New use of sildenafil and its salts in combination with ibuprofen

Abstract

The application discloses a new use of sildenafil and its salts in combination with ibuprofen. Through pharmacodynamics and toxicology experiments, the application first proposes and verifies that the combination of sildenafil and its salts (sildenafil citrate) and ibuprofen has a significant synergistic effect in treating inflammatory pain, and can effectively reduce the renal toxicity induced by long-term administration of ibuprofen. The application solves the problem that long-term or large-dose use of ibuprofen can induce significant renal toxicity, which seriously limits the long-term, standard and sufficient clinical application of ibuprofen. The composition provided by the application can enhance the analgesic effect of ibuprofen and reduce the renal toxicity of ibuprofen, and has important clinical conversion value and practical application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a novel use of sildenafil and its salt (sildenafil citrate) in combination with ibuprofen, particularly to the use of the combination in the preparation of drugs for the prevention and / or treatment of arthritis-related inflammatory pain, and the use of the combination in the preparation of drugs that reduce the nephrotoxic side effects caused by long-term or high-dose use of ibuprofen. Background Technology

[0002] Inflammatory pain is a common chronic pain condition caused by tissue damage, inflammatory response, or abnormal activation of the immune system. Clinically, it is frequently seen in diseases such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and post-traumatic chronic inflammation. These diseases are characterized by prolonged course, recurrent flare-ups, and are often accompanied by joint swelling and functional impairment. In severe cases, they can lead to joint deformities and disability, significantly reducing patients' quality of life. For example, the global prevalence of rheumatoid arthritis is approximately 0.5%-1%, representing a globally unmet clinical need and imposing a heavy socioeconomic burden. Currently, the treatment of inflammatory pain primarily relies on pharmacological intervention, with nonsteroidal anti-inflammatory drugs (NSAIDs) being the most commonly used first-line treatment.

[0003] Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the first-line treatment for inflammatory pain, with ibuprofen being the most widely used representative drug in clinical practice. As a classic propionate NSAID, ibuprofen exerts its antipyretic, analgesic, and anti-inflammatory effects by reversibly inhibiting the activity of cyclooxygenases (COX-1 and COX-2), blocking the metabolism of arachidonic acid into prostaglandins (PGE2, PGI2, etc.). Ibuprofen is one of the most representative and commonly used NSAIDs.

[0004] However, both clinical studies and basic experiments have confirmed that long-term or high-dose use of ibuprofen can induce significant nephrotoxicity. This core defect severely limits its long-term, standardized, and adequate clinical application. The specific mechanisms include: (1) Changes in renal hemodynamics: Ibuprofen inhibits COX-2-mediated prostaglandin synthesis, especially reducing the production of PGE2 and PGI2, leading to a decrease in the dilation capacity of the afferent arterioles of the glomerulus, and a significant reduction in renal blood flow and glomerular filtration rate (GFR). Long-term use can induce acute kidney injury or chronic renal insufficiency; (2) Damage to renal tubular epithelial cells: Ibuprofen and its metabolites accumulate in the renal tubules, directly inducing oxidative stress, mitochondrial dysfunction, and apoptosis in renal tubular epithelial cells; (3) Immune inflammatory response: Drug-induced subclinical interstitial nephritis can gradually progress during long-term use, accompanied by the risk of renal interstitial fibrosis. The aforementioned damage can lead to abnormalities in multiple renal function indicators: elevated serum creatinine and blood urea nitrogen; significant upregulation of early tubular injury markers KIM-1 and NGAL; and oxidative stress imbalance in renal tissue, manifested as elevated malondialdehyde (MDA) and decreased activity of antioxidant enzymes such as superoxide dismutase (SOD). Long-term use of NSAIDs can not only induce acute kidney injury but also increase the risk of chronic kidney disease.

[0005] Currently, there is a lack of ideal treatment strategies in clinical practice that can effectively relieve inflammatory pain while reducing or preventing NSAID-induced nephrotoxicity. Simply increasing the dose of NSAIDs can further exacerbate toxic side effects; simply discontinuing or reducing the dose can lead to inadequate pain control and recurrent inflammation. There is an urgent need for combination therapy strategies that "enhance efficacy and reduce toxicity" to achieve long-term safe treatment. Summary of the Invention

[0006] Purpose of the invention: The technical problem to be solved by the present invention is to provide a new use for the combined use of sildenafil and its salts with ibuprofen, addressing the shortcomings of the prior art.

[0007] Sildenafil is a highly selective phosphodiesterase type 5 (PDE5) inhibitor. It increases intracellular cGMP levels by inhibiting the degradation of cyclic guanosine monophosphate (cGMP) by PDE5, thereby activating the downstream protein kinase G (PKG) pathway and exerting smooth muscle relaxant and vasodilatory effects. It is approved by the FDA for the treatment of erectile dysfunction in men. In recent years, sildenafil has been explored for the treatment of patent ductus arteriosus and pulmonary hypertension in newborns, demonstrating clear potential for repurposing existing drugs.

[0008] To solve the above-mentioned technical problems, the present invention discloses the following technical solution: In a first aspect, the present invention discloses a pharmaceutical composition.

[0009] In some embodiments, the active ingredient of the pharmaceutical composition includes (i) sildenafil or a pharmaceutically acceptable salt thereof; and (ii) ibuprofen.

[0010] In some embodiments, a pharmaceutically acceptable salt of sildenafil is sildenafil citrate.

[0011] In some embodiments, the mass ratio of component (i) to component (ii) is 3-15:30; in some embodiments, the mass ratio of component (i) to component (ii) is 5-10:30.

[0012] In some embodiments, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0013] In some embodiments, the dosage form of the pharmaceutical composition is an oral formulation.

[0014] The pharmaceutical compositions described in this invention are compositions for the prevention and / or treatment of inflammatory pain diseases. In some embodiments, they are compositions for the prevention and / or treatment of inflammatory pain diseases and for reducing nephrotoxicity. In other embodiments, they are compositions for reducing ibuprofen nephrotoxicity.

[0015] In a second aspect, the present invention discloses the use of the pharmaceutical composition described in the first aspect in the preparation of a medicament for the prevention and / or treatment of inflammatory pain diseases.

[0016] In some embodiments, the inflammatory pain condition includes arthritis.

[0017] In some embodiments, the dosage of ibuprofen is 400-600 mg / day / person, such as 450 mg / day / person, 500 mg / day / person, or 550 mg / day / person. In animal experiments, the equivalent human dose of 30 mg / kg / day is 400 mg / day.

[0018] In some embodiments, the prevention and / or treatment of inflammatory pain disorders includes any one or more of the following: Increase the mechanical withdrawal reflex threshold; Increase the latency of the heat-shrink foot reflex; Reduce swelling in the ankle and foot joints; Reduce TNF-α mRNA expression.

[0019] In some embodiments, the prevention and / or treatment of inflammatory pain disorders further includes mitigating ibuprofen-induced nephrotoxicity. In some embodiments, mitigating ibuprofen-induced nephrotoxicity means reducing ibuprofen-induced nephrotoxicity, and in some examples includes any one or more of the following: Lower creatinine and blood urea nitrogen levels; Reduce MDA content; Increase SOD activity.

[0020] Thirdly, this invention discloses the use of sildenafil in the preparation of drugs that reduce the nephrotoxicity of ibuprofen.

[0021] In some embodiments, the reduction of ibuprofen-induced nephrotoxicity includes any one or more of the following: Lower creatinine and blood urea nitrogen levels; Reduce MDA content; Increase SOD activity.

[0022] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0023] This invention, through pharmacodynamic and toxicological experiments, proposes and verifies for the first time that the combined use of sildenafil and its salt (sildenafil citrate) with ibuprofen has a significant synergistic effect in the treatment of inflammatory pain, while effectively reducing the nephrotoxicity induced by long-term ibuprofen administration. This solves the problem in existing technologies where long-term or high-dose use of ibuprofen can induce significant nephrotoxicity, severely limiting its long-term, standardized, and adequate clinical application. The composition provided by this invention, which can both enhance the analgesic effect of ibuprofen and reduce its nephrotoxicity, has significant clinical translational value and practical application prospects. Detailed Implementation

[0024] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0025] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0026] Example 1:

[0027] 1. Experimental Materials Complete Freund's adjuvant (Beyotime Biotechnology Co., Ltd.), ibuprofen (Shanghai Aladdin Biochemical Technology Co., Ltd.), sildenafil (Shanghai Aladdin Biochemical Technology Co., Ltd.), serum creatinine and blood urea nitrogen assay kits (Sigma-Aldrich, USA); malondialdehyde (MDA) and superoxide dismutase (SOD) assay kits (Nanjing Jiancheng Bioengineering Institute); BCA protein quantification kit (Beyotime Biotechnology Co., Ltd.); reverse transcription cDNA kit (ThermoFisher Scientific, USA); real-time PCR kit (Takara Bio Inc.).

[0028] 2. Experimental Methods 2.1 Study on the therapeutic effect of sildenafil combined with ibuprofen on adjuvant arthritis rats (1) Construction of inflammatory pain model: Healthy SD rats (male, 6-8 weeks old, weighing 190-210g) were injected subcutaneously with Freund's adjuvant (CFA) 0.1mL in the right hind foot to induce an arthritis model and simulate the long-term inflammatory pain state of rheumatoid arthritis.

[0029] (2) Grouping and administration: Rats that did not develop the model were divided into a normal control group. Rats that successfully developed the model were randomly divided into 5 groups using a random number table: model group, ibuprofen monotherapy group, ibuprofen + sildenafil low-dose group, ibuprofen + sildenafil high-dose group, and sildenafil monotherapy group, with 5 rats in each group. Administration began on the second day after CFA modeling and was administered by gavage for 14 consecutive days, once a day. The normal control group and model group were administered an equal volume of physiological saline by gavage. The ibuprofen monotherapy group was administered ibuprofen 30 mg / kg / time by gavage. The ibuprofen + sildenafil low-dose group was administered ibuprofen 30 mg / kg / time combined with sildenafil 5 mg / kg / time by gavage. The ibuprofen + sildenafil high-dose group was administered ibuprofen 30 mg / kg / time combined with sildenafil 10 mg / kg / time by gavage. The sildenafil monotherapy group was administered sildenafil 10 mg / kg / time by gavage. Ibuprofen and sildenafil were prepared into suspensions using 0.5% CMC-Na solution. The concentration of ibuprofen was 6 mg / ml, and the low and high dose concentrations of sildenafil were 1 mg / ml and 2 mg / ml, respectively. The medication was administered by gavage at a rate of 0.5 ml / 100g.

[0030] (3) Pain behavioral experiments: The mechanical withdrawal reflex threshold in rats was determined using the up-down method. Rats were observed for 30 minutes to allow for adaptation. A gradient pressure nylon filament (von-Frey fiber) stimulation device was used to stimulate the mid-lateral aspect of the foot at a constant rate. When the filament deformed to 90° under pressure, this deformation was maintained for 5 seconds. A foot withdrawal or licking motion during the recording period was considered a valid response, and the mechanical withdrawal reflex threshold was determined. To eliminate the inter-test effect, each test was conducted at a 5-minute interval.

[0031] A fixed-point thermal radiant device was used to apply vertical stimulation to the central area of ​​the rat's paw at a constant rate of temperature increase. When the animal exhibited paw retraction or licking behavior, the device automatically recorded the latency value corresponding to the trigger temperature. Each rat underwent three independent measurements, with each measurement spaced 10 minutes apart. The average of the three data points was then recorded as the latency of the thermal paw retraction reflex.

[0032] Joint swelling detection: Before the test, the rats were placed in the test environment for 3 minutes to adapt. After the rats were calm, the volume of the metatarsophalangeal joint of the rat's hind limb on the model side and the contralateral side was measured using a water displacement toe volume measuring instrument. During the measurement, the bony prominence of the lateral malleolus was used as a uniform marker line. The hind limb was vertically immersed in the measuring tube to the marker line. After the liquid level stabilized, the value was read. Each rat's bilateral hind limbs were measured 3 times consecutively, with an interval of 1 minute between each measurement. The average value was taken as the final volume value. The contralateral hind limb was used as the self-control. The swelling degree of the foot and ankle joint was calculated according to the formula: swelling degree (%) = (volume of the model side hind limb - volume of the contralateral hind limb) / volume of the contralateral hind limb × 100%.

[0033] (4) Detection of tumor necrosis factor-α (TNF-α) Soft tissue from the right hind paw of rats was isolated, and excess tissue such as skin and fascia was removed. After rinsing with pre-cooled enzyme-free saline, the tissue was immediately flash-frozen in liquid nitrogen and stored at -80°C. For testing, the frozen paw tissue was taken, homogenized thoroughly with Trizol reagent under ice bath conditions, and extracted with chloroform, precipitated with isopropanol, washed with 75% anhydrous ethanol, and centrifuged. Total RNA was extracted, and the concentration and purity of RNA were determined using a nucleic acid detector. Samples with an A260 / A280 ratio between 1.8 and 2.0 were selected. Following the reverse transcription kit instructions strictly, a reaction system was prepared using qualified total RNA as a template to complete the reverse transcription and synthesize cDNA. The product was stored at low temperature in a sealed container for later use. Subsequently, using GAPDH as an internal reference gene and TNF-α specific primers, a reaction mixture containing SYBR Green DNA was prepared. The qPCR reaction system using Green fluorescent dye was configured with three replicates per sample and a blank control. The reaction plate was placed in a real-time quantitative PCR instrument, and amplification was performed according to the program of 95℃ pre-denaturation for 30s and 40 cycles (95℃ denaturation for 5s and 60℃ annealing extension for 30s). Fluorescence signals were collected during the amplification process. After amplification, the amplification specificity was verified by melting curve analysis. Finally, the Ct values ​​of each sample were obtained, and the relative mRNA expression level of TNF-α in rat paw tissue of each group was calculated using the 2⁻ΔΔCt method.

[0034] 2.2 Construction of ibuprofen-induced nephrotoxicity model and sildenafil intervention Twenty healthy male SD rats (6-8 weeks old, weighing 190-210g) were randomly divided into 5 groups (n=5 per group): ibuprofen monotherapy (400 mg / kg / dose), ibuprofen + sildenafil low-dose group (400 mg / kg / dose + 5 mg / kg / dose), ibuprofen + sildenafil high-dose group (400 mg / kg / dose + 10 mg / kg / dose), and sildenafil monotherapy (10 mg / kg / dose), administered once daily. Ibuprofen and sildenafil were prepared as suspensions in 0.5% CMC-Na solution, with ibuprofen concentration at 80 mg / ml and sildenafil low- and high-dose concentrations at 1 mg / ml and 2 mg / ml, respectively, administered by gavage at a rate of 0.5 ml / 100g. Rats in each group were administered the medication by gavage for 5 consecutive days to investigate ibuprofen-induced nephrotoxicity and the renal protective effect of sildenafil.

[0035] (1) Twelve hours after the last administration, rats were anesthetized by intraperitoneal injection of 10% chloral hydrate at a dose of 3 mL / kg. Whole blood samples were collected by puncture of the abdominal aorta. After standing at room temperature in the dark for 30 min, the samples were centrifuged at 4℃ and 3500 r / min for 10 min. The upper serum layer was separated, aliquoted, and stored in an ultra-low temperature freezer at -80℃ for later testing. The contents of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected by enzyme method using a fully automated biochemical analyzer or corresponding kit to assess the damage to glomerular filtration function in rats.

[0036] (2) Oxidative stress: After blood collection, rats were quickly euthanized, and both kidneys were removed under aseptic conditions. After removing the renal capsule, renal cortical tissue from the same location was excised. The tissue was rinsed with pre-cooled physiological saline to remove residual blood. After the surface moisture was absorbed by sterile filter paper, the tissue was accurately weighed and added to the pre-cooled physiological saline at a weight-to-volume ratio of 1:9. A 10% renal tissue homogenate was prepared using a low-temperature tissue homogenizer under ice bath conditions. The homogenate was centrifuged at 4000 r / min for 15 min at 4℃. The supernatant was separated, aliquoted, and stored in an ultra-low temperature freezer at -80℃ for later testing. The total protein concentration in the renal tissue homogenate supernatant was detected by the diquinoline carboxylic acid (BCA) method to correct the sample loading volume. Subsequently, the malondialdehyde (MDA) content in the renal tissue was detected by the thiobarbituric acid (TBA) colorimetric method and the superoxide dismutase (SOD) activity in the renal tissue was detected by the xanthine oxidase method to assess the degree of damage mediated by oxidative stress in the renal tissue.

[0037] 2.3 Statistical Analysis GraphPad software was used for statistical analysis of the experimental data. One-way ANOVA was used for comparisons among multiple groups, and the SNK-q test was used for pairwise comparisons. Bonferroni correction was used to adjust for multiple comparisons. p < 0.05 was considered statistically significant.

[0038] 3. Experimental Results (1) Synergistic therapeutic effect and mechanism of sildenafil combined with ibuprofen in adjuvant arthritis rats SD rats were injected subcutaneously into the right hind paw to induce an arthritis model. Normal control rats received no treatment. The adjuvant-induced arthritis rats were divided into a model group, an ibuprofen monotherapy group, an ibuprofen + sildenafil low-dose group, an ibuprofen + sildenafil high-dose group, and a sildenafil monotherapy group. The mechanical withdrawal reflex threshold, thermal withdrawal reflex latency, and ankle joint swelling were measured as behavioral indicators of pain.

[0039] The results of the mechanical withdrawal reflex threshold and thermal withdrawal reflex latency (Table 1) showed that, compared with the normal control group, the mechanical withdrawal reflex threshold and thermal withdrawal reflex latency in the model group rats were significantly reduced, indicating that the adjuvant arthritis model successfully induced stable mechanical hyperalgesia and thermal hyperalgesia. Ibuprofen alone significantly increased the mechanical pain threshold and thermal pain latency. Notably, both the low-dose and high-dose groups of ibuprofen combined with sildenafil showed stronger analgesic effects than ibuprofen alone, and exhibited a dose-dependent increasing trend. This result confirms that sildenafil can synergistically enhance the anti-hyperalgesic effect of ibuprofen.

[0040] The swelling of the ankle joint (Table 2) showed that, compared with the normal control group, the swelling of the ankle joint in the model group rats was significantly increased, and the adjuvant arthritis model induced a significant joint inflammation response. Ibuprofen alone significantly reduced the swelling. The combination of sildenafil and ibuprofen further enhanced the anti-inflammatory and swelling-reducing effects. The swelling in both the low-dose and high-dose combination groups was significantly lower than that in the ibuprofen-only group, with the high-dose group showing better results. This result suggests that sildenafil may exert a synergistic anti-inflammatory and swelling-reducing effect with ibuprofen by dilating blood vessels, improving blood circulation in the local inflammatory area, and promoting the clearance of inflammatory substances.

[0041] TNF-α mRNA expression (Table 3) showed that, compared with the normal control group, TNF-α mRNA expression in the plantar tissue of the model group was significantly upregulated, indicating that the inflammation model successfully induced high expression of pro-inflammatory factors. Ibuprofen alone could partially downregulate TNF-α expression, and sildenafil alone also showed a certain inhibitory effect. The inhibitory effect on TNF-α expression was more significant in the combination therapy groups, with the expression levels in both the low-dose and high-dose combination groups being significantly lower than those in the ibuprofen alone group. These results suggest that sildenafil may more effectively inhibit inflammatory signal transduction at the transcriptional level by synergistically inhibiting ibuprofen, which may be the potential molecular mechanism of its synergistic effect.

[0042] Table 1. Effects of sildenafil combined with ibuprofen on pain threshold in adjuvant arthritis rats.

[0043] Note: Compared with the model group, *P<0.05, **P<0.01; compared with the normal control group, #P<0.05, ##P<0.01.

[0044] Table 2. Effects of sildenafil combined with ibuprofen on foot and ankle joint swelling in adjuvant arthritis rats.

[0045] Note: Compared with the model group, *P<0.05, **P<0.01; compared with the normal control group, #P<0.05, ##P<0.01.

[0046] Table 3. Effects of sildenafil combined with ibuprofen on TNF-α mRNA expression in the foot and ankle joints of adjuvanted arthritis rats.

[0047] Note: Compared with the model group, *P<0.05, **P<0.01; compared with the normal control group, #P<0.05, ##P<0.01.

[0048] (2) The protective effect and mechanism of sildenafil on renal function in rats with ibuprofen-induced nephrotoxicity Healthy SD rats were randomly divided into four groups: ibuprofen monotherapy group, ibuprofen + sildenafil low-dose group, ibuprofen + sildenafil high-dose group, and sildenafil monotherapy group, with five rats in each group. Rats in each group were administered ibuprofen by gavage for five consecutive days to investigate ibuprofen-induced nephrotoxicity and the renal protective effect of sildenafil.

[0049] Renal function results (Table 4) showed that serum creatinine and blood urea nitrogen in the ibuprofen monotherapy group were significantly higher than those in the normal control group, indicating that continuous administration of high-dose ibuprofen can induce significant glomerular filtration function impairment. Renal function indicators in the sildenafil monotherapy group were similar to those in the normal control group, indicating that sildenafil itself has no nephrotoxicity. Sildenafil combination therapy dose-dependently improved ibuprofen-induced renal function abnormalities and significantly reduced creatinine and blood urea nitrogen levels. This result indicates that sildenafil has a significant protective effect against ibuprofen-induced nephrotoxicity.

[0050] The results of renal tissue oxidative indicators (Table 5) showed that the MDA content in the renal tissue of the ibuprofen monotherapy group was significantly higher than that of the normal control group, while the SOD activity was significantly lower, presenting a typical pattern of oxidative stress imbalance. Sildenafil combination therapy effectively reversed the oxidative stress state. In the high-dose combination group, the MDA content decreased significantly and the SOD activity increased significantly, suggesting that the protective effect of sildenafil is closely related to its ability to reduce oxidative damage in renal tissue.

[0051] Table 4. Effects of sildenafil on renal function in rats with ibuprofen-induced nephrotoxicity.

[0052] Note: Compared with the normal control group, *P<0.05, **P<0.01; compared with the ibuprofen monotherapy group, #P<0.05, ##P<0.01.

[0053] Table 5. Effects of sildenafil on renal oxidative parameters in ibuprofen-induced nephrotoxic rats.

[0054] Note: Compared with the normal control group, *P<0.05, **P<0.01; compared with the ibuprofen monotherapy group, #P<0.05, ##P<0.01.

[0055] 4. Conclusion This invention is the first to investigate the synergistic and toxicity-reducing effects of combined sildenafil and ibuprofen in the treatment of inflammatory pain. In an adjuvanted arthritis rat model, the combination of sildenafil and ibuprofen significantly enhanced the mechanical pain threshold and thermal pain latency, reduced joint swelling, and further downregulated the expression of the inflammatory factor TNF-α, demonstrating a superior synergistic anti-inflammatory and analgesic effect compared to ibuprofen alone. In a high-dose ibuprofen-induced nephrotoxicity model, the combination of sildenafil and ibuprofen dose-dependently improved renal function indicators (serum creatinine, blood urea nitrogen) and reduced renal tissue oxidative stress (decreased MDA, increased SOD). These results indicate that sildenafil effectively reduces ibuprofen-induced nephrotoxicity through multiple mechanisms, including mitigating oxidative stress damage, while synergistically enhancing its anti-inflammatory and analgesic effects. This study provides a novel synergistic and toxicity-reducing combination therapy strategy for the clinical treatment of inflammatory pain, with clear clinical translational value and broad application prospects.

[0056] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A pharmaceutical composition, characterized in that, This includes (i) sildenafil or a pharmaceutically acceptable salt thereof; and (ii) ibuprofen.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutically acceptable salt of sildenafil is sildenafil citrate.

3. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of component (i) to component (ii) is 3-15:

30.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

5. Use of the pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for the prevention and / or treatment of inflammatory pain diseases.

6. The use according to claim 5, characterized in that, The inflammatory pain conditions mentioned include arthritis.

7. The use according to claim 5, characterized in that, The dosage of ibuprofen is 400-600 mg / day.

8. The use according to claim 5, characterized in that, The prevention and / or treatment of inflammatory pain disorders includes any one or more of the following: Increase the mechanical withdrawal reflex threshold; Increase the latency of the heat-shrink foot reflex; Reduce swelling in the ankle and foot joints; Reduce TNF-α mRNA expression.

9. The use according to claim 5 or 8, characterized in that, The prevention and / or treatment of inflammatory pain disorders also includes improving ibuprofen-induced nephrotoxicity.

10. Use of sildenafil in the preparation of drugs that reduce the nephrotoxicity of ibuprofen.

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