Pharmaceutical composition with synergistic antipyretic, analgesic and anti-inflammatory effects and application

Abstract

The invention provides a pharmaceutical composition with synergistic antipyretic, analgesic and anti-inflammatory effects and application, and belongs to the technical field of medicines. The pharmaceutical composition with synergistic antipyretic, analgesic and anti-inflammatory effects, provided by the invention, is prepared from 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, the drug effect of the pharmaceutical composition is superior to that of each drug which is independently used, and the composite nanoparticles prepared by self-assembling baicalein and 2, 4-decadienal have relatively good dispersity and stability. The composite nanoparticle provided by the invention has a synergistic effect and can be used for treating 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 having 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 vital role in various biological processes, including pain, fever, inflammation, angiogenesis, and tumorigenesis. During the metabolism and synthesis of PGE2, free arachidonic acid (AA) is enzymatically converted into prostaglandin G2 (PGG2) by cyclooxygenase (COX1 / 2), and then reduced to the precursor metabolite prostaglandin H2 (PGH2). The last step of PGE2 biosynthesis is then catalyzed by prostaglandin E2 synthase (PGES), converting PGH2 into active PGE2. There are three main subtypes of PGES: cytoplasmic PGES (cPGES), and microsomal subtypes of PGES-1 (mPGES1) and mPGES-2.

[0003] COX2 and mPGES1 are two inducible synthases that can rapidly respond to the stimulation of stress responses such as inflammation, thus 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 the treatment of inflammation, pain, and fever worldwide. However, PGE2 terminal synthases, especially mPGES1, selectively inhibit downstream mPGES1 activity in the AA-PGE2 lipid metabolism pathway, which can effectively slow down the overexpression of PGE2 and avoid the toxic side effects caused by inflammatory substances such as PGF2 and PGD2 downstream of PGH2, and 12-HETE downstream of LOX, representing 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 of 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), as shown in structural formula II, is a volatile oil component in 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] Nano drug delivery systems have attracted much attention due to their great potential in improving drug solubility and enhancing drug accumulation at the target site. In recent years, self-assembled nano drugs have attracted more and more research interest due to their high drug loading, simple preparation process, avoidance of artificial modification, and ability to effectively reduce the immune response and toxicity caused by the carrier. Natural small molecule self-assembly systems are favored due to their excellent biocompatibility, controllable degradability, and possible synergistic pharmacological activity. Chinese patents disclose that baicalin and berberine [CN117281779A] are combined as natural product drugs to prepare nanoparticles, which have both antibacterial and antioxidant effects; L-gossypol and dihydroartemisinin [CN116173009A] are combined to prepare nanoparticles for the treatment of liver cancer and cervical cancer; berberine and rhein [CN116268399A] are coordinated to obtain self-assembled natural high-efficiency photothermal antibacterial nanoparticles. Nevertheless, 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 consisting 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 reverse phase solvent precipitation method;

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

[0017] Further 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, and specifically include the following steps:

[0019] Baicalein and 2,4-decadienal are dissolved in organic solvents respectively, mixed to obtain a mixed solution, and then the mixed solution is 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 100-200nm.

[0020] Further preferably, the organic solvent is dimethyl sulfoxide (DMSO), methanol (MeOH), ethyl acetate (EA) or ethanol (EtOH); the ultrasonic parameters are set as: 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 selection of the 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 1s and stop for 2s, 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 composite nanoparticle of a pharmaceutical composition prepared by the above-mentioned preparation method.

[0023] A fourth 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 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] A 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 drug composition or the composite nanoparticles of the above-mentioned drug 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 uses baicalein and 2,4-decadienal in combination, or prepares the two into stable nanoparticles, which can play a synergistic effect, and the drug effect of 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 baicalein and 2,4-decadienal are used in combination, the function is clear and there is no obvious toxic and side effect. While significantly improving the therapeutic effect, the dosage is reduced, the treatment cost is reduced, and the risk of toxic and side effects is reduced, and there is a good application prospect. 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 drawings required for use in the embodiments will be briefly introduced below. 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 creative work.

[0031] Figure 1 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 were investigated; wherein, 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 content determination of interleukin-6 (IL-6).

[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 The preparation conditions of baicalein and 2,4-decadienal self-assembled nanoparticles were investigated; A was different solvents, B was different ultrasonic times, and C was different pH values. The particle size, PDI and Zeta potential values ​​were investigated.

[0034] Figure 4 This is an investigation of the antipyretic effect of baicalein and 2,4-decadienal composite nanoparticles on LPS-induced fever in mice; wherein, 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 contents 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 The aim of this study was to investigate the improvement effect of baicalein and 2,4-decadienal composite nanoparticles on collagen-induced rheumatoid arthritis in mice; wherein, A was the arthritis index (AI), B was the pain threshold of mice, C was serum PGE2, D was tumor necrosis factor-α (TNF-α), E was interleukin-1β (IL-1β), and F was 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 should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

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

[0039] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation 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 a conflict with any incorporated document, the content 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 of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are 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 compatibility combinations can bring into play the synergistic effect of drugs to improve the efficacy, reduce the probability of drug resistance, reduce the dosage of a single drug in the composition, and thus reduce toxic and side effects. It has great advantages in the treatment of chronic diseases with complex pathogenesis regulated by multiple genes. The present invention studies the synergistic effect of the combined use of baicalin and 2,4-decadienal, and prepares the two into composite nanoparticles by self-assembly, which are used to inhibit the treatment of diseases such as fever, inflammation or pain caused by overexpression of PGE2. After searching, there is no patent for the use of a pharmaceutical composition of baicalin and 2,4-decadienal for the treatment of inflammation, pain or fever caused by overexpression of PGE2, nor is there a pharmaceutical preparation for the above-mentioned pharmaceutical composition as an antipyretic, analgesic and anti-inflammatory agent.

[0043] The pharmaceutical composition or composite nanoparticles provided by the present invention can effectively inhibit the overexpression of PGE2 in inflammatory reactions, thereby alleviating the symptoms of inflammation-induced fever, infectious pneumonia, rheumatoid arthritis and other inflammation-related diseases. After the present invention uses baicalein and 2,4-decadienal in combination, the effect of inhibiting the overexpression of PGE2 is significantly greater than the effect of baicalein and 2,4-decadienal when 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 protection scope of the present invention.

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

[0046] Baicalein (B-00520-5 g) used in the experiment of the present invention was purchased from Xiensi 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 Solebow Technology Co., Ltd. The ELISA kits involved were all purchased from Jianglai Biotechnology Co., Ltd., and the specific item numbers were 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 a catalog number of CL-0190.

[0048] In a specific embodiment of the present invention, the KM and C57BL / 6J mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Under standard pathogen-free conditions, dietary management was performed according to feeding standards, and experimental operations were in accordance with the requirements of the "Guide to the Use and Care of Laboratory Animals and Animal Experiment Management Regulations".

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

[0050] In order to investigate the synergistic effect of baicalein and 2,4-decadienal in inhibiting the expression of PGE2 at the cellular level in vitro, RAW 264.7 cells were inoculated in 96-well plates and cultured overnight. The experiment used LPS (1μg / mL) to stimulate the model, and different concentrations of baicalein and 2,4-decadienal were given at the same time, as well as the combination of the two drugs to investigate the expression and secretion of cellular PGE2. The concentrations of baicalein for a single dose were 10μM, 1μM, and 0.1μM; the concentrations of 2,4-decadienal for a single dose were 10μM, 1μM, and 0.1μM. The concentrations of baicalein and 2,4-decadienal in the combination were 5μM, 0.5μM, and 0.05μM, respectively. After 24 hours of administration, the cell supernatant was collected, and the PGE2 content in the sample was detected using an ELISA kit. CompuSyn software was used to analyze the synergistic index (CI value) of the two drugs after single or combined intervention. Among them, <1 represents synergistic effect, =1 represents additive effect, and >1 represents antagonistic effect. Figure 1 As shown in A, when baicalein and 2,4-decadienal were used together, when the compatibility ratio of the two was in the range of 10:1 to 1:10, the CI value was <1, indicating that the compatibility within this range had a synergistic inhibitory effect on LPS-induced PGE2 overexpression. When the compatibility ratio of baicalein and 2,4-decadienal was 10:1, the CI value was the smallest, indicating that the optimal ratio was 10:1.

[0051] Subsequently, the same method was used under the optimal compatibility conditions to investigate the effects of 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. After LPS (1 μg / mL) was used to stimulate the model, aspirin was used as a positive control (10 μM). The results are shown in Figure 1 As shown in Figures B, C, D, and E, at the same dose, the combined effect of baicalin and 2,4-decadienal was significantly better than that of either alone, indicating that baicalin 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 dripped into 5 ml of water under ultrasonic conditions. After 6 hours of water dialysis to remove the solvent, the particle size, PDI and Zeta potential values ​​were measured. The results are as follows Figure 2 As shown, 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 combination dose is 10:1.

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

[0055] Using the anti-solvent precipitation method of Example 2, baicalein and 2,4-decadienal were dissolved in different organic solvents, and then dropped into aqueous solutions with different pH values ​​under different ultrasonic conditions to investigate the preparation conditions of the nanoparticles. Figure 3 As shown, 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 power 300 W, ultrasonic 1 s stop 2 s, ultrasonic 0 to 10 minutes, among which the Zeta potential of ultrasonic 4 minutes is the most stable; the results of the solution pH investigation found that the Zeta potential of the nanoparticles in the neutral to alkaline pH range (pH = 7-11) is relatively stable, 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 DMSO respectively, mixed evenly, and dropped into 1 mL of water (pH = 7) under ultrasonic conditions (ultrasonic power 300 W, ultrasonic 1 s stop 2 s, ultrasonic 4 minutes) to prepare composite nanoparticles, and a fever model was established by intraperitoneal injection of LPS in mice, and the antipyretic efficacy of BD nanoparticles in mice was investigated.

[0058] Specifically, 48 KM male mice were randomly divided into 8 groups, including blank control group, model group, aspirin positive control group (100 mg / kg), baicalin group (30 mg / kg), 2,4-decadienal group (3 mg / kg), BD high-dose baicalin + 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 baicalin 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 show that baicalein and 2,4-decadienal composite nanoparticles (BD) have a synergistic antipyretic effect, and the effect of 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 relieving pneumonia in mice

[0060] Referring to the method of Example 3, methanol was used as a solvent to prepare baicalein and 2,4-decadienal nanoparticles (BD): 6 mg baicalein and 0.6 mg 2,4-decadienal were dissolved in 60 μL methanol, vortexed and mixed evenly, and then dropped into 1 mL of water (pH = 7) under ultrasonic conditions (ultrasonic power 300 W, 1 s on, 2 s off, 4 minutes of ultrasonication) to prepare composite nanoparticles. 20 μL of freshly prepared Pseudomonas aeruginosa PA 14 strain (5×10 7) in normal saline 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 administration was performed, and blood was collected 20 hours later to examine the expression of inflammatory factors. The results are shown in Figure 5 As shown in the figure, 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 baicalin 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] Referring to the method of Example 3, ethanol was used as a solvent to prepare baicalein and 2,4-decadienal nanoparticles (BD): 6 mg baicalein and 0.6 mg 2,4-decadienal were dissolved in 100 μL ethanol respectively, mixed evenly, and then dropped into 3 mL water (pH = 7) under ultrasonic conditions to prepare composite nanoparticles. A rheumatoid arthritis model was established using collagen-induced mice, and the therapeutic effect of the prepared BD nanoparticles on rheumatoid arthritis was investigated in vivo.

[0064] Specifically, 30 C57BL / 6J male mice were randomly divided into 5 groups, including a blank control group, a model group, a diclofenac sodium positive control group (10 mg / kg), a BD medium-dose group (10 mg / kg+1 mg / kg), and a BD low-dose group (3 mg / kg+0.3 mg / kg). The primary immunization was made by mixing chicken type II collagen (CII, Chondex, Washington, USA) and complete Freund's adjuvant (CFA, Sigma-Aldrich, St. Louis, Missouri, USA) in a 1:1 ratio to prepare 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, Missouri, USA) was injected at a different site from the primary injection. On the 28th day after modeling, the model mice that had been immunized with collagen were randomly divided into groups and received intraperitoneal drug treatment. The swelling of the four joints of the mice was observed in real time. Blood samples were collected on the 56th day for efficacy analysis of rheumatoid arthritis.

[0065] The arthritis index was evaluated based on the degree of erythema, swelling, and deformation of the four joints of the mice, and the severity of arthritis was scored on a five-point scale, with the highest possible score being 16 points. If the mouse's arthritis index score exceeded 4 points, it was considered that arthritis was 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 dose groups of BD could significantly improve the arthritis index of mice with rheumatoid arthritis. The pain threshold of mice was measured on the 56th day, and it was found that both the medium and low dose groups of BD could improve 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 baicalin and 2,4-decadienal can effectively relieve rheumatoid arthritis in vivo. ### ,p<0.001. Compared with the model group, **,p<0.01; ***,p<0.001.

[0067] The organic solvents (dimethyl sulfoxide, methanol, ethyl acetate, ethanol) listed in Example 3 of the present invention can all be used to prepare the composite nanoparticles mentioned in the present invention. However, considering the boiling point and toxicity during industrial production, methanol and ethanol are easier to remove, so Examples 5 and 6 use these two solvents to prepare composite nanoparticles, respectively, and investigate their antipyretic effects on mice and the effects of relieving pneumonia in mice, 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 principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that It is composed of baicalein and 2,4-decadienal in a molar ratio of 10:1 to 1:

10.

2. A method for preparing composite nanoparticles of a pharmaceutical composition, characterized in that: The composite nanoparticles were prepared by self-assembly of baicalein and 2,4-decadienal through reverse phase solvent precipitation method. The molar ratio of baicalein to 2,4-decadienal is 10:1 to 1:

10.

3. The method for preparing the composite nanoparticles of the pharmaceutical composition according to claim 2, characterized in that: The composite nanoparticles are prepared by self-assembly using the reversed phase solvent precipitation method, and specifically include 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.

4. The method for preparing the composite nanoparticles of the pharmaceutical composition according to claim 3, 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, total ultrasonic 1 to 10 minutes; the pH value of the self-assembly system is 7-11.

5. A pharmaceutical composition composite nanoparticle prepared by the preparation method according to any one of claims 2 to 4.

6. Use of the pharmaceutical composition according to claim 1 or the composite nanoparticles of the pharmaceutical composition according to claim 5 in the preparation of a drug for alleviating fever caused by overexpression of PGE2.

7. Use of the pharmaceutical composition according to claim 1 or the composite nanoparticles of the pharmaceutical composition according to claim 5 in the preparation of a drug for relieving pain caused by overexpression of PGE2.

8. Use of the pharmaceutical composition according to claim 1 or the composite nanoparticles of the pharmaceutical composition according to claim 5 in the preparation of a drug for alleviating inflammation caused by overexpression of PGE2.

9. A drug having synergistic antipyretic, analgesic and anti-inflammatory effects, characterized in that: The raw materials include the pharmaceutical composition according to claim 1 or the pharmaceutical composition composite nanoparticles according to claim 5, and pharmaceutically acceptable excipients.

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