A pharmaceutical composition containing flurbiprofen and its application

Abstract

The present invention discloses a flurbiprofen-containing pharmaceutical composition and its application, relating to the field of biopharmaceuticals. The pharmaceutical composition comprises flurbiprofen and a COX inhibitor as active ingredients. The COX inhibitor is Compound I having the following chemical formula: #imgabs0#. In this pharmaceutical composition, the mass ratio of flurbiprofen to Compound I is between 2:1 and 1:2. This pharmaceutical composition maintains or enhances the analgesic and anti-inflammatory effects of flurbiprofen while reducing its gastric toxicity and side effects, resulting in a relatively safe treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a flurbiprofen-containing pharmaceutical composition and application thereof. Background Art

[0002] Inflammation plays a crucial role in the development of many complex diseases, such as autoimmune diseases, metabolic syndrome, neurodegenerative diseases, cardiovascular diseases, and cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs), a major class of anti-inflammatory drugs, have become the most commonly used medication. Prostaglandins (PGs) play a crucial regulatory role in inflammation, and all NSAIDs work by inhibiting PG production. Cyclooxygenase (COX) catalyzes the metabolism of arachidonic acid (AA) to PGs and their analogs, making COX an important target for anti-inflammatory drugs. However, long-term use of non-selective COX inhibitors is associated with toxic side effects such as gastric ulcers and bleeding, limiting their use. Selective COX-2 inhibitors were initially considered a safer alternative to traditional NSAIDs. Moderately selective COX-2 inhibitors may reduce their cardiotoxicity.

[0003] Flurbiprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) with antipyretic, anti-inflammatory, and analgesic properties. It is primarily used clinically to treat inflammatory diseases and physiological pain. Currently, most formulations on the market are oral, and while they have some clinical efficacy, they can also cause adverse reactions such as gastrointestinal disturbances.

[0004] Existing technical research shows that the combined use of NSAIDs and gastric acid suppressants can reduce gastric damage caused by NSAIDs and reduce their side effects. Proton pump inhibitors belong to a large category of gastric acid suppressants. Common proton pump inhibitors in clinical practice include omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole.

[0005] Chinese patent document CN201480033480.X discloses a treatment method for intestinal diseases caused by NSAIDs. After administering NSAIDs to patients with pain or inflammation, rifaximin and a proton pump inhibitor are administered to prevent or treat gastric damage caused by NSAIDs. Chinese patent document CN201810115299.3 discloses a compound preparation containing flurbiprofen axetil. The preparation contains two active pharmaceutical ingredients, flurbiprofen axetil and a proton pump inhibitor. This allows patients to effectively prevent and treat gastric damage caused by flurbiprofen axetil while using it to treat inflammation or pain, further reducing side effects after medication. Chinese patent document CN201410317848.7 discloses a compound preparation containing ketoprofen and omeprazole. In the compound preparation, ketoprofen is in the form of micro-sustained-release tablets and omeprazole is in the form of enteric-coated micropellets. The micro-tablets and micropellets are then filled into the same capsule and administered to the patient simultaneously, which can prevent gastrointestinal damage caused by ketoprofen.

[0006] However, existing literature reports have not found a compound preparation that can reduce the gastric damage side effects of flurbiprofen and improve its safety. The present invention provides a pharmaceutical composition containing flurbiprofen, which can reduce the gastric damage caused by flurbiprofen by combining flurbiprofen with a COX inhibitor. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a flurbiprofen-containing pharmaceutical composition and its application. The pharmaceutical composition comprises flurbiprofen and a COX inhibitor as active ingredients, and can maintain or enhance the analgesic and anti-inflammatory effects of flurbiprofen while reducing its gastric toxicity and side effects, thereby providing a relatively high safety profile.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a flurbiprofen-containing pharmaceutical composition, wherein the active pharmaceutical ingredients include flurbiprofen and a COX inhibitor.

[0010] Furthermore, the COX inhibitor is a compound I having the following chemical formula:

[0011]

[0012] Furthermore, in the pharmaceutical composition, the mass ratio of flurbiprofen to compound I is 2:1 to 1:2.

[0013] Exemplarily, the mass ratio of the two is 2:1, 1:1, 1:2.

[0014] Furthermore, the pharmaceutical composition further comprises additives, and the additives include pharmaceutical excipients.

[0015] Furthermore, the pharmaceutical excipients include one or two or more of methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, carbomer, poloxamer, starch, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, glycerol, propylene glycol and Tween 80.

[0016] Furthermore, the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, granules, solutions, suspensions, pills, and dripping pills.

[0017] Furthermore, the tablets include ordinary tablets, dispersible tablets, and sustained-release tablets.

[0018] Furthermore, the tablet also includes a double-layer tablet compressed from component 1 comprising flurbiprofen and component 2 comprising a COX inhibitor.

[0019] In a second aspect, the present invention also provides use of the flurbiprofen-containing pharmaceutical composition in the preparation of analgesic and anti-inflammatory drugs.

[0020] The present invention has the following beneficial effects:

[0021] 1. Compound I in the pharmaceutical composition of the present invention is a novel aromatic heterocyclic compound, which is used as a COX inhibitor in the present invention and has a moderately selective inhibitory effect on COX-1 (cyclooxygenase-1) and COX-2 (cyclooxygenase-2).

[0022] 2. The active pharmaceutical ingredients of the pharmaceutical composition provided by the present invention are composed of flurbiprofen and compound I. The pharmaceutical composition can maintain or enhance the analgesic and anti-inflammatory effects of flurbiprofen while reducing its gastric damage toxicity and side effects, and has a high safety profile. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings used in the description of the embodiments.

[0024] Figure 1 This is a graph showing the inhibition rate of compound I (01-177) on COX-2 provided in an embodiment of the present invention.

[0025] Figure 2 This is a graph showing the inhibition rate of compound I (01-177) on COX-1 provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0026] As used herein:

[0027] "Prepared from" is synonymous with "comprising." As used herein, the terms "comprising," "including," "having," "containing," or any other variations thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0028] When each parameter is expressed as a range, a preferred range, or a range limited by a series of upper preferred values ​​and lower preferred values, this should be understood to specifically disclose all ranges formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed alone. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including the range "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described in this article, unless otherwise stated, the range is intended to include its end values ​​and all integers and fractions within the range.

[0029] In order to better illustrate the content of the present invention, the present invention is further verified by specific examples below. It is particularly noted that the examples are only for more direct description of the present invention, they are only a part of the present invention, and cannot constitute any limitation to the present invention.

[0030] The invention provides a flurbiprofen-containing pharmaceutical composition, wherein the effective pharmaceutical ingredients of the composition include flurbiprofen and a COX inhibitor.

[0031] As a preferred embodiment, the COX inhibitor is compound I having the following chemical formula:

[0032]

[0033] Compound I (hereinafter referred to as 01-177) is a newly synthesized novel aromatic heterocyclic compound, whose Chinese name is [5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone. In the present invention, it is used as a COX inhibitor, exhibiting moderately selective inhibition of COX-1 (cyclooxygenase-1) and COX-2 (cyclooxygenase-2).

[0034] As a preferred embodiment, in the pharmaceutical composition of the present invention, the mass ratio of flurbiprofen to compound I is 2:1 to 1:2. For example, the mass ratio includes but is not limited to 2:1, 1:1, and 1:2.

[0035] Furthermore, the pharmaceutical composition may include additives, including pharmaceutical excipients. Pharmaceutical excipients include, but are not limited to, molding excipients and dissolution aids, such as methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, carbomer, poloxamer, starch, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, glycerol, propylene glycol, and Tween 80. Pharmaceutical excipients include, but are not limited to, one or more of the above excipients.

[0036] Furthermore, the dosage forms of the pharmaceutical composition include, but are not limited to, tablets, capsules, granules, solutions, suspensions, pills, and dripping pills. Tablets include conventional tablets, dispersible tablets, sustained-release tablets, bilayer tablets, and the like. Those skilled in the art will appreciate that the pharmaceutical composition of the present invention can be in various dosage forms prepared by adding the active pharmaceutical ingredients flurbiprofen and Compound I to pharmaceutically acceptable excipients. Specifically, the appropriate dosage form is selected based on the properties of the drug and the patient's need for convenient use.

[0037] The present invention is further described below through specific examples.

[0038] Example 1

[0039] This embodiment provides a method for preparing compound I (01-177), which specifically comprises the following steps:

[0040] Step 1: Preparation of 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine: Add crude 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (55 g) to glacial acetic acid (50 mL) and 3-aminopyrazole (17 g). Reflux for 1 hour. Pour the reaction mixture into ice water, whereupon a large amount of solid precipitated. Filter and dry the filter cake to obtain the title compound (48 g). (ESI) m / z = 294.1 [M+H]+.

[0041] Step 2: Preparation of [5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (Compound I): Weigh cyclopentanoic acid (22.9 g) into a reaction flask, add thionyl chloride (50 mL), react at 50°C for approximately 0.5 h, and concentrate under reduced pressure to obtain cyclopentanecarbonyl chloride for use. Weigh 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (14.7 g), dissolve in dichloromethane (100 mL), add AlCl₃ (26.7 g), and slowly add the resulting cyclopentanecarbonyl chloride dropwise to the above reaction solution. React at room temperature for 0.5 h. The system was poured into water, extracted with dichloromethane, separated, and silica gel was added to the organic phase to mix the sample. The product was purified by column chromatography (eluent: n-hexane: ethyl acetate = 10:1) to obtain the target compound (5.5 g).

[0042] The chemical reaction formula of the above preparation process of Compound I is as follows:

[0043]

[0044] The present invention also characterized the product obtained by the preparation method, and its nuclear magnetic resonance (NMR) information is as follows:

[0045] 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.37(d,J=9.0Hz,2H),8.29(s,1H),7.16(d,J=8.9Hz,2 H),4.26–4.14(m,1H),3.88(s,3H),2.05–1.94(m,2H),1.89–1.81(m,2H),1.72–1.65(m,4H). (ESI)m / z=390.1[M+H] + .

[0046] The present invention also tested compound I for cyclooxygenase inhibitory activity, as follows:

[0047] (1) COX-2 inhibitory activity

[0048] 1. Materials

[0049] Cyclooxygenase-2 (COX-2) inhibitor screening kit (Shanghai Beyotime Biotechnology Co., Ltd., catalog number: S0168);

[0050] 96-well black plate (Corning);

[0051] Spearhead (Epend);

[0052] COX-1 enzyme (Cayman, Cat. No. 17616);

[0053] DMSO (CNW, catalog number: T3760300);

[0054] Multifunctional microplate reader (TECAN, catalog number: SPARK);

[0055] Vortex mixer (IKA, catalog number: Vortex 2);

[0056] Mini centrifuge (SCILOGEX, catalog number: S1010).

[0057] 2. Test process

[0058] 1) Add assay buffer, COX-2 working solution, cofactor working solution, and sample solution to a 100 μl reaction system in sequence and incubate at 37°C for 10 min.

[0059] 2) Add the probe and substrate arachidonic acid.

[0060] 3) Incubate at 37°C for 10 min.

[0061] 4) Detection (excitation wavelength: 560 nm, emission wavelength: 590 nm).

[0062] 3. Handling of test samples and positive drugs

[0063] Take an appropriate amount of the inhibitor to be measured and prepare a solution of appropriate concentration using COX-2 Assay Buffer, pure water, DMSO or other appropriate solvents. If necessary, prepare an appropriate concentration gradient for use.

[0064] Take an appropriate amount of celecoxib (100 μM) and dilute it with DMSO to the desired concentration (e.g. 200 nM)

[0065] 4. Calculation

[0066] Inhibition rate (%) = (RFU 100％酶活性对照 -RFU 样品 ) / (RFU 100％酶活性对照 -RFU 空白对照 )×100%

[0067] (II) COX-1 inhibitory activity

[0068] The cyclooxygenase-2 (COX-2) inhibitor screening kit (Cat. No. S0168) from Shanghai Biyuntian Biotechnology Co., Ltd. and recombinant human cyclooxygenase 1 (Cat. No. 17616) from Cayman Chemical Co., Ltd. were used, and the method was the same as that for the COX-2 inhibitory activity test.

[0069] The activity test results are shown in Table 1 below:

[0070] Table 1 IC inhibition of COX-1 and COX-2 by compound I 50

[0071]

[0072] The above results indicate that compound I provided in this example has moderately selective inhibitory effects on both COX-1 and COX-2.

[0073] The present invention also provides examples for preparing different dosage forms of the pharmaceutical compositions. Compound I (01-177) in the pharmaceutical compositions described in the following preparation examples was prepared in Example 1; flurbiprofen was obtained from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd., batch number TF20190901. For examples in which specific conditions are not specified, conventional conditions or those recommended by the manufacturer were followed. Reagents and instruments used, for which the manufacturer is not specified, are commercially available conventional products.

[0074] Example 2

[0075] An anti-inflammatory and analgesic compound tablet comprises the following components by weight:

[0076] Flurbiprofen 10g

[0077] 01-177 10g

[0078] The remaining pharmaceutical excipients are commonly used excipients for preparing tablets.

[0079] Preparation process: Prepared according to the conventional preparation process of tablets.

[0080] Example 3

[0081] An anti-inflammatory and analgesic compound capsule comprises the following components by weight:

[0082] Flurbiprofen 20g

[0083] 01-177 20g

[0084] The remaining pharmaceutical excipients are commonly used excipients for preparing capsules.

[0085] Preparation process: Prepared according to the conventional preparation process of capsules.

[0086] Example 4

[0087] The invention discloses an anti-inflammatory and analgesic compound double-layer tablet, which is a double-layer tablet consisting of component 1 and component 2.

[0088] (1) Component 1 includes the following components by weight:

[0089]

[0090] Preparation process of component 1: Flurbiprofen is passed through a 100-mesh sieve, mannitol, lactose, and microcrystalline cellulose are passed through an 80-mesh sieve, the prescribed amount of flurbiprofen and mannitol, lactose, and microcrystalline cellulose are weighed and mixed evenly, and an appropriate amount of 6% PVP (polyvinyl pyrrolidone) 95% ethanol solution is added to granulate, dried at 60°C, and sieved through a 16-mesh sieve to form the dry granules, and the prescribed amount of magnesium stearate is added to the dry granules.

[0091] (1) Component 2 includes the following components by weight:

[0092]

[0093] Preparation process of component 2: 01-177 is passed through a 100-mesh sieve, pregelatinized starch and mannitol are passed through an 80-mesh sieve, the prescribed amount of 01-177, pregelatinized starch and mannitol are weighed and mixed evenly, an appropriate amount of 6% PVP solution in 95% ethanol is added to granulate, the mixture is dried at 60°C, and the dry granules are sieved through a 16-mesh sieve, and the prescribed amount of micropowder silica gel is added to the dry granules.

[0094] The above two components are punched using a double-layer tablet press to obtain a double-layer tablet.

[0095] Example 5

[0096] An anti-inflammatory and analgesic compound dispersible tablet comprises the following components by weight:

[0097]

[0098] Preparation process: Pass the prescribed amount of flurbiprofen and 01-177 through a 100-mesh sieve, pass carboxymethylcellulose calcium, cross-linked polyvinyl pyrrolidone, and microcrystalline cellulose through an 80-mesh sieve, mix well, add an appropriate amount of 10% starch slurry to granulate, add magnesium stearate, and then press into tablets.

[0099] Example 6

[0100] An anti-inflammatory and analgesic compound granule comprises the following components by weight:

[0101] Flurbiprofen 15g

[0102] 01-177 15g

[0103] The remaining pharmaceutical excipients are commonly used excipients for preparing granules.

[0104] Preparation process: Prepared according to the conventional preparation process of granules.

[0105] Example 7

[0106] An anti-inflammatory and analgesic compound tablet comprises the following components by weight:

[0107] Flurbiprofen 45g

[0108] 01-177 45g

[0109] The remaining pharmaceutical excipients are commonly used excipients for preparing tablets.

[0110] Preparation process: Prepared according to the conventional preparation process of tablets.

[0111] Example 8

[0112] An anti-inflammatory and analgesic compound sustained-release tablet comprises the following components by weight:

[0113] Flurbiprofen 20g

[0114] 01-177 20g

[0115] Hydroxypropyl methylcellulose 3-80g

[0116] Polyvinylpyrrolidone 1-100g

[0117] Lactose 5-85g

[0118] 1~100g of micro powder silica gel

[0119] Preparation process: Evenly mix the prescribed amount of flurbiprofen, 01-77, lactose and hydroxypropyl methylcellulose, add polyvinyl pyrrolidone to granulate, dry at 40℃~80℃, reconstitute the dry granules, add the prescribed amount of micro powder silica gel to the dry granules, mix well, and punch out special-shaped tablets.

[0120] Example 9

[0121] This embodiment also provides an anti-inflammatory and analgesic solution, the preparation method of which comprises the following steps:

[0122] (1) Preparation of Compound I solution: Add the aqueous solution containing the additive to a predetermined weight of Compound I prepared in Example 1 while stirring, and mix thoroughly to obtain a Compound I solution of a predetermined concentration;

[0123] (2) Preparation of flurbiprofen solution: adding an aqueous solution containing an additive to a predetermined weight of flurbiprofen while stirring, and mixing thoroughly to obtain a flurbiprofen solution of a predetermined concentration;

[0124] (3) Preparation of the pharmaceutical composition: The Compound I solution obtained in step (1) and the Flurbiprofen solution obtained in step (2) are mixed and stirred uniformly according to a preset volume ratio to obtain a pharmaceutical composition compound preparation.

[0125] The pharmaceutical excipient additives used in this embodiment are methylcellulose and Tween 80. The mass percentage concentration of methylcellulose in the aqueous solution of methylcellulose and Tween 80 is 0.5%; the volume concentration of Tween 80 in the aqueous solution containing methylcellulose and Tween 80 is 0.1%. The mass volume concentration of Compound I in the Compound I solution is 1 mg / mL. The mass volume concentration of flurbiprofen in the flurbiprofen solution is 1 mg / mL. This embodiment uses the solutions of the above concentrations as examples for description. The preparation methods of each solution are as follows:

[0126] First weigh 1g of methylcellulose and mix it with a small amount of pure water to fully dissolve it, then dilute the volume to 200mL to make a 0.5% methylcellulose solution.

[0127] Then, 0.2 mL of Tween 80 was taken and the volume was made up to 200 mL with 0.5% methyl cellulose. After stirring evenly, 200 mL of an aqueous solution containing 0.5% methyl cellulose and 0.1% Tween 80 was obtained.

[0128] Then, use a calibrated graduated cylinder to measure 100 mL of pure water into a beaker. Mark the meniscus of the liquid surface on the outer wall of the beaker with a marker. Allow to dry and set aside. Weigh 0.1 g of Compound I (No. 01-177) into a graduated beaker and add an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80 while stirring. Stir until thoroughly mixed to obtain 100 mL of a 1 mg / mL 01-177 solution.

[0129] Then, use a calibrated graduated cylinder to measure 100 mL of pure water into a beaker. Mark the meniscus on the outer wall of the beaker with a marker. Allow to dry and set aside. Weigh 0.1 g of flurbiprofen into a graduated beaker and add an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80 while stirring. Stir until thoroughly mixed to obtain 100 mL of a 1 mg / mL flurbiprofen solution.

[0130] Finally, the prepared 1 mg / mL 01-177 solution and 1 mg / mL flurbiprofen solution were mixed and stirred uniformly according to a volume ratio (1:1, 2:1, 1:2) to obtain the anti-inflammatory and analgesic solution.

[0131] In order to further verify the medicinal effect of the pharmaceutical composition of the present invention, the following in vivo efficacy test was performed:

[0132] (1) Rat toe swelling test

[0133] Experimental method: 54 SD rats that passed the quarantine were selected, half male and half female, weighing 180-220 g, and randomly divided into: model control group, flurbiprofen (10 mg / kg) group, 01-177 (10 mg / kg) group, 01-177 + flurbiprofen compound (5 + 5 mg / kg) group, 01-177 + flurbiprofen compound (5 + 2.5 mg / kg) group, 01-177 + flurbiprofen compound (2.5 + 5 mg / kg) group, with 6 animals in each group.

[0134] Before administration, different drugs were prepared into 1, 0.5, and 2% aqueous solutions containing 0.5% methylcellulose and 0.1% Tween 80.

[0135] The rats in each group were orally gavaged with the test substance at a concentration of 0.25 mg / mL at 10 mL / kg once daily for 5 consecutive days. The model control group received an equal volume of solvent. After the last dose, all rats in the remaining groups, except the normal group, were injected with 0.5% carrageenan (0.2 mL / rat) under the plantar fascia of the right hind paw to induce inflammation. The normal group received an equal volume of 0.9% sodium chloride injection. The right hind paw volume of each rat was measured using a toe volume meter before inflammation and 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after inflammation, and the degree of swelling was calculated.

[0136] The swelling measurement results of rats in each group are shown in Table 2. The weight changes of rats in each group after administration are shown in Figure 2. Figure 2 :

[0137] Table 2 Rat toe swelling test results

[0138]

[0139] Note: **P≤0.01, *P≤0.05 compared with the model control group.

[0140] According to the data in Table 2 above, compared with the model control group, the degree of paw swelling of rats in the flurbiprofen group, the 01-177 group, and the 1-177 + flurbiprofen (5 + 5 mg / kg) compound group was significantly reduced 0.5 h after inflammation. The degree of paw swelling of rats in the 01-177 + flurbiprofen (5 + 5 mg / kg) compound group was even lower, indicating a better anti-inflammatory effect (P ≤ 0.05 or P ≤ 0.01).

[0141] Table 3. Changes in rat body weight

[0142]

[0143] Note: **P≤0.01, *P≤0.05 compared with the model control group.

[0144] As shown in Table 3, compared with the model control group, the weight gain of animals in the flurbiprofen 10 mg / kg administration group was significantly reduced (P<0.01), showing a certain degree of toxicity; there was no obvious abnormality in the weight of animals in the 01-177 group and the pharmaceutical composition group, indicating that the pharmaceutical composition compound preparation provided by the present invention can significantly reduce the gastric damage toxicity of flurbiprofen compared with flurbiprofen alone.

[0145] (2) Acetic acid writhing test in mice

[0146] Forty-eight ICR mice that passed quarantine were selected, half male and half female, weighing 18-22 g. They were randomly divided into model control group, flurbiprofen (20 mg / kg) group, 01-177 (20 mg / kg) group, 01-177 + flurbiprofen compound (10 + 10 mg / kg) group, 01-177 + flurbiprofen compound (10 + 5 mg / kg) group, and 01-177 + flurbiprofen compound (5 + 10 mg / kg) group, with 6 animals in each group.

[0147] Before administration, different drugs were prepared at concentrations of 1, 0.5, and 0.25 mg / mL using an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80. Each group of animals was orally gavaged with the test substance at 20 mL / kg once daily for five consecutive days. The model control group received an equal volume of solvent. One hour after the last dose, 0.6% acetic acid was injected intraperitoneally at 10 mL / kg. The mice were immediately observed following acetic acid injection. A writhing response was defined as one instance of hind limb and trunk extension, abdominal inward retraction, or buttocks elevation. The latency of the writhing response and the number of writhings within 15 minutes were recorded.

[0148] The test results are shown in Tables 4 and 5 below.

[0149] Table 4 Results of acetic acid writhing test in mice

[0150] Group Dosage (mg / kg) Incubation period (s) Number of twists (times) Model control group - 330.0±121.0 20.2±8.6 Flurbiprofen group 20 612.7±325.6 13.5±16.7 Group 01-177 20 675.3±271.8* 4.7±9.5* 01-177+flurbiprofen group 10+10 657.7±231.3* 6.2±10.4* 01-177+flurbiprofen group 10+5 728.5±190.2** 4.0±6.2** 01-177+flurbiprofen group 5+10 447.3±219.3 12.8±9.5

[0151] Note: **P≤0.01, *P≤0.05 compared with the model control group.

[0152] Table 5 Effects of each group on the body weight of mice

[0153] Group Dosage (mg / kg) Day 1 of medication Day 3 of medication Day 5 of medication Model control group - 23.3±1.1 24.0±1.0 25.6±1.6 Flurbiprofen group 20 23.4±1.5 22.3±1.5 21.7±0.7** Group 01-177 20 24.4±1.0 25.4±0.8 25.9±0.9 01-177+flurbiprofen group 10+10 23.0±1.4 22.2±2.5 22.8±2.5* 01-177+flurbiprofen group 10+5 23.1±0.9 23.4±1.4 24.8±1.5 01-177+flurbiprofen group 5+10 24.4±0.7 23.6±2.0 23.2±1.5*

[0154] Note: Compared with the model control group * P≤0.05, ** P≤0.01.

[0155] According to the results in Tables 4-5 above, the administration of 01-177 and flurbiprofen at 20 mg / kg significantly reduced the number of writhing times in mice (P<0.05) and prolonged the writhing latency (P<0.05), showing a significant analgesic effect; however, the administration of flurbiprofen at 20 mg / kg resulted in a significant decrease in the weight of mice (P<0.05), and 2 / 6 animals in this group died during clinical observation; no animals died when 01-177 + flurbiprofen (10+10 / 10+5 mg / kg) was administered in combination, and the combination had similar or stronger efficacy and fewer toxic side effects than flurbiprofen alone.

[0156] In summary, compound 01-177 exhibited strong activity in both mouse analgesia and rat paw edema models. The pharmaceutical composition prepared from 01-177 and flurbiprofen provided by the present invention can enhance the efficacy of flurbiprofen alone while also reducing the gastric damage toxicity of flurbiprofen.

[0157] The above descriptions are only some preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition containing flurbiprofen, characterized in that, The active pharmaceutical ingredients of the pharmaceutical composition are flurbiprofen and a COX inhibitor; the COX inhibitor is a compound I having the following chemical formula: 。 2. The pharmaceutical composition containing flurbiprofen according to claim 1, wherein In the pharmaceutical composition, the mass ratio of flurbiprofen to compound I is 2:1 to 1:

2.

3. The pharmaceutical composition containing flurbiprofen according to claim 2, characterized in that In the pharmaceutical composition, the mass ratio of flurbiprofen to compound I is 2:1, 1:1 or 1:

2.

4. The pharmaceutical composition containing flurbiprofen according to any one of claims 1 to 3, wherein The pharmaceutical composition further comprises additives, and the additives include pharmaceutical excipients.

5. The pharmaceutical composition containing flurbiprofen as claimed in claim 4, wherein The pharmaceutical excipients include one or two or more of methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, carbomer, poloxamer, starch, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, glycerol, propylene glycol and Tween 80.

6. The pharmaceutical composition containing flurbiprofen as claimed in claim 4, characterized in that The dosage forms of the pharmaceutical composition include tablets, capsules, granules, solutions, suspensions, and pills.

7. The pharmaceutical composition containing flurbiprofen according to claim 6, wherein Tablets include ordinary tablets, dispersible tablets, and sustained-release tablets.

8. The pharmaceutical composition containing flurbiprofen according to claim 6, wherein The tablet also includes a bilayer tablet compressed from component 1 comprising flurbiprofen and component 2 comprising a COX inhibitor.

9. Use of the flurbiprofen-containing pharmaceutical composition according to any one of claims 1 to 8 in the preparation of analgesic and anti-inflammatory drugs.

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