), respectively, the degradation product B (i.e. impurity 1 in the present application) is increased to 0.73% and 0.30% respectively after being left at 60 ℃ for 30 days, which means that increasing the amount of polyethylene glycol 400 can inhibit the increase of impurity 1, and the compositions 1007 and 1008 of the present application are left at 25 ℃, 40 ℃ and 60 ℃ for 30 days respectively, the result and the increase range of impurity 1 are shown in table 7-3.

TABLE 7-3 impurity 1 results

The results show that the composition of the application can still inhibit the growth of the impurity 1 under the condition of not containing the polyethylene glycol 400, and ensure the stability of the composition.

(2) Stability comparison with compositions containing Cyclodextrin

Cyclodextrin is generally used as a stabilizer to improve the stability of the drug after inclusion. The disclosed patent uses hydroxypropyl beta cyclodextrin and sulfobutyl beta cyclodextrin to prepare meloxicam solution, and uses hydroxypropyl beta cyclodextrin as an example to carry out comparative test and examine the stability of two different system compositions. Samples were prepared according to the formulation of tables 7-4, sterilized at 121℃for 15min, left in the light conditions, and examined for changes in the relevant substances, the results being shown in tables 7-5.

Tables 7 to 4 composition

Table 7-5 comparative substances

The results show that the overall impurity growth of the compositions containing hydroxypropyl beta cyclodextrin is significantly higher than that of the compositions of the present application.

Example 8

Compositions containing different osmolality adjusting agents

Samples containing different osmotic pressure regulators were prepared according to Table 8-1, pH was adjusted to 7.5-8.0 with an appropriate amount of citric acid, heat-wet sterilized at 121℃for 15min, and placed at 60℃to examine the relevant substances, and the results are shown in tables 8-2 and 8-3.

Table 8-1 compositions containing additional osmolarity adjusting agents

TABLE 8-2 results on substances

TABLE 8-3 Total impurity increase amplitude for compositions

Example 9

Antioxidant-containing composition

Samples were prepared according to the recipe of Table 9-1 to examine the stability effect of different antioxidants on the composition. Adjusting pH to 7.5-8.0 with appropriate amount of citric acid, sterilizing at 121deg.C for 15min under heat and humidity, standing under illumination for 5 days, and detecting appearance and related substances, wherein the results are shown in tables 9-2 and 9-3.

Table 9-1 composition

TABLE 9-2 5 day light appearance results

Composition and method for producing the same	1002	1046	1047	1048	1049	1050
							Appearance of	No change	Brown yellow	No change	No change	No change	No change

TABLE 9-3 results on substances

Example 10

Drug adsorption studies

The adsorption influence of the infusion bag on the medicine is examined by adopting a polypropylene infusion bag, the compositions with different pH values are prepared according to the composition shown in the table 10-1, the compositions are subpackaged into the polypropylene infusion bag after being filtered, the polypropylene infusion bag is subjected to damp-heat sterilization at 121 ℃ for 15min, the polypropylene infusion bag is placed under the illumination condition for 5 days, and the content change of the compositions is examined, and the results are shown in the table 10-2.

TABLE 10-1 composition

TABLE 10-2 content variation

The applicant states that the present invention is described by way of the above embodiments in terms of the technical solutions of the present invention, but the present invention is not limited to the above solutions, i.e. it does not mean that the present invention must be implemented in dependence on the above solutions. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.

Claims

1. A formulation of meloxicam at low concentration comprising a solution of meloxicam at a concentration of between 0.001mg/ml and 3mg/ml, the formulation having a pH of between 6.5 and 10.0.

2. The formulation of claim 1, wherein the formulation comprises:

a. Meloxicam as active component;

b. a pharmaceutically acceptable basic stabilizer;

c. pharmaceutically acceptable acidic stabilizers.

3. The formulation of claim 1, wherein the formulation is free of polyethylene glycol, cyclodextrin, amino acids.

4. The formulation of claim 1, wherein the formulation is free of ascorbic acid, cysteine hydrochloride.

5. The formulation of claim 1, wherein the formulation is free of one or more of organic solvents, surfactants, amino acids, antioxidants.

6. The formulation of claim 1, wherein the solution of meloxicam has a pH of 6.8 to 10.0; preferably having a pH of 7.0 to 9.0; preferably having a pH of 7.0 to 8.0; more specifically, has a pH of 6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10.0.

7. Formulation according to claim 1, characterized in that the concentration of meloxicam of the formulation is 0.06mg/ml-1mg/ml, more particularly 0.001、0.003、0.006、0.010、0.012、0.014、0.016、0.018、0.020、0.022、0.024、0.026、0.028、0.030、0.032、0.034、0.036、0.038、0.040、0.042、0.044、0.046、0.048、0.050、0.052、0.054、0.056、0.058、0.060、0.062、0.064、0.066、0.068、0.070、0.072、0.074、0.076、0.078、0.080、0.082、0.084、0.084、0.086、0.088、0.090、0.092、0.094、0.096、0.098、0.1、0.15、0.2、0.25、0.3、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1、1.5、2、2.5、3mg/ml.

8. The formulation of claim 1, wherein the pharmaceutically acceptable alkaline stabilizer is selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, diethanolamine, arginine, lysine, histidine; preferably one or more of meglumine, tromethamine and sodium hydroxide.

9. Formulation according to claim 1, characterized in that the molar ratio of meloxicam and alkaline stabilizer is 1:1 to 1:90, preferably 1:5 to 1:90, preferably 1:9 to 1:60, preferably 1:9 to 1:50, more preferably 1:9 to 1:30; more specifically, the molar ratio of meloxicam to the alkaline stabilizer is 1:1、1:1.8、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20、1:21、1:22、1:23、1:24、1:25、1:26、1:27、1:28、1:29、1:30、1:31、1:32、1:33、1:34、1:35、1:36、1:37、1:38、1:39、1:40、1:41、1:42、1:43、1:44、1:45、1:46、1:47、1:48、1:49、1:50、1:51、1:52、1:53、1:54、1:55、1:56、1:57、1:58、1:59、1:60、1:61、1:62、1:63、1:64、1:65、1:66、1:67、1:68、1:69、1:70、1:71、1:72、1:73、1:74、1:75、1:76、1:77、1:78、1:79、1:80、1:81、1:82、1:83、1:84、1:85、1:86、1:87、1:88、1:89、1:90;, preferably, the alkaline stabilizer is meglumine, and the molar ratio of meloxicam to meglumine is 1:5-1:50; preferably, the alkaline stabilizer is tromethamine, and the molar ratio of meloxicam to tromethamine is 1:15-1:60; preferably, the alkaline stabilizer is sodium hydroxide, and the molar ratio of meloxicam to sodium hydroxide is 1:1.8-1:60, preferably 1:5-1:60.

10. The formulation of claim 1, wherein the pH is adjusted with an acidic stabilizer.

11. The formulation of claim 1, wherein the pharmaceutically acceptable acidic stabilizer is selected from one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate, potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid and malic acid.

12. The formulation of claim 1, wherein the formulation may further comprise d. an osmolality adjusting agent.

13. The formulation according to claim 12, wherein the osmolality adjusting agent is selected from one or more of sodium chloride, mannitol, lactose, glucose, sorbitol and glycerol, preferably one or more of sodium chloride, glucose, sorbitol, mannitol.

14. Formulation according to claim 1, characterized in that the solution of meloxicam is treated under at least one sterilization technique, preferably with a damp-heat sterilization technique, with an irradiation sterilization technique or with a filter sterilization technique.

15. The formulation of claim 1, wherein the solution of meloxicam is provided in a) a vial having a septum; b) A syringe, infusion bag or sealable bottle; or c) in a container, wherein the container comprises indicia indicating that the pharmaceutical formulation has been autoclaved.

16. The formulation of claim 1, wherein the solution of meloxicam is provided in an ampoule.

17. Use of a formulation according to any one of claims 1-16 for the manufacture of a medicament for the treatment of postoperative pain relief, rheumatoid arthritis, painful osteoarthritis, ankylosing spondylitis, preferably said formulation is a liquid formulation, such as an injection, in particular an intravenous injection.

18. A method of producing the formulation of any one of claims 1-16.

19. The method of claim 18, further comprising lyophilizing the solution.

20. The method of claim 18, wherein the formulation further comprises a lyoprotectant.

21. The method of claim 20, wherein the lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol, and polyvinylpyrrolidone, preferably one or more of mannitol, lactose, trehalose, sucrose, and polyvinylpyrrolidone.

22. A pharmaceutical formulation prepared by the method of any one of claims 18-21.

23. A product comprising a lyophilized formulation of meloxicam prepared from a solution comprising the pharmaceutical formulation of any one of claims 1-16.

24. A kit comprising package insert containing a sealed container containing the pharmaceutical formulation of claims 1-16.

25. A kit comprising package instructions comprising a sealed container comprising the product comprising a lyophilized formulation of meloxicam according to claim 23.

26. The kit of claim 25, further comprising a diluent container comprising a pharmaceutically acceptable diluent, wherein: a) The diluent is glucose injection, sodium chloride injection, ringer's lactate solution or water for injection; b) The diluent is contained in a sealable bottle or infusion bag; and/or c) the kit further comprises instructions for mixing the formulation and the diluent; preferably, the glucose injection is 5% glucose injection, preferably, the sodium chloride injection is 0.9% sodium chloride injection.