An injection of meloxicam and a preparation method and use thereof

Abstract

This invention provides an injectable meloxicam, its preparation method, and its uses. The injectable formulation comprises meloxicam, an external aqueous phase, and liposomes. The liposomes contain an internal aqueous phase, which is a salt solution containing metal ions. The meloxicam can form an insoluble salt with the metal ions and be stably loaded in the aqueous phase within the liposomes. This injectable formulation has a high drug loading capacity and good storage stability. After intravenous injection into the bloodstream, it can rapidly release the drug to exert an analgesic effect. It can also be used for local injection in joint cavities to improve local analgesia and anti-inflammatory effects and reduce the dosage required for systemic administration.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and in particular to an injectable form of meloxicam, its preparation method, and its uses. Background Technology

[0002] Postoperative pain is acute pain that occurs after surgery. Actively implementing effective postoperative analgesia measures to relieve pain is a key aspect of accelerating recovery and improving patient comfort and quality of life. (Guidelines for Postoperative Pain Management by Clinical Pharmacists, Guangdong Pharmaceutical Association, 2019.1) Currently, opioids are the most commonly used drugs in clinical practice for treating moderate to severe pain. They exert their analgesic effect by binding to opioid receptors in the peripheral and central nervous systems (spinal cord and brain). Strong opioids include morphine, fentanyl, pethidine, and sufentanil, which have the advantages of strong analgesic effects, no organ toxicity, and no ceiling effect. However, opioids may cause respiratory depression, nausea, vomiting, and intestinal obstruction. Furthermore, opioids have the potential for addiction and dependence. Therefore, non-opioid drugs have always been a hot topic in postoperative analgesia research, especially in the control of acute postoperative pain.

[0003] Meloxicam (MLX) is a novel nonsteroidal anti-inflammatory drug (NSAID) launched in South Africa in 1996 by Boehringer Ingelheim in Germany. As a selective inhibitor of cyclooxygenase-2 (COX-2), meloxicam has excellent anti-inflammatory and analgesic effects and is widely used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and other musculoskeletal pain (such as lower back pain). It can also be used for postoperative pain relief in patients with mild to moderate pain. Because meloxicam's inhibitory activity against COX-2 is greater than its inhibitory activity against cyclooxygenase-1 (COX-1), its blood (platelet), gastrointestinal, renal, and cardiovascular side effects are fewer than those of COX-1 inhibitors. Compared with traditional NSAIDs such as naproxen, ibuprofen, and piroxicam, meloxicam has similar anti-inflammatory and analgesic effects, but significantly improved gastrointestinal tolerance. Patients rarely experience gastrointestinal perforation, bleeding, or ulceration during treatment, and nausea and vomiting are also less common. Therefore, meloxicam is expected to become a non-opioid analgesic for controlling moderate to severe postoperative pain. However, its high lipid solubility (LogP = 2.47) and extremely low water solubility result in a long time to reach peak concentration after oral administration, approximately 4 to 5 hours, which limits its application in acute moderate to severe pain.

[0004] To accelerate the onset of action of meloxicam, researchers have developed various formulations. For systemic analgesia, currently only one meloxicam nanocrystal injection (trade name Anjeso) is available. Administered once daily intravenously for postoperative analgesia, this nanocrystal injection takes effect rapidly after a rapid intravenous bolus, significantly relieving moderate to severe pain. However, its rapid intravenous injection and the physical instability of the nanocrystals pose potential risks. For local analgesics, the main formulations include transdermal meloxicam delivery systems, such as gels, liposomes, patches, and microemulsions. Transdermal delivery systems can maintain a certain drug concentration at the administration site and keep plasma concentrations low, avoiding gastrointestinal irritation and reducing systemic adverse reactions. However, transdermal delivery struggles to overcome the skin's stratum corneum barrier, and meloxicam's high lipid solubility also affects the amount of drug reaching the dermis. As of 2016, only one transdermal meloxicam delivery system had been successfully marketed. (Jianmin Chen, YunhuaGao. Strategies for meloxicam delivery to and across the skin: a review[J]. Drug Delivery, 2016, 23(8).). Summary of the Invention

[0005] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide an injectable meloxicam, its preparation method and uses, in order to solve the problems in the prior art.

[0006] To achieve the above and other related objectives, the present invention is obtained through the following technical solution.

[0007] The present invention provides a liposome for loading meloxicam, the liposome containing an internal aqueous phase, the internal aqueous phase being a salt solution containing metal ions, wherein the meloxicam is capable of complexing with the metal ions.

[0008] Preferably, the metal ion is selected from calcium ions, zinc ions, copper ions, magnesium ions, manganese ions, or cobalt ions.

[0009] Preferably, the pH value of the salt solution is 6.0 to 8.0.

[0010] Preferably, the liposomes include one or both of phospholipids and cholesterol.

[0011] This invention provides an injectable meloxicam, the raw material components of which include: meloxicam, an aqueous phase and liposomes as described above; the aqueous phase contains at least water.

[0012] Preferably, the concentration of meloxicam is greater than or equal to 0.01 mg / mL based on the volume of the injection; and / or, the external aqueous phase further contains one or more of meglumine, sucrose, or glucose.

[0013] Preferably, the meloxicam is loaded into the liposome.

[0014] The present invention also discloses a method for preparing an injectable as described above, wherein meloxicam, an aqueous phase and liposomes are mixed.

[0015] The present invention also discloses the use of the above-described injectable preparation as an injectable analgesic.

[0016] The present invention also discloses an anti-inflammatory preparation, comprising an injectable and cytotoxic drug as described above, or an injectable and immunomodulatory drug as described above.

[0017] Preferably, the cytotoxic drug is doxorubicin or doxorubicin hydrochloride.

[0018] Preferably, the cytotoxic drug and / or the immunomodulatory drug are loaded in the liposome.

[0019] The present invention also discloses the use of the anti-inflammatory agent as described above in the preparation of a drug for treating tumors.

[0020] The injectable formulation described in this application has a high drug loading capacity and good storage stability. After intravenous injection into the bloodstream, meloxicam can be rapidly released to exert a systemic analgesic effect. It can also be used for local injection in joint cavities to maintain local drug concentration for a longer period of time, improve local analgesia and anti-inflammatory effects, and reduce the dosage of systemic administration. Attached Figure Description

[0021] Figure 1 Standard curve of meloxicam (MLX) aqueous solution.

[0022] Figure 2 The precipitate formed when meloxicam is mixed with a metal ion salt solution.

[0023] Figure 3 Cryo-transmission electron microscopy image of meloxicam liposomes with calcium acetate as the internal aqueous phase.

[0024] Figure 4 Encapsulation efficiency, storage stability, and release profile of meloxicam liposomes with calcium acetate as the internal aqueous phase.

[0025] Figure 5 Encapsulation efficiency, storage stability, and release profile of meloxicam liposomes with calcium chloride as the internal aqueous phase.

[0026] Figure 6Encapsulation efficiency, storage stability, and release profile of meloxicam liposomes with zinc acetate as the internal aqueous phase.

[0027] Figure 7 Encapsulation efficiency, storage stability, and release profile of meloxicam liposomes with copper sulfate as the internal aqueous phase.

[0028] Figure 8 Encapsulation efficiency, storage stability, and release profile of meloxicam liposomes with magnesium chloride as the internal aqueous phase.

[0029] Figure 9 Encapsulation efficiency, storage stability and release profile of meloxicam liposomes with cobalt chloride as the internal aqueous phase.

[0030] Figure 10 Encapsulation efficiency, storage stability, and release profile of meloxicam liposomes with manganese chloride as the internal aqueous phase.

[0031] Figure 11 Encapsulation efficiency of meloxicam and doxorubicin monopeptides with manganese chloride as the internal aqueous phase.

[0032] Figure 12 Encapsulation efficiency of meloxicam-doxorubicin co-loaded liposomes with manganese chloride as the internal aqueous phase.

[0033] Figure 13 Inhibitory effect of meloxicam-doxomil co-loaded liposomes on (doxomil-resistant) K562 cells.

[0034] Figure 14 The cumulative release rate of liposomes with different internal aqueous phases was simulated by local injection. Detailed Implementation

[0035] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification.

[0036] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the respective manufacturers.

[0037] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0038] The inventive concept of this invention lies in providing an injectable meloxicam liposome formulation. Unlike existing meloxicam liposomes prepared by thin-film dispersion, the meloxicam liposome formulation provided by this method employs an active drug loading method. This method utilizes the combination of meloxicam and metal ions in the aqueous phase of the liposome to form an insoluble salt (precipitate), allowing meloxicam to effectively enter the aqueous phase of the liposome and achieve stable loading.

[0039] This application first provides a liposome for loading meloxicam, wherein the liposome contains an internal aqueous phase, which is a salt solution containing metal ions, and the meloxicam can complex with the metal ions to form an insoluble salt. Preferably, the metal ions are selected from calcium ions, zinc ions, copper ions, magnesium ions, manganese ions, or cobalt ions. Preferably, the pH value of the salt solution is 6.0 to 8.0. Preferably, the liposome includes one or two of phospholipids and cholesterol. The applicant unexpectedly discovered in this application that this liposome has a high meloxicam loading capacity and good storage stability.

[0040] This application also discloses an injectable meloxicam, the injectable comprising the following raw material components: meloxicam, an aqueous phase, and liposomes as described above; the aqueous phase contains at least water. Preferably, the concentration of meloxicam is greater than or equal to 0.01 mg / mL based on the volume of the injectable. Preferably, the aqueous phase further contains one or more of meglumine, sucrose, or glucose.

[0041] Preferably, the meloxicam is loaded into the liposome.

[0042] The preparation method of the above-mentioned injection is as follows: meloxicam, external aqueous phase and liposome are mixed.

[0043] When diluted in large volumes (e.g., intravenous injection), meloxicam can be rapidly released for the control of acute pain and systemic analgesia for moderate to severe pain; when injected locally, such as into the joint cavity, meloxicam liposomes can be slowly released, maintaining local drug concentrations for a longer period of time, improving local analgesia and anti-inflammatory effects, and reducing the dosage required for systemic administration.

[0044] Furthermore, new research indicates that inflammatory factors in the tumor microenvironment, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), affect the infiltration of immune cells, including T cells, into tumors through complex signaling pathways (Jose R. Conejo-Garcia, Breaking barriers for T cells by targeting the EPHA2 / TGF-β / COX-2 axis in pancreatic cancer, J Clin Invest. 2019; 129(9):3521-3523), or influence the resistance of tumor cells to cytotoxic drugs, thereby reducing the effectiveness of tumor immunotherapy or chemotherapy. Considering that another major function of meloxicam is to exert an anti-inflammatory effect by inhibiting COX-2, the meloxicam liposomes with stable drug loading proposed in this invention are expected to improve the effectiveness of immunotherapy or chemotherapy by correcting the inflammatory tumor microenvironment through combined use with cytotoxic drugs or immunotherapies.

[0045] In one specific embodiment, the cytotoxic drug is doxorubicin or doxorubicin hydrochloride.

[0046] In a preferred embodiment, the cytotoxic drug and / or the immunomodulatory drug are loaded in the liposome.

[0047] This application also discloses a specific method for preparing the aforementioned liposomes, which can be done using conventional coating methods in the prior art. Specifically, the method can be as follows: mixing an organic solvent solution of the lipid with an inner aqueous phase to obtain a liposome suspension; then removing metal salts from the outer aqueous phase of the liposome by dialysis. The pH of the outer aqueous phase is generally 6-7. Thus, a pH gradient and a metal salt concentration gradient exist between the inner and outer aqueous phases of the liposome. In a preferred embodiment, the temperature for preparing the liposome suspension is 45-85°C.

[0048] Example 1

[0049] This embodiment describes a method for detecting meloxicam.

[0050] In this embodiment, a standard curve for meloxicam is established as follows.

[0051] Ultraviolet (UV) detection and analysis method was used: the detection instrument was TECAN. 200PRO; detection wavelength: 362nm; detection temperature: 25℃; detection plate: 96-well plates, UV-transparent; detection volume 200 μl.

[0052] (1) Accurately weigh 2 mg of meloxicam and add it to 2 mL of sodium hydroxide solution (pH ~ 10). Vortex until completely dissolved to prepare a 1 mg / mL meloxicam stock solution.

[0053] (2) Meloxicam aqueous solution was mixed with ultrapure water and serially diluted to obtain meloxicam standard solutions with concentrations of 5 μl / mL, 10 μl / mL, 15 μl / mL, 20 μl / mL, 30 μl / mL and 40 μl / mL. The meloxicam standard solutions of the above concentrations were detected by UV method, and the detection results are shown in Table 1.

[0054] Table 1 UV detection values ​​of meloxicam aqueous solutions at different concentrations

[0055]

[0056] A standard curve was established based on the results shown in Table 1. The working curve is as follows: Figure 1 As shown. The UV standard curve for meloxicam aqueous solution is Y = 0.0306X + 0.0126 (n = 6), R² = 1, indicating a good fit.

[0057] Example 2

[0058] This example illustrates the solubilization of meloxicam and the formation of insoluble salts between meloxicam and metal ions.

[0059] 2.1 Solubilizing effect of hydroxypropyl-β-cyclodextrin (HPCD) on meloxicam

[0060] A certain amount of HPCD (Shanghai Shifeng Biotechnology Co., Ltd.) was dissolved in deionized water to prepare HPCD solutions with concentrations of 0%, 10%, 20%, and 30%. 2 mL of each HPCD solution was taken, and approximately 2 mg of meloxicam was added to each solution. After vortexing for 5 min, the mixture was shaken for 24 h on a ThermoMixer C (Eppendorf) at 37°C. After centrifugation, the UV absorbance of meloxicam in the supernatant was measured. The solubility of meloxicam in HPCD solutions of different concentrations was calculated according to the working curve in Example 1.

[0061] 2.2 Solubilizing effect of meglumine on meloxicam

[0062] The meglumine used in this embodiment was purchased from Bailingwei Technology Co., Ltd.

[0063] Weigh appropriate amounts of meglumine and excess meloxicam to prepare solutions containing 10 mg / mL, 20 mg / mL, and 30 mg / mL of meglumine. Incubate the solutions at 37°C with shaking at 500 rpm for 24 hours. After centrifugation, measure the UV absorbance of meloxicam in the supernatant. Calculate the solubility of meloxicam in different concentrations of meglumine according to the working curve in Example 1.

[0064] Table 2 Saturated solubility of meloxicam in different solubilizing solutions

[0065]

[0066] As shown in Table 2, HPCD has a certain solubilizing effect on meloxicam, and the higher the concentration of HPCD, the stronger the solubilizing effect. However, meglumine has a much greater solubilizing effect on meloxicam than HPCD.

[0067] 2.3 Meloxicam solution combines with metal ions to form insoluble precipitates.

[0068] Following the method described in section 2.2, a meloxicam solution solubilized with meglumine (concentration approximately 16 mg / mL) was prepared; solutions of calcium acetate, calcium chloride, zinc acetate, copper sulfate, magnesium chloride, cobalt chloride, and manganese chloride, each with a concentration of 300 mM, were also prepared. Each 50 μl of meloxicam solution was added to one 1 mL of each metal ion solution. Meloxicam was able to bind with all of these metal ions, forming insoluble precipitates. Figure 2 )

[0069] Example 3

[0070] This embodiment describes the preparation and characterization of meloxicam liposomes using calcium acetate solution as the internal aqueous phase.

[0071] All phospholipids used in this embodiment were purchased from Lipoid GmbH, Germany. Specifically, hydrogenated soybean phospholipids (HSPC, molecular weight 783.8); polyethylene glycol-modified phospholipids specifically distearate-phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000); cholesterol (CHOL, molecular weight 386.7); and meloxicam was purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd.

[0072] It should be noted that the phospholipids used in the following examples are all hydrogenated soybean phospholipids from Lipoid; the polyethylene glycol phospholipids used are all distearate phosphatidylethanolamine-polyethylene glycol from Lipoid; the cholesterol used is all cholesterol from Lipoid; and the meloxicam used is all purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd.

[0073] 3.1 Preparation of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0074] The preparation method is as follows:

[0075] (1) Prepare calcium acetate aqueous solutions with concentrations of 150mM, 300mM, and 500mM respectively, and adjust the pH to 8.0 with hydrochloric acid;

[0076] (2) Hydrogenated soybean lecithin: distearate phosphatidylethanolamine-polyethylene glycol 2000: cholesterol were melted in anhydrous ethanol at a molar ratio of 3:1:1 to obtain an ethanol mixture solution of lipids.

[0077] (3) Add 3 mL of the calcium acetate solution prepared in step (1) to the ethanol mixture of lipids obtained in step (2), and place it in a water bath at 60°C for 30 minutes with stirring to fully hydrate the lipids and obtain a relatively uniform liposome suspension.

[0078] (4) Using a liposome extruder, the liposome suspension obtained in step (3) is extruded through a carbon membrane with a specific pore size in sequence to control the particle size and uniformity of blank liposomes.

[0079] (5) The liposomes obtained in step (4) are placed in a dialysis bag with a molecular weight cutoff of 10 kDa. A 10% sucrose aqueous solution, which is isotonic with human body, is used as the dialysis medium. The volume ratio of sample to dialysis medium is 1:1000. Dialysis is performed to remove calcium acetate from the aqueous phase outside the liposomes, resulting in an outer aqueous phase composed of 10% sucrose and an inner aqueous phase composed of calcium acetate solution. A blank liposome is formed by the phospholipid bilayer. The aqueous phase inside the liposomes has a certain pH and calcium acetate concentration gradient. Specifically, the inner aqueous phase of the lipid bilayer is a calcium acetate aqueous solution, and the outer aqueous phase of the lipid bilayer is a sucrose aqueous solution (pH 6-7).

[0080] (6) Prepare an aqueous solution of meglumine containing 8 mg / mL meloxicam by following the method of preparing the meloxicam-meglumine solution (molar ratio of 1:1) in Example 2.

[0081] (7) Take an appropriate amount of meloxicam solution and mix it with blank liposomes according to the drug-liposome ratio of 0.05, 0.1 and 0.2, and incubate at 60°C for 30 min to prepare meloxicam liposome solution.

[0082] 3.2. Characterization of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0083] 3.2.1 Particle size of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0084] The prepared meloxicam liposomes were diluted 100 times with deionized water, and the particle size was measured using a Zetasizer ZS90 (Malvin Company, UK). As shown in Table 3, the particle size of the meloxicam liposomes was around 100 nm, and the particle size distribution (PDI) was less than 0.1.

[0085] 3.2.2 Morphology of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0086] Approximately 5 μl of meloxicam liposomes prepared with 300 mM calcium acetate solution as the internal aqueous phase (drug-liposome ratio 0.1) was added dropwise to a 300-mesh Lacy copper mesh (TedPella, USA). Excess solution was aspirated, and the liposomes were quickly immersed in liquid ethane. The morphology of the liposomes was observed using cryo-transmission electron microscopy (FEITalos, Thermo Scientific, USA) at 120 kV. The results are as follows: Figure 3 (B represents blank liposomes, and C represents drug-loaded liposomes). Meloxicam liposomes are spherical with an average particle size of approximately 100 nm; some liposomes exhibit a "bowl-shaped" structure on their inner wall. Figure 3 (As indicated by the white arrow in the middle) This is likely because meloxicam, being a poorly soluble compound, precipitates on the inner side of the lipid membrane after entering the aqueous phase within the liposome. Therefore, it achieves a high encapsulation efficiency and drug loading, is less prone to leakage, and exhibits good storage stability.

[0087] 3.2.2 Encapsulation efficiency of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0088] The prepared meloxicam liposomes were diluted 50 times with ultrapure water, and an appropriate amount of Dowex resin (Sigma-Aldrich) was added. The mixture was shaken thoroughly to adsorb unencapsulated meloxicam. After standing, 200 μl of the supernatant was taken, and the absorbance of meloxicam in the liposomes before and after the addition of resin was measured using the UV detection method described in Example 1. The content was then calculated.

[0089] The encapsulation efficiency (EE) of meloxicam liposomes is calculated using the following formula:

[0090]

[0091] Miner represents the amount of meloxicam in the liposomal formulation after resin adsorption of free drug, i.e., the amount of meloxicam encapsulated by liposomes; Mtotal represents the total amount of meloxicam in the liposomal formulation before resin adsorption. The results are shown in Table 3. The formulated meloxicam liposomes exhibit a high encapsulation efficiency. Specifically, when the calcium acetate concentration in the aqueous phase increased from 150 mM to 300 mM, the drug loading capacity of the liposomes significantly increased with increasing calcium acetate concentration; however, the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0092] Table 3. Particle size and encapsulation efficiency of meloxicam liposomes with calcium acetate solution as the internal aqueous phase.

[0093]

[0094] 3.3 Storage stability of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0095] Meloxicam liposomes with calcium acetate as the internal aqueous phase were stored at 4°C. Samples were taken after a certain number of days, diluted 50-fold, and the encapsulation efficiency was measured according to the method in 3.2.2 to investigate the stability of meloxicam liposomes with calcium acetate as the internal aqueous phase. Figure 4 As shown in (B), none of the three different concentrations of calcium acetate showed significant leakage in the internal water solution within 30 days, thus demonstrating good storage stability.

[0096] 3.4 In vitro release of meloxicam liposomes with calcium acetate solution as the internal aqueous phase

[0097] Meloxicam liposomes containing calcium acetate solutions of varying concentrations as the internal aqueous phase were used. Physiological saline was used as the release medium, and sufficient Dowex resin was added to adsorb free drug, creating a funneling condition. The mixture was shaken at 37°C and 100 rpm on a shaker (THZ-C thermostatic shaker, China). Samples were taken at different time points (0 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, and 24 h). After standing, the supernatant was collected, and the meloxicam content encapsulated in the liposomes was determined by UV method. The cumulative release rate of meloxicam at different time points was calculated. Figure 4 As shown in (C), within 4 hours, the cumulative drug release of the formulations with calcium acetate solutions of different concentrations as the internal aqueous phase was greater than 80%, and the release slowed down after 4 hours.

[0098] Example 4

[0099] This embodiment describes the preparation and characterization of meloxicam liposomes using calcium chloride solution as the internal aqueous phase.

[0100] 4.1 Preparation of meloxicam liposomes with calcium chloride solution as the internal aqueous phase

[0101] Prepare aqueous solutions of calcium chloride with concentrations of 150 mM, 300 mM, and 500 mM, and adjust the pH to 7.5 with hydrochloric acid; prepare meloxicam liposomes with calcium chloride as the internal aqueous phase according to the preparation method in 3.1 of Example 3.

[0102] 4.2 Characterization of meloxicam liposomes with calcium chloride solution as the internal aqueous phase

[0103] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam liposomes prepared using calcium chloride as the internal aqueous phase were determined. The results are shown in Table 4. The particle size of the prepared liposomes was all within 100 ± 10 nm, and the particle size distribution (PDI) was less than 0.1. When the calcium chloride concentration increased from 150 mM to 300 mM, the drug loading capacity of the liposomes increased significantly with increasing calcium chloride concentration; however, the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0104] Table 4. Particle size and encapsulation efficiency of meloxicam liposomes with calcium chloride solution as the internal aqueous phase.

[0105]

[0106] 4.3 Storage stability of meloxicam liposomes with calcium chloride solution as the internal aqueous phase

[0107] Following the method in 3.3 of Example 3, meloxicam liposomes with sodium acetate concentrations of 150 mM, 300 mM, and 500 mM in the above-mentioned internal aqueous phase were taken and stored in a refrigerator at 4°C to investigate the stability of meloxicam liposomes with calcium chloride as the internal aqueous phase. Figure 5 As shown in (B), under storage conditions of 4℃, the three different concentrations of calcium chloride as an internal water agent did not show significant leakage within 30 days, thus demonstrating good storage stability.

[0108] 4.4 In vitro release rate of meloxicam liposomes with calcium chloride solution as the internal aqueous phase

[0109] Meloxicam liposomes with different concentrations of calcium chloride solution as the internal aqueous phase were used. Following the in vitro drug release rate characterization method described in Example 3.4, the cumulative percentage of meloxicam released from the liposomes at different time points was calculated. The results are as follows: Figure 5 As shown in (C), within 4 hours, the cumulative drug release of the three different concentrations of calcium chloride solution as the internal aqueous phase was greater than 80%, and the release slowed down after 4 hours.

[0110] Example 5

[0111] This embodiment describes the preparation and characterization of meloxicam liposomes using zinc acetate solution as the internal aqueous phase.

[0112] 5.1 Preparation of meloxicam liposomes with zinc acetate solution as the internal aqueous phase

[0113] Zinc acetate aqueous solutions with concentrations of 150 mM, 300 mM, and 500 mM were prepared, and the pH was adjusted to 6.0 with hydrochloric acid. Meloxicam liposomes with zinc acetate as the internal aqueous phase were prepared according to the preparation method in 3.1 of Example 3.

[0114] 5.2 Characterization of meloxicam liposomes with zinc acetate solution as the internal aqueous phase

[0115] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam liposomes prepared using zinc acetate as the internal aqueous phase were determined. The results are shown in Table 5. The particle size of the meloxicam liposomes was approximately 155 ± 5 nm. The particle size distribution (PDI) was less than 0.1. When the zinc acetate concentration increased from 150 mM to 300 mM, the drug loading capacity of the liposomes increased significantly with increasing zinc acetate concentration; however, the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0116] Table 5. Particle size and encapsulation efficiency of meloxicam liposomes with zinc acetate solution as the internal aqueous phase.

[0117]

[0118] 5.3 Storage stability of meloxicam liposomes with zinc acetate solution as the internal aqueous phase

[0119] Following the method described in Example 3.3, meloxicam liposomes with zinc acetate solutions of different concentrations as the internal aqueous phase were taken and stored at 4°C. The stability of meloxicam liposomes with zinc acetate as the internal aqueous phase was investigated, and the results are as follows: Figure 6 As shown in (B), the three formulations with zinc acetate of different concentrations as the internal aqueous phase did not leak after 30 days, thus demonstrating good storage stability.

[0120] 5.4 In vitro release rate of meloxicam liposomes with zinc acetate solution as the internal aqueous phase

[0121] Meloxicam liposomes with different concentrations of zinc acetate solution as the internal aqueous phase were used. Following the in vitro drug release rate characterization method described in Example 3.4, the cumulative percentage of meloxicam released from the liposomes at different time points was calculated. The results are as follows: Figure 6 As shown in (C), within 4 hours, the cumulative drug release of the three formulations with zinc acetate of different concentrations as the internal aqueous phase was greater than 70%, and the release slowed down after 4 hours.

[0122] Example 6

[0123] Example 6: Preparation and characterization of meloxicam liposomes with copper sulfate solution as the internal aqueous phase.

[0124] 6.1 Preparation of meloxicam liposomes with copper sulfate solution as the internal aqueous phase

[0125] Copper sulfate aqueous solutions with concentrations of 150 mM, 300 mM, and 500 mM were prepared, and the pH was adjusted to 7.0 with hydrochloric acid. Meloxicam liposomes with copper sulfate as the internal aqueous phase were prepared according to the preparation method in 3.1 of Example 3.

[0126] 6.2 Characterization of meloxicam liposomes with copper sulfate solution as the internal aqueous phase

[0127] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam liposomes prepared using copper sulfate as the internal aqueous phase were determined. The results are shown in Table 6. The particle size of the meloxicam liposomes was approximately 130 ± 5 nm. The particle size distribution (PDI) was less than 0.1. When the copper sulfate concentration increased from 150 mM to 300 mM, the drug loading capacity of the liposomes increased significantly with increasing copper sulfate concentration; however, the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0128] Table 6. Particle size and encapsulation efficiency of meloxicam liposomes with copper sulfate solution as the internal aqueous phase.

[0129]

[0130] 6.3 Storage stability of meloxicam liposomes with copper sulfate solution as the internal aqueous phase

[0131] Following the method described in Example 3.3, meloxicam liposomes with copper sulfate solutions of different concentrations as the internal aqueous phase were taken and stored at 4°C. The stability of meloxicam liposomes with copper sulfate as the internal aqueous phase was investigated, and the results are as follows: Figure 7 As shown in (B), the three formulations with copper sulfate of different concentrations as the internal aqueous phase did not leak after 30 days, thus demonstrating good storage stability.

[0132] 6.4 In vitro release rate of meloxicam liposomes with copper sulfate solution as the internal aqueous phase

[0133] Meloxicam liposomes with different concentrations of copper sulfate solution as the internal aqueous phase were used. Following the in vitro drug release rate characterization method described in Example 3.4, the cumulative percentage of meloxicam released from the liposomes at different time points was calculated. The results are as follows: Figure 7 As shown in (C), within 4 hours, the cumulative drug release of the three formulations with copper sulfate of different concentrations as the internal aqueous phase was greater than 70%, and the release slowed down after 4 hours.

[0134] Example 7

[0135] This embodiment describes the preparation and characterization of meloxicam liposomes using magnesium chloride solution as the internal aqueous phase.

[0136] 7.1 Preparation of meloxicam liposomes with magnesium chloride solution as the internal aqueous phase

[0137] Magnesium chloride aqueous solutions with concentrations of 150 mM, 300 mM, and 500 mM were prepared, and the pH was adjusted to 6.5 with hydrochloric acid. Meloxicam liposomes with magnesium chloride as the internal aqueous phase were prepared according to the preparation method in 3.1 of Example 3.

[0138] 7.2 Characterization of meloxicam liposomes with magnesium chloride solution as the internal aqueous phase

[0139] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam liposomes prepared using magnesium chloride as the internal aqueous phase were determined. The results are shown in Table 7. The particle size of the meloxicam liposomes was approximately 110 ± 5 nm. The particle size distribution (PDI) was less than 0.1. When the magnesium chloride concentration increased from 150 mM to 300 mM, the drug loading capacity of the liposomes increased significantly with increasing magnesium chloride concentration; however, the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0140] Table 7. Particle size and encapsulation efficiency of meloxicam liposomes with magnesium chloride solution as the internal aqueous phase.

[0141]

[0142] 7.3 Storage stability of meloxicam liposomes with magnesium chloride solution as the internal aqueous phase

[0143] Following the method described in Example 3.3, meloxicam liposomes with magnesium chloride solutions of different concentrations as the internal aqueous phase were taken and stored in a 4°C refrigerator. The stability of the meloxicam liposomes with magnesium chloride as the internal aqueous phase was investigated, and the results are as follows: Figure 8 As shown in (B), the three formulations with magnesium chloride of different concentrations as the internal aqueous phase did not show significant leakage after 30 days, thus demonstrating good storage stability.

[0144] 7.4 In vitro release rate of meloxicam liposomes with magnesium chloride solution as the internal aqueous phase

[0145] Meloxicam liposomes with different concentrations of magnesium chloride solution as the internal aqueous phase were used. Following the in vitro drug release rate characterization method described in Example 3.4, the cumulative percentage of meloxicam released from the liposomes at different time points was calculated. The results are as follows: Figure 8 As shown in (C), within 4 hours, the cumulative drug release of the three formulations with magnesium chloride of different concentrations as the internal aqueous phase was greater than 70%, and the release slowed down after 4 hours.

[0146] Example 8

[0147] This embodiment describes the preparation and characterization of meloxicam liposomes using cobalt chloride solution as the internal aqueous phase.

[0148] 8.1 Preparation of meloxicam liposomes with cobalt chloride solution as the internal aqueous phase

[0149] Cobalt chloride aqueous solutions with concentrations of 150 mM, 300 mM, and 500 mM were prepared, and the pH was adjusted to 6.0 with hydrochloric acid. Meloxicam liposomes with cobalt chloride as the internal aqueous phase were prepared according to the preparation method in 3.1 of Example 3.

[0150] 8.2 Characterization of meloxicam liposomes with cobalt chloride solution as the internal aqueous phase

[0151] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam liposomes prepared using cobalt chloride as the internal aqueous phase were determined. The results are shown in Table 8. The particle size of the meloxicam liposomes was approximately 120 ± 5 nm. The particle size distribution (PDI) was less than 0.1. When the cobalt chloride concentration increased from 150 mM to 300 mM, the drug loading capacity of the liposomes increased significantly with increasing cobalt chloride concentration; however, the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0152] Table 8. Particle size and encapsulation efficiency of meloxicam liposomes with cobalt chloride solution as the internal aqueous phase.

[0153]

[0154] 8.3 Storage stability of meloxicam liposomes with cobalt chloride solution as the internal aqueous phase

[0155] Following the method described in Example 3.3, meloxicam liposomes with different concentrations of cobalt chloride solution as the internal aqueous phase were taken and stored in a 4°C refrigerator. The stability of meloxicam liposomes with cobalt chloride as the internal aqueous phase was investigated, and the results are as follows: Figure 9 As shown in (B), the three formulations with cobalt chloride of different concentrations as the internal aqueous phase did not show significant leakage after 30 days, thus demonstrating good storage stability.

[0156] 8.4 In vitro release rate of meloxicam liposomes with cobalt chloride solution as the internal aqueous phase

[0157] Meloxicam liposomes with different concentrations of cobalt chloride solution as the internal aqueous phase were used. Following the in vitro drug release rate characterization method described in Example 3.4, the cumulative percentage of meloxicam released from the liposomes at different time points was calculated. The results are as follows: Figure 9 As shown in (C), within 4 hours, the cumulative drug release of the three formulations with cobalt chloride as the internal aqueous phase was greater than 70%, and the release slowed down after 4 hours.

[0158] Example 9

[0159] This embodiment describes the preparation and characterization of meloxicam liposomes using manganese chloride solution as the internal aqueous phase.

[0160] 9.1 Preparation of meloxicam liposomes with manganese chloride solution as the internal aqueous phase

[0161] Prepare aqueous solutions of manganese chloride with concentrations of 150 mM, 300 mM, and 500 mM, and adjust the pH to 6.5 with hydrochloric acid; prepare meloxicam liposomes with manganese chloride as the internal aqueous phase according to the preparation method in 3.1 of Example 3.

[0162] 9.2 Characterization of meloxicam liposomes with manganese chloride solution as the internal aqueous phase

[0163] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam liposomes prepared using manganese chloride as the internal aqueous phase were determined. The results are shown in Table 9. Figure 10 As shown, the particle size of meloxicam liposomes was approximately 120 ± 5 nm. The particle size distribution (PDI) was less than 0.1. When the manganese chloride concentration increased from 150 mM to 300 mM, the drug loading capacity of the liposomes increased significantly with the increase of manganese chloride concentration, but the increase in encapsulation efficiency slowed down after exceeding 300 mM.

[0164] Table 9. Particle size and encapsulation efficiency of meloxicam liposomes with manganese chloride solution as the internal aqueous phase.

[0165]

[0166]

[0167] 9.3 Storage stability of meloxicam liposomes with manganese chloride solution as the internal aqueous phase

[0168] Following the method described in Example 3.3, meloxicam liposomes with different concentrations of manganese chloride solution as the internal aqueous phase were taken and stored in a 4°C refrigerator. The stability of meloxicam liposomes with manganese chloride as the internal aqueous phase was investigated, and the results are as follows: Figure 10 As shown in (B), the three formulations with manganese chloride of different concentrations as the internal aqueous phase did not show significant leakage after 30 days, thus demonstrating good storage stability.

[0169] 9.4 In vitro release rate of meloxicam liposomes with manganese chloride solution as the internal aqueous phase

[0170] Meloxicam liposomes with different concentrations of manganese chloride solution as the internal aqueous phase were used. Following the in vitro drug release rate characterization method described in Example 3.4, the cumulative percentage of meloxicam released from the liposomes at different time points was calculated. The results are as follows: Figure 10 As shown in (C), within 4 hours, the cumulative release of the three formulations with different concentrations of manganese chloride as the internal aqueous phase was greater than 70%, and the release slowed down after 4 hours.

[0171] Example 10

[0172] This example demonstrates the analgesic effect of meloxicam liposome intravenous injection.

[0173] The analgesic effect of intravenous meloxicam liposome injection was evaluated using a mouse writhing model.

[0174] Fifty SPF-grade Kunming mice, weighing 18–22 g, were randomly divided into four groups of 10 mice each (half male, half female). The groups included a negative control group (saline), a positive control group (meroxanam injection, Boehringer Ingelheim), a meloxicam suspension group, a meloxicam liposome group, and a blank liposome group. The liposome group consisted of blank liposomes and meloxicam-loaded liposomes (approximately 2 mg / mL) prepared in Example 3 using calcium acetate as the internal aqueous phase. Except for the meloxicam suspension, which was administered intraperitoneally, all other groups received the meloxicam via tail vein administration. The meloxicam dosage was 2 mg / kg for all groups.

[0175] Twenty minutes after each group was injected with the drug, 1% glacial acetic acid was injected into the peritoneum to create an abdominal pain pathological model. The mice were then placed in an inverted graduated cylinder, and the number of writhing movements within 15 minutes was observed and recorded. The inhibition rate was calculated as follows: Inhibition rate = (average number of writhing movements in the drug-treated group - average number of writhing movements in the negative control group) / average number of writhing movements in the negative control group × 100%.

[0176] One-way ANOVA was used to analyze differences between groups. A p-value < 0.05 was considered statistically significant, and a p-value < 0.01 was considered highly statistically significant. The results are shown in Table 10.

[0177] Table 10. Inhibitory effect of meloxicam on acetic acid-induced writhing response in mice (meloxacin dose 2 mg / kg)

[0178]

[0179]

[0180] The results showed that, compared with the suspension, meloxicam liposomes can rapidly release the drug into the bloodstream after intravenous injection, exhibiting an analgesic effect similar to that of the injection.

[0181] Example 11

[0182] This embodiment describes the preparation and characterization of meloxicam-doxacin co-loaded liposomes with manganese chloride as the internal aqueous phase.

[0183] 11.1 Preparation of meloxicam-doxacin co-loaded liposomes with manganese chloride solution as the internal aqueous phase

[0184] (1) Prepare a 300mM manganese chloride aqueous solution and adjust the pH to 7 with hydrochloric acid;

[0185] (2) Prepare blank manganese chloride liposomes according to the methods in 3.1(1) to (5) of Example 3;

[0186] (3) Prepare meloxicam-meglumine aqueous solution (concentration of 8 mg / mL) according to the method in Example 2;

[0187] (4) Accurately weigh 10 mg of doxorubicin hydrochloride, dissolve it in 10% sucrose to 1 mL, and prepare a 10 mg / mL doxorubicin hydrochloride solution.

[0188] (5) Add doxorubicin hydrochloride solution and meloxicam solution to blank liposomes at total drug-liposome ratios of 0.1, 0.2 and 0.3 (molecular ratio of meloxicam to doxorubicin hydrochloride 1:1). Incubate at 60℃ for 30 min to prepare meloxicam-doxorubicin co-loaded liposome solutions.

[0189] In addition, using the manganese chloride liposomes in (2), meloxicam solution or doxorubicin hydrochloride solution were added to the liposomes at drug-liposome ratios of 0.05, 0.1 and 0.15 respectively to prepare meloxicam-loaded liposomes or doxorubicin-loaded liposomes.

[0190] 11.2 Characterization of meloxicam-doxacin co-loaded liposomes with manganese chloride solution as the internal aqueous phase

[0191] Following the method described in 3.2 of Example 3, the particle size and encapsulation efficiency of meloxicam-doxacin co-loaded liposomes prepared with manganese chloride as the internal aqueous phase were determined (Table 11 and 3.2). Figure 12 ), and compared with the particle size and encapsulation efficiency of liposomes loaded with meloxicam or doxorubicin (Table 12 and ). Figure 11 The particle size of the co-loaded drug liposomes was approximately 110 ± 5 nm, and the particle size distribution (PDI) was less than 0.1. Co-loading of doxorubicin with meloxicam significantly improved the encapsulation efficiency of doxorubicin. Figure 11 The lipid ratio in traditional Chinese medicine refers to the molar ratio of a single drug to lipids. Figure 12 In this context, the drug-lipid ratio refers to the ratio of the total molar amount of meloxicam and doxorubicin to the molar amount of lipids.

[0192] Table 11. Particle size and encapsulation efficiency of meloxicam-doxacin co-loaded liposomes with manganese chloride solution as the internal aqueous phase.

[0193]

[0194] Table 12. Particle size and encapsulation efficiency of liposomes loaded with meloxicam or doxorubicin, using manganese chloride solution as the internal aqueous phase.

[0195]

[0196] Example 12

[0197] This example demonstrates the cytotoxicity of meloxicam-doxacin co-loaded liposomes against doxorubicin-resistant K562 cells:

[0198] (1) K562 cells were added at a density of 1×10⁶ cells per well. 5Different concentrations of doxorubicin mono-loaded liposomes, meloxicam mono-loaded liposomes, and meloxicam-doxorubicin co-loaded liposomes were seeded into 96-well plates, and incubated for 48 h. After incubation, 10 μL of CCK-8 reagent (Beyotime) was added to each well, and incubated for 4 h. After incubation, the absorbance of each well was measured at a wavelength of 450 nm.

[0199] (2) Doxorubicin-resistant K562 cells were cultured at 1×10⁶ cells per well. 5 Different concentrations of doxorubicin mono-loaded liposomes, meloxicam mono-loaded liposomes, and meloxicam-doxorubicin co-loaded liposomes were seeded into 96-well plates, and incubated for 48 h. After incubation, 10 μL of CCK-8 reagent (Beyotime) was added to each well, and incubated for 4 h. After incubation, the absorbance of each well was measured at a wavelength of 450 nm. The results are as follows. Figure 13 The results showed that meloxicam-doxime co-loaded liposomes had a significantly higher inhibitory effect on doxorubicin-resistant K562 cells than doxorubicin-only liposomes, while meloxicam-only liposomes had no significant inhibitory effect on cells. These results suggest that co-loading with meloxicam is beneficial in reducing tumor cell resistance to doxorubicin.

[0200] Example 13

[0201] This embodiment examines the drug release rate at the injection site after local injection of liposomes.

[0202] This embodiment uses the dialysis bag method to determine the drug release rate of liposomes: liposomes are placed in a dialysis bag and then in a small volume of release medium. Since only the drug released from the liposomes can diffuse from the dialysis bag into the release medium, the drug release rate of the liposomes can be determined by measuring the drug concentration in the release medium at different time points. It should be noted that the drug release rate determination method in this embodiment differs from the method in Example 3.4. Example 3.4 involves directly adding liposomes to the release medium to simulate the situation where liposomes are significantly diluted by blood after intravenous injection; in 3.4, resin is used to adsorb the drug released from the liposomes to simulate the immediate removal of the drug from the bloodstream after release. In this embodiment, the dialysis bag method is used to determine the drug release rate of liposomes primarily to simulate the situation where there is a small amount of release medium at the injection site and the released drug remains locally for a period of time.

[0203] The specific steps are as follows:

[0204] Take 100 μl of meloxicam liposomes containing 300 mM calcium acetate, copper sulfate, magnesium chloride, and manganese chloride (drug-liposome ratio 0.1) from Examples 3, 6, 7, and 9, respectively, and place them in a dialysis bag (Spectrumlabs, model 132570) with a cutoff molecular weight of 10000. Immerse the dialysis bag containing the liposomes in 5 ml of release medium (physiological saline containing 0.2% SDS (w / v)) and gently stir in a 37°C water bath. Take 200 μl of release medium at 0, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, respectively, and add the same volume of fresh release medium. Determine the concentration of meloxicam in the solution using the UV method (Example 1) and calculate the cumulative release rate of meloxicam at different time points. Take another 100 μl of meloxicam-meglumine aqueous solution with a concentration of 100 μg / ml, add it to the dialysis bag, and determine the release rate using the same method.

[0205] The cumulative release rates of meloxicam solution and liposomes are as follows: Figure 14 As shown, within 12 hours, the cumulative release of meloxicam liposomes reached 50%, after which the drug release rate plateaued. In contrast, meloxicam solution was completely absorbed into the release medium in approximately 2 hours, indicating that meloxicam can diffuse rapidly through the dialysis bag used, and the dialysis bag does not impede the release of meloxicam.

[0206] The cumulative release rate of meloxicam liposomes is calculated using the following formula:

[0207]

[0208] C n V represents the concentration of the sample taken at each of the nth time points; n The total volume of the released medium; C i and V i , i, and d, represent the sample concentration and sampling volume at the i-th time point, respectively; W is the dosage; EE% is the meloxicam encapsulation rate.

[0209] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A meloxicam injection, characterized in that, The injectable preparation comprises meloxicam, an external aqueous phase, and liposomes; the meloxicam is loaded into the liposomes; the liposomes comprise hydrogenated soybean lecithin, distearylphosphatidylethanolamine-polyethylene glycol 2000, and cholesterol, in a molar ratio of hydrogenated soybean lecithin:distearylphosphatidylethanolamine-polyethylene glycol 2000:cholesterol = 3:1:1; the external aqueous phase is a 10% sucrose aqueous solution; the liposomes contain an internal aqueous phase, which is a 300 mM calcium acetate solution; the meloxicam is capable of forming a precipitate with calcium ions; the method of loading meloxicam into the liposomes is an active drug delivery method, which includes at least the following steps: (1) Hydrogenated soybean lecithin: distearate phosphatidylethanolamine-polyethylene glycol 2000:cholesterol were dissolved in anhydrous ethanol at a molar ratio of 3:1:1 to obtain an ethanol mixture of lipids; (2) 300 mM calcium acetate solution with pH adjusted to 8.0 by hydrochloric acid was added to the ethanol mixture of lipids, and the mixture was placed in a water bath at 60°C with stirring for 30 minutes to obtain a liposome suspension; (3) The liposome suspension was sequentially squeezed through a carbon membrane with a specific pore size in a liposome extruder to control the particle size and uniformity of blank liposomes; (4) The blank liposomes were placed in a dialysis bag with a molecular weight cutoff of 10 kDa, and the liposomes were subjected to dialysis. A 10% sucrose aqueous solution was used as the dialysis medium. The volume ratio of the sample to the dialysis medium was 1:1000. Dialysis was performed to remove calcium acetate from the aqueous phase outside the liposomes, resulting in an outer aqueous phase composed of a pH of 6-7 and a 10% sucrose aqueous solution, an inner aqueous phase composed of a calcium acetate solution, and a blank liposome composed of a phospholipid bilayer. (5) The blank liposomes were mixed with a meloxicam-meglumine solution with a molar ratio of 1:1 according to the drug-liposome ratio of 0.1, 0.2, or 0.

3. The concentration of meloxicam in the meloxicam-meglumine solution was 8 mg / mL. The mixture was incubated at 60°C for 30 minutes to obtain a meloxicam liposome solution.

2. The injectable preparation according to claim 1, characterized in that, Based on the volume of the injection, the concentration of meloxicam is greater than or equal to 0.01 mg / mL.

3. The use of the injectable formulation as described in claim 1 or 2 in the preparation of an analgesic for injection.

4. An anti-inflammatory agent, characterized in that, This includes injectable and cytotoxic drugs as described in claim 1 or 2, or injectable and immunomodulatory drugs as described in claim 1 or 2.

5. The use of the anti-inflammatory agent as described in claim 4 in the preparation of a medicament for treating tumors.

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