A pharmaceutical composition with synergistic antipyretic, analgesic and anti-inflammatory effects and its application

Abstract

The present invention provides a pharmaceutical composition and application with synergistic antipyretic, analgesic and anti-inflammatory effects, belonging to the field of pharmaceutical technology. The pharmaceutical composition with synergistic antipyretic, analgesic and anti-inflammatory effects provided by the present invention is composed of baicalein and 2,4-decadienal in a molar ratio of 10:1 to 1:10. The pharmaceutical composition has a synergistic effect in vivo and in vitro, and its drug efficacy is better than the use of each drug alone, and the composite nanoparticles prepared by self-assembly of baicalein and 2,4-decadienal have good dispersibility and stability. The composite nanoparticles provided by the present invention have a synergistic effect and can be used for the treatment of diseases such as inflammation, pain and fever.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition with synergistic antipyretic, analgesic and anti-inflammatory effects and its application. Background Art

[0002] Prostaglandin E2 (PGE2) is the most highly expressed prostaglandin in the human body and plays a crucial role in various biological processes, including pain, fever, inflammation, angiogenesis, and tumorigenesis. During PGE2 metabolism and synthesis, free arachidonic acid (AA) is enzymatically converted to prostaglandin G2 (PGG2) by cyclooxygenase (COX1 / 2), which is then reduced to the precursor metabolite prostaglandin H2 (PGH2). Prostaglandin E2 synthase (PGES) then catalyzes the final step in PGE2 biosynthesis, converting PGH2 into active PGE2. There are three main PGES isoforms: cytoplasmic PGES (cPGES) and the microsomal isoforms PGES-1 (mPGES1) and mPGES-2.

[0003] COX2 and mPGES1 are two inducible synthases that can rapidly respond to stimuli such as inflammation and other stress responses, thereby playing an important role in regulating physiological processes, including inflammation, fever, and pain perception. Currently, drugs targeting COX2, such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), are the most widely used therapies for treating inflammation, pain, and fever worldwide. However, PGE2 terminal synthases, particularly mPGES1, in the AA-PGE2 lipid metabolism pathway, selectively inhibiting downstream mPGES1 activity can effectively reduce PGE2 overexpression, avoid the toxic side effects caused by inflammatory substances such as PGF2 and PGD2 downstream of PGH2, and 12-HETE downstream of LOX, and represent a new therapeutic target. Compared with non-selective COX inhibitors, mPGES1 inhibitors provide a safer anti-inflammatory strategy.

[0004] Baicalein is one of the flavonoid compounds with the highest content in the traditional Chinese medicine Scutellaria baicalensis and is the main active ingredient in Scutellaria baicalensis. It is shown in structural formula I and has multiple biological activities, including antipyretic, anti-inflammatory, antioxidant, and anti-tumor.

[0005]

[0006] Structural Formula I

[0007] 2,4-decadienal (DAL), shown in structural formula II, is a volatile oil component of the traditional Chinese medicine Bupleurum chinense. It is a highly active α,β-unsaturated aldehyde with significant antipyretic and anti-inflammatory effects.

[0008]

[0009] Structural Formula II

[0010] Nanodrug delivery systems have attracted considerable attention due to their potential for improving drug solubility and enhancing drug accumulation at target sites. In recent years, self-assembled nanomedicines have garnered increasing research interest due to their high drug loading capacity, simple preparation process, avoidance of artificial modification, and ability to effectively reduce carrier-induced immune responses and toxicity. Natural small molecule self-assembly systems are highly sought after due to their excellent biocompatibility, controllable degradability, and potential for synergistic pharmacological activity. Chinese patents disclose the combination of baicalin and flavonoids [CN117281779A] as natural product drugs, prepared into nanoparticles with both antibacterial and antioxidant properties; the combination of L-gossypol and dihydroartemisinin [CN116173009A] into nanoparticles for the treatment of liver and cervical cancer; and the coordination reaction of berberine and rhein [CN116268399A] to produce self-assembled, natural, and highly efficient photothermal antibacterial nanoparticles. Despite this, current research on self-assembled nanomedicines mainly focuses on their physicochemical properties and in vitro effects, while there is still relatively little research on their synergistic mechanisms and in vivo action processes. Summary of the Invention

[0011] In view of this, the object of the present invention is to provide a pharmaceutical composition and application having synergistic antipyretic, analgesic and anti-inflammatory effects.

[0012] In order to achieve the above object, the present invention provides the following technical solutions:

[0013] One of the technical solutions of the present invention is a pharmaceutical composition composed of baicalein and 2,4-decadienal in a molar ratio of 10:1 to 1:10.

[0014] Further preferably, the pharmaceutical composition consists of baicalein and 2,4-decadienal in a molar ratio of 10:1.

[0015] The second technical solution of the present invention is a method for preparing composite nanoparticles of a pharmaceutical composition, wherein baicalein and 2,4-decadienal are self-assembled to prepare the composite nanoparticles by a reversed-phase solvent precipitation method;

[0016] The molar ratio of baicalein to 2,4-decadienal is 10:1 to 1:10.

[0017] More preferably, the molar ratio of baicalein to 2,4-decadienal is 10:1.

[0018] The composite nanoparticles are prepared by self-assembly using the reversed-phase solvent precipitation method, which specifically includes the following steps:

[0019] Baicalein and 2,4-decadienal are dissolved in organic solvents respectively and mixed to obtain a mixed solution, which is then dropped into water under ultrasonic conditions for self-assembly to obtain the composite nanoparticles. The composite nanoparticles prepared by the present invention have a particle size range of 100-200 nm.

[0020] Further preferably, the organic solvent is dimethyl sulfoxide (DMSO), methanol (MeOH), ethyl acetate (EA) or ethanol (EtOH); the ultrasonic parameters are set to: power 300W, ultrasonic 1s stop 2s, total ultrasonic 1 to 10 minutes; the pH value of the self-assembly system is 7-11. The present invention adjusts the pH value of the self-assembly system by adding an acid-base regulator to water. The present invention does not specifically limit the choice of acid-base regulator, and the acid-base regulator commonly used by those skilled in the art can be selected, for example: ammonia water.

[0021] Further preferably, the organic solvent is dimethyl sulfoxide; the ultrasonic parameters are set as: power 300W, ultrasonication for 1 second and pause for 2 seconds, for a total of 4 minutes; and the pH value of the water is 7.

[0022] The third technical solution of the present invention is a pharmaceutical composition composite nanoparticle prepared by the above preparation method.

[0023] A fourth technical solution of the present invention is a use of the above-mentioned pharmaceutical composition or composite nanoparticles of the above-mentioned pharmaceutical composition in the preparation of a drug for alleviating fever caused by overexpression of PGE2.

[0024] A fifth technical solution of the present invention is a use of the above-mentioned pharmaceutical composition or the composite nanoparticles of the above-mentioned pharmaceutical composition in the preparation of a drug for relieving pain caused by overexpression of PGE2.

[0025] The sixth technical solution of the present invention is a use of the above-mentioned pharmaceutical composition or the composite nanoparticles of the above-mentioned pharmaceutical composition in the preparation of a drug for alleviating inflammation caused by overexpression of PGE2.

[0026] The seventh technical solution of the present invention is a drug with synergistic antipyretic, analgesic and anti-inflammatory effects, the raw materials of which include the above-mentioned pharmaceutical composition or the composite nanoparticles of the above-mentioned pharmaceutical composition, and pharmaceutically acceptable excipients.

[0027] Further preferably, the dosage form of the drug having synergistic antipyretic, analgesic and anti-inflammatory effects is granules, tablets, capsules, injections, gels, patches, sprays, oral liquids, pills or ointments.

[0028] The present invention discloses the following technical effects:

[0029] The present invention combines baicalein and 2,4-decadienal, or prepares them into stable nanoparticles, both of which can exert a synergistic effect. The drug efficacy of the drug in inhibiting the overexpression of PGE2 is greater than that of each drug used alone, and has a significant improvement effect on fever caused by overexpression of PGE2, pneumonia caused by infection, and rheumatoid arthritis. After the combined use of baicalein and 2,4-decadienal, its function is clear and there are no obvious toxic and side effects. While significantly improving the therapeutic effect, it can reduce the dosage, reduce treatment costs, and reduce the risk of toxic and side effects, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0031] Figure 1 This study investigated the synergistic index (CI) of the combination of baicalein and 2,4-decadienal in inhibiting LPS-induced PGE2 overexpression in RAW 264.7 cells, as well as the synergistic effect of inhibiting inflammatory factors; where A is the synergistic index investigation, B is PGE2, C is tumor necrosis factor-α (TNF-α), D is interleukin-1β (IL-1β), and E is the determination of interleukin-6 (IL-6) content.

[0032] Figure 2 The drug concentration ratio of baicalein and 2,4-decadienal self-assembled nanoparticles was investigated; wherein, A is the particle size and particle size distribution uniformity (Polydispersity index, PDI) of the nanoparticles, and B is the Zeta potential value.

[0033] Figure 3 This study investigated the preparation conditions of baicalein and 2,4-decadienal self-assembled nanoparticles; A. Investigation of different solvents, B. Investigation of different ultrasonic times, and C. Investigation of particle size, PDI, and Zeta potential values ​​under different pH conditions.

[0034] Figure 4 This figure investigates the antipyretic effect of baicalein and 2,4-decadienal composite nanoparticles on LPS-induced fever in mice; A is a statistical graph of thermal imaging of mice, and B is the determination of PGE2 content in serum.

[0035] Figure 5To investigate the improvement effect of baicalein and 2,4-decadienal composite nanoparticles on pneumonia in mice caused by Pseudomonas aeruginosa; to determine the levels of: A PGE2, B tumor necrosis factor-α (TNF-α), C interleukin-1β (IL-1β), and D interleukin-6 (IL-6) in mouse serum.

[0036] Figure 6 This study investigated the improvement effect of baicalein and 2,4-decadienal composite nanoparticles on collagen-induced rheumatoid arthritis in mice; where A is the arthritis index (AI), B is the pain threshold of mice, C is serum PGE2, D is tumor necrosis factor-α (TNF-α), E is interleukin-1β (IL-1β), and F is the content determination of interleukin-6 (IL-6). DETAILED DESCRIPTION

[0037] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0038] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value within any stated value or stated range, and each smaller range between any other stated value or intermediate value within the stated range, is also encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0039] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0040] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be exemplary only.

[0041] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0042] The use of drug combinations can leverage drug synergy to enhance efficacy, reduce the incidence of drug resistance, and reduce the dosage of individual drugs in the combination, thereby reducing toxic and side effects. This approach offers significant advantages in the treatment of chronic diseases with complex pathogenesis regulated by multiple genes. The present invention investigates the synergistic effects of baicalein and 2,4-decadienal in combination, and prepares them into composite nanoparticles through self-assembly for the treatment of diseases such as fever, inflammation, or pain caused by PGE2 overexpression. A search has revealed no patents disclosing pharmaceutical compositions of baicalein and 2,4-decadienal for the treatment of inflammation, pain, or fever caused by PGE2 overexpression, nor any patents for the use of such compositions as antipyretic, analgesic, and anti-inflammatory pharmaceutical preparations.

[0043] The pharmaceutical composition or composite nanoparticles provided by the present invention can effectively inhibit the overexpression of PGE2 during inflammatory reactions, thereby alleviating the symptoms of inflammation-related diseases such as inflammation-induced fever, infectious pneumonia, and rheumatoid arthritis. The combination of baicalein and 2,4-decadienal in the present invention is significantly more effective in inhibiting PGE2 overexpression than when baicalein and 2,4-decadienal are used alone.

[0044] The present invention does not limit the dosage form of the drug, and all dosage forms accepted in the pharmaceutical field are within the scope of protection of the present invention.

[0045] In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.

[0046] Baicalein (B-00520-5 g) used in the experiments of the present invention was purchased from Xiens Biochemical Technology Co., Ltd., 2,4-decadienal (D303153-25 g) was purchased from Aladdin Biochemical Technology Co., Ltd., and lipopolysaccharide (LPS, L8880-10 mg) was purchased from Beijing Solebold Technology Co., Ltd. All ELISA kits involved were purchased from Jianglai Biotechnology Co., Ltd., with specific product numbers of prostaglandin (PGE2) (JL12640-96T), tumor necrosis factor-α (TNF-α) (JL10484-96T), interleukin-1β (IL-1β) (JL18442-96T), and interleukin-6 (IL-6) (JL20268-96T).

[0047] In a specific embodiment of the present invention, the RAW 264.7 cells are mouse mononuclear macrophage leukemia cells purchased from Wuhan Pronocell Life Science Co., Ltd. with the product number CL-0190.

[0048] In a specific embodiment of the present invention, the KM and C57BL / 6J mice were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. They were maintained under standard pathogen-free conditions and fed according to feeding standards. Experimental procedures were in compliance with the requirements of the "Guide to the Use and Care of Laboratory Animals and Animal Experimentation Management Regulations."

[0049] Example 1 Investigation of the synergistic effect of baicalein and 2,4-decadienal in inhibiting PGE2 expression

[0050] To investigate the synergistic effect of baicalein and 2,4-decadienal in inhibiting cellular PGE2 expression in vitro, RAW 264.7 cells were seeded in 96-well plates and cultured overnight. LPS (1 μg / mL) was used to establish a model. Baicalein and 2,4-decadienal were administered at varying concentrations, as well as in combination, to assess PGE2 expression and secretion. Baicalein was administered at single doses of 10 μM, 1 μM, and 0.1 μM; 2,4-decadienal was administered at single doses of 10 μM, 1 μM, and 0.1 μM. The concentrations of baicalein and 2,4-decadienal in the combined treatments were 5 μM, 0.5 μM, and 0.05 μM, respectively. Cell supernatants were collected 24 hours after administration, and PGE2 levels were determined using an ELISA kit. CompuSyn software was used to analyze the synergistic index (CI) of the two drugs, either alone or in combination. Among them, <1 represents synergistic effect, =1 represents additive effect, and >1 represents antagonistic effect. Figure 1 As shown in Figure A, when baicalein and 2,4-decadienal are used together, the CI value is <1 when the ratio of the two is between 10:1 and 1:10, indicating that the combination has a synergistic inhibitory effect on LPS-induced PGE2 overexpression within this range. The CI value is minimized when the ratio of baicalein to 2,4-decadienal is 10:1, indicating that the optimal ratio is 10:1.

[0051] Subsequently, the same method was used to investigate the effects of the drugs alone or in combination on the expression of prostaglandins (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in RAW 264.7 cells under the optimal compatibility conditions. The model was stimulated with LPS (1 μg / mL) and aspirin was used as a positive control (10 μM). The results are shown in Figure 2. Figure 1 As shown in Figures B, C, D, and E, at the same dose, the combined effect of baicalein and 2,4-decadienal was significantly better than that of either alone, indicating that baicalein and 2,4-decadienal have synergistic anti-inflammatory effects in vitro. ###,p<0.001. Compared with the lipopolysaccharide group, *,p<0.05; **,p<0.01; ***,p<0.001; compared with the baicalein group, △ ,p<0.05; △△ ,p<0.01; compared with the 2,4-decadienal group, ○○ ,p<0.01; ○○○ ,p<0.001.

[0052] Example 2 Investigation of the optimal drug ratio of baicalein and 2,4-decadienal self-assembled nanoparticles

[0053] Since the combination of baicalein and 2,4-decadienal in Example 1 can produce a synergistic effect, the anti-solvent precipitation method was used to self-assemble the two into composite nanoparticles to investigate the optimal ratio of the drugs. Specifically, baicalein and 2,4-decadienal were dissolved in ethanol respectively, and the above solutions with different ratios were mixed and then dropped into 5 ml of water under ultrasonic conditions. After dialysis with water for 6 hours to remove the solvent, the particle size, PDI and Zeta potential values ​​were measured. The results are as follows. Figure 2 As shown in the figure, nanoparticles can be formed when the ratio of baicalein and 2,4-decadienal is between 50:1 and 1:50 (molar ratio), and the Zeta potential is most stable when the ratio is 10:1.

[0054] Example 3. Preparation conditions of baicalein and 2,4-decadienal self-assembled nanoparticles

[0055] Using the antisolvent precipitation method of Example 2, baicalein and 2,4-decadienal were dissolved in different organic solvents and added dropwise to aqueous solutions of different pH values ​​under different ultrasonic conditions to investigate the preparation conditions of the nanoparticles. Figure 3 As shown in the figure, different organic solvents, such as dimethyl sulfoxide (DMSO), methanol (MeOH), ethyl acetate (EA), and ethanol (EtOH), can be used to prepare composite nanoparticles. Based on the particle size and Zeta potential value, DMSO is preferred. The ultrasonic conditions are 300W power, 1s supersonication and 2s pause, and 0 to 10 minutes of ultrasonication, among which the Zeta potential of 4 minutes of ultrasonication is the most stable. The results of the solution pH investigation show that the Zeta potential of nanoparticles is relatively stable in the neutral to alkaline pH range (pH = 7-11), among which pH = 7 is preferred.

[0056] Example 4. Investigation of the antipyretic effect of baicalein and 2,4-decadienal composite nanoparticles on mice

[0057] Referring to the method in Example 3, DMSO was used as a solvent to prepare baicalein and 2,4-decadienal composite nanoparticles (BD): 6 mg of baicalein and 0.6 mg of 2,4-decadienal were dissolved in 10 μL of DMSO, mixed evenly, and added dropwise to 1 mL of water (pH = 7) under ultrasonic conditions (ultrasonic power 300 W, supersonic 1 s pause 2 s, ultrasonic 4 minutes) to prepare composite nanoparticles. A fever model was established in mice by intraperitoneal injection of LPS, and the antipyretic efficacy of BD nanoparticles in mice was investigated.

[0058] Specifically, 48 KM male mice were randomly divided into 8 groups: blank control group, model group, aspirin positive control group (100 mg / kg), baicalein group (30 mg / kg), 2,4-decadienal group (3 mg / kg), BD high-dose baicalein + 2,4-decadienal group (30 mg / kg + 3 mg / kg), BD medium-dose group (10 mg / kg + 1 mg / kg), and BD low-dose group (3 mg / kg + 0.3 mg / kg). Figure 4 As shown in Figure A, different doses of BD groups can relieve LPS-induced fever, and the antipyretic effect of the combined group at the same dose is better than that of the group receiving baicalein and 2,4-decadienal alone. The PGE2 content in the serum of mice was then measured, and the results were consistent with the above antipyretic effect ( Figure 4 The above results indicate that baicalein and 2,4-decadienal composite nanoparticles (BD) have a synergistic antipyretic effect, and the effect of the combined treatment is better than that of single drug treatment. ### ,p<0.001; compared with the lipopolysaccharide group, *,p<0.05; **,p<0.01; ***,p<0.001; compared with the baicalein group, △ , p<0.05; compared with the 2,4-decadienal group, ○○ ,p<0.01; ○○○ ,p<0.001.

[0059] Example 5. Effect of baicalein and 2,4-decadienal composite nanoparticles on alleviating pneumonia in mice

[0060] Referring to the method of Example 3, baicalein and 2,4-decadienal nanoparticles (BD) were prepared using methanol as the solvent: 6 mg of baicalein and 0.6 mg of 2,4-decadienal were dissolved in 60 μL of methanol, vortexed and mixed evenly, and then added dropwise to 1 mL of water (pH = 7) under ultrasonic conditions (ultrasonic power 300 W, 1 second on, 2 seconds off, ultrasonic for 4 minutes) to prepare composite nanoparticles. 20 μL of freshly prepared Pseudomonas aeruginosa PA 14 strain (5×10 7) in a normal saline suspension and dripped into the nasal cavity of mice to induce acute lung infection and establish an acute pneumonia model, and investigate the effect of the composite nanoparticles on alleviating pneumonia in mice.

[0061] Specifically, 36 KM male mice were randomly divided into 6 groups: blank control group, model group, aspirin positive control group (100 mg / kg), BD high-dose group (30 mg / kg + 3 mg / kg), BD medium-dose group (10 mg / kg + 1 mg / kg), and BD low-dose group (3 mg / kg + 0.3 mg / kg). After modeling and infection, intraperitoneal drug intervention was performed, and blood was collected 20 hours later to examine the expression of inflammatory factors. The results are as follows Figure 5 As shown in the results, different doses of BD groups significantly inhibited the expression of PGE2, TNF-α, IL-1β, and IL-6 in mouse serum, indicating that nanoparticles (BD) prepared from baicalein and 2,4-decadienal can effectively alleviate acute pneumonia in mice caused by Pseudomonas aeruginosa, and have a good dose-dependent relationship. ### ,p<0.001. Compared with the model group, **,p<0.01; ***,p<0.001.

[0062] Example 6. Improvement effect of baicalein and 2,4-decadienal composite nanoparticles on rheumatoid arthritis in mice

[0063] Following the method of Example 3, baicalein and 2,4-decadienal nanoparticles (BD) were prepared using ethanol as the solvent: 6 mg of baicalein and 0.6 mg of 2,4-decadienal were dissolved in 100 μL of ethanol, mixed thoroughly, and then added dropwise to 3 mL of water (pH = 7) under ultrasonic conditions to prepare composite nanoparticles. A rheumatoid arthritis model was established in collagen-induced mice, and the therapeutic efficacy of the prepared BD nanoparticles against rheumatoid arthritis was evaluated in vivo.

[0064] Thirty C57BL / 6J male mice were randomly divided into five groups: a blank control group, a model group, a diclofenac sodium positive control group (10 mg / kg), a medium-dose BD group (10 mg / kg + 1 mg / kg), and a low-dose BD group (3 mg / kg + 0.3 mg / kg). The primary immunization consisted of a 1:1 mixture of chicken type II collagen (CII, Chondex, WA, USA) and complete Freund's adjuvant (CFA, Sigma-Aldrich, St. Louis, MO, USA) to form an emulsion. On day 0, male C57BL / 6J mice (18-22 g) were intradermally injected with 0.1 mL of CII emulsion (0.5 mg / mL) containing Mycobacterium tuberculosis. On day 21, a booster injection consisting of collagen and incomplete Freund's adjuvant (IFA, Sigma-Aldrich, St. Louis, MO, USA) was administered at a different site from the primary injection. Twenty-eight days after modeling, the collagen-immunized mice were randomly divided into groups and received intraperitoneal drug therapy. Swelling in all four joints of the mice was observed in real time. Blood samples were collected on day 56 for analysis of the efficacy of the rheumatoid arthritis treatment.

[0065] The arthritis index was assessed based on the degree of erythema, swelling, and deformation of the four joints of the mice. The severity of arthritis was scored on a five-point scale, with the highest possible score being 16. If the mouse's arthritis index score exceeded 4 points, arthritis was considered successfully induced; if the score was less than 4 points, the mouse was considered to have no arthritis. The specific scoring criteria are: 0 points: no visible changes; 1 point: swelling and / or redness only in one finger or toe; 2 points: swelling and / or redness affecting multiple fingers or toes, accompanied by mild paw swelling, or mild ankle or wrist swelling; 3 points: moderate paw swelling and redness; 4 points: severe paw swelling and redness, accompanied by ankylosis.

[0066] The results are as follows Figure 6 As shown in Figure A, starting from the 31st day after treatment, the medium and low doses of BD groups significantly improved the arthritis index of rheumatoid arthritis mice. The pain threshold of mice was measured on the 56th day, and it was found that both the medium and low doses of BD groups improved the pain index ( Figure 6 At the same time, the results of the detection of the expression of PGE2, TNF-α, IL-1β, and IL-6 in serum showed that both the medium and low dose groups of BD could significantly inhibit the expression of the above inflammatory factors ( Figure 6 C, D, E, F). The above results show that BD nanoparticles composed of baicalein and 2,4-decadienal can effectively alleviate rheumatoid arthritis in vivo. Compared with the blank group, ### ,p<0.001. Compared with the model group, **,p<0.01; ***,p<0.001.

[0067] The organic solvents listed in Example 3 (dimethyl sulfoxide, methanol, ethyl acetate, and ethanol) can all be used to prepare the composite nanoparticles described in the present invention. However, considering the boiling point and toxicity of methanol and ethanol during industrial production, these two solvents are more easily removed. Therefore, in Examples 5 and 6, composite nanoparticles were prepared using these two solvents, respectively, and their antipyretic and pneumonia-alleviating effects on mice were investigated, providing a feasible solution for industrial production.

[0068] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. Use of a pharmaceutical composition composite nanoparticle in the preparation of a rheumatoid arthritis drug, characterized in that: The preparation method of the composite nanoparticles of the pharmaceutical composition comprises the following steps: self-assembling baicalein and 2,4-decadienal by a reversed-phase solvent precipitation method to prepare the composite nanoparticles; The molar ratio of baicalein to 2,4-decadienal is 10:1 to 1:

10.

2. The use according to claim 1, characterized in that The composite nanoparticles are prepared by self-assembly using the reversed-phase solvent precipitation method, which specifically includes the following steps: Baicalein and 2,4-decadienal are dissolved in organic solvents respectively and then mixed to obtain a mixed solution. Then, under ultrasonic conditions, the mixed solution is dropped into water for self-assembly to obtain the composite nanoparticles.

3. The use according to claim 2, characterized in that The organic solvent is dimethyl sulfoxide, methanol, ethyl acetate or ethanol; the ultrasonic parameters are set as follows: power 300W, ultrasonic 1s and stop 2s, and a total ultrasonic time of 1 to 10 minutes; the pH value of the self-assembly system is 7-11.

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