CN116173221A

CN116173221A - Pharmaceutical composition with synergistic analgesic effect and application thereof

Info

Publication number: CN116173221A
Application number: CN202211093615.4A
Authority: CN
Inventors: 张桂森; 陈衍铭; 肖欣怡; 庄涛; 孙振骁
Original assignee: Jiangsu Ocean University
Current assignee: Jiangsu Ocean University
Priority date: 2022-09-08
Filing date: 2022-09-08
Publication date: 2023-05-30

Abstract

The invention discloses a pharmaceutical composition with a synergistic analgesic effect and application thereof, wherein the pharmaceutical composition consists of a medicine A and a medicine B; drug A is one or more of Kv7 potassium channel openers, drug B is one or more of antihistamines, drug A is Kv7 potassium channel openers retigabine, flupirtine or pharmaceutically acceptable salts or solvates thereof, and drug B is antihistamine drugs promethazine and/or fexofenadine or pharmaceutically acceptable salts or solvates thereof. The invention proves that three drug combinations of flupirtine-promethazine, flupirtine-fexofenadine and retigabine-promethazine can produce synergistic analgesic effect through evaluating the radiation analysis methods of gold standard, and the like of drug interaction, has strong and durable analgesic effect, can avoid or reduce toxic and side effects of drugs, has good application prospect, and provides a new strategy for clinical effective analgesic.

Description

Pharmaceutical composition with synergistic analgesic effect and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a pharmaceutical composition with a synergistic analgesic effect and application thereof.

Background

The international pain community defines pain as an unpleasant sensory and emotional experience associated with, or similar to, actual or potential tissue damage. Pain can be further classified into acute pain, persistent pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain, visceral pain, somatic pain, etc., according to the concepts underlying the anatomical and neurobiological principles. Today, pain has severely affected the quality of life of patients, making patients afflicted, and therefore, active and effective treatment of pain is of great importance.

Analgesia can be achieved in a variety of ways, and the use of drugs is the basis for analgesic treatment. However, no analgesic has met all the requirements of an ideal analgesic, nor has any analgesic been found to have analgesic effect on all types of pain, a single analgesic cannot meet all the requirements of an ideal analgesic treatment, and the development of a novel powerful analgesic is slow, and the combined use of existing drugs is considered as a reasonable way to achieve greater clinical efficacy without increasing risk factors. For this reason, various analgesic drugs are used in combination clinically in order to produce synergistic effects between the drugs through analgesic effects of various mechanisms, thereby improving therapeutic effects.

In recent years, potassium ion channels are regarded as new targets for analgesic drug action, and clinically developed drugs are mainly potassium channel openers. The neuronal Kv7 channel (KCNQ) is located mainly at the front of axons, and when cells are in a state close to between resting potential and action potential firing threshold, the Kv7 channel can affect resting membrane potential and help to stabilize neuronal excitability and limit repetitive discharges. Flupirtine (Flupirtine) has a structure shown in formula I, and can stabilize cell membrane potential and block pain impulse conduction by activating inward rectifying potassium ion channel and adjusting potassium ion outflow. Flupirtine was first approved in germany in the 80 s of the 20 th century, while licensed in many european countries (germany, italy, portugal, etc.) and china and brazil for the treatment of various pains, although the approved indications vary from country to country, they are effective in musculoskeletal pain, tension headache, tumor pain, dysmenorrhea-related pain, surgical and traumatic pain. Occasional nausea, stomach discomfort, diarrhea, constipation, dizziness, sweating, dry mouth, elevated serum aminotransferase, and vision impairment. Retigabine (alias: ezetimibe, ezogabine), which has the structure shown in formula II, is a structural analogue of flupirtine, has broad spectrum and strong anticonvulsant properties in vitro and in vivo, is the first Kv7 channel opener approved by the United states FDA, and is effective in most preclinical epileptic animal models. In addition, retigabine is also effective in many pain models and is expected to be useful in other neurological disorders including migraine and neuropathic pain, among others.

Antihistamines have proven to be adjuvant analgesics in animal and human studies, and they are widely used for pre-operative analgesia, post-operative pain and cancer pain. In different studies, H ₁ Antagonists have been shown to have analgesic effects. Fexofenadine, structure shown in formula III, is a selective non-sedated H ₁ Receptor antagonists exhibit remarkable analgesic and anti-inflammatory properties in both the rat chemical pain and acute inflammation models; promethazine is the first generation H ₁ The structure of the antagonist is shown as formula IV, and the antagonist shows analgesic activity in a plurality of mice pain models. Studies have been reported to show that antihistamines have an auxiliary analgesic effect on opioids or non-steroidal anti-inflammatory drugs, but there has been no study on the combination of Kv7 potassium channel openers and antihistamines.

Isoradiometric analysis is a gold standard for assessing drug interactions. The core criteria of the method is to select an effect level and experimentally determine the dosages of drug a alone, drug B alone and combinations (a, B) that produce this effect, the line connecting the dosages that produce the same effect being called the equivalent line, whereas the combined drug effect can be expressed as a/a+b/b=γ, when γ=1, then the interactions between the drugs are additive; when gamma < 1, then the interactions between the drugs are synergistic; when γ > 1, then the interaction between the drugs is antagonistic. In particular, 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 is _t ＝γZ _add (Z _add ,additive total for a specified effect；Z _t ,total dose for a specified effect)。

Therefore, the invention utilizes the combination of the Kv7 potassium channel opener and the antihistamine drug to generate synergistic analgesic effect through various mechanisms so as to obtain better analgesic effect, minimize side effect and better meet clinical medication requirements.

Disclosure of Invention

The invention aims at overcoming the defects of the prior art and provides a pharmaceutical composition with a synergistic analgesic effect and application thereof, so as to solve the problems of the prior art.

In order to achieve the above purpose, the present invention provides the following technical solutions: a pharmaceutical composition with synergistic analgesic effect comprises a drug A and a drug B; the medicine A is one or more of Kv7 potassium ion channel openers, and the medicine B is one or more of antihistamines.

As a preferable technical scheme of the invention, the medicine A is Kv7 potassium ion channel opener retigabine, flupirtine or pharmaceutically acceptable salt or solvate thereof.

As a preferred technical scheme of the invention, the drug B is antihistamine promethazine and/or fexofenadine or pharmaceutically acceptable salt or solvate thereof.

As a preferable technical scheme of the invention, the mass ratio of the medicine A to the medicine B is 0.05-40:1.

As a preferred embodiment of the present invention, the amount of flupirtine or a pharmaceutically acceptable salt or solvate thereof corresponds to 15 to 300mg flupirtine, the amount of retigabine or a pharmaceutically acceptable salt or solvate thereof corresponds to 37.5 to 150mg retigabine, the amount of promethazine or a pharmaceutically acceptable salt or solvate thereof corresponds to 7.5 to 75mg promethazine, and the amount of fexofenadine or a pharmaceutically acceptable salt or solvate thereof corresponds to 75 to 225mg fexofenadine.

As a preferable technical scheme of the invention, the pharmaceutical composition can be prepared into oral solid preparations, including common tablets, orally disintegrating tablets, dispersible tablets, buccal tablets, chewable tablets, sustained release tablets, controlled release tablets, granules, powder, pills, controlled release capsules and sustained release capsules.

The use of a pharmaceutical composition in the treatment of pain-related disorders including, but not limited to, visceral pain, inflammatory pain, neuropathic pain, acute pain, and chronic pain.

The invention has the beneficial effects that: the invention proves that three drug combinations of flupirtine-promethazine, flupirtine-fexofenadine and retigabine-promethazine can produce synergistic analgesic effect through evaluating the radiation analysis methods of gold standard, and the like of drug interaction, has strong and durable analgesic effect, can avoid or reduce toxic and side effects of drugs, has good application prospect, and provides a new strategy for clinical effective analgesic.

Drawings

FIG. 1 is a graph showing analgesic effects of retigabine-promethazine combination in a mouse torsion acetate model;

FIG. 2 is an isoradiometric analysis of the interaction of retigabine-promethazine combination in a mouse torsion acetate model;

FIG. 3 is a graph showing analgesic effect of flupirtine-promethazine combination in a mouse torsion acetate model;

FIG. 4 is an isoradiometric analysis of flupirtine-promethazine combination interactions in a mouse torsion acetate model;

FIG. 5 is a graph showing analgesic effect of flupirtine-fexofenadine combination in a mouse torsion acetate model;

FIG. 6 is an isoradiometric analysis of the interaction of flupirtine-fexofenadine combination in a mouse torsion acetate model;

FIG. 7 is a graph showing analgesic effects of flupirtine-promethazine combination in a mouse formalin pain model;

FIG. 8 is an isoradiogram showing the interaction of flupirtine-promethazine combination in a mouse formalin pain model;

FIG. 9 is a graph showing analgesic effect of flupirtine-fexofenadine combination in a mouse formalin pain model;

FIG. 10 is an isoradiometric analysis of flupirtine-fexofenadine combination interactions in a mouse formalin pain model;

FIG. 11 is a graph showing analgesic effects of flupirtine-promethazine combination in paclitaxel-induced neuropathic pain models in mice;

FIG. 12 is an isoradiogram showing the interaction of flupirtine-promethazine combination in paclitaxel-induced neuropathic pain models in mice;

FIG. 13 is a graph showing analgesic effects of flupirtine-fexofenadine combination in paclitaxel-induced neuropathic pain models in mice;

FIG. 14 is an isoradiogram showing the interaction of flupirtine-fexofenadine combination in paclitaxel-induced neuropathic pain models in mice;

FIG. 15 is a graph showing the analgesic effect of flupirtine-promethazine combination in a carrageenan-induced inflammatory pain model in mice;

FIG. 16 is an isoradiogram showing the interaction of flupirtine-promethazine combination in carrageenan-induced inflammatory pain models in mice;

FIG. 17 is a graph showing the analgesic effect of flupirtine-fexofenadine combination in a carrageenan-induced inflammatory pain model in mice;

FIG. 18 is an isoradiogram showing the interaction of flupirtine-fexofenadine combination in carrageenan-induced inflammatory pain models in mice;

fig. 19 is a graph showing the evaluation of the side effects of flupirtine-promethazine and flupirtine-fexofenadine combination in a fatigue bar test.

Detailed Description

The following embodiments of the present invention will be described in detail with reference to the drawings so that the advantages and features of the present invention can be more readily understood by those skilled in the art, and thus the scope of the present invention is more clearly defined. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.

The invention provides a pharmaceutical composition with a synergistic analgesic effect, which consists of a medicine A and a medicine B; drug A is one or more of Kv7 potassium ion channel openers, and drug B is one or more of antihistamines;

the medicine A is Kv7 potassium ion channel opener retigabine, flupirtine or pharmaceutically acceptable salt or solvate thereof;

drug B is antihistamine promethazine and/or fexofenadine or pharmaceutically acceptable salt or solvate thereof; the mass ratio of the medicine A to the medicine B is 0.05-40:1;

the use of the pharmaceutical composition in the treatment of pain-related disorders including, but not limited to, visceral pain, inflammatory pain, neuropathic pain, acute pain, and chronic pain.

Experimental animals: SPF-grade female ICR mice were used for the experiment, weighing 20-30 grams. The temperature (22.+ -. 1 ℃) was controlled for 8 animals per cage and the light/dark cycle was 12 hours.

Experimental materials: flupirtine (Flu), retigabine (Ret), fexofenadine (Promethazine, pro) and Promethazine (Fexofenadine, fex) are available from ala Ding Shiji (Shanghai) limited.

Example 1:

the embodiment is the evaluation of the analgesic effect of the retigabine-promethazine combination in a mouse acetic acid torsion model;

female mice were weighed and randomly grouped, 8 per group. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. The mice were injected with acetic acid intraperitoneally, resulting in a large area of pain stimulation in the deep abdominal cavity that was more permanent. After each dosage group is administrated by lavage for 30min, 0.1mL/10g of 1% acetic acid solution is injected into the abdominal cavity, and the twisting times of mice in 0-45min after the acetic acid is injected into the abdominal cavity are observed and recorded, so that the analgesic effect of the retigabine-promethazine combined administration is analyzed. The analgesic effect was calculated according to the following formula (%) = [ (number of times of torsion in control group-number of torsion in drug group)/number of times of torsion in control group]X 100%. ED of retigabine and promethazine was calculated ₅₀ When combined, the two doses are set to be 1/2ED ₅₀ +1/2ED ₅₀ ，1/4ED ₅₀ +1/4ED ₅₀ ，1/8ED ₅₀ +1/8ED ₅₀ 。

Experimental dose grouping settings are as in table 1:

table 1: experimental grouping of retigabine-promethazine combination in mouse acetic acid torsion model

Experimental results: both retigabine and promethazine can inhibit the number of writhing times in a dose dependent relationship. In the retigabine group, the analgesic effects of the low, medium and high doses of 5, 10 and 20mg/kg are 52.88 percent, 60.43 percent and 74.46 percent respectively, and the ED of the retigabine is obtained ₅₀ = 4.515mg/kg; in the promethazine group, the analgesic effects of the low, medium and

high doses

1, 3 and 5mg/kg are respectively 30.94%, 44.84% and 52.88%, and the ED of promethazine is obtained ₅₀ = 4.176mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Pro 2.10mg/kg+Ret 2.26mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Pro 1.04mg/kg+Ret 1.13mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effects of (Pro 0.52mg/kg+ret 0.56 mg/kg) were 78.06%, 65.83% and 53.88%, respectively, which were significantly higher than those of each of the individual groups. Z is analyzed by data _add ＝4.35mg/kg，Z _t ＝0.902mg/kg，γ＝Z _t /Z _add =0.207 < 1, indicating that the combination of retigabine and promethazine has a synergistic effect, see in fig. 1 and 2 for details.

Example 2:

the embodiment is the evaluation of analgesic effect of flupirtine-promethazine combined administration in a mouse acetic acid torsion model;

female mice were weighed and randomly grouped, 8 per group. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. The mice were injected with acetic acid intraperitoneally, resulting in a large area of pain stimulation in the deep abdominal cavity that was more permanent. After each dosage group is administrated by lavage for 30min, 0.1mL/10g of 1% acetic acid solution is injected into the abdominal cavity, and the twisting times of mice within 0-45min after the acetic acid is injected into the abdominal cavity are observed and recorded, so that the analgesic effect of flupirtine-promethazine combined administration is analyzed. The analgesic effect was calculated according to the following formula (%) = [ (number of times of torsion in control group-number of torsion in drug group)/number of times of torsion in control group]X 100%. Calculation of ED of flupirtine and promethazine ₅₀ When combined, the two doses are set to be 1/2ED ₅₀ +1/2ED ₅₀ ，1/4ED ₅₀ +1/4ED ₅₀ ，1/8ED ₅₀ +1/8ED ₅₀ 。

Experimental dose grouping settings are as in table 2:

table 2: experimental grouping of flupirtine-promethazine combination in a mouse acetic acid torque model;

experimental results: flupirtine and promethazine both inhibited the number of writhing in a dose dependent relationship. In flupirtine group, the analgesic effect of the low, medium and high doses of 4.3, 13 and 39mg/kg is 28.42 percent respectively61.15%, 80.39%, ED of flupirtine ₅₀ =9.42 mg/kg; in the promethazine group, the analgesic effects of the low, medium and

high doses

1, 3 and 5mg/kg are respectively 30.94%, 44.84% and 52.88%, and the ED of promethazine is obtained ₅₀ = 4.176mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Pro 2.10mg/kg+Flu 4.71mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Pro 1.04mg/kg+Flu 2.36mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effect of (Pro 0.52 mg/kg+Flu1.18mg/kg) was 75.90%, 53.24% and 37.70%, respectively, which was significantly higher than that of each of the individual groups. Z is analyzed by data _add ＝6.80mg/kg，Z _t ＝2.763mg/kg，γ＝Z _t /Z _add =0.406 < 1, indicating that flupirtine and promethazine combined have a synergistic effect, see in detail fig. 3 and 4.

Example 3:

the embodiment is the evaluation of analgesic effect of flupirtine-fexofenadine combination in a mouse acetic acid torsion model;

female mice were weighed and randomly grouped, 8 per group. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. The mice were injected with acetic acid intraperitoneally, resulting in a large area of pain stimulation in the deep abdominal cavity that was more permanent. After each dosage group is administrated by lavage for 30min, 0.1mL/10g of 1% acetic acid solution is injected into the abdominal cavity, and the twisting times of mice in 0-45min after the acetic acid is injected into the abdominal cavity are observed and recorded, so that the analgesic effect of the flupirtine-fexofenadine combination is analyzed. The analgesic effect was calculated according to the following formula (%) = [ (number of times of torsion in control group-number of torsion in drug group)/number of times of torsion in control group]X 100%. Calculation of ED of flupirtine and fexofenadine ₅₀ When combined, the two doses are set to be 1/2ED ₅₀ +1/2ED ₅₀ ，1/4ED ₅₀ +1/4ED ₅₀ ，1/8ED ₅₀ +1/8ED ₅₀ 。

Experimental dose grouping settings are as in table 3:

table 3: experimental grouping of flupirtine-fexofenadine combination in mouse acetic acid torsion model

Experimental results: both flupirtine and fexofenadine inhibit the number of writhing in a dose dependent relationship. In flupirtine group, the analgesic effects of low, medium and high doses of 4.3, 13 and 39mg/kg are 28.42%, 61.15% and 80.39% respectively, and ED of flupirtine is obtained ₅₀ =9.42 mg/kg; in the fexofenadine group, the analgesic effects of the three doses of 10, 15 and 20mg/kg are respectively 32.01%, 56.12% and 68.35%, and ED of the fexofenadine ₅₀ =13.82 mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Fex 6.91mg/kg+Flu4.71mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Fex 3.46mg/kg+Flu 2.36mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effects of (Fex 1.73 mg/kg+Flu1.18 mg/kg) were 61.15%, 47.12% and 34.17%, respectively, which were significantly higher than those of each of the individual groups. Z is analyzed by data _add ＝11.65mg/kg，Z _t ＝6.635mg/kg，γ＝Z _t /Z _add =0.571 < 1, indicating that flupirtine and fexofenadine in combination have a synergistic effect, see in detail fig. 5 and 6.

Example 4:

the present example is an evaluation of analgesic effect of flupirtine-promethazine combination in a mouse formalin pain model.

For formalin testing of mice, we used the ZH-PAN801 automated pain analysis system. On the day of the experiment, a small metal ring was placed on the right hind paw of female ICR mice. Mice were allowed to acclimate for at least 30 minutes in plexiglas containers prior to testing. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. After 30min of intragastric administration, the mice were subcutaneously injected with 1% formalin solution on their right hind paw, immediately after which the animals were placed in an automated pain analyzer and the movements of the injected formalin paw were recorded. The number of lifts per minute was recorded during the next 45 minutes. Formalin injectionThe latter 0-10min is defined as phase I and 10-45min is defined as phase II. The analgesic effect was calculated according to the following formula, analgesic effect (%) = [ (number of times of foot lifting in control group-number of times of foot lifting in drug group)/number of times of foot lifting in control group]X 100%. Calculation of ED of flupirtine and promethazine ₅₀ When combined, the two doses are set to be 1/2ED ₅₀ +1/2ED ₅₀ ，1/4ED ₅₀ +1/4ED ₅₀ ，1/8ED ₅₀ +1/8ED ₅₀ 。

Experimental dose grouping settings are as in table 4:

table 4: experimental grouping of flupirtine-promethazine combination in mouse formalin pain model

Experimental results: flupirtine and promethazine both can inhibit the number of foot lifting times of phase II in a dose-dependent relationship, but have no obvious inhibition effect on phase I. In flupirtine group, the analgesic effects of low, medium and high doses of 4.3, 13 and 39mg/kg are respectively 13.0%, 36.2% and 75.5%, and ED of flupirtine ₅₀ =18.42 mg/kg; in the promethazine group, the analgesic effects of the low, medium and

high doses

1, 3 and 5mg/kg are 21.91%, 36.29% and 55.46%, respectively, and the ED of promethazine is obtained ₅₀ = 4.486mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Pro 2.24mg/kg+Flu 9.21mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Pro 1.12mg/kg+Flu 4.61mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effect of phase II (Pro 0.56mg/kg+flu 2.30 mg/kg) was 69.42%, 47.13% and 22.73% respectively, which is significantly higher than that of each of the individual groups. Z is analyzed by data _add ＝11.44mg/kg，Z _t ＝6.397mg/kg，γ＝Z _t /Z _add =0.559 < 1, indicating that flupirtine and promethazine combined have a synergistic effect, see in fig. 7 and 8 for details.

Example 5:

the present example is an analgesic effect evaluation of flupirtine-fexofenadine combination in a mouse formalin pain model.

For formalin testing of mice, we causedAn automated pain analysis system using ZH-PAN 801. On the day of the experiment, a small metal ring was placed on the right hind paw of female ICR mice. Mice were allowed to acclimate for at least 30 minutes in plexiglas containers prior to testing. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. After 30min of intragastric administration, the mice were subcutaneously injected with 1% formalin solution on their right hind paw, immediately after which the animals were placed in an automated pain analyzer and the movements of the injected formalin paw were recorded. During the next 45 minutes, the number of lifts per minute was recorded. Phase I was defined as 0-10min after formalin injection, and phase II was defined as 10-45 min. The analgesic effect was calculated according to the following formula, analgesic effect (%) = [ (number of times of foot lifting in control group-number of times of foot lifting in drug group)/number of times of foot lifting in control group]X 100%. Calculation of ED of flupirtine and fexofenadine ₅₀ When combined, the two doses are set to be 1/2ED ₅₀ +1/2ED ₅₀ ，1/4ED ₅₀ +1/4ED ₅₀ ，1/8ED ₅₀ +1/8ED ₅₀ 。

Experimental dose grouping settings are as in table 5:

table 5: experimental grouping of flupirtine-fexofenadine combination in mouse formalin pain model

Experimental results: flupirtine and fexofenadine can inhibit the number of foot lifting times of phase II in a dose-dependent relationship, but have no obvious inhibition effect on phase I. In flupirtine group, the analgesic effects of low, medium and high doses of 4.3, 13 and 39mg/kg are respectively 13.0%, 36.2% and 75.5%, and ED of flupirtine ₅₀ = 5.056mg/kg; in the fexofenadine group, the analgesic effects of the three doses of 10, 15 and 20mg/kg are 41.41%, 53.82% and 65.62% respectively, and the ED of the fexofenadine is obtained ₅₀ =12.98 mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Fex 6.49mg/kg+Flu 9.21mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Fex 3.46mg/kg+Flu4.61 mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ (Fex 1.62mg/kg+flu 2.30 mg/kg) phase II ballastThe pain effects are 63.46%, 48.66% and 36.63% respectively, which are obviously higher than those of each single administration group. Z is analyzed by data _add ＝15.69mg/kg，Z _t ＝8.032mg/kg，γ＝Z _t /Z _add =0.512 < 1, indicating that flupirtine and fexofenadine combination have a synergistic effect, see in detail fig. 9 and 10.

Example 6:

this example is an evaluation of analgesic effect of flupirtine-promethazine combination in paclitaxel-induced neuropathic pain model in mice.

Peripheral painful neuropathy in mice was induced by intraperitoneal injection of paclitaxel. Mice were intraperitoneally injected with paclitaxel (2 mg/kg) at a dose of 0.1mL/10g, 1 time daily for 5 consecutive days. Baseline mechanical thresholds were assessed the day prior to the induction of neuropathic pain. Mice were tested for mechanical hypersensitivity behavior using the ZH-ZKL plantar stinging system and the ZH-PAN801 automated pain analysis system. Briefly, in a quiet room, mice were placed in a test room on an overhead metal grid and allowed to acclimate for 30 minutes. The wire is then lifted and a linearly increasing force is applied to the hind paw. The stop signal is automatically obtained when the animal moves the paw away. The foot shrinkage threshold after mechanical stimulation is automatically recorded in grams. After a period of acclimation, each mouse was tested 3 times on the right posterior sole to obtain baseline values. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. Subsequently, each group was assayed for mechanical foot-reduction threshold at 30, 60, 90, 120, 180, 240 minutes after dosing, respectively. The analgesic effect was calculated according to the following formula (%) = = (maximum MWT after administration-post-modeling baseline)/(pre-modeling baseline-post-modeling baseline) ×100.

Experimental dose grouping settings are as in table 6:

table 6: experimental grouping of flupirtine-promethazine combination in paclitaxel-induced neuropathic pain models in mice

Experimental results: there was no significant difference in mechanical footage threshold (MWT) for each group of animals on the baseline day. Paclitaxel-treated mice had significantly reduced MWT on day 7 after the first administration compared to the pre-molding baseline. Thus, mice treated with paclitaxel exhibited mechanical hypersensitivity behavior on day 7 after the first administration of paclitaxel, consistent with previous evidence. Flupirtine and promethazine both reverse mechanical hypersensitivity behavior in a dose dependent relationship. In flupirtine group, four doses from low to high of 4.3, 13, 26 and 39mg/kg had analgesic effects of 38.09%, 49.53%, 59.70% and 65.41%, respectively, and ED of flupirtine ₅₀ =11.97 mg/kg; in the promethazine group, the analgesic effects of 1, 3, 5 and 10mg/kg of four dosages from low to high are 24.75%, 41.15%, 48.47%, 62.39%, respectively, and ED of promethazine ₅₀ = 5.081mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Pro 2.54mg/kg+Flu 5.99mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Pro1.27mg/kg+Flu 2.99mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effect of (Pro 0.64 mg/kg+Flu1.50mg/kg) was 74.36%, 56.95% and 39.69%, respectively, which were significantly higher than that of each of the individual groups. Z is analyzed by data _add ＝8.49mg/kg，Z _t ＝3.205mg/kg，γ＝Z _t /Z _add =0.376 < 1, indicating that flupirtine and promethazine combined have a synergistic effect, see in fig. 11 and 12 for details.

Example 7:

this example is an evaluation of analgesic effect of flupirtine-fexofenadine combination in paclitaxel-induced neuropathic pain models in mice.

Experimental dose grouping settings are as follows in table 7:

table 7: experimental grouping of flupirtine-fexofenadine combination in paclitaxel-induced neuropathic pain models in mice

Experimental results: there was no significant difference in mechanical footage threshold (MWT) for each group of animals on the baseline day. Paclitaxel-treated mice had significantly reduced MWT on day 7 after the first administration compared to the pre-molding baseline. Thus, mice treated with paclitaxel exhibited mechanical hypersensitivity behavior on day 7 after the first administration of paclitaxel, consistent with previous evidence. Flupirtine and promethazine both reverse mechanical hypersensitivity behavior in a dose dependent relationship. In flupirtine group, four doses from low to high of 4.3, 13, 26 and 39mg/kg had analgesic effects of 38.09%, 49.53%, 59.70% and 65.41%, respectively, and ED of flupirtine ₅₀ =11.97 mg/kg; in the fexofenadine group, the analgesic effect of the four doses of 10, 15, 20 and 30mg/kg from low to high is 29.62%, 40.88%, 52.73% and 66.03%, respectively, of ED of fexofenadine ₅₀ =18.81 mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Fex 9.41mg/kg+Flu 5.99mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Fex 4.70mg/kg+Flu 2.99mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effects of (Fex 2.35 mg/kg+Flu1.50mg/kg) were 62.95%, 52.12% and 43.64%, respectively, which were significantly higher than those of each of the individual groups. Z is analyzed by data _add ＝15.35mg/kg，Z _t ＝6.239mg/kg，γ＝Z _t /Z _add =0.406 < 1, indicating that flupirtine and fexofenadine combination have a synergistic effect, see in detail fig. 13 and 14.

Example 8:

this example is an evaluation of analgesic effect of flupirtine-promethazine combination in carrageenan-induced inflammatory pain model in mice.

Acute inflammation of foot swelling was induced by subcutaneous carrageenan injection into the sole of the right rear foot of the mice. In a quiet room, mice were placed in a test room on an overhead metal grid and allowed to acclimate for 30 minutes before baseline values were obtained using the ZH-ZKL plantar stinging system. The mice were subcutaneously injected with 1% carrageenan 0.02mL in the sole after right foot, waiting 3 hours, and after the feet were fully swollen, the post-molding baseline value was determined. Each group was given therapeutic drugs by gavage, and the model group was given an equal volume of physiological saline by gavage. Subsequently, each group was assayed for mechanical foot-reduction threshold at 30, 60, 90, 120, 180, 240 minutes after dosing, respectively. The analgesic effect was calculated according to the following formula (%) = = (maximum MWT after administration-post-modeling baseline)/(pre-modeling baseline-post-modeling baseline) ×100.

Experimental dose grouping settings are as in table 8:

table 8: experimental grouping of flupirtine-promethazine combination in carrageenan-induced inflammatory pain models in mice

Experimental results: mouse soleThere was no significant difference in mechanical foot-reduction threshold (MWT) for each group of animals prior to subcutaneous injection of carrageenan. The MWT of mice was significantly reduced 3 hours after 1% carrageenan injection compared to the pre-molding baseline. Flupirtine and promethazine both reverse mechanical hypersensitivity behavior in a dose dependent relationship. In flupirtine group, the analgesic effects of low, medium and high doses of 2, 4.3 and 13mg/kg are respectively 20.29%, 44.67% and 78.20%, and ED of flupirtine ₅₀ = 5.056mg/kg; in the promethazine group, the analgesic effects of 1, 3, 5 and 10mg/kg from low to high are 26.46%, 40.27%, 51.32%, 61.55% respectively, and ED of promethazine ₅₀ = 4.923mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Pro 2.46mg/kg+Flu 2.53mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Pro 1.23mg/kg+Flu 1.26mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effects of (Pro 0.62mg/kg+flu 0.63 mg/kg) were 71.76%, 51.84% and 37.06%, respectively, which were significantly higher than those of each of the individual groups. Z is analyzed by data _add ＝4.99mg/kg，Z _t ＝2.06mg/kg，γ＝Z _t /Z _add =0.412 < 1, indicating that flupirtine and promethazine combined have a synergistic effect, see in fig. 15 and 16 for details.

Example 9:

this example is an evaluation of analgesic effect of flupirtine-fexofenadine combination in carrageenan-induced inflammatory pain model in mice.

Experimental dose grouping settings are as follows in table 9:

table 9: experimental grouping of flupirtine-fexofenadine combination in carrageenan-induced inflammatory pain models in mice

Experimental results: there was no significant difference in mechanical foot contraction threshold (MWT) for each group of animals prior to plantar subcutaneous injection of carrageenan in mice. The MWT of mice was significantly reduced 3 hours after 1% carrageenan injection compared to the pre-molding baseline. Both flupirtine and fexofenadine reverse mechanical hypersensitivity behavior in a dose dependent relationship. In flupirtine group, the analgesic effects of low, medium and high doses of 2, 4.3 and 13mg/kg are respectively 20.29%, 44.67% and 78.20%, and ED of flupirtine ₅₀ = 5.056mg/kg; in the fexofenadine group, the analgesic effects of the four

doses

10, 15, 20 and 30mg/kg from low to high are 27.79%, 40.88%, 53.75% and 69.26% respectively, and ED of fexofenadine ₅₀ =18.43 mg/kg. 1/2ED in combination ₅₀ +1/2ED ₅₀ (Fex 9.22mg/kg+Flu 2.53mg/kg)，1/4ED ₅₀ +1/4ED ₅₀ (Fex 4.61mg/kg+Flu 1.26mg/kg)，1/8ED ₅₀ +1/8ED ₅₀ The analgesic effects of (Fex 2.31mg/kg+flu 0.63 mg/kg) were 76.60%, 54.67% and 37.75%, respectively, which were significantly higher than those of each of the individual groups. Z is analyzed by data _add ＝11.76mg/kg，Z _t ＝4.66mg/kg，γ＝Z _t /Z _add =0.396 < 1, indicating that flupirtine and fexofenadine combination have synergistic effects, see in detail fig. 17 and 18.

Example 10:

the example is the evaluation of the side effects of flupirtine-promethazine and flupirtine-fexofenadine combination in a fatigue bar rotation experiment.

The effect of flupirtine-promethazine and flupirtine-fexofenadine combination on motor coordination or sedation in mice was evaluated using a rotating stick fatigue machine. The mice were placed on a ZH-600B rotarod fatigue tester, accelerated to 40rpm, and the time for all mice to stay on the rotarod was recorded. Each group was evaluated for 8 mice, the average of which was defined as drop latency. Mice were trained for three consecutive days, and those mice with a drop latency of 300 seconds (baseline value) on day 3 were transferred to the test phase. On the day of the experiment, drop latency of each rat was recorded at 30, 60, 90, 120, 180, 240 minutes post-dose, with the maximum drop latency set at 300 seconds.

Experimental dose grouping settings are as in table 10:

table 10: grouping of flupirtine-promethazine and flupirtine-fexofenadine combination in fatigue bar rotation experiments;

experimental results: as shown in fig. 19, the flupirtine-promethazine combination (flu5.99 mg/kg+pro 2.54 mg/kg) and flupirtine-fexofenadine combination (Flu 5.99mg/kg+fex 9.41 mg/kg) mice did not have significant differences in residence time (drop latency) on the rotor bars compared to the placebo group, and the mice did not show dyskinesia and/or sedative side effects. However, the drop latency of flupirtine group (39 mg/kg) was significantly reduced compared to the placebo group, and mice tended to experience dyskinesia and/or sedation.

Example 11:50mg/25mg flupirtine maleate-promethazine hydrochloride tablet compound tablet;

table 11:50mg/25mg flupirtine maleate-promethazine hydrochloride tablet prescription composition (1000 tablets)

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The preparation process comprises the following steps: dissolving flupirtine maleate and promethazine hydrochloride in 100mL of ethanol to obtain a main drug solution; adding poloxamer 407 and PEG6000 into 100mL of ethanol, heating and stirring to dissolve to obtain adjuvant solution. And uniformly mixing the main medicine solution and the auxiliary material solution, and then carrying out vacuum drying to obtain the material. And crushing the materials to 100 meshes to obtain solid dispersion powder. And then, putting the solid dispersion powder, starch and microcrystalline cellulose into a granulator, dry-mixing uniformly, adding 100mL of adhesive ethanol, and shearing and granulating to obtain granules. The obtained granules were wet-granulated by a 20-mesh sieve and then transferred to a boiling dryer. And (3) sieving the dried granules with a 20-mesh sieve, finishing the granules, adding magnesium stearate, uniformly mixing, and tabletting.

Example 12:20mg/10mg flupirtine maleate-fexofenadine hydrochloride tablet compound tablet;

table 12:20mg/10mg flupirtine-fexofenadine tablet prescription composition (1000 tablets)

The preparation process comprises the following steps: dissolving flupirtine maleate, fexofenadine hydrochloride and citric acid in 300mL ethanol, drying under reduced pressure at 40 ℃ to remove ethanol, sieving the dried product with a 80-mesh sieve, uniformly mixing with lactose, microcrystalline cellulose and carboxymethyl starch sodium with a prescription of 100 meshes, mixing with magnesium stearate, and tabletting.

The foregoing examples represent only a few embodiments of the present description, which are described in more detail and are not to be construed as limiting the scope of the description. It should be noted that variations and modifications can be made by those skilled in the art without departing from the spirit of the present description, which falls within the scope of the present description.

Claims

1. A pharmaceutical composition with synergistic analgesic effect, characterized in that: the medicine composition consists of medicine A and medicine B; the medicine A is one or more of Kv7 potassium ion channel openers, and the medicine B is one or more of antihistamines.

2. A pharmaceutical composition with synergistic analgesic effect as claimed in claim 1, wherein: the medicine A is Kv7 potassium ion channel opener retigabine, flupirtine or pharmaceutically acceptable salt or solvate thereof.

3. A pharmaceutical composition with synergistic analgesic effect as claimed in claim 1, wherein: the drug B is antihistamine promethazine and/or fexofenadine or pharmaceutically acceptable salts or solvates thereof.

4. A pharmaceutical composition with synergistic analgesic effect as claimed in claim 1, wherein: the mass ratio of the medicine A to the medicine B is 0.05-40:1.

5. A pharmaceutical composition with synergistic analgesic effect according to claims 2-3, characterized in that: the flupirtine or the pharmaceutically acceptable salt or solvate thereof is equivalent to 15-300 mg flupirtine, retigabine or the pharmaceutically acceptable salt or solvate thereof is equivalent to 37.5-150 mg retigabine, promethazine or the pharmaceutically acceptable salt or solvate thereof is equivalent to 7.5-75 mg promethazine, and fexofenadine or the pharmaceutically acceptable salt or solvate thereof is equivalent to 75-225 mg fexofenadine.

6. A pharmaceutical composition with synergistic analgesic effect as claimed in claim 1, wherein: the pharmaceutical composition can be prepared into oral solid preparations, including common tablets, orally disintegrating tablets, dispersible tablets, buccal tablets, chewable tablets, sustained release tablets, controlled release tablets, granules, powder, pills, controlled release capsules and sustained release capsules.

7. Use of a pharmaceutical composition according to claim 1, characterized in that: the use of the pharmaceutical composition in the treatment of pain-related disorders including, but not limited to, visceral pain, inflammatory pain, neuropathic pain, acute pain, and chronic pain.