Pharmaceutical composition containing flurbiprofen and application thereof

Abstract

The invention discloses a flurbiprofen-containing pharmaceutical composition and application thereof, and relates to the field of biological medicines. Effective pharmaceutical ingredients of the pharmaceutical composition comprise flurbiprofen and a COX inhibitor, the COX inhibitor is a compound I with the following chemical structural formula: # imgabs0 #, and in the pharmaceutical composition, the mass ratio of flurbiprofen to the compound I is (2: 1)-(1: 2). The pharmaceutical composition can maintain or enhance the analgesic and anti-inflammatory drug effects of flurbiprofen, can also reduce the toxic and side effects of stomach injury, and is relatively high in safety.

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 vital role in the development of many complex diseases, such as autoimmune diseases, metabolic syndrome, neurodegenerative diseases, cardiovascular diseases and tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a large class of anti-inflammatory drugs and have become the most commonly used class of drugs. Prostaglandins (PG) play an important regulatory role in inflammation, and all NSAIDs work by inhibiting the production of PG. Cyclooxygenase (COX) can catalyze the metabolism of arachidonic acid (AA) to produce PG and its analogs, so COX has become an important target for anti-inflammatory drugs. However, long-term use of non-selective COX inhibitors is accompanied by the following toxic side effects: gastric ulcers, gastric bleeding and other gastric damage, which limits their use. Selective COX-2 inhibitors were initially considered to be safer alternatives to traditional NSAIDs. Moderately selective COX-2 inhibitors may reduce their cardiotoxicity.

[0003] Flurbiprofen is a widely used nonsteroidal anti-inflammatory drug (NSAIDs) with antipyretic, anti-inflammatory and analgesic effects. It is mostly used in the treatment of inflammatory diseases and physiological pain in patients. Most of the preparations on the current market are mainly oral. Although they have certain clinical effects, they are also prone to cause adverse reactions such as gastrointestinal disorders in patients after taking them.

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

[0005] Chinese patent document CN201480033480.X discloses a method for treating intestinal diseases caused by NSAID drugs. After NSAID drugs are administered to patients with pain or inflammation, rifaximin and proton pump inhibitors are administered to prevent or treat gastric damage caused by NSAID drugs. Chinese patent document CN201810115299.3 discloses a compound preparation containing flurbiprofen axetil, which contains two effective active ingredients of flurbiprofen axetil and proton pump inhibitors, so that patients can effectively prevent and treat gastric damage caused by flurbiprofen axetil while using flurbiprofen axetil to treat inflammation or pain, and further reduce the side effects of patients after medication. Chinese patent document CN201410317848.7 discloses a compound preparation containing ketoprofen and omeprazole, in which ketoprofen is a micro sustained-release tablet and omeprazole is an enteric-coated micropill, and then the micropill and micropill are filled into the same capsule, and the patient is administered with the drug at the same time, which can prevent gastrointestinal damage caused by ketoprofen.

[0006] However, there is no compound preparation that can reduce the gastric tract damage side effects of flurbiprofen and improve its safety reported in existing literature. The present invention intends to provide a pharmaceutical composition containing flurbiprofen, which can reduce gastric damage after flurbiprofen administration 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 pharmaceutical composition containing flurbiprofen and its application. The effective drug components of the pharmaceutical composition include flurbiprofen and a COX inhibitor, which can maintain or enhance the analgesic and anti-inflammatory effects of flurbiprofen while reducing its gastric damage toxicity and side effects, and has high safety.

[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 effective 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 between the two is 2:1, 1:1, 1:2.

[0014] Furthermore, the pharmaceutical composition also includes additives, and the additives include pharmaceutical excipients.

[0015] Furthermore, 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.

[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 above-mentioned 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 effective drug ingredients of the pharmaceutical composition provided by the present invention are composed of flurbiprofen and the 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 high safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the drawings in the description of the embodiment are briefly introduced below.

[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 variation 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 defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing 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 separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including ranges "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 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 components thereof include flurbiprofen and a COX inhibitor.

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

[0032]

[0033] Compound I (hereinafter referred to as No. 01-177) is a newly synthesized novel aromatic heterocyclic compound, and its 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 and has a moderately selective inhibitory effect on 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. Exemplarily, the mass ratio of the two includes but is not limited to 2:1, 1:1, and 1:2.

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

[0036] Further, the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, granules, solutions, suspensions, pills, and dripping pills. Tablets include ordinary tablets, dispersible tablets, sustained-release tablets, double-layer tablets, etc. As a person skilled in the art, it can be understood that the dosage form of the pharmaceutical composition of the present invention can be various dosage forms prepared by adding pharmaceutically acceptable pharmaceutical excipients to the active pharmaceutical ingredient flurbiprofen and compound I. Specifically, the corresponding dosage form is selected according to the nature of the drug and the patient's need for convenient medication.

[0037] The present invention is further described below by means of 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: Take crude 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (55 g), add glacial acetic acid (50 mL) and 3-aminopyrazole (17 g), and reflux for 1 h. Pour the reaction solution into ice water, and a large amount of solid precipitates. After filtering, 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) in a reaction bottle, add thionyl chloride (50 mL), react at 50°C for about 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), add dichloromethane (100 mL) to dissolve, add AlCl3 (26.7 g), and slowly drip the obtained cyclopentanecarbonyl chloride into the above reaction solution, and react at room temperature for 0.5 h. The system was poured into water, extracted with dichloromethane, separated, silica gel was added to the organic phase, and the sample was stirred. 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 characterizes 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 the cyclooxygenase inhibitory activity of compound I, as follows:

[0047] (I) COX-2 inhibitory activity

[0048] 1. Materials

[0049] Cyclooxygenase-2 (COX-2) inhibitor screening kit (Shanghai Biotech 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 No.: 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 test 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 is 560 nm, emission wavelength is 590 nm).

[0062] 3. Handling of samples to be tested and positive drugs

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

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

[0070] Table 1 IC of Compound I against COX-1 and COX-2 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 of preparation of different dosage forms of the pharmaceutical composition. Compound I (01-177) in the pharmaceutical composition of the following preparation examples is prepared in Example 1; the source of flurbiprofen is Hunan Jiudian Hongyang Pharmaceutical Co., Ltd., batch number: TF20190901. If the specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[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 other 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 composed 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, an appropriate amount of 6% PVP (polyvinyl pyrrolidone) 95% ethanol solution is added to granulate, the granules are dried at 60°C, and the dry granules are sieved through a 16-mesh sieve, 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 95% ethanol solution is added to granulate, the mixture is dried at 60°C, the dry granules are sieved through a 16-mesh sieve, and the prescribed amount of micro-powder 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 for granulation, 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 other 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] Polyvinyl pyrrolidone 1~100g

[0117] Lactose 5-85g

[0118] Micro powder silica gel 1~100g

[0119] Preparation process: Evenly mix the prescribed amount of flurbiprofen, 01-77, lactose and hydroxypropyl methylcellulose, add polyvinyl pyrrolidone to granulate, dry at 40°C to 80°C, reconstitute the dried granules, add the prescribed amount of micro-powdered 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 analgesic solution, the preparation method of which comprises the following steps:

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

[0123] (2) Preparation of flurbiprofen solution: adding an aqueous solution containing an additive to a preset weight of flurbiprofen while stirring, and mixing thoroughly to obtain a flurbiprofen solution of a preset 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 evenly according to a preset volume ratio to obtain a pharmaceutical composition compound preparation.

[0125] The pharmaceutical excipient additives 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 is described by taking the above-mentioned solutions as examples. 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 make up to 200mL to prepare 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, and 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, and then use a marker to mark the meniscus of the liquid surface on the outer wall of the beaker. After drying, weigh 0.1 g of compound I (No. 01-177) into a marked beaker, add an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80 while stirring, and stir until fully mixed to obtain 100 mL of 1 mg / mL 01-177 solution.

[0129] Then, use a calibrated graduated cylinder to measure 100 mL of pure water into a beaker, and then use a marker to mark the meniscus of the liquid surface on the outer wall of the beaker, and let it dry for later use. Weigh 0.1 g of flurbiprofen into a marked beaker, add an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80 while stirring, and stir until fully mixed to obtain 100 mL of 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 evenly according to a volume ratio (1:1, 2:1, 1:2) to obtain the anti-inflammatory 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] (A) Rat toe swelling test

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

[0134] Before administration, different drugs were prepared into 1, 0.5,

[0135] The concentration of 0.25mg / mL was used, and the animals in each group were given different test substances by oral gavage at 10mL / kg, once a day, for 5 consecutive days. The model control group was given an equal volume of solvent. After the last administration, except for the normal group, the rats in the other groups were injected with 0.5% carrageenan 0.2mL / rat under the plantar fascia of the right hind paw to induce inflammation. The normal group was given an equal volume of 0.9% sodium chloride injection. The volume of the right hind paw toes of the rats in each group was measured with a toe volume meter before inflammation, 30min, 1h, 2h, 4h, and 6h after inflammation, and the swelling degree was calculated.

[0136] The swelling measurement results of rats in each group are shown in Table 2, and the weight changes of rats in each group after administration are shown in 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 toe swelling of rats in the flurbiprofen group, 01-177 group and 1-177 + flurbiprofen (5 + 5 mg / kg) compound group was significantly reduced 0.5 h after inflammation. The toe swelling of rats in the 01-177 + flurbiprofen (5 + 5 mg / kg) compound preparation 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 certain 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] (II) Acetic acid writhing test in mice

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

[0147] Before administration, different drugs were prepared into 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 given different test substances by oral gavage at 20 mL / kg, once a day, for 5 consecutive days, and the model control group was given an equal volume of solvent. 1 hour after the last administration, 0.6% acetic acid was injected intraperitoneally at 10 mL / kg, and the state of the mice after the injection of acetic acid was immediately observed. One twisting reaction was defined as one time when the hind limbs and trunk of the mouse were extended, the abdomen was sunken, and the buttocks were raised, and the latency of the twisting reaction and the number of twists within 15 minutes were recorded.

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

[0149] Table 4 Results of the 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 01-177 Group 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** 01-177 Group 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 body 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 less toxic side effects than flurbiprofen alone.

[0156] In summary, compound 01-177 showed strong activity in both mouse analgesia and rat paw swelling models. The pharmaceutical composition prepared from 01-177 and flurbiprofen provided by the present invention can enhance the efficacy of flurbiprofen alone and reduce 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 protection scope of the present invention.

Claims

1. A pharmaceutical composition containing flurbiprofen, characterized in that, The effective drug ingredients of the pharmaceutical composition include flurbiprofen and a COX inhibitor.

2. The pharmaceutical composition containing flurbiprofen according to claim 1, characterized in that The COX inhibitor is a compound I having the following chemical formula:

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 to 1:

2.

4. 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.

5. The flurbiprofen-containing pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The pharmaceutical composition further comprises additives, and the additives comprise pharmaceutical excipients.

6. The pharmaceutical composition containing flurbiprofen as claimed in claim 5, characterized in that 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.

7. The flurbiprofen-containing pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The dosage forms of the pharmaceutical composition include tablets, capsules, granules, solutions, suspensions, pills, and dripping pills.

8. The pharmaceutical composition containing flurbiprofen as claimed in claim 7, characterized in that Tablets include ordinary tablets, dispersible tablets and sustained-release tablets.

9. The pharmaceutical composition containing flurbiprofen as claimed in claim 7, characterized in that: The tablet also includes a bilayer tablet compressed from component 1 comprising flurbiprofen and component 2 comprising a COX inhibitor.

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

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