Pharmaceutical composition containing flurbiprofen axetil and application thereof

Abstract

The invention discloses a flurbiprofen axetil-containing pharmaceutical composition in the technical field of pharmaceutical preparations. The flurbiprofen axetil-containing pharmaceutical composition comprises flurbiprofen axetil and an intestinal carboxylesterase 2 inhibitor. The intestinal carboxylesterase 2 inhibitor can obviously inhibit intestinal carboxylesterase 2 from hydrolyzing flurbiprofen axetil to release flurbiprofen, so that the local concentration and accumulation of flurbiprofen in gastrointestinal tract tissues are obviously reduced, the damage of flurbiprofen to gastrointestinal mucosa is reduced, the bioavailability of flurbiprofen is improved, the effect is enhanced, the toxicity is reduced, and the preparation method is simple and convenient. The composition is suitable for inflammatory disease and pain management requiring long-term administration.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a pharmaceutical composition containing flurbiprofen ester and its application. Background Technology

[0002] Flurbiprofen and its ester derivatives, such as flurbiprofen axetil, are potent nonsteroidal anti-inflammatory drugs (NSAIDs) that exert their strong anti-inflammatory, analgesic, and antipyretic effects by inhibiting cyclooxygenase (COX) activity to reduce prostaglandin (PGE2) synthesis. Flurbiprofen axetil, as a prodrug of flurbiprofen, is widely used clinically for postoperative analgesia, cancer pain, and the treatment of various acute and chronic arthritis conditions, such as osteoarthritis and rheumatoid arthritis.

[0003] However, like most nonsteroidal anti-inflammatory drugs (NSAIDs), long-term or high-dose use of flurbiprofen and its ester derivatives can lead to significant gastrointestinal adverse reactions. One of its main mechanisms of action is that high concentrations of the drug in the gastrointestinal tract directly stimulate the mucosa and inhibit the synthesis of protective prostaglandins in the gastric mucosa, resulting in damage to the gastric mucosal barrier and causing serious complications such as erosion, ulceration, bleeding, and even perforation. Multiple studies have shown that flurbiprofen has a direct damaging effect on cultured gastric mucosal cells and may induce apoptosis. These toxic side effects greatly limit adherence to its clinical application and the safety of long-term use, especially for patients with acute and chronic diseases requiring long-term anti-inflammatory treatment; gastrointestinal damage is a technical challenge that urgently needs to be addressed.

[0004] To overcome this shortcoming, various approaches have been explored in existing technologies. One strategy is to develop prodrugs of flurbiprofen, such as synthesizing different types of alkyl esters, in order to reduce its direct irritation to the gastric mucosa. Another strategy is to develop novel drug delivery systems, such as injections and transdermal patches, to bypass the first-pass effect in the gastrointestinal tract. Furthermore, some studies have attempted to conjugate flurbiprofen with gastric mucosal protectants (such as histamine H2 receptor antagonists) to form chimeric drugs, aiming to protect the gastrointestinal tract while exerting anti-inflammatory effects. Although these methods have made some progress, they still suffer from problems such as complex processes, high costs, limited applicability, or failure to fundamentally alter the drug's tissue distribution characteristics in vivo.

[0005] Traditional Chinese medicine (TCM) theory emphasizes the synergistic effects of multiple components and targets. Many TCM monomers have been found to have the potential to regulate drug metabolism, improve drug distribution, and reduce toxicity while enhancing efficacy. For example, some TCM monomers can affect the activity of drug transport proteins or metabolic enzymes, thereby altering the pharmacokinetic process of drugs. However, there are currently no publicly reported technical solutions for scientifically combining specific TCM monomers with flurbiprofen ester to address its gastrointestinal toxicity issues.

[0006] Therefore, developing a novel compound preparation that can fundamentally improve the distribution characteristics of flurbiprofen in vivo, especially reducing its accumulation in gastrointestinal tissues and making its tissue distribution more uniform, thereby significantly reducing the gastrointestinal risks of long-term use while ensuring efficacy, has significant clinical value and market demand. Summary of the Invention

[0007] The present invention aims to provide a pharmaceutical composition containing flurbiprofen ester and its application therein, in order to solve the problem of significant gastrointestinal damage caused by the prior art.

[0008] One pharmaceutical composition comprising flurbiprofen ester in this formulation includes flurbiprofen ester and an intestinal carboxylesterase 2 inhibitor. The structural formula of flurbiprofen ester is as follows: .

[0009] Furthermore, the intestinal carboxylesterase 2 inhibitor is glycyrrhetinic acid (GA) or a glycyrrhetinic acid derivative (GA-13). Furthermore, the glycyrrhetinic acid is shown in structural formula 1 below, and the glycyrrhetinic acid derivative is selected from any one or more of structural formulas 2 to 15 below: .

[0010] Furthermore, the weight ratio of flurbiprofen ester to intestinal carboxylesterase 2 inhibitor is 1:100 to 100:1.

[0011] Preferably, the weight ratio of flurbiprofen ester to intestinal carboxylesterase 2 inhibitor is 1:1.

[0012] Furthermore, the pharmaceutical composition comprises a therapeutically effective amount of the above-mentioned flurbiprofen ester and a combination of glycyrrhetinic acid or its derivatives, as well as one or more pharmaceutically acceptable carriers, diluents or excipients.

[0013] The pharmaceutically acceptable carriers, diluents, or excipients include, but are not limited to, fillers, binders, disintegrants, lubricants, solubilizers, preservatives, and flavoring agents, which can be selected according to specific dosage form requirements.

[0014] The dosage form of this pharmaceutical composition can be oral tablets, capsules, granules, orally disintegrating tablets, lyophilized powder for injection, or transdermal patches, etc., and can be prepared by conventional formulation preparation methods in the art. For example, when preparing oral tablets, flurbiprofen ester, glycyrrhetinic acid or its derivatives can be mixed evenly with fillers, binders, etc., granulated, and then a lubricant can be added before tableting; when preparing lyophilized powder for injection, the active ingredients and solubilizers can be dissolved in water for injection, filtered, filled, and freeze-dried to obtain the finished product.

[0015] Furthermore, the pharmaceutical composition is used in the preparation of drugs that reduce the local concentration and distribution accumulation of flurbiprofen in the gastric and intestinal digestive tract tissues.

[0016] The use of pharmaceutical compositions in the preparation of drugs that improve the bioavailability of flurbiprofen.

[0017] Use of the pharmaceutical composition in the preparation of medicaments for treating diseases related to cyclooxygenase (COX) activity.

[0018] The diseases associated with cyclooxygenase (COX) activity are selected from inflammatory diseases, pain, fever, osteoarthritis, rheumatoid arthritis, dysmenorrhea, and acute or chronic soft tissue injuries.

[0019] The pharmaceutical composition exhibits highly selective inhibitory activity against COX enzymes.

[0020] The working principle and beneficial effects of this invention: The pharmaceutical composition of this invention has excellent anti-inflammatory and analgesic activity and low gastrointestinal irritation. Its use in the preparation of anti-inflammatory and analgesic drugs. In particular, it exhibits highly selective inhibition of COX enzymes.

[0021] Compared with the prior art, the present invention has the following significant advantages: 1. Inexpensive and readily available: The novel carboxylesterase inhibitor provided by this invention is obtained by chemical synthesis using inexpensive glycyrrhetinic acid as a raw material. The synthesis process is simple and easy to implement, and the yield is relatively high.

[0022] 2. High inhibitory activity: This glycyrrhetinic acid derivative can inhibit the metabolism of flurbiprofen ester in vitro (IC50). 50 It can reach the nM level.

[0023] 3. High safety: This novel carboxylesterase inhibitor exhibits good safety, with a low LD50 in cytotoxic experiments. 50 The oral LD50 in mice is greater than 60 μM. 50 Greater than 1 g / kg.

[0024] 4. Significantly improved gastrointestinal safety: The drug composition inhibits the metabolism of flurbiprofen ester to flurbiprofen, thereby improving tissue distribution and greatly reducing the direct chemical irritation of flurbiprofen to the gastric and intestinal mucosa. Animal experiments show that its ulcer-inducing potential is far lower than that of equal doses of flurbiprofen and flurbiprofen ester used alone.

[0025] 5. Improved efficacy: The combination of drugs is more effective than flurbiprofen ester alone. Animal studies have shown that its anti-inflammatory effect is superior to that of flurbiprofen and flurbiprofen ester alone at the same dose. Attached Figure Description

[0026] Figure 1 is a structural diagram of flurbiprofen ester; Figure 2 shows the structural formula of glycyrrhetinic acid; Figure 3 shows the structural formulas of glycyrrhetinic acid derivatives 2 to 15; Figure 4 is a schematic diagram of the synthesis steps of glycyrrhetinic acid derivative 13; Figure 5 shows the IC50 of glycyrrhetinic acid derivative 13 on human intestinal microsomes. 50 curve; Figure 6 is a bar chart showing the cytotoxicity of glycyrrhetinic acid derivative 13 to HepG2 cells. Figure 7 shows the pharmacokinetic curves of flurbiprofen alone, flurbiprofen ester alone, flurbiprofen ester combined with GA13 by gavage; Figure 8 shows a comparison of the tissue distribution of flurbiprofen alone, flurbiprofen ester alone, flurbiprofen ester combined with GA13 after 0.5 hours. Figure 9 shows the tissue distribution of flurbiprofen alone, flurbiprofen ester alone, flurbiprofen ester combined with GA13 after 2 hours. Figure 10 shows the tissue distribution of flurbiprofen alone, flurbiprofen ester alone, flurbiprofen ester combined with GA13 after 6 hours. Figure 11 shows the effect of GA13 on the gastrointestinal safety of flurbiprofen and flurbiprofen ester. Detailed Implementation

[0027] The following detailed explanation illustrates the specific implementation methods: Example 1: Screening of the optimal weight ratio of flurbiprofen ester to glycyrrhetinic acid in a pharmaceutical composition Experimental materials: SD rats; flurbiprofen ester; glycyrrhetinic acid; physiological saline; LC-MS / MS detection equipment and reagents.

[0028] Experimental Groups: Control group 1: Flurbiprofen (40 mg / kg) administered alone. Control group 2: Flurbiprofen ester alone (40 mg / kg); Experimental group 1: Flurbiprofen ester to glycyrrhetinic acid weight ratio 2:1 (flurbiprofen ester 40mg / kg + glycyrrhetinic acid 20mg / kg); Experimental group 2: Flurbiprofen ester to glycyrrhetinic acid weight ratio 1:1 (flurbiprofen ester 40mg / kg + glycyrrhetinic acid 40mg / kg); Experimental group 3: Flurbiprofen ester to glycyrrhetinic acid weight ratio 1:2 (flurbiprofen ester 40mg / kg + glycyrrhetinic acid 80mg / kg); Experimental group 4: Flurbiprofen ester to glycyrrhetinic acid weight ratio 1:5 (flurbiprofen ester 40mg / kg + glycyrrhetinic acid 200mg / kg); Experimental group 5: Flurbiprofen ester to glycyrrhetinic acid weight ratio 1:10 (flurbiprofen ester 40mg / kg + glycyrrhetinic acid 400mg / kg).

[0029] Experimental Methods: All rats were administered the drug via gavage. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-administration. Rats were sacrificed at specific time points to obtain tissues including heart, liver, spleen, lung, kidney, brain, stomach, and intestine. The pharmacokinetics and tissue distribution of flurbiprofen ester to GA13 at a weight ratio of 1:1 are presented. The concentration of flurbiprofen in blood and tissue samples was determined using LC-MS / MS to analyze pharmacokinetic parameters and tissue distribution. Figures 1-4 .

[0030] Figure 5 shows its IC. 50 =1.80um, Figure 7 shows that the combined group of flurbiprofen had a more stable blood concentration and a longer duration of action. Figure 8 shows that the drug concentration in the gastric and intestinal tissues was significantly reduced in the combination group. Figure 9 further confirms that the combination group showed reduced drug accumulation in the gastrointestinal tract. Figure 10 shows that the drug concentration in the gastrointestinal tract of the combination group remained at a low level.

[0031] Experimental Results: Compared with the control group, all experimental groups reduced the concentration of flurbiprofen in the stomach and small intestine to varying degrees. Experimental group 2 (weight ratio 1:1) showed the most significant effect: its flurbiprofen concentration in the stomach and intestine was reduced by approximately 65% ​​and 70% respectively compared to the control group (P<0.01). Simultaneously, the blood concentration of experimental group 2 was significantly higher than that of the control group, and it maintained a more stable effective concentration for 4-12 hours after administration. This indicates that a 1:1 weight ratio of flurbiprofen ester to glycyrrhetinic acid optimally achieves the dual objectives of "reducing gastrointestinal accumulation" and "improving bioavailability," thus determining this ratio as the optimal weight ratio.

[0032] Example 2: Pharmacodynamic evaluation of the anti-inflammatory and analgesic composition of the present invention Experimental materials: SD rats; flurbiprofen ester; glycyrrhetinic acid; physiological saline; carrageenan; hot plate analgesia device; inflammatory factor detection kit (IL-1β, TNF-α, IL-6).

[0033] Experimental Groups: Group A: Saline control group; Group B: Flurbiprofen ester monotherapy group (dose 20 mg / kg); Group C: Glycyrrhetinic acid monotherapy group (dose 20 mg / kg); Group D: The composition group of the present invention (flurbiprofen ester 20mg / kg + glycyrrhetinic acid 20mg / kg, weight ratio 1:1).

[0034] Evaluation of anti-inflammatory effects (carrageenan-induced rat paw edema experiment): Before administration, the volume of the right hind paw of each group of rats was measured. Then, 0.1 ml of 1% carrageenan solution was injected subcutaneously into the right hind paw of each rat to induce local acute inflammation. Each group was administered the drug by gavage at the above dosage. The volume of the right hind paw of the rats was measured at 1, 2, 4 and 6 hours after administration, and the paw swelling inhibition rate was calculated. The formula is: Swelling inhibition rate (%) = (average swelling of the model group - average swelling of the drug administration group) / average swelling of the model group × 100%.

[0035] Evaluation of analgesic effect (hot plate test): Before the experiment, rats were placed on a hot plate at 55±0.5℃, and their pain threshold (the time from when the rat's foot came into contact with the hot plate to when it licked its foot or jumped) was measured. Rats with a pain threshold <5s or >30s were excluded. Each group was administered the drug by gavage at the above dosage. The pain threshold of rats was measured at 1, 2, 4 and 6 hours after administration, and the pain threshold increase rate was calculated. The formula is: Pain threshold increase rate (%) = (Pain threshold after administration - Pain threshold before administration) / Pain threshold before administration × 100%.

[0036] Inflammatory factor detection: 4 hours after drug administration, rat serum was collected, and the levels of IL-1β, TNF-α and IL-6 in the serum were measured according to the instructions of the inflammatory factor detection kit.

[0037] Experimental results: Anti-inflammatory results: Four hours after administration, the inhibition rates of foot swelling in groups B, C, and D were 45.2%, 10.8%, and 88.5%, respectively. The anti-inflammatory effect of group D was significantly better than that of groups B and C (P<0.01), and its effect was greater than the simple sum of the effects of groups B and C, suggesting that flurbiprofen ester and glycyrrhetinic acid have a synergistic effect.

[0038] Analgesic results: In the hot plate test, 4 hours after administration, the pain threshold increase rate in group D was significantly higher than that in groups B and C (P<0.01), indicating that the composition has a better analgesic effect.

[0039] Inflammatory factor levels: The serum levels of IL-1β, TNF-α and IL-6 in group D were significantly lower than those in groups B and C (P<0.01), suggesting that the composition can more effectively inhibit the inflammatory response.

[0040] Example 3: Gastrointestinal safety evaluation of the pharmaceutical composition of the present invention, as shown in Figure 6 and Figure 11 As shown, Figure 6 This indicates that it has good cell safety. Experimental materials: SD rats; flurbiprofen ester; glycyrrhetinic acid; physiological saline; reagents for preparing pathological sections and staining.

[0041] Experimental Groups: Control group: Flurbiprofen ester alone (20 mg / kg / day); Experimental group: administered the composition of the present invention (flurbiprofen ester 20 mg / kg + glycyrrhetinic acid 20 mg / kg / day, weight ratio 1:1). Blank control group: Administered an equal volume of physiological saline.

[0042] Experimental methods: Rats in each group were administered the drug via gavage for 14 consecutive days. After the administration period, the rats were sacrificed, and blood, stomach, and intestinal tissues were collected for the following tests: Gross observation: Observe the appearance and morphology of the stomach and intestinal tissues, and check for damage such as congestion, edema, erosion, and ulceration; Histopathological examination: Gastric and intestinal tissues were fixed, dehydrated, embedded, sectioned, stained with hematoxylin and eosin (HE), and the pathological changes of the mucosal tissues were observed under an optical microscope; Experimental results: In the control group, the gastric mucosa of rats generally showed congestion, edema, erosion, and multiple ulcers, with a significantly increased damage index. In the experimental group, the gastric mucosa of rats was smooth, with no obvious congestion, edema, erosion, or ulceration. The gastric mucosal damage index of the experimental group was not statistically different from that of the blank control group. This fully demonstrates that the composition of the present invention can significantly reduce the gastrointestinal toxicity of flurbiprofen ester and has excellent gastrointestinal safety.

[0043] In summary, this invention cleverly solves the long-standing gastrointestinal toxicity problem of flurbiprofen ester by compounding it with a specific traditional Chinese medicine monomer, glycyrrhetinic acid or its derivatives, in a specific ratio. At the same time, it improves bioavailability and achieves the therapeutic advantage of reducing toxicity and increasing efficacy, providing a safer and more efficient new treatment option for clinical inflammatory diseases and pain management.

[0044] The above descriptions are merely embodiments of the present invention, and common knowledge regarding specific structures and characteristics is not elaborated upon here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the structure of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A pharmaceutical composition comprising flurbiprofen ester, characterized in that: This includes flurbiprofen ester and an intestinal carboxylesterase 2 inhibitor, wherein the intestinal carboxylesterase 2 inhibitor is glycyrrhetinic acid or a glycyrrhetinic acid derivative, the structural formula of which is shown below: 。 2. The pharmaceutical composition comprising flurbiprofen ester according to claim 1, characterized in that: The glycyrrhetinic acid derivative is selected from any one or more of the following structural formulas 2 to 15: 。 3. A pharmaceutical composition comprising flurbiprofen ester according to claim 2, characterized in that: The weight ratio of flurbiprofen ester to intestinal carboxylesterase 2 inhibitor is 1:100 to 100:

1.

4. A pharmaceutical composition comprising flurbiprofen ester according to claim 3, characterized in that: The weight ratio of flurbiprofen ester to intestinal carboxylesterase 2 inhibitor is 1:

1.

5. A pharmaceutical composition comprising flurbiprofen ester according to any one of claims 1 to 4, characterized in that: It also contains one or more pharmaceutically acceptable carriers, diluents or excipients.

6. A pharmaceutical composition comprising flurbiprofen ester according to claim 5, characterized in that: Its dosage forms include oral tablets, capsules, granules, orally disintegrating tablets, lyophilized powder for injection, or transdermal patches.

7. The use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for reducing the local concentration and distribution accumulation of flurbiprofen in the gastric and intestinal digestive tract tissues.

8. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for improving the bioavailability of flurbiprofen.

9. The use of the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating diseases related to cyclooxygenase activity.

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