A pharmaceutical composition with a synergistic analgesic effect and its application

Abstract

The present invention discloses a pharmaceutical composition with a synergistic analgesic effect and its application. The pharmaceutical composition is composed of drug A and drug B; drug A is one or more of Kv7 potassium channel openers, and drug B is one or more of antihistamine drugs. Drug A is a Kv7 potassium channel opener such as retigabine, flupirtine or a pharmaceutically acceptable salt or solvate thereof, and drug B is an antihistamine drug such as promethazine and / or fexofenadine or a pharmaceutically acceptable salt or solvate thereof. By evaluating the "gold standard" for drug interaction - the isobolographic analysis method, the present invention proves in visceral pain, inflammatory pain and neuropathic pain models that the three drug combinations of flupirtine - promethazine, flupirtine - fexofenadine and retigabine - promethazine can produce a synergistic analgesic effect, with a strong and lasting analgesic effect, and can avoid or reduce drug toxic and side effects, having good application prospects and providing a new strategy for effective clinical analgesia.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and specifically to a pharmaceutical composition having a synergistic analgesic effect and its application. Background Art

[0002] The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or a similar experience. According to the concepts of anatomical and neurobiological bases, pain can be further classified into acute pain, persistent pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, visceral pain, somatic pain, etc. Nowadays, pain has seriously affected the quality of life of patients and made them suffer a lot. Therefore, it is of great significance to actively and effectively treat pain.

[0003] Analgesia can be achieved by various methods, and the use of drugs is the basis of analgesic treatment. However, so far, no single analgesic can meet all the requirements of an ideal analgesic, nor has any analgesic been found to be effective against all types of pain. A single analgesic cannot meet all the requirements of ideal analgesic treatment, and the development of new and potent painkillers is relatively slow. The combined use of existing drugs is considered a reasonable way to achieve greater clinical efficacy without increasing risk factors. Therefore, various analgesics are clinically used in combination in order to produce a synergistic effect between drugs through the analgesic effects of various mechanisms and improve the efficacy.

[0004] In recent years, potassium ion channels have been regarded as new targets for the action of analgesic drugs, and the drugs under clinical development are mainly potassium channel openers. Neuron Kv7 channels (KCNQ) are mainly located at the front end of the axon. When the cell is in a state between the near-resting potential and the action potential excitation threshold, the Kv7 channels can affect the resting membrane potential and contribute to stabilizing neuronal excitability and restricting repetitive firing. Flupirtine, whose structure is shown in Formula I, can activate inward rectifier potassium ion channels and simultaneously regulate potassium ion efflux, capable of stabilizing the cell membrane potential and blocking the conduction of pain impulses. Flupirtine was first approved in Germany in the 1980s and is also licensed in many European countries (such as Germany, Italy, Portugal, etc.) as well as in China and Brazil for the treatment of various pains. Although the approved indications vary among countries, they are effective for musculoskeletal pain, tension headache, cancer pain, pain related to dysmenorrhea, surgical and traumatic pain. Adverse reactions such as nausea, stomach discomfort, diarrhea, constipation, dizziness, sweating, dry mouth, elevated serum aminotransferase and visual disturbances are occasionally seen. Retigabine (alias: Ezogabine), whose structure is shown in Formula II, is a structural analogue of flupirtine and has broad-spectrum and strong anticonvulsant properties in vivo and in vitro. It is the first Kv7 channel opener approved for use by the US FDA and is effective in the vast majority of preclinical epilepsy animal models. In addition, retigabine is also effective in many pain models and is expected to be used for other neurological diseases, including migraine and neuropathic pain, etc.

[0005]

[0006] Antihistamine drugs have been proven to be adjuvant analgesics in both animal and human studies and are widely used for preoperative analgesia, postoperative pain and cancer pain. In different studies, H1 antagonists have shown analgesic effects. Fexofenadine, whose structure is shown in Formula III, is a selective non-sedating H1 receptor antagonist and exhibits significant analgesic and anti-inflammatory properties in both rat chemical pain and acute inflammation models; Promethazine is a first-generation H1 antagonist, whose structure is shown in Formula IV, and shows analgesic activity in multiple mouse pain models. Reported studies have shown that antihistamine drugs have adjuvant analgesic effects on opioid drugs or non-steroidal anti-inflammatory drugs, but there has been no study on the combination of Kv7 potassium ion channel openers and antihistamine drugs.

[0007]

[0008] The isobolographic analysis method is the gold standard for evaluating drug interactions. The core criterion of this method is to select an effect level and determine the doses of drug A alone, drug B alone, and the combination (a, b) that produces this effect through experiments. The line connecting the doses that produce the same effect is called the isobole, and the combined drug effect can be expressed as a / A + b / B = γ. When γ = 1, the interaction between the drugs is additive; when γ < 1, the interaction between the drugs is synergistic; when γ > 1, the interaction between the drugs is antagonistic. Specifically, Z t = a + b, a = p A Z t , b = p B Z t , Z t = γ A / (P A + R pB ), R = A / B, Z add = A / (P A + R pB ), so Z t = γZ add (Z add , additive total for a specified effect; Z t , total dose for a specified effect).

[0009] Therefore, the present invention utilizes the combination of a Kv7 potassium channel opener and an antihistamine drug to produce a synergistic analgesic effect through multiple mechanisms, so as to obtain a better analgesic effect and minimize side effects, better meeting the clinical drug use requirements. SUMMARY OF THE INVENTION

[0010] The object of the present invention is to address the deficiencies of the prior art and provide a drug composition with a synergistic analgesic effect and its application to solve the problems raised in the above background art.

[0011] To achieve the above object, the present invention provides the following technical solution: A drug composition with a synergistic analgesic effect, which is composed of drug A and drug B; drug A is one or more of Kv7 potassium channel openers, and drug B is one or more of antihistamine drugs.

[0012] As a preferred technical solution of the present invention, drug A is retigabine, flupirtine, or a pharmaceutically acceptable salt or solvate thereof, which are Kv7 potassium channel openers.

[0013] As a preferred technical solution of the present invention, the drug B is an antihistamine drug promethazine and / or fexofenadine or a pharmaceutically acceptable salt or solvate thereof.

[0014] As a preferred technical solution of the present invention, the mass ratio of the drug A to the drug B is 0.05 - 40:1.

[0015] As a preferred technical solution of the present invention, the amount of flupirtine or a pharmaceutically acceptable salt or solvate thereof is equivalent to 15 - 300 mg of flupirtine, the amount of retigabine or a pharmaceutically acceptable salt or solvate thereof is equivalent to 37.5 - 150 mg of retigabine, the amount of promethazine or a pharmaceutically acceptable salt or solvate thereof is equivalent to 7.5 - 75 mg of promethazine, and the amount of fexofenadine or a pharmaceutically acceptable salt or solvate thereof is equivalent to 75 - 225 mg of fexofenadine.

[0016] As a preferred technical solution of the present invention, the pharmaceutical composition can be made into oral solid preparations, including ordinary tablets, orally disintegrating tablets, dispersible tablets, buccal tablets, chewable tablets, sustained-release tablets, controlled-release tablets, granules, powders, pills, controlled-release capsules and sustained-release capsules.

[0017] Use of a pharmaceutical composition, use of the pharmaceutical composition in the treatment of pain-related diseases, the pain-related diseases including but not limited to visceral pain, inflammatory pain, neuropathic pain, acute pain and chronic pain.

[0018] Advantages of the present invention: By using the "gold standard" for evaluating drug interactions - isobolographic analysis, in visceral pain, inflammatory pain and neuralgia models, it is proved that the three drug combinations of flupirtine - promethazine, flupirtine - fexofenadine and retigabine - promethazine can produce a synergistic analgesic effect, with a strong and lasting analgesic effect, and can avoid or reduce drug toxic and side effects, having a good application prospect, and providing a new strategy for effective clinical analgesia. Description of the Drawings

[0019] Figure 1 It is the analgesic effect diagram of the combined use of retigabine - promethazine in the acetic acid writhing model of mice;

[0020] Figure 2 It is the isobolographic analysis diagram of the interaction of the combined use of retigabine - promethazine in the acetic acid writhing model of mice;

[0021] Figure 3 It is the analgesic effect diagram of the combined use of flupirtine - promethazine in the acetic acid writhing model of mice;

[0022] Figure 4 It is the isobolographic analysis diagram of the interaction of the combined use of flupirtine - promethazine in the acetic acid writhing model of mice;

[0023] Figure 5 The analgesic effect diagram of flupirtine-fexofenadine combination in the acetic acid writhing model of mice;

[0024] Figure 6 The isobolographic analysis diagram of the interaction of flupirtine-fexofenadine combination in the acetic acid writhing model of mice;

[0025] Figure 7 The analgesic effect diagram of flupirtine-promethazine combination in the formalin-induced pain model of mice;

[0026] Figure 8 The isobolographic analysis diagram of the interaction of flupirtine-promethazine combination in the formalin-induced pain model of mice;

[0027] Figure 9 The analgesic effect diagram of flupirtine-fexofenadine combination in the formalin-induced pain model of mice;

[0028] Figure 10 The isobolographic analysis diagram of the interaction of flupirtine-fexofenadine combination in the formalin-induced pain model of mice;

[0029] Figure 11 The analgesic effect diagram of flupirtine-promethazine combination in the paclitaxel-induced neuropathic pain model of mice;

[0030] Figure 12 The isobolographic analysis diagram of the interaction of flupirtine-promethazine combination in the paclitaxel-induced neuropathic pain model of mice;

[0031] Figure 13 The analgesic effect diagram of flupirtine-fexofenadine combination in the paclitaxel-induced neuropathic pain model of mice;

[0032] Figure 14 The isobolographic analysis diagram of the interaction of flupirtine-fexofenadine combination in the paclitaxel-induced neuropathic pain model of mice;

[0033] Figure 15 The analgesic effect diagram of flupirtine-promethazine combination in the carrageenan-induced inflammatory pain model of mice;

[0034] Figure 16 The isobolographic analysis diagram of the interaction of flupirtine-promethazine combination in the carrageenan-induced inflammatory pain model of mice;

[0035] Figure 17 The analgesic effect diagram of flupirtine-fexofenadine combination in the carrageenan-induced inflammatory pain model of mice;

[0036] Figure 18 Equal-radiation analysis chart of the interaction of flupirtine-fexofenadine combination in a carrageenan-induced inflammatory pain model in mice;

[0037] Figure 19 Side effect evaluation chart of flupirtine-promethazine and flupirtine-fexofenadine combinations in the rotating rod test for fatigue. Detailed implementation manners

[0038] The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0039] The present invention provides a pharmaceutical composition having a synergistic analgesic effect, which is composed of drug A and drug B; drug A is one or more of Kv7 potassium channel openers, and drug B is one or more of antihistamine drugs;

[0040] Drug A is retigabine, flupirtine or a pharmaceutically acceptable salt or solvate thereof, which is a Kv7 potassium channel opener;

[0041] Drug B is promethazine and / or fexofenadine or a pharmaceutically acceptable salt or solvate thereof, which is an antihistamine drug; the mass ratio of drug A to drug B is 0.05-40:1;

[0042] Application of the pharmaceutical composition in the treatment of pain-related diseases, including but not limited to visceral pain, inflammatory pain, neuropathic pain, acute pain and chronic pain.

[0043] Experimental animals: SPF-grade female ICR mice weighing 20-30 g were used in the experiment. 8 experimental animals were placed in each cage, and the temperature was controlled at (22±1°C), with a 12-hour light / dark cycle.

[0044] Experimental materials: Flupirtine (Flu), Retigabine (Ret), Promethazine (Pro) and Fexofenadine (Fex) were purchased from Aladdin Reagent (Shanghai) Co., Ltd.

[0045] Example 1:

[0046] This example is the evaluation of the analgesic effect of retigabine-promethazine combination in a mouse acetic acid writhing model;

[0047] Female mice were weighed and randomly divided into groups of 8. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. Mice were intraperitoneally injected with acetic acid to cause a large area and relatively persistent pain stimulus in the deep part of the abdomen. After 30 min of gavage administration in each dose group, 0.1 mL / 10 g of 1% acetic acid solution was intraperitoneally injected, and the writhing times of the mice within 0 - 45 min after intraperitoneal injection of acetic acid were observed and recorded to analyze the analgesic effect of the combination of retigabine and promethazine. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = [(writhing times in the control group - writhing times in the drug group) / writhing times in the control group] × 100%. The ED 50 of retigabine and promethazine was calculated. When administered in combination, the doses of the two drugs were set as 1 / 2ED 50 +1 / 2ED 50 , 1 / 4ED 50 +1 / 4ED 50 , 1 / 8ED 50 +1 / 8ED 50 .

[0048] The experimental dose groups were set as shown in Table 1:

[0049] Table 1: Experimental grouping of the combination of retigabine - promethazine in the acetic acid writhing model of mice

[0050]

[0051] Experimental results: Both retigabine and promethazine could inhibit the writhing times in a dose - dependent manner. In the retigabine group, the analgesic effects of the low, medium, and high doses of 5, 10, and 20 mg / kg were 52.88%, 60.43%, and 74.46% respectively, and the ED 50 of retigabine = 4.515 mg / kg; in the promethazine group, the analgesic effects of the low, medium, and high doses of 1, 3, and 5 mg / kg were 30.94%, 44.84%, and 52.88% respectively, and the ED 50 of promethazine = 4.176 mg / kg. In the combination group, the analgesic effects of 1 / 2ED 50 +1 / 2ED 50 (Pro 2.10 mg / kg + Ret 2.26 mg / kg), 1 / 4ED 50 +1 / 4ED 50 (Pro 1.04 mg / kg + Ret 1.13 mg / kg), 1 / 8ED 50 +1 / 8ED 50 (Pro 0.52 mg / kg + Ret 0.56 mg / kg) were 78.06%, 65.83%, and 53.88% respectively, which were significantly higher than those of each single - drug group. After data analysis, Z add= 4.35 mg / kg, Z t = 0.902 mg / kg, γ = Z t / Z add = 0.207 < 1, indicating that the combination of retigabine and promethazine has a synergistic effect. See Figure 1 and Figure 2 .

[0052] Example 2:

[0053] This example is the evaluation of the analgesic effect of flupirtine-promethazine combination in a mouse acetic acid writhing model;

[0054] Female mice were weighed and randomly divided into groups of 8. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. Mice were intraperitoneally injected with acetic acid to cause a large area and relatively persistent pain stimulus in the deep part of the abdomen. 30 minutes after gavage administration, each dose group was intraperitoneally injected with 0.1 mL / 10 g of 1% acetic acid solution, and the number of writhing times of the mice within 0 - 45 minutes after intraperitoneal injection of acetic acid was observed and recorded to analyze the analgesic effect of the flupirtine-promethazine combination. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = [(number of writhing times in the control group - number of writhing times in the drug group) / number of writhing times in the control group] × 100%. The ED 50 of flupirtine and promethazine was calculated. When administered in combination, the doses of the two drugs were set as 1 / 2 ED 50 + 1 / 2 ED 50 , 1 / 4 ED 50 + 1 / 4 ED 50 , 1 / 8 ED 50 + 1 / 8 ED 50 .

[0055] The experimental dose groups were set as shown in Table 2:

[0056] Table 2: Experimental grouping of flupirtine-promethazine combination in a mouse acetic acid writhing model;

[0057]

[0058] Experimental results: Both flupirtine and promethazine could inhibit the number of writhing times in a dose-dependent manner. In the flupirtine group, the analgesic effects of the low, medium, and high doses of 4.3, 13, and 39 mg / kg were 28.42%, 61.15%, and 80.39% respectively, and the ED 50 of flupirtine = 9.42 mg / kg; in the promethazine group, the analgesic effects of the low, medium, and high doses of 1, 3, and 5 mg / kg were 30.94%, 44.84%, and 52.88% respectively, and the ED 50 of promethazine = 4.176 mg / kg. In the combination group, 1 / 2 ED 50+1 / 2 ED 50 (Pro 2.10 mg / kg + Flu 4.71 mg / kg), 1 / 4 ED 50 +1 / 4 ED 50 (Pro 1.04 mg / kg + Flu 2.36 mg / kg), 1 / 8 ED 50 +1 / 8 ED 50 (Pro 0.52 mg / kg + Flu 1.18 mg / kg) had analgesic effects of 75.90%, 53.24%, and 37.70% respectively, which were significantly higher than those of each single-drug group. After data analysis, Z add = 6.80 mg / kg, Z t = 2.763 mg / kg, γ = Z t / Z add = 0.406 < 1, indicating that the combination of flupirtine and promethazine has a synergistic effect. See Figure 3 and Figure 4 .

[0059] Example 3:

[0060] This example is the evaluation of the analgesic effect of flupirtine-fexofenadine combination in a mouse acetic acid writhing model;

[0061] Female mice were weighed and randomly divided into groups of 8 each. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. The mice were intraperitoneally injected with acetic acid to cause a large-area and relatively persistent pain stimulus in the deep part of the abdomen. 30 minutes after gavage administration, each dose group was intraperitoneally injected with 0.1 mL / 10 g of 1% acetic acid solution, and the number of writhing times of the mice within 0 - 45 minutes after intraperitoneal injection of acetic acid was observed and recorded to analyze the analgesic effect of flupirtine-fexofenadine combination. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = [(number of writhing times in the control group - number of writhing times in the drug group) / number of writhing times in the control group] × 100%. The ED 50 of flupirtine and fexofenadine was calculated. When administered in combination, the doses of the two drugs were set as 1 / 2 ED 50 + 1 / 2 ED 50 , 1 / 4 ED 50 + 1 / 4 ED 50 , 1 / 8 ED 50 + 1 / 8 ED 50 .

[0062] The experimental dose groups were set as shown in Table 3:

[0063] Table 3: Experimental grouping of flupirtine-fexofenadine combination in a mouse acetic acid writhing model

[0064]

[0065]

[0066] Experimental results: Both flupirtine and fexofenadine can inhibit the number of writhing in a dose-dependent manner. In the flupirtine group, the analgesic effects of the low, medium, and high doses of 4.3, 13, and 39 mg / kg were 28.42%, 61.15%, and 80.39% respectively, and the ED 50 of flupirtine = 9.42 mg / kg; in the fexofenadine group, the analgesic effects of the low, medium, and high doses of 10, 15, and 20 mg / kg were 32.01%, 56.12%, and 68.35% respectively, and the ED 50 of fexofenadine = 13.82 mg / kg. In the combination group, the analgesic effects of 1 / 2ED 50 +1 / 2ED 50 (Fex 6.91 mg / kg + Flu 4.71 mg / kg), 1 / 4ED 50 +1 / 4ED 50 (Fex 3.46 mg / kg + Flu 2.36 mg / kg), 1 / 8ED 50 +1 / 8ED 50 (Fex 1.73 mg / kg + Flu 1.18 mg / kg) were 61.15%, 47.12%, and 34.17% respectively, which were significantly higher than those of each single drug group. After data analysis, Z add = 11.65 mg / kg, Z t = 6.635 mg / kg, γ = Z t / Z add = 0.571 < 1, indicating that the combination of flupirtine and fexofenadine has a synergistic effect, as shown in Figure 5 and Figure 6 .

[0067] Example 4:

[0068] This example is the evaluation of the analgesic effect of flupirtine - promethazine combination in a mouse formalin-induced pain model.

[0069] For the formalin test in mice, we used the ZH-PAN801 automatic pain analysis system. On the day of the experiment, a small metal ring was put on the right hind paw of female ICR mice. Before the test, the mice were allowed to acclimate in a plexiglass container for at least 30 minutes. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. After 30 minutes of gavage administration in each dose group, a 1% formalin solution was subcutaneously injected into the right hind plantar surface of the mice, and then the animals were immediately placed into the automatic pain analyzer to record the movement of the paw injected with formalin. In the next 45 minutes, the number of times of lifting the foot was recorded every minute. The 0-10 minutes after formalin injection was defined as phase I, and 10-45 minutes was defined as phase II. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = [(number of times of lifting the foot in the control group - number of times of lifting the foot in the drug group) / number of times of lifting the foot in the control group] × 100%. The ED 50 of flupirtine and promethazine was calculated. When administered in combination, the doses of the two drugs were set as 1 / 2ED 50 +1 / 2ED 50 , 1 / 4ED 50 +1 / 4ED 50 , 1 / 8ED 50 +1 / 8ED 50 .

[0070] The experimental dose groups were set as shown in Table 4:

[0071] Table 4: Experimental grouping of flupirtine-promethazine combination in a mouse formalin-induced pain model

[0072]

[0073] Experimental results: Both flupirtine and promethazine could inhibit the number of times of lifting the foot in phase II in a dose-dependent manner, but had no obvious inhibitory effect on phase I. In the flupirtine group, the analgesic effects of the low, medium, and high doses of 4.3, 13, and 39 mg / kg were 13.0%, 36.2%, and 75.5% respectively, and the ED 50 of flupirtine = 18.42 mg / kg; in the promethazine group, the analgesic effects of the low, medium, and high doses of 1, 3, and 5 mg / kg were 21.91%, 36.29%, and 55.46% respectively, and the ED 50 of promethazine = 4.486 mg / kg. In the combination group, 1 / 2ED 50 +1 / 2ED 50 (Pro 2.24 mg / kg + Flu 9.21 mg / kg), 1 / 4ED 50 +1 / 4ED 50 (Pro 1.12 mg / kg + Flu 4.61 mg / kg), 1 / 8ED 50 +1 / 8ED 50The II-phase analgesic effects of (Pro 0.56 mg / kg + Flu 2.30 mg / kg) were 69.42%, 47.13%, and 22.73% respectively, which were significantly higher than those of each single drug group. After data analysis, Z add = 11.44 mg / kg, Z t = 6.397 mg / kg, γ = Z t / Z add = 0.559 < 1, indicating that the combination of flupirtine and promethazine has a synergistic effect. See Figure 7 and Figure 8 .

[0074] Example 5:

[0075] This example is the evaluation of the analgesic effect of flupirtine-fexofenadine combination in a mouse formalin-induced pain model.

[0076] For the formalin test in mice, we used the ZH-PAN801 automatic pain analysis system. On the day of the experiment, a small metal ring was put on the right hind paw of female ICR mice. Before the test, the mice were allowed to acclimatize in a plexiglass container for at least 30 minutes. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. 30 minutes after gavage administration in each dose group, a 1% formalin solution was subcutaneously injected into the right hind plantar surface of the mice, and then the animals were immediately placed in the automatic pain analyzer to record the movement of the paw injected with formalin. In the next 45 minutes, the number of times of lifting the foot was recorded every minute. The 0 - 10 minutes after formalin injection was defined as phase I, and 10 - 45 minutes was defined as phase II. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = [(number of times of lifting the foot in the control group - number of times of lifting the foot in the drug group) / number of times of lifting the foot in the control group] × 100%. The ED 50 of flupirtine and fexofenadine was calculated. When combined administration, the doses of the two drugs were set as 1 / 2ED 50 + 1 / 2ED 50 , 1 / 4ED 50 + 1 / 4ED 50 , 1 / 8ED 50 + 1 / 8ED 50 .

[0077] The experimental dose grouping is set as shown in Table 5:

[0078] Table 5: Experimental grouping of flupirtine-fexofenadine combination in a mouse formalin-induced pain model

[0079]

[0080] Experimental results: Both flupirtine and fexofenadine can inhibit the number of phase II foot lifts in a dose-dependent manner, but have no obvious inhibitory effect on phase I. In the flupirtine group, the analgesic effects of the low, medium, and high doses of 4.3, 13, and 39 mg / kg were 13.0%, 36.2%, and 75.5% respectively, and the ED 50 of flupirtine was 5.056 mg / kg; in the fexofenadine group, the analgesic effects of the low, medium, and high doses of 10, 15, and 20 mg / kg were 41.41%, 53.82%, and 65.62% respectively, and the ED 50 of fexofenadine was 12.98 mg / kg. In the combination drug group, the analgesic effects of 1 / 2 ED 50 +1 / 2 ED 50 (Fex 6.49 mg / kg + Flu 9.21 mg / kg), 1 / 4 ED 50 +1 / 4 ED 50 (Fex 3.46 mg / kg + Flu 4.61 mg / kg), 1 / 8 ED 50 +1 / 8 ED 50 (Fex 1.62 mg / kg + Flu 2.30 mg / kg) on phase II were 63.46%, 48.66%, and 36.63% respectively, which were significantly higher than those of each single drug group. After data analysis, Z add was 15.69 mg / kg, Z t was 8.032 mg / kg, and γ = Z t / Z add = 0.512 < 1, indicating that the combination of flupirtine and fexofenadine has a synergistic effect, as shown in Figure 9 and Figure 10 .

[0081] Example 6:

[0082] This example is the evaluation of the analgesic effect of the combination of flupirtine and promethazine in a mouse model of paclitaxel-induced neuropathic pain.

[0083] Peripheral pain neuropathy was induced in mice by intraperitoneal injection of paclitaxel. Mice were intraperitoneally injected with paclitaxel (2 mg / kg) at a dose of 0.1 mL / 10 g once a day for 5 consecutive days. The baseline mechanical threshold was evaluated one day before inducing neuropathic pain. The mechanical hypersensitivity behavior of mice was tested using the ZH-ZKL plantar sting system and the ZH-PAN801 automatic pain analysis system. Briefly, in a quiet room, the mice were placed in a test chamber on an elevated metal grid and allowed to acclimate for 30 min. Then the wire was lifted, and a linearly increasing force was applied to the hind paw. When the animal moved its paw away, a stop signal was automatically obtained. The paw withdrawal threshold after mechanical stimulation was automatically recorded in grams. After an adaptation period, each mouse was tested 3 times on the right hind plantar to obtain the baseline value. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. Subsequently, the mechanical paw withdrawal thresholds of each mouse were measured at 30, 60, 90, 120, 180, and 240 minutes after administration in each group. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = (Maximum MWT after administration - Baseline after modeling) / (Baseline before modeling - Baseline after modeling) × 100.

[0084] The experimental dose groups were set as shown in Table 6:

[0085] Table 6: Experimental grouping of flupirtine-promethazine combination in a paclitaxel-induced mouse model of neuropathic pain

[0086]

[0087]

[0088] Experimental results: On the baseline day, there were no significant differences in the mechanical paw withdrawal thresholds (MWT) among the animals in each group. Compared with the baseline before modeling, on the 7th day after the first administration, the MWT of the mice treated with paclitaxel was significantly decreased. Therefore, mechanical hypersensitivity behavior occurred in the mice treated with paclitaxel on the 7th day after the first administration of paclitaxel, which was consistent with previous evidence. Both flupirtine and promethazine could reverse the mechanical hypersensitivity behavior in a dose-dependent relationship. In the flupirtine group, the analgesic effects of the four doses from low to high, 4.3, 13, 26, and 39 mg / kg, were 38.09%, 49.53%, 59.70%, and 65.41% respectively, and the ED 50 of flupirtine = 11.97 mg / kg; in the promethazine group, the analgesic effects of the four doses from low to high, 1, 3, 5, and 10 mg / kg, were 24.75%, 41.15%, 48.47%, and 62.39% respectively, and the ED 50 of promethazine = 5.081 mg / kg. In the combination group, 1 / 2ED 50 +1 / 2ED 50(Pro 2.54 mg / kg + Flu 5.99 mg / kg), 1 / 4 ED 50 + 1 / 4 ED 50 (Pro 1.27 mg / kg + Flu 2.99 mg / kg), 1 / 8 ED 50 + 1 / 8 ED 50 (Pro 0.64 mg / kg + Flu 1.50 mg / kg) had analgesic effects of 74.36%, 56.95%, and 39.69% respectively, which were significantly higher than those of each single drug group. After data analysis, Z add = 8.49 mg / kg, Z t = 3.205 mg / kg, γ = Z t / Z add = 0.376 < 1, indicating that the combination of flupirtine and promethazine has a synergistic effect. See Figure 11 and Figure 12 .

[0089] Example 7:

[0090] This example is the evaluation of the analgesic effect of the combination of flupirtine-fexofenadine in a mouse model of paclitaxel-induced neuropathic pain.

[0091] Peripheral pain neuropathy in mice was induced by intraperitoneal injection of paclitaxel. Mice were intraperitoneally injected with paclitaxel (2 mg / kg) at a dose of 0.1 mL / 10 g once a day for 5 consecutive days. The baseline mechanical threshold was evaluated one day before inducing neuropathic pain. The mechanical hypersensitivity behavior of mice was tested using the ZH-ZKL plantar sting system and the ZH-PAN801 automatic pain analysis system. Briefly, in a quiet room, the mice were placed in a test chamber on an elevated metal grid and allowed to adapt for 30 min. Then the wire was lifted, and a linearly increasing force was applied to the hind paw. A stop signal was automatically obtained when the animal moved its paw away. The paw withdrawal threshold after mechanical stimulation was automatically recorded in grams. After an adaptation period, each mouse was tested 3 times on the right hind plantar to obtain the baseline value. Each group was given the treatment drug by gavage, and the model group was given an equal volume of normal saline by gavage. Subsequently, the mechanical paw withdrawal threshold of each mouse was measured at 30, 60, 90, 120, 180, and 240 minutes after administration. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = (Maximum MWT after administration - Baseline after modeling) / (Baseline before modeling - Baseline after modeling) × 100.

[0092] The experimental dose grouping is set as shown in Table 7:

[0093] Table 7: Experimental grouping of the combination of flupirtine-fexofenadine in a mouse model of paclitaxel-induced neuropathic pain

[0094]

[0095] Experimental results: On the baseline day, there were no significant differences in the mechanical withdrawal threshold (MWT) among the animals in each group. Compared with the baseline before modeling, on the 7th day after the first administration, the MWT of the mice treated with paclitaxel was significantly decreased. Therefore, the mice treated with paclitaxel showed mechanical hypersensitivity behavior on the 7th day after the first administration of paclitaxel, which was consistent with previous evidence. Both flupirtine and promethazine could reverse the mechanical hypersensitivity behavior in a dose-dependent relationship. In the flupirtine group, the analgesic effects of the four doses from low to high, 4.3, 13, 26, and 39 mg / kg, were 38.09%, 49.53%, 59.70%, and 65.41% respectively, and the ED 50 of flupirtine = 11.97 mg / kg; in the fexofenadine group, the analgesic effects of the four doses from low to high, 10, 15, 20, and 30 mg / kg, were 29.62%, 40.88%, 52.73%, and 66.03% respectively, and the ED 50 of fexofenadine = 18.81 mg / kg. In the combination drug group, the analgesic effects of 1 / 2 ED 50 + 1 / 2 ED 50 (Fex 9.41 mg / kg + Flu 5.99 mg / kg), 1 / 4 ED 50 + 1 / 4 ED 50 (Fex 4.70 mg / kg + Flu 2.99 mg / kg), 1 / 8 ED 50 + 1 / 8 ED 50 (Fex 2.35 mg / kg + Flu 1.50 mg / kg) were 62.95%, 52.12%, and 43.64% respectively, which were significantly higher than those of each single drug group. After data analysis, Z add = 15.35 mg / kg, Z t = 6.239 mg / kg, γ = Z t / Z add = 0.406 < 1, indicating that the combination of flupirtine and fexofenadine has a synergistic effect, as shown in Figure 13 and Figure 14 .

[0096] Example 8:

[0097] This example is the evaluation of the analgesic effect of the combination of flupirtine - promethazine in a carrageenan - induced mouse inflammatory pain model.

[0098] Acute inflammation of foot swelling was induced by subcutaneous injection of carrageenan into the right hind plantar surface of mice. In a quiet room, the mice were placed in a test chamber on an elevated metal grid and allowed to acclimate for 30 min. Then, the baseline value was obtained using the ZH-ZKL plantar pain system. 0.02 mL of 1% carrageenan was subcutaneously injected into the right hind plantar surface of the mice. After waiting for 3 hours until their feet were fully swollen, the baseline value after modeling was measured. Each group was given the therapeutic drug by gavage, and the model group was given an equal volume of normal saline by gavage. Subsequently, the mechanical withdrawal threshold of each mouse was measured at 30, 60, 90, 120, 180, and 240 minutes after administration in each group. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = (maximum MWT after administration - baseline after modeling) / (baseline before modeling - baseline after modeling) × 100.

[0099] The experimental dose groups were set as shown in Table 8:

[0100] Table 8: Experimental grouping of flupirtine-promethazine combination in a carrageenan-induced mouse inflammatory pain model

[0101]

[0102]

[0103] Experimental results: Before subcutaneous injection of carrageenan into the mouse plantar surface, there was no significant difference in the mechanical withdrawal threshold (MWT) among the groups of animals. Compared with the baseline before modeling, 3 hours after injection of 1% carrageenan, the MWT of the mice decreased significantly. Both flupirtine and promethazine could reverse the mechanical hypersensitivity behavior in a dose-dependent relationship. In the flupirtine group, the analgesic effects of the low, medium, and high doses of 2, 4.3, and 13 mg / kg were 20.29%, 44.67%, and 78.20% respectively, and the ED 50 of flupirtine = 5.056 mg / kg; in the promethazine group, the analgesic effects of the four doses from low to high of 1, 3, 5, and 10 mg / kg were 26.46%, 40.27%, 51.32%, and 61.55% respectively, and the ED 50 of promethazine = 4.923 mg / kg. In the combination drug group, 1 / 2ED 50 +1 / 2ED 50 (Pro 2.46 mg / kg + Flu 2.53 mg / kg), 1 / 4ED 50 +1 / 4ED 50 (Pro 1.23 mg / kg + Flu 1.26 mg / kg), 1 / 8ED 50 +1 / 8ED 50(Pro 0.62mg / kg + Flu 0.63mg / kg)'s analgesic effects were 71.76%, 51.84%, and 37.06% respectively, which were significantly higher than those of each single drug group. After data analysis, Z add = 4.99mg / kg, Z t = 2.06mg / kg, γ = Z t / Z add = 0.412 < 1, indicating that the combination of flupirtine and promethazine has a synergistic effect. See Figure 15 and Figure 16 .

[0104] Example 9:

[0105] This example is the evaluation of the analgesic effect of flupirtine-fexofenadine combination in a carrageenan-induced mouse inflammatory pain model.

[0106] Acute inflammation of foot swelling was induced by subcutaneous injection of carrageenan into the right hind paw of mice. In a quiet room, the mice were placed in a test chamber on an elevated metal grid and allowed to adapt for 30 min. Then, the baseline value was obtained using the ZH-ZKL plantar pain system. 0.02 mL of 1% carrageenan was subcutaneously injected into the right hind paw of the mice. After waiting for 3 hours until their feet were fully swollen, the baseline value after modeling was measured. Each group was given the treatment drug by gavage. The model group was given an equal volume of normal saline by gavage. Subsequently, the mechanical withdrawal threshold of each mouse was measured at 30, 60, 90, 120, 180, and 240 minutes after drug administration. The analgesic effect was calculated according to the following formula: Analgesic effect (%) = (maximum MWT after drug administration - baseline after modeling) / (baseline before modeling - baseline after modeling) × 100.

[0107] The experimental dose groups were set as shown in Table 9:

[0108] Table 9: Experimental grouping of flupirtine-fexofenadine combination in a carrageenan-induced mouse inflammatory pain model

[0109]

[0110] Experimental results: Before subcutaneous injection of carrageenan into the mouse foot, there was no significant difference in the mechanical withdrawal threshold (MWT) among the groups of animals. Compared with the baseline before modeling, the MWT of the mice was significantly reduced 3 hours after injection of 1% carrageenan. Both flupirtine and fexofenadine could reverse the mechanical hypersensitivity behavior in a dose-dependent relationship. In the flupirtine group, the analgesic effects of the low, medium, and high doses of 2, 4.3, and 13 mg / kg were 20.29%, 44.67%, and 78.20% respectively. The ED 50= 5.056 mg / kg; In the fexofenadine group, the analgesic effects of four doses from low to high, 10, 15, 20, and 30 mg / kg, were 27.79%, 40.88%, 53.75%, and 69.26% respectively. The ED 50 of fexofenadine was 18.43 mg / kg. In the combination group, 1 / 2 ED 50 + 1 / 2 ED 50 (Fex 9.22 mg / kg + Flu 2.53 mg / kg), 1 / 4 ED 50 + 1 / 4 ED 50 (Fex 4.61 mg / kg + Flu 1.26 mg / kg), 1 / 8 ED 50 + 1 / 8 ED 50 (Fex 2.31 mg / kg + Flu 0.63 mg / kg) had analgesic effects of 76.60%, 54.67%, and 37.75% respectively, which were significantly higher than those of each single-drug group. After data analysis, Z add = 11.76 mg / kg, Z t = 4.66 mg / kg, γ = Z t / Z add = 0.396 < 1, indicating that the combination of flupirtine and fexofenadine has a synergistic effect. See Figure 17 and Figure 18 .

[0111] Example 10:

[0112] This example is the evaluation of the side effects of the combination of flupirtine-promethazine and flupirtine-fexofenadine in the rotarod test for fatigue.

[0113] A rotarod fatigue tester was used to evaluate the effects of the combination of flupirtine-promethazine and flupirtine-fexofenadine on the motor coordination or sedation of mice. The mice were placed on the ZH-600B rotarod fatigue tester and accelerated to 40 rpm, and the time that all mice stayed on the rotarod was recorded. Eight mice were evaluated in each group, and their average value was defined as the fall latency. The mice were trained continuously for three days, and those mice with a fall latency of 300 seconds (baseline value) on the 3rd day were transferred to the test phase. On the day of the experiment, the fall latency of each rat was recorded at 30, 60, 90, 120, 180, and 240 minutes after drug administration, and the maximum fall latency was set at 300 seconds.

[0114] The experimental dose groups were set as shown in Table 10:

[0115] Table 10: Grouping of the combination of flupirtine-promethazine and flupirtine-fexofenadine in the rotarod test for fatigue;

[0116]

[0117] Experimental results: As Figure 19 shown, compared with the blank control group, there was no significant difference in the retention time (falling latency) of mice in the rotating rod test between the flupirtine-promethazine combination group (Flu 5.99 mg / kg + Pro 2.54 mg / kg) and the flupirtine-fexofenadine combination group (Flu 5.99 mg / kg + Fex 9.41 mg / kg), and no signs of motor incoordination and / or sedative side effects were observed in the mice. However, the falling latency of the flupirtine group (39 mg / kg) was significantly shorter than that of the blank control group, and the mice showed a tendency of motor incoordination and / or sedation.

[0118] Example 11: 50 mg / 25 mg compound tablet of flupirtine maleate - promethazine hydrochloride;

[0119] Table 11: Prescription composition of 50 mg / 25 mg flupirtine maleate - promethazine hydrochloride tablets (1000 tablets)

[0120]

[0121]

[0122] Preparation process: Dissolve flupirtine maleate and promethazine hydrochloride in 100 mL of ethanol to obtain the main drug solution; add poloxamer 407 and PEG6000 to 100 mL of ethanol, heat and stir to dissolve to obtain the auxiliary material solution. Mix the main drug solution and the auxiliary material solution evenly, then perform vacuum drying to obtain the material. Crush the material to 100 meshes to obtain the solid dispersion powder. Then put the solid dispersion powder, starch, and microcrystalline cellulose into a granulator, dry mix evenly, add 100 mL of binder ethanol, and shear granulate to obtain the granulated material. Screen the obtained granulated material through a 20-mesh sieve for wet sizing and transfer it to a fluidized bed dryer. Screen the dried granules through a 20-mesh sieve for sizing, then add magnesium stearate and mix evenly, and press tablets to obtain the product.

[0123] Example 12: 20 mg / 10 mg compound tablet of flupirtine maleate - fexofenadine hydrochloride;

[0124] Table 12: Prescription composition of 20 mg / 10 mg flupirtine - fexofenadine tablets (1000 tablets)

[0125]

[0126] Preparation process: Dissolve flupirtine maleate, fexofenadine hydrochloride, and citric acid in 300 mL of ethanol, remove ethanol under reduced pressure at 40 °C, screen the dried product through an 80-mesh sieve, mix evenly with the prescription amount of lactose, microcrystalline cellulose, and sodium carboxymethyl starch that have passed through a 100-mesh sieve, then mix with magnesium stearate, and press tablets.

[0127] The above embodiments merely represent several implementation manners of this specification. The description thereof is relatively specific and detailed, but it should not be construed as a limitation to the scope of the patent of this specification. It should be noted that for those of ordinary skill in the art, without departing from the concept of this specification, several modifications and improvements can still be made, and these all fall within the protection scope of this specification.

Claims

1. A pharmaceutical composition with a synergistic analgesic effect, characterized in that: The pharmaceutical composition is composed of drug A and drug B; drug A is one or more of Kv7 potassium channel openers, and drug B is one or more of antihistamine drugs; Drug A is flupirtine, a Kv7 potassium channel opener, or a pharmaceutically acceptable salt thereof; Drug B is promethazine, fexofenadine, or a pharmaceutically acceptable salt thereof, which are antihistamine drugs; The mass ratio of drug A to drug B is 0.05 - 40:

1.

2. The pharmaceutical composition with a synergistic analgesic effect according to claim 1, characterized in that: The amount of flupirtine or a pharmaceutically acceptable salt thereof is equivalent to 15 - 300 mg of flupirtine; The amount of promethazine or a pharmaceutically acceptable salt thereof is equivalent to 7.5 - 75 mg of promethazine; The amount of fexofenadine or a pharmaceutically acceptable salt thereof is equivalent to 75 - 225 mg of fexofenadine.

3. The pharmaceutical composition with a synergistic analgesic effect according to claim 1, characterized in that: The pharmaceutical composition can be made into oral solid preparations, including ordinary tablets, orally disintegrating tablets, dispersible tablets, buccal tablets, chewable tablets, sustained-release tablets, controlled-release tablets, granules, powders, pills, controlled-release capsules, and sustained-release capsules.

4. Use of a pharmaceutical composition according to any one of claims 1-3 in the preparation of a medicament for treating pain, characterized in that: The pain is selected from visceral pain, inflammatory pain, and neuropathic pain.

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