Meloxicam nanocrystal freeze-dried powder pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a meloxicam nanocrystal freeze-dried powder pharmaceutical composition. The meloxicam nanocrystal freeze-dried powder pharmaceutical composition comprises meloxicam, a stabilizer and a freeze-drying protective additive, the freeze-drying protective agent comprises one or more of saccharides, salts, polyhydric alcohols, amino acids and polymers. The meloxicam nanocrystal freeze-dried powder pharmaceutical composition disclosed by the invention is prepared by taking meloxicam as an active ingredient and matching with pharmaceutically acceptable auxiliary materials through a specific process. The prepared freeze-dried powder is full in appearance, complete in form, excellent in redissolving performance and good in storage stability, meanwhile, the prepared meloxicam nanocrystal freeze-dried powder can be used as an intermediate preparation, addition of a large number of freeze-drying protective agents in a traditional process can be avoided, and the production cost is reduced. The compound can be further processed and prepared into a plurality of pharmaceutically acceptable transdermal delivery preparations such as gel, plaster and the like. Compared with conventional oral tablets, the transdermal preparation has the advantages of no gastrointestinal tract first-pass effect, reduction of systemic drug exposure, improvement of patient compliance and the like.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a meloxicam nanocrystal lyophilized powder pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] With the aging global population and the increase in patients with chronic diseases, the clinical demand for non-addictive analgesics has increased dramatically. In 2024, the U.S. Food and Drug Administration (FDA) officially listed non-opioid drugs as first-line analgesics, with nonsteroidal anti-inflammatory drugs (NSAIDs) as the mainstream clinical choice. Meloxicam, for example, has excellent anti-inflammatory, analgesic, and antipyretic effects and is commonly used clinically to relieve pain caused by musculoskeletal diseases, osteoarthritis, and rheumatoid arthritis. The core mechanism of action of NSAIDs is to inhibit cyclooxygenase (COX) activity, reduce prostaglandin (PG) production, thereby blocking inflammatory responses and pain signal transmission, without affecting central opioid receptors and posing no risk of addiction. There are two subtypes of COX in the body: COX-1 and COX-2. COX-1 is continuously expressed and participates in physiological processes such as gastric mucosal protection, platelet aggregation, and renal blood flow regulation; COX-2 is inducible, with low levels in normal tissues, but can be activated by cytokines and synthesize large amounts of PGs under inflammatory conditions. Meloxicam primarily inhibits COX-2 selectively, while also exhibiting weak activity against COX-1, with a corresponding IC50 value. 50 With half-lives of 0.49 μM and 36.6 μM, respectively, it combines efficacy comparable to other NASIDs with lower toxicity and superior safety. Furthermore, meloxicam's longer half-life allows for once-daily dosing, improving patient adherence.

[0003] However, research has found NSAIDs SWhen delivered orally, NSAIDs often cause adverse reactions such as gastrointestinal bleeding, indigestion, and potential cardiovascular risks. In response, countries like the US and Europe have provided recommended routes of administration for NSAIDs. For example, in the treatment of pain conditions such as osteoarthritis, topical application of NSAIDs should be prioritized before oral administration to reduce systemic drug exposure and minimize side effects. Currently available marketed dosage forms of meloxicam include tablets, suspensions, capsules, granules, and injections. Research on transdermal formulations is limited, primarily due to the solubility of the API itself. Publicly available research on meloxicam transdermal formulations relies heavily on solubilizers or co-solvents, which can lead to high toxicity and strong irritation in practical use. For instance, patent CN106924223A discloses a method using a 2:1 ethanol-acetone mixture to dissolve meloxicam, followed by mixing with pressure-sensitive adhesive and a transdermal penetration enhancer to prepare a patch. Patent CN119174741A mainly describes the preparation of a poultice by dissolving meloxicam with a drug-soluble solubilizer and surfactant, followed by mixing with a matrix phase. Patent CN1322523A uses propylene glycol-ethanol-water (1:1:2) as a mixed solvent, combined with Tween 80, hydroxypropyl-β-cyclodextrin and azone to form a mixed solution, and then with a carbomer gel matrix to form meloxicam gel.

[0004] Nanocrystal technology, as a key means to solve the problem of poor drug solubility, has core advantages including small particle size, large specific surface area, significantly improved drug solubility and bioavailability, no need for carrier materials, only a small amount of stabilizer, no need for large amounts of solubilizers or cosolvents, and near 100% drug loading. In transdermal delivery, drug nanocrystals can also improve skin adhesion and permeability, enhance hair follicle retention, and are not easily removed. Its limitations lie in the fact that nanosuspensions are prone to stability problems such as particle aggregation, growth, and crystal form transformation, and have a high water content, making them difficult to directly load into semi-solid matrices, often requiring further processing such as freeze-drying or spray drying. However, conventional freeze-dried nanocrystal powders have problems such as easy hygroscopicity and the need for a large amount of protective agent. At the same time, common freeze-drying protective agents are non-functional excipients, which can hinder subsequent formulation screening, release performance, and other research and development work for topical formulations. Summary of the Invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a meloxicam nanocrystal lyophilized powder pharmaceutical composition. The pharmaceutical composition provided by the present invention has low water content, high stability, is easy to store, and has a low lyophilization protection dose. The nanocrystal lyophilized powder can be used as an intermediate preparation to prepare various pharmaceutically acceptable transdermal drug delivery formulations such as gels and patches. Compared with conventional oral tablets, these transdermal formulations have advantages such as no first-pass effect in the gastrointestinal tract, reduced systemic drug exposure, and improved patient compliance, providing a new local drug delivery regimen for clinical anti-inflammatory and analgesic treatment.

[0006] The present invention provides a meloxicam nanocrystal lyophilized powder pharmaceutical composition, comprising meloxicam, a stabilizer, and a lyophilization protectant.

[0007] The freeze-drying protectant includes one or more of sugars, salts, polyols, amino acids, and polymers.

[0008] The sugars include lactose, sucrose, and trehalose; the salts include inorganic salts and buffer salts; the amino acids include glycine or alanine; and the polyols include one or more of mannitol, sorbitol, glycerol, and propylene glycol.

[0009] Preferably, the freeze-drying protectant is selected from one or more of trehalose or polymers; more preferably, the freeze-drying protectant is selected from polymers such as poloxamer, povidone, etc., and particularly preferably poloxamer 407.

[0010] Low addition amounts can improve the storage stability of nanocrystalline lyophilized powder drugs without hindering their use as intermediates in the development of subsequent drug formulations.

[0011] According to the present invention, the stabilizer includes surfactants, natural polymers or synthetic polymers;

[0012] The surfactant is selected from ionic surfactants, nonionic surfactants, or amphoteric surfactants; the ionic surfactants include sodium dodecyl sulfate or hexadecyltrimethylammonium bromide; the nonionic surfactants commonly include polysorbate 80, sorbitan sesquioleate, poloxamer, or polyoxyethylene castor oil derivatives.

[0013] The natural polymers include gelatin, gum arabic, chitosan, or sodium alginate;

[0014] The synthetic polymers include polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, or sodium carboxymethyl cellulose.

[0015] The inventors have discovered that the above-mentioned specific freeze-drying protectant, especially the polymer component therein, has a superior effect compared to other freeze-drying protectants. In particular, when used in synergy with stabilizers, the "steric hindrance" effect of the polymer can be used to suppress the Austmann ripening phenomenon of nanocrystals during the nucleation, growth and drying stages, thereby significantly improving the protective effect.

[0016] According to the present invention, the weight ratio of meloxicam to stabilizer is 1:1 to 20:1; preferably 3:1 to 5:1; specifically, it can be 1:1, 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; or any value within the range of the above two.

[0017] In some specific embodiments, the weight ratio of meloxicam to the lyophilization protectant is 10:1 to 1:10. Preferably, the weight ratio of meloxicam to the lyophilization protectant is 5:1 to 1:2, and more preferably, the weight ratio of meloxicam to the lyophilization protectant is 4:1 to 1:1. Specifically, it can be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, or any value within a range of the above.

[0018] The water content of the lyophilized pharmaceutical composition of the present invention is 0-8%, preferably 0-2%, and more preferably 0.02-0.7%. Specifically, it can be 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8%.

[0019] According to the present invention, the Z-average of the meloxicam nanocrystalline lyophilized powder pharmaceutical composition is 200 nm to 800 nm, and the PDI is 0.1 to 0.5. Preferably, the Z-average of the lyophilized powder pharmaceutical composition is 250 nm to 450 nm, and the PDI is 0.1 to 0.35.

[0020] This invention provides a method for preparing the above-mentioned lyophilized powder pharmaceutical composition, comprising the following steps:

[0021] A) Preparation of meloxicam nanosuspension;

[0022] B) The meloxicam nano suspension was freeze-dried.

[0023] This invention prepares meloxicam nanosuspension by acid-base precipitation assisted by mechanical stirring or homogenization.

[0024] The present invention specifically includes the preparation of meloxicam nanosuspension:

[0025] a1) Meloxicam and stabilizer are dissolved in an alkaline solution to obtain an alkaline phase;

[0026] a2) Add an acidic solution to the alkaline phase under uniform dispersion, and then add a lyophilization protectant to obtain the product.

[0027] The types and proportions of the stabilizers and lyophilization protectants have been clearly described above and will not be repeated here.

[0028] The acidic solution is a hydrochloric acid solution, and the alkaline solution is a sodium hydroxide solution, with the corresponding acidic and alkaline substances in the acid and alkali phases being fed in an equimolar ratio.

[0029] Addressing the technical shortcomings of traditional nanocrystal preparation processes (ball milling, high-pressure homogenization), such as reliance on high-power equipment, high energy consumption (ball milling energy consumption ≥5kWh / kg, high-pressure homogenization requires maintaining 50-200MPa high pressure), and limitations on large-scale production, this invention creatively proposes an acid-base precipitation-assisted mechanical stirring method, which combines the advantages of simple process, controllable process, cost-saving and high efficiency, providing a new approach for process scale-up and industrial production.

[0030] An acidic solution is added to the alkaline phase under uniform dispersion conditions. The dispersion conditions are: homogenization or mechanical stirring to maintain a rapid and uniform mixing state of the solution. The homogenization speed is 4000~11000 rpm or the stirring speed is 500~1000 rpm.

[0031] Then add the freeze-drying protectant to obtain the product; after adding the freeze-drying protectant, stir for 10 minutes or longer to ensure that the freeze-drying protectant is completely dissolved.

[0032] Meloxicam nano suspension was freeze-dried.

[0033] In some specific embodiments, the freeze-drying includes pre-freezing, a first stage of primary drying, a second stage of primary drying, and desorption drying.

[0034] According to the present invention, the pre-freezing temperature in the pre-freezing stage is -40 ~ -45℃, the cooling time is 60 ~ 240 min, and the duration is 120 ~ 360 min;

[0035] Specifically, the pre-freezing temperature is -40℃, -41℃, -42℃, -43℃, -44℃, or -45℃; the cooling time can be 60min, 80min, 100min, 120min, 140min, 160min, 180min, 200min, 220min, or 240min; and the duration can be 120min, 140min, 160min, 180min, 200min, 220min, 240min, 260min, 280min, 300min, 320min, 340min, or 360min.

[0036] The first stage of the drying process is set at a temperature of -40 to -45°C, a duration of 120 to 720 minutes, and a vacuum level of 0.1 to 0.3 mbar.

[0037] The specific temperature settings for the first stage can be -40℃, -41℃, -42℃, -43℃, -44℃, or -45℃; the specific durations can be 120min, 170min, 220min, 270min, 320min, 370min, 420min, 470min, 520min, 570min, 620min, 670min, or 720min.

[0038] The second stage of the primary drying process is set to a temperature of -20 to -30°C, a heating / cooling time of 120 to 360 min, a duration of 240 to 720 min, and a vacuum level of 0.1 to 0.3 mbar.

[0039] The specific temperature settings for the second stage can be -20℃, -21℃, -22℃, -23℃, -24℃, -25℃, -26℃, -27℃, -28℃, -29℃, and -30℃.

[0040] The specific heating and cooling times can be 120 min, 170 min, 220 min, 270 min, 320 min, and 360 min; the specific durations can be 240 min, 290 min, 340 min, 390 min, 440 min, 490 min, 540 min, 590 min, 640 min, 690 min, and 720 min.

[0041] The set temperature for analytical drying is 10 ~ 25℃, the heating and cooling time is 40 ~ 360 min, the duration is 240 ~ 720 min, and the set vacuum degree is 0.0 ~ 0.1 mbar.

[0042] The drying temperature can be 10℃, 15℃, 20℃, or 25℃; the specific heating and cooling times can be 40min, 90min, 140min, 190min, 240min, 290min, 340min, or 360min.

[0043] The duration can be 240 min, 290 min, 340 min, 390 min, 440 min, 490 min, 540 min, 590 min, 640 min, 690 min, or 720 min.

[0044] The present invention utilizes the combined effect of the above-mentioned freeze-drying parameters to achieve a superior freeze-drying effect compared to other parameters within the above parameter range.

[0045] The meloxicam nanocrystalline lyophilized powder pharmaceutical composition of this invention uses meloxicam as the active ingredient, combined with pharmaceutically acceptable excipients, and is prepared through a specific process. The average particle size (Z-average) of the drug nanocrystals is 250 nm to 450 nm, the polydispersity index (PDI) is 0.1 to 0.35, and the particle size distribution is uniform. The lyophilized powder prepared by this invention has a full appearance, intact morphology, and excellent resolvability; furthermore, after a small amount of polymer coating and freeze-drying curing treatment, it has a low water content (0.02 to 0.7%), and its storage stability is significantly improved.

[0046] The present invention also provides the use of the lyophilized powder pharmaceutical composition described in any one of the above claims in the preparation of transdermal formulations.

[0047] The transdermal formulations described in this invention are pharmaceutically acceptable transdermal formulations, including but not limited to patches, gels, creams, etc., used to meet the huge demand for transdermal delivery of meloxicam for local administration in clinical analgesia.

[0048] This invention innovatively uses the prepared meloxicam nanocrystal lyophilized powder as an intermediate preparation, avoiding the addition of large amounts of lyophilization protectants in traditional processes. It can be further processed into various pharmaceutically acceptable transdermal drug delivery formulations such as gels and patches. Compared with conventional oral tablets, these transdermal formulations have advantages such as no first-pass effect in the gastrointestinal tract, reduced systemic drug exposure, and improved patient compliance, providing a new local drug delivery regimen for clinical anti-inflammatory and analgesic treatment.

[0049] The present invention provides a gel patch comprising the lyophilized powder pharmaceutical composition described in any one of the above technical solutions.

[0050] The gel patch of the present invention further includes one or more of the following: a hydrophilic skeleton material, a filler, a thickener, a moisturizer, a crosslinking agent, a transdermal penetration enhancer, a pH adjuster, and a metal chelating agent; the above percentages are by mass.

[0051] Specifically, the thickener is one or more of gelatin, gum arabic, polyvinyl alcohol, hydroxypropyl methylcellulose, polyacrylic acid, or polyvinylpyrrolidone; the preferred addition amount is 1 wt%-15 wt%.

[0052] The hydrophilic framework material is one or more of completely neutralized sodium polyacrylate, partially neutralized sodium polyacrylate, polyacrylic acid, or carbomer; the preferred addition amount is 5wt%-25wt%.

[0053] The filler is one or more of titanium dioxide, diatomaceous earth, saponified clay, calcium carbonate, micronized silica gel, starch, talc, or kaolin; the preferred addition amount is 0wt%-30wt%.

[0054] The moisturizer is one or more of glycerin, propylene glycol, or polyethylene glycol; the preferred amount added is 10wt%-60wt%.

[0055] The crosslinking agent is one or more of aluminum hydroxyl, aluminum trichloride, or aluminum hydroxide; the preferred addition amount is 0.05 wt%-0.5 wt%.

[0056] The transdermal penetration enhancer is one or more of azone, menthol, menthyl phthalate, oleic acid, oleyl alcohol, Tween, Span, isopropyl myristate, or cromatathan; the preferred addition amount is 0 wt%-5 wt%.

[0057] The pH adjuster is one or more of the following: citric acid / sodium citrate, tartaric acid / sodium tartrate, sodium dihydrogen phosphate / disodium hydrogen phosphate, or lactic acid / sodium lactate;

[0058] The metal chelating agent is one or more of edetate, disodium edetate, or calcium sodium edetate.

[0059] This invention provides a method for preparing the gel patch described in the above technical solution, comprising:

[0060] S1) Dissolve the thickener in the aqueous phase to obtain phase A;

[0061] S2) The hydrophilic skeleton material, filler, thickener, moisturizer, crosslinking agent, meloxicam nanocrystal lyophilized powder drug composition, transdermal penetration enhancer, pH adjuster and metal chelating agent are mixed to obtain phase B;

[0062] S3) Mix phase A and phase B to obtain phase C;

[0063] S4) The C phase is coated and cut to obtain the gel patch.

[0064] The components and proportions described above have been clearly described in this invention and will not be repeated here.

[0065] The preparation method of the gel patch provided by the present invention first dissolves or swells the tackifier in the aqueous phase to obtain phase A.

[0066] A hydrophilic framework material, filler, thickener, humectant, crosslinking agent, meloxicam nanocrystal lyophilized powder drug composition, transdermal penetration enhancer, pH adjuster and metal chelating agent are mixed to obtain phase B;

[0067] The present invention preferably uses a double planetary mixer for premixing, wherein the premixing is preferably carried out at 50-60 rpm for 20-30 minutes.

[0068] Phase A and Phase B are mixed to obtain Phase C; further mixing is carried out using a dual planetary mixer at 50-60 rpm for 20-30 minutes to obtain Phase C.

[0069] The C phase is coated and cut to obtain the gel patch. According to the preset size, the C phase is coated and cut using a hydrogel patch coating machine to obtain the meloxicam nanocrystal gel patch.

[0070] Beneficial technical effects of the present invention:

[0071] 1) This invention organically combines freeze-drying technology with nanocrystal technology, prioritizing a small amount of polymer as a freeze-drying protectant, fundamentally solving the stability problems commonly found in nano-suspensions, such as particle aggregation, particle size increase, and crystal transformation. The resulting freeze-dried powder pharmaceutical composition has the advantages of excellent resolubility, high stability, and easy storage, while effectively avoiding the drawbacks of conventional processes that require large amounts of freeze-drying protectants (non-functional excipients for subsequent pharmaceutical formulations), eliminating the adverse effects of such non-functional excipients on the development of nanocrystalline freeze-dried powder as an intermediate in subsequent pharmaceutical formulations.

[0072] 2) The nanocrystalline lyophilized powder pharmaceutical composition provided by the present invention significantly improves the skin adhesion, permeability and hair follicle targeting retention of the drug due to its size advantage, effectively improving the transdermal effect of meloxicam; it avoids the problem of using a large amount of solubilizers / co-solvents, improves product safety from the source, and avoids skin irritation.

[0073] 3) The nanocrystalline lyophilized powder pharmaceutical composition provided by the present invention can be used as an intermediate preparation, loaded into semi-solid matrices such as creams, gels, and plasters, and processed into pharmaceutically acceptable transdermal preparations to achieve local administration of meloxicam, filling the gap in the clinical analgesic treatment demand for transdermal delivery of meloxicam, and has extremely high application value. Attached Figure Description

[0074] Figure 1 The images shown are from Example 1. (a) is an image of the meloxicam nanocrystalline lyophilized powder, and (b) is an image of the meloxicam nanocrystalline lyophilized powder after reconstitution.

[0075] Figure 2 The PXRD superimposed diffraction patterns of meloxicam nanocrystalline freeze-dried powder after 0 days without freeze-drying protectant and after 5 days and 10 days under high temperature and light conditions, respectively, in Example 1 without freeze-drying protectant and without mannitol, sucrose, trehalose, or poloxamer 407 as freeze-drying protectant.

[0076] Figure 3The TGA test results of meloxicam nanocrystalline lyophilized powders in Examples 2, 9, and 16 are shown in the figure.

[0077] Figure 4 The in vitro release results of Example 17 (Meloxicam nanocrystal gel), Comparative Example 1 (Meloxicam gel), and Comparative Example 2 (Meloxicam gel (containing ethanol)) are shown in the figure.

[0078] Figure 5 The results are microscopic observations of Example 18 (Meloxicam Nanocrystal Gel Patch) at 0 days and at 25℃ 6M, 30℃ 6M and Comparative Example 4 (Meloxicam Gel Patch (Pre-dissolved)) at 0 days. Detailed Implementation

[0079] This invention provides a meloxicam nanocrystalline lyophilized powder pharmaceutical composition, its preparation method, and its application. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the same result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and fall within the scope of protection of this invention. The method and application of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the method and application described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0080] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0081] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0082] In this application, the term "and / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, or B existing alone. A and B can be singular or plural.

[0083] In this application, "at least one" means one or more, and "more than one" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or multiple items.

[0084] It should be understood that the order of the steps or the order in which certain actions are performed is not important as long as the invention remains operational. Furthermore, two or more steps or actions can be performed simultaneously.

[0085] The use of any and all instances or exemplary language such as “e.g.” or “including” in this document is merely intended to better illustrate the invention and is not intended to limit the scope of the invention unless the claims are made. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of the invention.

[0086] Furthermore, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Therefore, unless explicitly stated otherwise, it should be understood that all ranges, quantities, values, and percentages used in this disclosure are modified with the word "approximately". Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range.

[0087] It should be understood that in the various embodiments of this application, the order of the above processes does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.

[0088] The embodiments and comparative examples of this invention describe some examples, in which the embodiments illustrate certain implementations of the invention. However, this does not mean that the effects of the invention can only be achieved in these examples.

[0089] To further illustrate the present invention, the following detailed description, in conjunction with embodiments, provides a meloxicam nanocrystal lyophilized powder pharmaceutical composition, its preparation method, and its application.

[0090] Example 1: Investigation of the type and dosage of freeze-drying protectant

[0091] Meloxicam, polysorbate 80, and poloxamer 407 were dissolved in 0.05M NaOH solution to prepare an alkaline phase (meloxicam concentration 1%, w / v, drug to stabilizer mass ratio 3:1, polysorbate 80 and poloxamer 407 mass ratio 1:1). Simultaneously, 0.5M hydrochloric acid solution was used as the acid phase, with a volume ratio of 1:10 between the two phases and a total batch size of 1 L, ensuring equimolar ratios. The acid phase was added to the alkaline phase (meloxicam solution) under stirring at 700 rpm to form a meloxicam nanocrystal suspension. Then, mannitol, sucrose, trehalose, and poloxamer 407 were added as lyophilization protectants (drug to lyophilization protectant mass ratio 8:1 ~ 1:3) or no lyophilization protectant was added. The mixture was stirred for 10 min to dissolve, dispensed into vials, and freeze-dried according to the lyophilization parameters in Table 1.

[0092] Table 1: Freeze-drying parameters

[0093]

[0094] The main evaluation indicators for the meloxicam lyophilized powder system were its appearance, reconstitution rate, particle size after reconstitution, polydispersity index (PDI), and zeta potential. The appearance of the lyophilized powder was also observed to ensure it was plump and free of wrinkles. Furthermore, the reconstitution of the system under different types and concentrations of lyophilization protectants was compared to screen suitable lyophilization protectants for the meloxicam nanocrystal suspension system.

[0095] The method for testing the particle size and potential of nano-suspensions is as follows: after diluting the sample 100 times, the particle size, PDI and Zeta potential are tested using a nanoparticle size and potential analyzer (ZETASIZER PRO, Malvern).

[0096] The particle size and potential testing methods for lyophilized powder are as follows: Add 2 to 2.5 ml of purified water to each bottle of lyophilized powder, shake well, observe the redispersion rate of the lyophilized powder, take a sample, dilute it 100 times, and use a nanoparticle size potential analyzer to test the particle size, PDI and Zeta potential.

[0097] Table 2: Results of redispersibility test of nanocrystalline lyophilized powder

[0098]

[0099] The appearance of meloxicam nanocrystalline lyophilized powder with and without different lyophilization protectants is shown in the attached figure. Figure 1 As shown in (a), the freeze-dried powders in the figure, from left to right, contain mannose, sucrose, trehalose, poloxamer 407, and no freeze-dried powder, respectively. All groups of freeze-dried powders have relatively full and intact shapes; they can all be rapidly reconstituted within a few seconds of contact with water, and their appearance after reconstitution is shown in the attached figure. Figure 1 As shown in (b).

[0100] The particle size test results of meloxicam nanocrystalline lyophilized powder before and after lyophilization and reconstitution are shown in Table 2. The particle size and Zeta potential of the nano-suspension before lyophilization were tested. The results showed that adding different types and amounts of lyophilizing protectants to the nanocrystalline solution had no significant effect on the particle size and Zeta potential of the nanocrystalline solution system. The particle size of each group before lyophilization was between 249.6 and 310.5 nm, and the Zeta potential was between -13.9 and -12.8 mV. After reconstitution, the particle size of the lyophilized powder was tested. In the group without added lyophilizing protectant, visible particles were present after reconstitution and dilution. In the mannitol group, particle precipitation occurred at the bottom of the vial after a period of time after reconstitution. In the sucrose, trehalose, and poloxamer 407 groups, no particle precipitation occurred at the bottom of the vial after a period of time after reconstitution, indicating good reconstitution effect. The trehalose group had the smallest particle size after reconstitution, approximately ~279.3 nm; the sucrose group had a particle size of approximately ~304.5 nm; the poloxamer 407 group had a particle size of approximately ~320 nm; and the mannitol group had the largest particle size, approximately ~409.4 nm. There was no significant difference in the amount of different freeze-drying protectants used in the trehalose, sucrose, and poloxamer 407 groups; however, in the mannitol group, the particle size increased with increasing mannitol content after reconstitution. Compared to sugars, the poloxamer 407 group achieved better reconstitution results at lower addition levels (4:1, 8:1).

[0101] The crystal stability of the freeze-dried powder was investigated after 5 and 10 days of exposure to high temperature and light. The XRD test results are attached. Figure 3 As shown, the crystal form of the lyophilized powders containing mannitol, trehalose, poloxamer, and without a lyophilization protectant showed no significant change under light and high temperature conditions. However, in the sucrose group, the characteristic peaks of sucrose were more pronounced under high temperature conditions, indicating that sucrose tends to crystallize at high temperatures. Based on particle size, potential, PDI, reconstitution state, and XRD results, trehalose and poloxamer are preferred as lyophilization protectants for the meloxicam nanocrystalline lyophilized powder described in this invention.

[0102] Example 2

[0103] Meloxicam, polysorbate 80, and poloxamer 407 were added to a 0.05M NaOH solution and dissolved by stirring at 40°C to prepare an alkaline phase (meloxicam concentration 2%, w / v, drug to stabilizer mass ratio 4:1, polysorbate 80 and poloxamer 407 1:3). Simultaneously, a 0.5M hydrochloric acid solution was used as the acid phase, with a volume ratio of 1:10 between the two phases, and a total batch size of 600 ml, ensuring equimolar ratios. Under mechanical stirring at 600 rpm, the acid phase was added to the alkaline phase (meloxicam solution) to form a meloxicam nanocrystal suspension. No lyophilization protectant was added. The suspension was dispensed into vials and freeze-dried according to the lyophilization parameters in Table 1 to prepare meloxicam nanocrystal lyophilized powder.

[0104] Example 3: Based on Example 2, trehalose was added as a freeze-drying protectant, and the mass ratio of drug to trehalose was 1:1 to prepare meloxicam nanocrystal freeze-dried powder.

[0105] Example 4: Based on Example 2, trehalose was added as a freeze-drying protectant, and the mass ratio of drug to trehalose was 1:3 to prepare meloxicam nanocrystal freeze-dried powder.

[0106] Example 5: Based on Example 2, poloxamer 407 was added as a freeze-drying protectant, with a drug-to-poloxamer 407 mass ratio of 4:1, to prepare meloxicam nanocrystalline freeze-dried powder.

[0107] Example 6: Based on Example 2, poloxamer 407 was added as a freeze-drying protectant, with a drug-to-poloxamer 407 mass ratio of 8:1, to prepare meloxicam nanocrystal freeze-dried powder.

[0108] Example 7

[0109] Meloxicam, polysorbate 80, and poloxamer 407 were added to a 0.05M NaOH solution and dissolved by stirring at 50°C to prepare an alkaline phase (meloxicam concentration 2%, w / v, drug to stabilizer mass ratio 4:1, polysorbate 80 and poloxamer 407 1:1). Simultaneously, a 0.5M hydrochloric acid solution was used as the acid phase, with a volume ratio of 1:10 between the two phases, and a total batch size of 600 ml, ensuring equimolar ratios. Under homogenization at 9000 rpm, the acid phase was added to the alkaline phase (meloxicam solution) to form a meloxicam nanocrystal suspension. No lyophilization protectant was added. The suspension was dispensed into vials and freeze-dried according to the lyophilization parameters in Table 1 to prepare meloxicam nanocrystal lyophilized powder.

[0110] Example 8: Based on Example 7, trehalose was added as a freeze-drying protectant, and the mass ratio of drug to trehalose was 1:1 to prepare meloxicam nanocrystal freeze-dried powder.

[0111] Example 9: Based on Example 7, trehalose was added as a freeze-drying protectant, and the mass ratio of drug to trehalose was 1:3 to prepare meloxicam nanocrystal freeze-dried powder.

[0112] Example 10: Based on Example 7, poloxamer 407 was added as a freeze-drying protectant, with a drug-to-poloxamer 407 mass ratio of 4:1, to prepare meloxicam nanocrystalline freeze-dried powder.

[0113] Example 11: Based on Example 7, poloxamer 407 was added as a freeze-drying protectant, with a drug-to-poloxamer 407 mass ratio of 8:1, to prepare meloxicam nanocrystalline freeze-dried powder.

[0114] Example 12

[0115] Meloxicam, polysorbate 80, and poloxamer 407 were added to a 0.05M NaOH solution and dissolved by sonication to prepare an alkaline phase (meloxicam concentration 2%, w / v, drug to stabilizer mass ratio 2:1, polysorbate 80 and poloxamer 407 1:3). Simultaneously, a 0.5M hydrochloric acid solution was used as the acid phase, with a volume ratio of 1:10 between the two phases and a total batch size of 600 ml, ensuring equimolar ratios. Under rapid stirring at 800 rpm, the acid phase was added to the alkaline phase (meloxicam solution) to form a meloxicam nanocrystal suspension. No lyophilization protectant was added. The suspension was dispensed into vials and freeze-dried according to the lyophilization parameters in Table 1 to prepare meloxicam nanocrystal lyophilized powder.

[0116] Example 13: Based on Example 12, trehalose was added as a freeze-drying protectant, and the mass ratio of drug to trehalose was 1:1 to prepare meloxicam nanocrystal freeze-dried powder.

[0117] Example 14: Based on Example 12, trehalose was added as a freeze-drying protectant, and the mass ratio of drug to trehalose was 1:3 to prepare meloxicam nanocrystal freeze-dried powder.

[0118] Example 15: Based on Example 12, poloxamer 407 was added as a freeze-drying protectant, with a drug-to-poloxamer 407 mass ratio of 4:1, to prepare meloxicam nanocrystal freeze-dried powder.

[0119] Example 16: Based on Example 12, poloxamer 407 was added as a freeze-drying protectant, with a drug-to-poloxamer 407 mass ratio of 8:1, to prepare meloxicam nanocrystalline freeze-dried powder.

[0120] The moisture content of the lyophilized powder samples from Examples 2-16 above was tested to ensure their storage stability.

[0121] Table 3: Test results of moisture content of freeze-dried powder

[0122]

[0123] The schematic diagrams of the TGA test results of the lyophilized powders in Examples 2 to 16 are attached. Figure 3The test results are shown in Table 3. The results show that the lyophilized powder without the addition of a lyophilization protectant has a low moisture content, approximately 0.13% to 0.20%, but the reconstitution effect is poor, and large particles are visible to the naked eye. When trehalose is used as a lyophilization protectant, the lyophilized powder has a high moisture content, and this content increases further with the amount of trehalose used, reaching approximately 2.17% to 6.67%. This is detrimental to the stability of the lyophilized powder during storage, easily leading to clumping, collapse, moisture absorption, and adhesion, hindering its use as an intermediate preparation for subsequent drug formulation development. When poloxamer 407 is used as a lyophilization protectant, the lyophilized powder has a low moisture content, approximately 0.02% to 0.29%, and this moisture content does not increase significantly during long-term storage, making it suitable for long-term storage as an intermediate preparation.

[0124] Particle size, PDI, and potential of several batches of optimized lyophilized powder were tested during the stability period after reconstitution to further ensure its long-term storage stability.

[0125] Table 4: Test results of the stability of lyophilized powder

[0126]

[0127] The results of the reconstitution test during the stability period of the lyophilized powders in Examples 8, 9, 10, and 15 are shown in Table 4. The results show that the meloxicam nanocrystalline lyophilized powder (with trehalose and poloxamer as lyophilization protectants) can still be rapidly redispersed after being placed at 25°C for 1 month. After dilution, there are no obvious visible particles. The particle size after redispersibility is ~330 nm, and the PDI is ~0.2, indicating good stability.

[0128] In summary, based on a comprehensive evaluation of appearance, particle size, potential, PDI, reconstituted state, XRD, powder moisture content, storage stability (25℃, 1M), and the ratio of drug to lyophilization protectant, the lyophilized powder prepared using poloxamer 407 as a lyophilization protectant exhibits rapid redispersibility, meets the required particle size after redispersibility, demonstrates good stability, and has a low moisture content, avoiding the hygroscopic problem associated with sugar-based protectants. Therefore, a high molecular weight polymer is preferred as the lyophilization protectant for meloxicam nanocrystalline lyophilized powder, with poloxamer being a more preferred option. Furthermore, the low drug / lyophilization protectant ratio facilitates the use of this lyophilized powder as an intermediate in subsequent formulation development without affecting the composition of the subsequent drug formulation.

[0129] Example 17: Development of a transdermal meloxicam nanocrystal gel formulation

[0130] Add 3.0 g of carbomer to 200 ml of water and stir slowly for 30 min until fully swollen. Add an appropriate amount of sodium hydroxide solution and stir to prepare a blank gel matrix. Then add an appropriate amount of optimized meloxicam nanocrystal lyophilized powder (containing 0.7 g of drug) and 5.0 g of isopropyl myristate, stir to mix thoroughly, discharge, and package.

[0131] Comparative Example 1: Development of Meloxicam Gel Transdermal Formulation

[0132] A blank gel matrix was prepared as described in Example 17. Then, 0.7 g of meloxicam (untreated) and 5.0 g of isopropyl myristate were added, and the mixture was stirred thoroughly, discharged, and packaged.

[0133] Comparative Example 2: Development of a meloxicam gel transdermal formulation (containing ethanol)

[0134] Add 3.0 g of carbomer to 200 ml of 35% ethanol solution and stir slowly for 30 min until fully swollen. The total batch size is 200 ml. Add an appropriate amount of sodium hydroxide solution and stir to prepare a blank gel matrix. Then add 0.7 g of meloxicam (untreated) and 5.0 g of isopropyl myristate, stir thoroughly to mix, discharge, and dispense.

[0135] In vitro release test:

[0136] During the preparation process, in Comparative Example 1, meloxicam was difficult to disperse directly in water due to its hydrophobic nature, resulting in significant clumping. In Comparative Example 2, an appropriate amount of ethanol was added to dissolve and disperse the meloxicam. Subsequently, in vitro release comparisons were performed using a Franz diffusion cell for Example 17, Comparative Example 1, and Comparative Example 2. The results are as follows... Figure 4 As shown in the figure. The release comparison results show the release rate as follows: Example 17 > Comparative Example 2 > Comparative Example 1, i.e., meloxicam nanocrystal gel > meloxicam gel (containing ethanol) > meloxicam gel (without ethanol). After 4 hours, the meloxicam nanocrystal gel released approximately 16.76%, the meloxicam gel (containing ethanol) released approximately 9.03%, and the meloxicam gel released only 2.17%. Furthermore, the meloxicam nanocrystal gel was almost completely released in the end, with the meloxicam gel (containing ethanol) ultimately releasing approximately 77.45% cumulatively, while the meloxicam gel ultimately released only 24.4%. Loading meloxicam nanocrystal lyophilized powder as an intermediate formulation into the gel matrix significantly improves the poor solubility of meloxicam and also avoids the potential skin irritation safety issues associated with solubilizers (such as ethanol).

[0137] Example 18: Development of Meloxicam Nanocrystalline Gel Patch

[0138] 1) Aqueous phase preparation: Dissolve 150.0g of gelatin and add 400.0g of polyacrylic acid solution, mix well to obtain phase A;

[0139] 2) Matrix premixing: 250.0g of partially neutralized sodium polyacrylate, 20.0g of kaolin, 20.0g of talc, 500.0g of glycerin, 200.0g of propylene glycol, 6.0g of aluminum hydroxyl, an appropriate amount of optimized meloxicam nanocrystalline lyophilized powder (containing 18.5g of drug), 30.0g of Tween, 30.0g of isopropyl myristate, 5.0g of menthol, 30.0g of tartaric acid, 5.0g of sodium tartrate, and 10.0g of disodium edetate were premixed using a double planetary mixer at 60 rpm for 20 min to obtain phase B;

[0140] 3) Matrix mixing: Phase A is added to Phase B and further mixed using a dual planetary mixer at 60 rpm for 30 min to obtain Phase C;

[0141] 4) Cutting and coating: According to the preset size, the C phase is coated and cut using a hydrogel plaster coating machine to obtain meloxicam nanocrystal gel plaster.

[0142] Comparative Example 3: Development of Meloxicam Gel Patch

[0143] 1) Aqueous phase preparation: Dissolve 150.0g of gelatin and add 400.0g of polyacrylic acid solution, mix well to obtain phase A;

[0144] 2) Matrix premixing: 250.0g of partially neutralized sodium polyacrylate, 20.0g of kaolin, 20.0g of talc, 500.0g of glycerol, 200.0g of propylene glycol, 6.0g of aluminum hydroxyl, 18.5g of meloxicam, 30.0g of Tween, 30.0g of isopropyl myristate, 5.0g of menthol, 30.0g of tartaric acid, 5.0g of sodium tartrate, and 10.0g of disodium edetate were premixed using a double planetary mixer at 60 rpm for 20 min to obtain phase B;

[0145] 3) Matrix mixing: Phase A is added to Phase B and further mixed using a dual planetary mixer at 60 rpm for 30 min to obtain Phase C;

[0146] 4) Cutting and coating: According to the preset size, use a hydrogel plaster coating machine to coat and cut the C phase to obtain meloxicam gel plaster.

[0147] Comparative Example 4: Development of Meloxicam Gel Patch (Pre-dissolved)

[0148] 1) Aqueous phase preparation: Dissolve 150.0g of gelatin and add 400.0g of polyacrylic acid solution, mix well to obtain phase A;

[0149] 2) Matrix premixing: 250.0g of partially neutralized sodium polyacrylate, 20.0g of kaolin, 20.0g of talc, 500.0g of glycerin, 18.5g of meloxicam, 225g of N-methylpyrrolidone (for drug solubilization), 200.0g of propylene glycol, 6.0g of aluminum hydroxyl, 30.0g of Tween, 30.0g of isopropyl myristate, 5.0g of menthol, 30.0g of tartaric acid, 5.0g of sodium tartrate, and 10.0g of disodium edetate were premixed using a dual planetary mixer at 60 rpm for 20 min to obtain phase B;

[0150] 3) Matrix mixing: Phase A is added to Phase B and further mixed using a dual planetary mixer at 60 rpm for 30 min to obtain Phase C;

[0151] 4) Cutting and coating: According to the preset size, use a hydrogel plaster coating machine to coat and cut the C phase to obtain meloxicam gel plaster (pre-dissolved).

[0152] During the comparative research and development process, the proportion of water in phase A was controlled to ensure that the amount of medicine per unit area of ​​the plaster was consistent.

[0153] Observation of appearance characteristics:

[0154] Appearance observations were performed on Examples 18, 3, and 4. Examples 18 and 4 showed a pale yellow paste, while Comparative Example 3 showed a yellowish-green appearance with noticeable surface granules. This is mainly because meloxicam itself is hydrophobic, and the particles are relatively large, making it difficult to disperse in the paste. In contrast, meloxicam nanocrystals and dissolved meloxicam can be dispersed better in the paste.

[0155] Microscopic observation:

[0156] Subsequently, Example 18 and Comparative Example 4 were observed under a microscope, and the results are shown in the appendix. Figure 5 As shown, the distribution of drug nanocrystals in the meloxicam nanocrystal gel patch was observed at 0 days, 6 months at 25℃, and 6 months at 30℃. The results showed that the prepared meloxicam nanocrystal gel patch had good stability, with no significant agglomeration after 6 months of storage at 25℃ and 30℃. This was mainly attributed to poloxamer inhibiting the agglomeration of nanocrystal particles through steric hindrance during the nanocrystal preparation stage. In contrast, in Comparative Example 4, meloxicam was directly added to the gel patch in dissolved form, and a large number of particles appeared under a microscope at 0 days. This indicates that after the drug is dissolved and loaded into the matrix, it is difficult to maintain the dissolved state, and irregular large-diameter drug crystals are easily precipitated, which in turn affects the in vitro release and efficacy of the patch.

[0157] In vitro release test:

[0158] The in vitro release of the above-mentioned Examples 18, 3, and 4 was compared using a Franz diffusion cell, and the results are shown in Table 5. The comparison results show that the release rate is: Example 18 > Comparative Example 4 > Comparative Example 3, i.e., meloxicam nanocrystalline gel patch > meloxicam gel patch (pre-dissolved) > meloxicam gel patch. After 4 hours, the meloxicam nanocrystalline gel patch released approximately 15.46%, the meloxicam gel patch (pre-dissolved) released approximately 8.79%, and the meloxicam gel patch released only 3.21%. Furthermore, the meloxicam nanocrystalline gel patch was almost completely released in the end, with the meloxicam gel patch (pre-dissolved) ultimately releasing approximately 30% cumulatively, and the meloxicam gel patch ultimately releasing only 23% cumulatively. It is evident that loading meloxicam nanocrystal lyophilized powder as an intermediate formulation into the gel patch matrix can significantly improve the problem of poor meloxicam drug solubility, avoid the potential skin irritation safety issues of solubilizers (such as ethanol), and mitigate the risk of crystal precipitation during formulation preparation after drug dissolution.

[0159] Table 5: In vitro release results of meloxicam gel patch

[0160]

[0161] Methods for pharmacodynamic studies in rats (modeling and administration):

[0162] Using Example 18 as the self-developed formulation group, in vivo animal studies were conducted to determine the feasibility of using meloxicam nanocrystal lyophilized powder as an intermediate formulation loaded into gel patches. Meloxicam is mainly available in oral tablets and capsules; therefore, the oral gavage group served as control group 1 in the rat efficacy study. Flurbiprofen gel patches are mainstream commercially available anti-inflammatory and analgesic patches both domestically and internationally, widely used in the treatment of various diseases such as osteoarthritis, muscle soreness, and frozen shoulder; therefore, they were selected as control group 2 in this animal experiment.

[0163] Male Wistar rats (n=24), weighing approximately 200 g, were randomly divided into four groups: a model group, an oral gavage group, a self-made meloxicam gel patch group, and a commercially available flurbiprofen gel patch group. Hair was first removed from the right hind paw of the rats, and a layer of hair removal cream was applied to the surface. After 3 minutes, the cream was removed. Before modeling, the thickness of the right hind paw was measured using calipers as the initial value at 0 h. Subsequently, 0.2 mL of 1% carrageenan-saline suspension was injected subcutaneously into the right hind paw to induce inflammation and pain. The model group received no drug treatment, while the other groups received meloxicam nanocrystal gel patches (2.0 cm × 3.5 cm), commercially available flurbiprofen gel patches (2.0 cm × 3.5 cm), or oral gavage, respectively. Adhesive tape was used to secure the patches to prevent the rats from biting them.

[0164] Anti-inflammatory test method: Rats were administered the drug for 6 h. During the entire process, the thickness of the right hind paw of the rats was measured with vernier calipers. The paw thickness of the rats was measured at 2, 4, 6, 8 and 10 h after modeling.

[0165] The efficacy of the drugs in each group was judged based on the degree of paw swelling in rats. The lower the paw thickness, the better the anti-inflammatory effect of the drug. The results of the anti-inflammatory experiment are shown in Table 6. After modeling, the paw thickness of the model group rats increased significantly and remained swollen for 10 hours, indicating successful modeling. Compared with the model group, the nanocrystalline gel patch of Example 18 and the commercially available flurbiprofen gel patch both showed a significant reduction in rat paw thickness from 2 to 10 hours. The gavage group showed a significant reduction in rat paw thickness at 6 and 8 hours, with no significant difference at other times.

[0166] In summary, the anti-inflammatory efficacy of the self-made meloxicam nanocrystal gel patch is not inferior to that of commercially available flurbiprofen gel patch, and it shows a faster onset of action, longer duration of action, and more obvious anti-inflammatory and swelling-reducing effects compared to the oral gavage group.

[0167] Table 6: Results of anti-inflammatory experiment in rats (foot thickness, mm)

[0168]

[0169] Analgesia experimental method: Before modeling, the pain threshold of rats was measured as the initial value at 0 h. After modeling, rats were administered the drug for 6 h, and the pain threshold was measured at 2, 4, 6, 8 and 10 h after modeling.

[0170] The analgesic effect in rats was assessed based on the 50% paw withdrawal threshold (50% PWT). A higher 50% PWT indicates a better analgesic effect. The results of the analgesic experiment are shown in Table 7. The results showed that after injection of carrageenan, the pain threshold of the model group rats immediately decreased, indicating that carrageenan could induce severe pain in rats, and the model was successfully established. The model group gradually recovered spontaneously after 4 hours, with a slight increase in the pain threshold. This phenomenon persisted until 10 hours but did not return to the level at 0 hours. In Example 18 and the oral gavage group, the pain threshold of rats recovered to some extent between 2 and 6 hours, and significantly recovered at 8 hours. This phenomenon persisted until 10 hours and returned to the level at 0 hours. In comparison, the overall pain threshold of Example 18 was higher than that of the oral gavage group between 2 and 6 hours, showing a more significant analgesic effect. Commercially available flurbiprofen gel patches showed a slight recovery in the pain threshold of rats between 2 and 10 hours, but did not return to the level at 0 hours. In conclusion, the analgesic effect of homemade meloxicam gel patch is significantly better than that of commercially available flurbiprofen gel patch and oral gavage.

[0171] Table 7: Results of analgesia experiment in rats (50% foot withdrawal threshold, g)

[0172]

[0173] In summary, the efficacy of the self-prepared meloxicam nanocrystal gel patch is non-inferior to that of commercially available flurbiprofen gel patches, and it exhibits a faster onset of action, longer duration of action, and more pronounced anti-inflammatory and analgesic effects compared to the oral gavage group. In other words, compared to conventional oral tablets, the meloxicam nanocrystal gel patch prepared using meloxicam nanocrystal lyophilized powder as an intermediate preparation has advantages such as eliminating the first-pass effect in the gastrointestinal tract, reducing systemic drug exposure, and improving patient compliance.

[0174] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A meloxicam nanocrystal lyophilized powder pharmaceutical composition, characterized in that, It includes meloxicam, stabilizers, and lyophilization protectants; the lyophilization protectants include one or more of sugars, salts, polyols, amino acids, and polymers.

2. The lyophilized powder pharmaceutical composition according to claim 1, characterized in that, The freeze-drying protectant is one of sugars, salts, polymers, amino acids, and polyols; preferably a polymer; the polymer is poloxamer or povidone.

3. The lyophilized powder pharmaceutical composition according to claim 1, characterized in that, The weight ratio of meloxicam to stabilizer is 1:1 to 20:1; The weight ratio of meloxicam to the freeze-drying protectant is 10:1 to 1:

10.

4. The lyophilized powder pharmaceutical composition according to claim 1, characterized in that, The stabilizer includes surfactants, natural polymers, or synthetic polymers; The surfactant is selected from ionic surfactants, nonionic surfactants, or amphoteric surfactants; the ionic surfactants include sodium dodecyl sulfate or hexadecyltrimethylammonium bromide; the nonionic surfactants commonly include polysorbate 80, sorbitan sesquioleate, poloxamer, or polyoxyethylene castor oil derivatives. The natural polymers include gelatin, gum arabic, chitosan, or sodium alginate; The synthetic polymers include polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, or sodium carboxymethyl cellulose.

5. The lyophilized powder pharmaceutical composition according to claim 1, characterized in that, The meloxicam nanocrystalline lyophilized powder pharmaceutical composition has a Z-average of 200 nm to 800 nm and a PDI of 0.1 to 0.

5.

6. The lyophilized powder pharmaceutical composition according to claim 1, characterized in that, The water content of the meloxicam nanocrystalline lyophilized powder pharmaceutical composition is 0-8%, preferably 0-2%, and more preferably 0.02-0.7%.

7. A method for preparing the lyophilized powder pharmaceutical composition according to any one of claims 1 to 6, characterized in that, Includes the following steps: A) Preparation of meloxicam nanosuspension; B) The meloxicam nano suspension was freeze-dried.

8. The preparation method according to claim 7, characterized in that, Step A) specifically includes: a1) Meloxicam and stabilizer are dissolved in an alkaline solution to obtain an alkaline phase; a2) Add an acidic solution to the alkaline phase under uniform dispersion, and then add a lyophilization protectant to obtain the product.

9. The preparation method according to claim 7, characterized in that, Step B) The freeze-drying process includes pre-freezing, a first stage of primary drying, a second stage of primary drying, and desorption drying.

10. The preparation method according to claim 9, characterized in that, The The pre-freezing temperature during the pre-freezing stage is -40 ~ -45℃, the cooling time is 60 ~ 240 min, and the duration is 120 ~ 360 min; The first stage of the drying process is set at a temperature of -40 to -45°C, a duration of 120 to 720 minutes, and a vacuum level of 0.1 to 0.3 mbar. The second stage of the primary drying process is set to a temperature of -20 to -30°C, a heating / cooling time of 120 to 360 min, a duration of 240 to 720 min, and a vacuum level of 0.1 to 0.3 mbar. The set temperature for analytical drying is 10 ~ 25℃, the heating and cooling time is 40 ~ 360 min, the duration is 240 ~ 720 min, and the set vacuum degree is 0.0 ~ 0.1 mbar.

11. The use of the lyophilized powder pharmaceutical composition according to any one of claims 1 to 6 in the preparation of transdermal formulations.

12. The application according to claim 11, characterized in that, The transdermal formulation includes gels, gel patches, or creams.

13. A gel patch, characterized in that, The lyophilized powder pharmaceutical composition includes any one of claims 1 to 6.

14. The gel patch according to claim 13, characterized in that, It also includes one or more of the following: hydrophilic skeleton materials, fillers, thickeners, moisturizers, crosslinking agents, transdermal penetration enhancers, pH adjusters, and metal chelating agents; The thickener is one or more of gelatin, gum arabic, polyvinyl alcohol, hydroxypropyl methylcellulose, polyacrylic acid, or polyvinylpyrrolidone; The hydrophilic skeleton material is one or more of fully neutralized sodium polyacrylate, partially neutralized sodium polyacrylate, polyacrylic acid, or carbomer; The filler is one or more of titanium dioxide, diatomaceous earth, saponin, calcium carbonate, micronized silica gel, starch, talc, or kaolin. The moisturizer is one or more of glycerin, propylene glycol, or polyethylene glycol; The crosslinking agent is one or more of aluminum hydroxyl, aluminum trichloride, or aluminum hydroxide; The transdermal penetration enhancer is one or more of azone, menthol, menthyl ester, oleic acid, oleyl alcohol, Tween, Span, isopropyl myristate, or cromatathan. The pH adjuster is one or more of the following: citric acid / sodium citrate, tartaric acid / sodium tartrate, sodium dihydrogen phosphate / disodium hydrogen phosphate, or lactic acid / sodium lactate; The metal chelating agent is one or more of edetate, disodium edetate, or calcium sodium edetate.

15. A method for preparing the gel patch according to claim 13 or 14, characterized in that, include: S1) Dissolve or swell the thickener in the aqueous phase to obtain phase A; S2) The hydrophilic skeleton material, filler, thickener, moisturizer, crosslinking agent, meloxicam nanocrystal lyophilized powder drug composition, transdermal penetration enhancer, pH adjuster and metal chelating agent are mixed to obtain phase B; S3) Mix phase A and phase B to obtain phase C; S4) The C phase is coated and cut to obtain the gel patch.

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