Meloxicam nanocrystal medicine as well as low-energy-consumption preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a meloxicam nanocrystal medicine and a low-energy-consumption preparation method and application thereof, and the preparation method comprises the following steps: enabling an alkaline solution containing meloxicam and a stabilizer to be in contact with an acid solution, and forming meloxicam nanocrystals under the condition of mechanical stirring; the stabilizing agent is prepared from one or more of Tween and poloxamer. According to the method, an acid-base precipitation auxiliary mechanical stirring method is innovatively adopted, the bottleneck of a traditional high-energy-consumption technology is broken through, the meloxicam nanocrystals are obtained with low energy consumption without depending on energy-consumption technologies such as ball milling and high-pressure homogenization, and the prepared nanocrystal medicine is uniform in particle size and good in stability. The method has the advantages of simple process, controllable process, cost saving and high efficiency, and is easy for process amplification and industrial production. The prepared meloxicam nanocrystal medicine can effectively solve the problem of poor medicine solubility, and 90% of medicine can be dissolved out and released within 0.5 hour.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a meloxicam nanocrystalline drug and its low-energy preparation method and application. Background Technology

[0002] Traditional opioid analgesics work by inhibiting the pain center in the brain, providing strong pain relief. The analgesic effect can be increased by raising the dosage, but they are highly addictive, and opioid abuse has become a global public health challenge. In 2024, the U.S. Food and Drug Administration (FDA) officially listed non-opioid drugs as a first-line analgesic option. Simultaneously, the aging population has led to an increase in the number of patients with chronic pain, with 60% requiring long-term medication. Against this backdrop, non-opioid analgesics have been upgraded from an "alternative option" to a "core choice," and the market has subsequently entered a period of rapid growth, projected to reach hundreds of billions of dollars by 2030.

[0003] Non-opioid analgesics, primarily nonsteroidal anti-inflammatory drugs (NSAIDs), have garnered significant attention due to their unique mechanism of action involving the inhibition of cyclooxygenase (COX). COX-1 is believed to provide prostaglandins (PGs) necessary for normal cellular homeostasis, while COX-2 can regulate growth and differentiation or modulate inflammatory responses to infection and injury. Therefore, inhibiting the COX mechanism is considered a molecular target for NASIDs. Among numerous NASIDs, cyclophosphamides have been found to preferentially inhibit the COX-2 pathway. For example, meloxicam (MLX) binds to the COX-2 enzyme and blocks its active site, inhibiting the biosynthesis of prostaglandin PGE2. Its selective inhibition of COX-2 is approximately 12 times that of COX-1, and its IC50 for COX-2 and COX-1 is significantly higher. 50 The values ​​were 0.49 μM and 36.6 μM, respectively. Compared with conventional NASIDs, meloxicam showed better anti-inflammatory and analgesic effects and fewer gastrointestinal toxic side effects. It is widely used in clinical practice to treat diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA).

[0004] However, as a Class II Biopharmaceutical Classification (BCS II) drug, meloxicam's extremely low solubility limits its wider application. Therefore, there is an urgent need to develop solubilization technologies to improve drug dissolution rate and bioavailability, thereby achieving better clinical outcomes.

[0005] Among the various solubilization technologies (such as nanocrystals, micelles, inclusion complexes, and liposomes), nanocrystal drugs have significant clinical advantages. They require no carrier materials, only a small amount of stabilizer to improve bioavailability, do not require extreme pH conditions for solubilization to reduce the adverse effects of solvents, and offer near 100% drug content. However, some currently available methods for preparing meloxicam nanocrystals often require long grinding times or high-pressure homogenization of the system, resulting in high energy consumption and long processing times.

[0006] In conclusion, developing a meloxicam nanocrystal drug preparation process that breaks through the bottlenecks of traditional high-energy-consuming technologies, shortens preparation time, simplifies the preparation process, makes the process controllable, and is cost-effective and efficient is necessary to improve the current problems of poor water solubility and low bioavailability of meloxicam. It has extremely high application value for industrial production and clinical application. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a meloxicam nanocrystalline drug and its low-energy-consumption preparation method and application, which can effectively improve the problem of poor drug solubility without the intervention of organic solvents, while breaking through the high-energy-consumption technical bottleneck of traditional nanocrystalline preparation, making it easy to scale up the process and industrialize production, providing technical support for the industrialization of poorly soluble drug solubilization, and the prepared meloxicam nanocrystalline drug has uniform particle size and good stability.

[0008] The low-energy-consumption preparation method of meloxicam nanocrystalline drug provided by this invention is prepared by acid-base precipitation-assisted mechanical stirring. This method achieves the preparation of meloxicam nanocrystalline drug suspension solely through mechanical stirring, eliminating the need for high-energy physical dispersion methods such as ball milling, high-pressure homogenization, or microfluidics.

[0009] To achieve the above objectives, the present invention provides a low-energy-consumption preparation method for meloxicam nanocrystal drugs, comprising the following steps:

[0010] A combination of an alkaline solution containing meloxicam and a stabilizer is brought into contact with an acidic solution to form meloxicam nanocrystals under mechanical stirring.

[0011] The stabilizer includes one or more of Tween and poloxamer.

[0012] The main innovative points of this invention are:

[0013] I. Avoiding the risk of organic solvent residue: Constructing a solvent-free crystallization system to ensure the safety and purity of drugs from the source.

[0014] Meloxicam crystals were prepared using an acid-base neutralization precipitation crystallization system without the intervention of organic solvents. This system drives the directional precipitation of the active pharmaceutical ingredient in the liquid phase through proton transfer. No organic solvents are introduced throughout the process, cutting off the solvent residue path from the source of the process. This effectively solves the industry pain point that organic solvents are difficult to completely remove in traditional processes, which can easily lead to excessive drug residues. It significantly improves the purity of the drug and the safety of clinical application, and completely avoids the potential risks of residual solvents to the human body.

[0015] II. By-product resource utilization: Achieve integrated "crystallization-excipient regulation", simplify the process and improve formulation stability.

[0016] This invention fully utilizes the characteristics of the reaction mechanism to directly convert sodium chloride, a byproduct generated in the acid-base neutralization precipitation crystallization system, into a functional excipient (as an osmotic pressure regulator in pharmaceutical formulations) without the need for additional separation and removal. This eliminates the need for traditional byproduct separation, simplifying the production process and reducing costs. It also avoids the compatibility risks that may arise from introducing new excipients, improves formulation stability, and achieves integrated process control of crystallization and excipient regulation.

[0017] III. Breaking through the bottleneck of high energy consumption technology: Establishing a low-energy-consumption nanocrystal preparation path to promote industrial application transformation.

[0018] Addressing the shortcomings of traditional nanocrystal preparation processes (ball milling, high-pressure homogenization), which rely on high-power equipment, have high energy consumption (ball milling requires ≥5kWh / kg, and high-pressure homogenization requires maintaining 50-200MPa high pressure), and limit large-scale production, this invention proposes an acid-base precipitation-assisted mechanical stirring method. This method fundamentally solves the industrialization bottleneck of traditional technologies, where "high energy consumption leads to high production costs, making it difficult for small and medium-sized enterprises to undertake." The low-energy-consumption nanocrystal preparation method proposed in this invention provides a new approach for industrial production, promoting the transformation of nanocrystalline drugs from "high-cost niche technology" to "low-cost large-scale application," and providing technical support for the industrialization of solubilization in the field of poorly soluble drugs.

[0019] Preferably, the low-energy-consumption preparation method includes the following steps:

[0020] (1) Dissolve meloxicam and stabilizer in an alkaline solution to form an alkaline phase, while using an acidic solution as the acidic phase;

[0021] (2) The alkaline phase is stirred by mechanical stirring, and the acid phase is added to the alkaline phase during continuous stirring;

[0022] (3) After the acid phase is added, continue stirring while maintaining the stirring state until a uniform precipitate is formed in the system to obtain meloxicam nanocrystal drug suspension.

[0023] First, an alkaline solution containing meloxicam and a stabilizer is provided. The meloxicam and stabilizer are dissolved in the alkaline solution to form an alkaline phase.

[0024] The stabilizer is preferably one or more of surfactants and polymers; more preferably, it is a combination of surfactants and polymers. The surfactants include, but are not limited to, ionic surfactants, nonionic surfactants, and amphoteric surfactants. Ionic surfactants include anionic surfactants and cationic surfactants. Ionic and amphoteric surfactants stabilize the nanocrystalline drug suspension system by inducing electrostatic repulsion between nanocrystalline drugs: they are first adsorbed onto the surface of the nanocrystalline drug, where the hydrophilic portion forms an electric double layer, giving the drug a charge; when drug particles approach each other, like charges repel and separate, ultimately preventing aggregation and stabilizing the suspension system. Nonionic surfactants and polymers stabilize the nanocrystalline drug suspension system through steric hindrance: they first adsorb the hydrophobic portion as a steric stabilizer, and their long hydrophilic chains extend outwards, restricting drug particle aggregation and maintaining system stability.

[0025] This invention employs an acid-base neutralization-assisted mechanical stirring method to prepare nanocrystalline drugs. Specifically, when the acid and base phases come into contact, meloxicam begins to precipitate crystals. At this time, the surfactant and polymer in the system exert a synergistic effect, which, together with mechanical stirring, can both inhibit the further growth of meloxicam crystals and maintain the long-term stability of the drug crystals.

[0026] In some specific embodiments, the stabilizer preferably includes one or more of Tween, poloxamer, sodium lauryl sulfate, and lecithin; more preferably, it includes one or more of Tween and poloxamer.

[0027] Experimental results show that meloxicam nanocrystals can be obtained using only mechanical stirring in the above stabilizer system, with extremely low energy consumption and high system stability.

[0028] In some specific embodiments, when one of the above substances is used as the stabilizer, some samples in the system may clump at the bottom, requiring manual shaking for further homogenization. To further improve the homogeneity and stability of the system, preferably, the stabilizer includes a first stabilizer and a second stabilizer.

[0029] The first stabilizer is preferably Tween, and the second stabilizer is preferably poloxamer. The synergistic use of Tween and poloxamer leverages the synergistic advantages of the surfactant and the polymer. Compared to a single stabilizer, the prepared meloxicam nanocrystals have smaller particle sizes and more uniform distribution, thus better maintaining the stability of the meloxicam nanocrystal suspension system.

[0030] The preferred mass ratio of the first stabilizer to the second stabilizer is 1:10 to 10:1, more preferably 1:4 to 4:1. Examples include 1:4, 2:3, 1:1, 3:2, and 4:1. Experimental results show that, under the above compounding ratios, the prepared meloxicam nanocrystals have uniform particle size, uniform distribution, and good stability.

[0031] In some preferred embodiments of the present invention, the Tween is preferably Tween 80; the poloxamer is preferably poloxamer 188 and / or poloxamer 407.

[0032] The weight ratio of meloxicam to the stabilizer is preferably 1:(0.01~50), more preferably 1:(0.01~10), even more preferably 1:(0.05~5), further preferably 1:(0.1~5), and most preferably 1:(0.3~1.0). Exemplary values ​​can be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, or any of the above values ​​as the upper or lower limit. Experimental results show that when the weight ratio of meloxicam to the stabilizer is greater than 1:0.25, the system is more stable.

[0033] The alkaline solution is preferably a sodium hydroxide solution, meaning that the alkaline compound in the alkaline solution is sodium hydroxide.

[0034] The concentration of meloxicam in the alkaline solution is preferably 0.1% to 1.0% (w / v), and for example, it can be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or any of the above values ​​as the upper or lower limit.

[0035] The concentration of the stabilizer in the alkaline solution is preferably 0.001% to 50% (w / v), preferably 0.075% to 0.2%, and for example, it can be 0.075%, 0.1%, 0.05%, 0.2%, or any of the above values ​​as the upper or lower limit.

[0036] In the alkaline solution, the concentration of sodium hydroxide is preferably 0.01~0.1 mol / L. For example, it can be 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 mol / L, or any of the above values ​​as the upper or lower limit.

[0037] The acidic solution is preferably a hydrochloric acid solution, meaning that the acidic compound in the acidic solution is hydrochloric acid. The concentration of the hydrochloric acid solution is preferably 0.1~1 mol / L, and for example, it can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mol / L, or any of the above values ​​as the upper or lower limit.

[0038] The preferred molar ratio of the alkaline compound in the alkaline solution to the acidic compound in the acidic solution is 1:1, meaning that the corresponding acidic and alkaline compounds in the acid and alkali phases are fed in an equal molar ratio.

[0039] Experimental results show that the method provided by this invention can prepare meloxicam nanocrystalline drug suspension without the need for high-energy physical dispersion methods such as ball milling, high-pressure homogenization or microfluidics. It can achieve the same effect as a multifunctional emulsifying disperser (a high-energy-consuming laboratory equipment), and can prepare a nanocrystalline drug suspension system with uniform particle size and good stability.

[0040] Preferably, in step (2), the time for adding the acid phase to the alkaline phase during continuous stirring is less than 5 minutes.

[0041] Preferably, the mechanical stirring specifically comprises:

[0042] By stirring, the liquid surface is kept in a state of continuous disturbance without any static areas, ensuring that the entire material participates in the flow. The minimum rotational speed that just achieves this liquid surface state is appropriate.

[0043] According to the low-energy preparation method of meloxicam nanocrystalline drug of the present invention, the method only requires adjusting the mechanical stirring to a suitable speed, that is, to make the liquid surface continuously disturbed and without static areas by stirring, so as to ensure that the whole material participates in the flow. It does not require a fixed stirring speed, but the minimum speed that just achieves the liquid surface state is preferred.

[0044] In some preferred embodiments, the rotation speed of the mechanical stirring is preferably 50 to 1000 rpm. For example, it can be 50, 100, 500, 600, 700, 800, 900, 1000 rpm, or any of the above values ​​as the upper or lower limit.

[0045] The preferred mechanical stirring time is 3 to 30 minutes. For example, it can be 3, 7, 11, 15, 20, 25, or 30 minutes, or any of the above values ​​can be used as the upper or lower limit.

[0046] In some specific implementations, after preparing the alkaline solution and the acidic solution, they are respectively designated as the alkaline phase and the acidic phase; the alkaline phase is stirred using a mechanical stirring method, and the speed is adjusted to a suitable speed. During continuous stirring, the acidic phase is added to the alkaline phase; after the acidic phase is added, the stirring is maintained until a uniform precipitate is formed in the system, thus obtaining the meloxicam nanocrystal drug suspension.

[0047] This invention has also been scaled up for mass production. The experimental results show that the low-energy-consumption preparation method of meloxicam nanocrystal drugs provided by this invention is suitable for the scaled-up and industrial production of meloxicam nanocrystal drugs, and can produce nanocrystal drug suspension systems with uniform particle size and good stability.

[0048] The method provided by this invention has the advantages of simple process, controllable process, cost-saving and high efficiency, providing new ideas for process scale-up and industrial production, promoting the transformation of nanocrystalline drugs from "high-cost niche technology" to "low-cost large-scale application", and providing technical support for the industrialization of poorly soluble drug solubilization.

[0049] Performance testing of the prepared meloxicam nanocrystals showed that the meloxicam nanocrystals prepared by the method provided in this invention are pale yellow powders with uniform and evenly distributed nano-sized particles, and the crystallinity of the drug is reduced. The nanocrystalline drug powder sample after nano-sizing treatment can greatly improve the poor solubility of the drug and effectively increase its dissolution rate, achieving approximately 90% dissolution after 0.5 h and reaching the dissolution plateau in about 2 h. Therefore, the method provided in this invention effectively improves the dissolution rate of the API by increasing its saturated solubility, significantly improving the original problem of poor API solubility and achieving higher drug bioavailability.

[0050] Based on this, the present invention also provides meloxicam nanocrystals prepared by the above preparation method.

[0051] The meloxicam nanocrystals obtained by this invention have a particle size range of 150 nm to 500 nm.

[0052] The present invention also provides a pharmaceutical composition comprising meloxicam nanocrystals prepared by the above preparation method, and excipients.

[0053] The present invention does not impose any special limitations on the excipients mentioned, and they can be any applicable excipients well known to those skilled in the art, or selected according to the dosage form. For example, they can be further processed and prepared into pharmaceutically acceptable formulations using conventional pharmaceutical formulation techniques in the art.

[0054] Further processing of the meloxicam nanocrystalline pharmaceutical composition may yield dosage forms including, but not limited to, one or more of the following: lyophilized powder, tablets, gels, capsules, and transdermal formulations.

[0055] Compared with the prior art, the present invention provides a low-energy preparation method for meloxicam nanocrystal drugs, comprising the following steps: contacting an alkaline solution including meloxicam and an acidic solution, and forming meloxicam nanocrystals under mechanical stirring; wherein the stabilizer includes one or more of Tween 80, poloxamer 188, and poloxamer 407.

[0056] This invention employs an acid-base precipitation-assisted mechanical stirring method to prepare meloxicam nanocrystals, achieving the following beneficial effects:

[0057] (1) The present invention uses an acid-base neutralization precipitation method without organic solvents to prepare nanocrystalline drugs, which solves the industry pain point that organic solvents are difficult to completely remove in traditional processes and easily lead to excessive drug residues from the source, significantly improves drug safety and purity, and completely avoids the potential risks of residual solvents to the human body.

[0058] (2) Realize the resource utilization of by-products. The by-product generated during the acid-base neutralization precipitation reaction is sodium chloride, which does not require additional separation and removal and can be directly used as an osmotic pressure regulator in pharmaceutical preparations. While eliminating the operation of separating by-products in traditional processes, simplifying the production process and reducing costs, it also avoids the compatibility risks that may be brought about by the introduction of new excipients and improves the stability of the preparation;

[0059] (3) The meloxicam nanocrystal drug prepared by the present invention does not require an additional carrier, achieves nearly 100% drug loading, improves the disadvantage of poor water solubility of meloxicam drugs, and achieves 90% drug dissolution and release within 0.5 hours.

[0060] (4) The low-energy-consumption preparation method of nanocrystalline drugs provided by the present invention breaks through the bottleneck of traditional high-energy-consumption technology by adopting acid-base precipitation-assisted mechanical stirring method. It does not rely on the high-energy-consumption processes such as ball milling and high-pressure homogenization of traditional nanocrystalline preparation, providing a new idea for industrial production and promoting the transformation of nanocrystalline drugs from "high-cost niche technology" to "low-cost large-scale application". Attached Figure Description

[0061] Figure 1 Appearance of meloxicam API powder before processing;

[0062] Figure 2 This is an image of the appearance of meloxicam nanocrystalline powder after nano-processing.

[0063] Figure 3 SEM images of meloxicam API powder before processing;

[0064] Figure 4 SEM image of meloxicam nanocrystalline powder after nano-processing;

[0065] Figure 5 XRD patterns of meloxicam powder before and after nano-sizing treatment;

[0066] Figure 6 The images show the in vitro dissolution results of meloxicam powder before and after nano-processing. Detailed Implementation

[0067] To further illustrate the present invention, a detailed description is provided below with reference to embodiments. However, it should be understood that these descriptions are merely for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims.

[0068] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0069] Example 1: Effect of stabilizers on the stability of meloxicam nanocrystal suspension

[0070] The procedure (total batch size 500 ml): Meloxicam (0.3% w / v) was dissolved in sodium hydroxide solution (0.05 mol / L) with different stabilizers (9 types, 0.1% w / v each) to prepare the alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) was used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the acidic and alkaline substances were added in an equimolar ratio. An electronic stirrer (RW20, IKA) was then turned on at 500 rpm, and the acidic phase was added to the alkaline phase during continuous stirring for 7 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of the meloxicam nanocrystal suspension were used as the main indicators of system stability (nanoparticle size potential analyzer, ZETASIZER PRO, Malvern), and the system stability was compared under different stabilizer conditions. The results are shown in Table 1.

[0071] Table 1. Test results of meloxicam nanocrystal suspension systems with different stabilizers

[0072]

[0073] Test results showed that among the nine stabilizers, Tween 80, poloxamer 188, poloxamer 407, sodium lauryl sulfate, and lecithin exhibited superior appearance and fine texture at day 0. Tween 80 and sodium lauryl sulfate also showed lower initial particle size and polydispersity index (PDI). The other stabilizers performed poorly in this system, resulting in noticeable granular texture and significant flocculent precipitate in the prepared solution. Considering the initial particle size, polydispersity index, sample appearance, and Zeta potential of the nanocrystalline drug suspension system, Tween 80, poloxamer 188, poloxamer 407, sodium lauryl sulfate, and lecithin showed the best performance. Tween 80, poloxamer 188, and poloxamer 407 demonstrated the most optimal results.

[0074] Example 2: Effect of compound stabilizers on the stability of meloxicam nanocrystal suspension

[0075] The procedure (total batch size 500 ml) is as follows: Meloxicam (concentration 0.3%, w / v) and different stabilizers (Tween 80, abbreviated as T80; Poloxamer 188, abbreviated as P188; Poloxamer 407, abbreviated as P407; concentration 0.1%, w / v) are dissolved in sodium hydroxide solution (0.05 mol / L) to prepare the alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) is used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the corresponding acidic and alkaline substances are added in an equimolar ratio. Then, an electronic stirrer (RW20, IKA) is turned on, set to a stirring speed of 500 rpm, and the acidic phase is added to the alkaline phase during continuous stirring for 7 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of meloxicam nanocrystal suspension were used as the main indicators for evaluating system stability (using a nanoparticle size potential analyzer, ZETASIZER PRO, Malvern). The stability of the system in the presence of different stabilizers was then compared. The results are shown in Table 2.

[0076] Table 2. Test results of meloxicam nanocrystal suspension systems with different stabilizer combinations

[0077]

[0078] Test results showed that the combined Tween 80 and poloxamer 188, or Tween 80 and poloxamer 407, produced milky white suspensions with a fine texture. Furthermore, parallel comparisons of initial particle size, polydispersity index, zeta potential, and subsequent stability showed that the Tween 80 and poloxamer 407 combination resulted in smaller, more uniformly distributed particles. The need for manual shaking to re-mix individual samples during the stability testing of the Tween 80-only system was also significantly reduced. In contrast, the surfactant-polymer combination system better maintained the stability of the meloxicam nanocrystal suspension.

[0079] Example 3: Effect of stabilizer formulation ratio on the stability of meloxicam nanocrystal suspension

[0080] The procedure (total batch size 500 ml) is as follows: Meloxicam (concentration 0.3%, w / v) and different stabilizers (T80 and P407 compounded at mass ratios of 1:4, 2:3, 1:1, 3:2, 4:1; concentration 0.1%, w / v) are dissolved in sodium hydroxide solution (0.05 mol / L) to prepare an alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) is used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the acidic and alkaline substances in both phases are added in an equimolar ratio. Then, an electronic stirrer (RW20, IKA) is turned on, set to a stirring speed of 500 rpm, and the acidic phase is added to the alkaline phase during continuous stirring for 7 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of meloxicam nanocrystal suspension were used as the main indicators for evaluating system stability (using a nanoparticle size potential analyzer, ZETASIZER PRO, Malvern). The stability of systems with different stabilizer formulations was then compared. The results are shown in Table 3.

[0081] Table 3. Test results of the meloxicam nanocrystalline suspension system composed of T80 and P407.

[0082]

[0083] Test results showed that when Tween 80 and poloxamer 407 were combined in different proportions, the overall solution was milky white and had a fine texture. Parallel comparisons of the initial particle size, polydispersity index, Zeta potential, and subsequent stability results revealed that the combination of Tween 80 and poloxamer 407 resulted in a system with uniform particle size distribution and good stability. This indicates that the system combines the advantages of both surfactants and polymers, and can better maintain the stability of the suspension compared to a single stabilizer.

[0084] Example 4: Effect of stabilizer concentration on the stability of meloxicam nanocrystal suspension

[0085] The procedure (total batch size 500 ml) is as follows: Meloxicam (0.3% w / v) and stabilizers of different concentrations (T80 and P407 in a 1:1 mass ratio, at concentrations of 0.075%, 0.1%, 0.15%, and 0.2% w / v) are dissolved in sodium hydroxide solution (0.05 mol / L) to prepare an alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) is used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the acidic and alkaline substances in both phases are added in an equimolar ratio. Then, an electronic stirrer (RW20, IKA) is turned on, set to a stirring speed of 500 rpm, and the acidic phase is added to the alkaline phase during continuous stirring for 7 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of the meloxicam nanocrystal suspension were used as the main indicators for evaluating system stability (using a nanoparticle size potential analyzer, ZETASIZER PRO, Malvern). The stability of the system under different stabilizer concentrations was then compared. The results are shown in Table 4.

[0086] Table 4. Test results of meloxicam nanocrystal suspension systems with different concentrations of T80 and P407.

[0087]

[0088] Test results showed that the Tween 80 and poloxamer 407 compound system, when studied at different concentration ratios, produced a milky white solution with a fine texture. Parallel comparisons of the initial particle size, polydispersity index, Zeta potential, and subsequent stability-related results revealed that at lower stabilizer concentrations (0.075%), the nanocrystalline suspension system showed a more significant increase in particle size and polydispersity index during the stability study period.

[0089] Example 5: Effect of mechanical stirring speed on the stability of meloxicam nanocrystal suspension

[0090] The procedure (total batch size 500 ml) is as follows: Meloxicam (concentration 0.3%, w / v) and a compounded stabilizer (T80 and P407 in a 1:1 mass ratio, concentration 0.1%, w / v) are dissolved in sodium hydroxide solution (0.05 mol / L) to prepare the alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) is used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the acidic and alkaline substances are added in an equimolar ratio. Then, an electronic stirrer (RW20, IKA) is turned on, and the stirring speed is investigated (500, 750, 1000 rpm). The acidic phase is added to the alkaline phase during continuous stirring for 7 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of meloxicam nanocrystal suspension were used as the main evaluation indicators (nanoparticle size potential analyzer, ZETASIZER PRO, Malvern) to compare the suspension systems under different preparation process parameters. The results are shown in Table 5.

[0091] Table 5. Test results of meloxicam nanocrystalline suspension system at different mechanical stirring speeds

[0092]

[0093] Test results showed that the Tween 80 and poloxamer 407 compound system, prepared under different stirring speeds (500 rpm, 750 rpm, 1000 rpm), generally exhibited a milky white liquid state with a fine texture. A parallel comparison of the initial particle size, polydispersity index, and zeta potential of the meloxicam nanocrystalline drug suspension system under different stirring speeds revealed that a smaller particle size and more uniform distribution of the nano-suspension system can be obtained within the 500-1000 rpm range, indicating that the aforementioned parameters are suitable for the preparation of the meloxicam nanocrystalline suspension system.

[0094] Example 6: Effect of mechanical stirring time on the stability of meloxicam nanocrystal suspension

[0095] The procedure (total batch size 500 ml) is as follows: Meloxicam (0.3% concentration, w / v) and a compounded stabilizer (T80 and P407 in a 1:1 mass ratio, 0.1% concentration, w / v) are dissolved in sodium hydroxide solution (0.05 mol / L) to prepare the alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) is used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the acidic and alkaline substances in both phases are added in an equimolar ratio. Then, an electronic stirrer (RW20, IKA) is turned on to investigate the stirring time. The stirring speed is set to 500 rpm, and the acidic phase is added to the alkaline phase during continuous stirring for 7, 15, and 30 min, respectively. The appearance, initial particle size, polydispersity index, and zeta potential of the meloxicam nanocrystal suspension are the main indicators for evaluating the system stability (nanoparticle size potential analyzer, ZETASIZER PRO, Malvern).

[0096] Table 6. Test results of meloxicam nanocrystalline suspension system under different mechanical stirring times.

[0097]

[0098] Test results showed that samples prepared by mechanical stirring for different durations (7, 15, and 30 min) were all milky white liquids with a fine texture. Parallel comparisons of the initial particle size, polydispersity index, and zeta potential of the meloxicam nanocrystalline drug suspension system revealed that the particle size, polydispersity index, and zeta potential of samples prepared with different stirring durations were similar. This indicates that under low-energy mechanical stirring methods, extending the stirring time does not significantly change the system state, and nanocrystalline drug suspension systems with uniform particle size and good stability can be prepared with different mechanical stirring durations.

[0099] Comparative Example 1: Effect of homogenization treatment on the stability of meloxicam nanocrystal suspension

[0100] The procedure (total batch size 500 ml) is as follows: Meloxicam (concentration 0.3%, w / v) and a compounded stabilizer (T80 and P407 in a 1:1 mass ratio, concentration 0.1%, w / v) are dissolved in sodium hydroxide solution (0.05 mol / L) to prepare the alkaline phase. Simultaneously, hydrochloric acid solution (0.5 mol / L) is used as the acidic phase, with a volume ratio of 1:10 between the acid and alkaline phases, meaning the acidic and alkaline substances in both phases are added in an equimolar ratio. Then, homogenization is performed using a multi-functional emulsifying disperser (T25digital, IKA) at 9000 rpm. The acidic phase is added to the alkaline phase during continuous stirring for 7 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of meloxicam nanocrystal suspension were used as the main indicators for evaluating system stability (nanoparticle size potential analyzer, ZETASIZER PRO, Malvern). The nanocrystal systems and their stability prepared by the low-energy preparation method (mechanical stirring) and the high-energy preparation method (high shear homogenization) in the examples were compared.

[0101] Table 7. Test results of the meloxicam nanocrystal suspension system compared with mechanical stirring and homogenization.

[0102]

[0103] Test results showed that samples prepared by both mechanical stirring (500 rpm, 7 min) and homogenization (9000 rpm, 7 min) were milky white liquids with a fine texture. Parallel comparisons of the initial particle size, polydispersity index, and Zeta potential of the meloxicam nanocrystalline drug suspension system showed similar results from both methods. This result also indicates that the meloxicam nanocrystalline suspension system prepared by mechanical stirring alone (a low-energy-consumption preparation method) can achieve the same effect as a multi-functional emulsifying disperser (a high-energy-consumption laboratory device), producing a nanocrystalline drug suspension system with uniform particle size and good stability.

[0104] Example 7: Effect of scale-up mechanical stirring process on the stability of meloxicam nanocrystal suspension

[0105] The procedure (total batch size 50 L) is as follows: First, add the prescribed amount of water to the mixing tank and maintain stirring. Stirring ensures the liquid surface is continuously agitated without any static areas, guaranteeing overall material flow. A fixed stirring speed is not required; the minimum speed needed to achieve this liquid surface state is preferable (in this embodiment, the tank is 100 L, with a three-bladed impeller, and a speed of 50-100 rpm is sufficient to meet this condition). Prepare a sodium hydroxide solution (0.05 mol / L). Then, add meloxicam (0.3% w / v) and a compounded stabilizer (T80 and P407 mixed in a 1:1 mass ratio, at a concentration of 0.1% w / v) until completely dissolved, resulting in the alkaline phase. Simultaneously, a hydrochloric acid solution (0.5 mol / L) was prepared in a beaker as the acid phase, with a volume ratio of 1:10 between the acid and base phases, meaning the acidic and base substances in both phases were added in an equimolar ratio. Then, while maintaining stirring in the mixing tank, the acid phase was added to the tank for 30 minutes. The appearance, initial particle size, polydispersity index, and zeta potential of the meloxicam nanocrystal suspension were used as the main indicators for system stability (using a nanoparticle size potential analyzer, ZETASIZER PRO, Malvern), to compare the adaptability of the mechanical stirring preparation process for large-scale system production. The results are shown in Table 8.

[0106] Table 8. Test results of meloxicam nanocrystal suspension systems with different batch sizes

[0107]

[0108] Test results showed that after scaling up the research system to a larger batch size (from 500 ml to 50 L), the corresponding samples were all milky white liquids with a fine texture. Parallel comparisons of the initial particle size, polydispersity index, and zeta potential of different batches of nanocrystalline drug suspensions revealed no significant changes in these parameters after scale-up. This indicates that the low-energy-consumption preparation method for meloxicam nanocrystalline drugs provided by this invention is suitable for the scale-up and industrial production of meloxicam nanocrystalline drugs, and can produce nanocrystalline drug suspensions with uniform particle size and good stability.

[0109] Example 8

[0110] Further freeze-drying of pilot-scale batches of samples and characterization of the corresponding nanocrystalline powders were conducted to determine whether the nanocrystalline drugs prepared by the low-energy-consumption preparation method of the present invention can improve the problem of poor solubility of APIs.

[0111] First, the appearance of meloxicam powder before and after nano-processing was compared, and the results are as follows: Figure 1 , 2As shown in the figure, meloxicam before treatment appeared as a yellow-green powder, while the nano-treated meloxicam nanocrystals appeared as a pale yellow powder. Further characterization of the microstructure of the samples was performed using scanning electron microscopy (SEM), and the results are shown below. Figure 3 , 4 As shown in the figure, the untreated meloxicam exhibited a large, blocky structure with uneven size distribution, while the nano-sized meloxicam nanocrystals exhibited a uniform, evenly distributed nano-sized particle structure. Subsequently, X-ray diffraction (XRD) was performed on the powder samples before and after treatment to characterize the relevant crystal structures of the drug. The results are shown in the figure. Figure 5 As shown in the figure, the untreated meloxicam drug exhibited strong crystalline characteristic peaks within the 2θ (10-30° range), with characteristic peaks at 13.06°, 14.98°, 18.59°, and 25.84°. In the corresponding spectrum of the nanocrystalline meloxicam powder after nano-treatment, the aforementioned API crystalline characteristic peaks still existed, but their intensity decreased, indicating that the crystallinity of the drug decreased during the preparation of meloxicam nanocrystals. Subsequently, the dissolution rate of the samples before and after treatment was compared using the flow-through cell method (under closed-loop conditions), and the results are as follows. Figure 6 As shown in the figure, flow cell tests revealed that the nanocrystalline drug powder samples treated with nano-sizing significantly improved the drug's poor solubility and effectively increased its dissolution rate. Approximately 90% dissolution was achieved after 0.5 hours, and the drug reached its dissolution plateau in about 2 hours. In contrast, untreated large-particle API samples required 24 hours to dissolve approximately 90%. The flow cell test results before and after drug treatment indicate that nano-sizing of meloxicam effectively improved the API's dissolution rate by increasing its saturated solubility, significantly addressing the original problem of poor API solubility.

[0112] Based on the results of the above embodiments, it can be seen that the low-energy-consumption preparation method of meloxicam nanocrystalline drug provided by the present invention can prepare nanocrystalline drugs with uniform particle size and good stability. The obtained nanocrystalline drugs can effectively improve the problem of poor solubility of meloxicam, achieving 90% drug dissolution and release within 0.5 hours. Simultaneously, a comparison was made between low-energy-consumption mechanical stirring and high-energy-consumption high-speed shearing. It was found that the low-energy-consumption preparation method provided by the present invention innovatively adopts an acid-base precipitation-assisted mechanical stirring method, which can achieve the preparation of nanocrystalline drugs with uniform particle size and good stability under low energy consumption, further breaking through the bottleneck of traditional high-energy-consumption technology, eliminating the need for energy-intensive processes such as ball milling and high-pressure homogenization. Furthermore, the low-energy-consumption preparation method of meloxicam nanocrystalline drug of the present invention can also achieve process scale-up research, meaning that it will further promote the transformation of nanocrystalline drugs from "high-cost niche technology" to "low-cost large-scale application," providing technical support for the industrialization of the solubilization of poorly soluble drugs.

[0113] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A low-energy-consumption preparation method for meloxicam nanocrystal drugs, comprising the following steps: A combination of an alkaline solution containing meloxicam and a stabilizer is brought into contact with an acidic solution to form meloxicam nanocrystals under mechanical stirring. The stabilizer includes one or more of Tween and poloxamer.

2. The low-energy preparation method according to claim 1, characterized in that, Includes the following steps: (1) Dissolve meloxicam and stabilizer in an alkaline solution to form an alkaline phase, while using an acidic solution as the acidic phase; (2) The alkaline phase is stirred by mechanical stirring, and the acid phase is added to the alkaline phase during continuous stirring; (3) After the acid phase is added, continue stirring while maintaining the stirring state until a uniform precipitate is formed in the system to obtain meloxicam nanocrystal drug suspension.

3. The preparation method according to claim 1, characterized in that, The alkaline solution is a sodium hydroxide solution, and the acidic solution is a hydrochloric acid solution; The molar ratio of the alkaline compound in the alkaline solution to the acidic compound in the acidic solution is 1:

1.

4. The preparation method according to claim 1, characterized in that, The stabilizer is selected from one or more of surfactants and polymers, preferably a combination of surfactants and polymers; The surfactants include ionic surfactants, nonionic surfactants, and amphoteric surfactants.

5. The preparation method according to claim 1, characterized in that, The weight ratio of meloxicam to the stabilizer is 1:(0.01~50).

6. The preparation method according to claim 1, characterized in that, The stabilizer includes a first stabilizer and a second stabilizer; The first stabilizer is Tween, and the second stabilizer is poloxamer; The mass ratio of the first stabilizer to the second stabilizer is 1:10 to 10:1, preferably 1:4 to 4:

1.

7. The preparation method according to any one of claims 1 or 6, characterized in that, The Tween is selected from Tween 80; The poloxamer is selected from poloxamer 188 and / or poloxamer 407.

8. The preparation method according to claim 1, characterized in that, The mechanical stirring specifically refers to: By stirring, the liquid surface is kept in a state of continuous disturbance without any static areas, ensuring that the entire material participates in the flow. The minimum rotational speed that just achieves this liquid surface state is appropriate.

9. The meloxicam nanocrystal drug prepared by the preparation method according to any one of claims 1 to 8.

10. A meloxicam nanocrystalline pharmaceutical composition comprising the meloxicam nanocrystalline pharmaceutical preparation prepared by any one of claims 1 to 8 and excipients.

11. The meloxicam nanocrystalline pharmaceutical composition according to claim 10, characterized in that, The dosage form of the composition is one or more of the following: lyophilized powder, tablet, gel, capsule, and transdermal preparation.

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