Pharmaceutical composition for preventing and / or treating pain and application thereof

Abstract

The invention discloses a pharmaceutical composition for preventing and / or treating pain and application thereof.The pharmaceutical composition contains a Sigma-1 receptor antagonist and a histamine H3 receptor antagonist / inverse agonist and has a synergistic analgesic effect on various pains, the curative effect of the pharmaceutical composition is remarkably superior to that of a single drug, the use dosage of the single drug can be reduced, and therefore the side effect of single drug dosage dependence is reduced; good application prospects are realized.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing and / or treating pain and application thereof, and in particular to a pharmaceutical composition for preventing and / or treating pain with synergistic effect. Background Art

[0002] The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or similar. Pain can be divided into nociceptive pain (from tissue damage), neuropathic pain (from nerve damage), and nociplastic pain (from nervous system sensitivity). Today, pain is considered the fifth sign of life and has become the third largest health problem for humans after cardiovascular and cerebrovascular diseases and tumors. It is of great significance in the field of life and health science research. At present, pain has seriously affected the quality of life of patients and caused a huge economic burden. The treatment and management of pain is a public health issue closely related to human life.

[0003] There are many ways to treat pain, but drug-based treatment remains the main treatment for pain. Although there are a large number of effective and widely used analgesics, such as opioids, nonsteroidal anti-inflammatory drugs, and some antidepressants, the safety and side effects of these drugs have limited their clinical use.

[0004] Sigma-1 receptor (σ1R) is a unique Ca 2+ Sensitive chaperone proteins are widely expressed in key areas responsible for pain control (such as the thalamus, periaqueductal gray matter, dorsal root ganglia, etc.). σ1R regulates the biological functions of a variety of pain-related chaperone proteins, including opioid receptors, cannabinoid receptors, N-methyl-D-aspartate receptors, etc. Therefore, the σ1R system has a pain-modulating effect. Under physiological conditions, σ1R antagonists do not change the normal pain threshold, but relieve abnormal pain or hyperalgesia caused by sensitization of the nociceptive sensory system under pathological conditions, and restore the abnormal pain threshold to normal physiological values. σ1R knockout mice have no obvious phenotypic abnormalities, respond normally to mechanical and thermal pain stimuli, and have reduced nociceptive behavior in neuropathic pain models, further verifying the therapeutic effect of σ1R antagonists in neuropathic pain. However, selective σ1R antagonists usually require relatively high doses to achieve the desired analgesic effect, and in rodent models, their therapeutic index is relatively low, which limits their clinical development and use.

[0005] Histamine H3 receptor (H3R) is closely related to the pain transmission pathway and is involved in central sensitization reactions. H3R blockade reduces spontaneous neuronal discharges and reduces the response of spinal cord nociceptive neurons to mechanical stimulation. H3R antagonists / inverse agonists only exert analgesic effects under pathological conditions. Compared with wild-type mice, H3R knockout mice have significantly weakened formalin-induced pain responses and are more sensitive to the analgesic effects of morphine. The above research results also show from another perspective that H3R antagonists / inverse agonists have a relieving effect on neuropathic pain. Although H3R antagonists / inverse agonists have strong analgesic effects, their analgesic effects are affected by their administration sites, and further efficacy is urgently needed. Summary of the invention

[0006] Purpose of the invention: The first purpose of the present invention is to provide a pharmaceutical composition with σ1R / H3R as a target, and the second purpose is to provide an application of the pharmaceutical composition in preventing and / or treating pain.

[0007] Technical solution: The pharmaceutical composition for preventing and / or treating pain of the present invention comprises a Sigma-1 receptor antagonist and a histamine H3 receptor antagonist / inverse agonist and a pharmaceutically acceptable carrier.

[0008] The pharmaceutical composition designed in the present invention adopts a multimodal analgesic strategy, which blocks different phases and targets of the pathophysiological mechanism of pain by combining analgesics and analgesic methods with different mechanisms of action, reduces peripheral and central sensitization, achieves better analgesic effect, and at the same time reduces the dosage of analgesics, thereby reducing adverse reactions of the drugs.

[0009] Preferably, the Sigma-1 receptor antagonist is selected from BD1063, NE100, S1RA, BD1047 or a pharmaceutically acceptable salt thereof,

[0010]

[0011] Preferably, the H3 receptor antagonist / inverse agonist is selected from JNJ5207852, GSK189254, A-960656 or a pharmaceutically acceptable salt thereof,

[0012]

[0013] More preferably, in the pharmaceutical composition, the Sigma-1 receptor antagonist and the histamine H3 receptor antagonist / inverse agonist have a synergistic analgesic effect and an effect of reducing their effective doses.

[0014] Further preferably, the pharmaceutically acceptable salts are salts of the compounds of the invention, prepared from compounds with specific substituents found in the invention and relatively non-toxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Citric acid, tartaric acid and methanesulfonic acid and similar acids; organic acid salts also include amino acids (such as arginine, etc.), glucuronic acid and other organic acid salts. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0015] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0016] Preferably, the weight ratio of the Sigma-1 receptor antagonist to the histamine H3 receptor antagonist / inverse agonist is 1:(0.2-20).

[0017] More preferably, the weight ratio of the Sigma-1 receptor antagonist to the histamine H3 receptor antagonist / inverse agonist is 1:(0.3-13).

[0018] Preferably, the pharmaceutical composition comprises any one of the following combinations:

[0019] (1) Combination of BD1063 and JNJ5207852;

[0020] (2) Combination of NE100 and JNJ5207852;

[0021] (3) Combination of S1RA and JNJ5207852.

[0022] More preferably, the pharmaceutical composition comprises any one of the following combinations:

[0023] (1) Combinations of BD1063 and JNJ5207852 in weight ratios of 1:12.2, 1:0.33, 1:0.52, and 1:2.5;

[0024] (2) combinations of NE100 and JNJ5207852 in weight ratios of 1:2.6, 1:0.33, 1:2.68, and 1:5;

[0025] (3) A combination of S1RA and JNJ5207852 in a weight ratio of 1.5:1.

[0026] Preferably, the pharmaceutically acceptable carrier can be an adjuvant widely used in the field of drug production. The adjuvant is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical adjuvant can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical adjuvant can include one or more of the following adjuvants: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0027] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0028] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0029] Preferably, the prescription of the unit preparation of the pharmaceutical composition is selected from any one of the following in parts by weight:

[0030]

[0031] or

[0032]

[0033]

[0034] or

[0035]

[0036] Further preferably, the prescription of the unit preparation of the pharmaceutical composition is selected from any one of the following in parts by weight:

[0037]

[0038] or

[0039]

[0040] or

[0041]

[0042]

[0043] Preferably, the pharmaceutical composition is in the form of a granule, a tablet, a capsule, or a powder.

[0044] The pharmaceutical composition of the present invention is used in the preparation of drugs for preventing and / or treating neuropathic pain, inflammatory pain, visceral pain, acute pain and chronic pain.

[0045] The pharmaceutical application for preventing and / or treating pain of the present invention also includes the direct combined application of a Sigma-1 receptor antagonist and a histamine H3 receptor antagonist / inverse agonist.

[0046] The combination form of the pharmaceutical composition of the present invention also includes a combination of a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition has a Sigma-1 receptor antagonist or a pharmaceutically acceptable salt thereof as an active ingredient, and the second pharmaceutical composition has a histamine H3 receptor antagonist / inverse agonist or a pharmaceutically acceptable salt thereof as an active ingredient.

[0047] Preferably, the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously or sequentially.

[0048] More preferably, when sequential administration is adopted, the first pharmaceutical composition can be administered first, or the second pharmaceutical composition can be administered first.

[0049] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0050] The pharmaceutical composition designed in the present invention has a synergistic effect in treating pain, can effectively reduce the dosage of a single drug, and reduce its dose-dependent toxic side effects. It has good clinical application prospects for various pains including neuropathic pain, inflammatory pain, visceral pain, acute pain, and chronic pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The analgesic effects of BD1063, NE100 and JNJ5207852 in the acute inflammatory pain model induced by carrageenan, where A is the effect of BD1063 on the mechanical pain threshold of mice, B is the change of AUC at different doses of BD1063, C is the effect of NE100 on the mechanical pain threshold of mice, D is the change of AUC at different doses of NE100, E is the effect of JNJ5207852 on the mechanical pain threshold of mice, and F is the change of AUC at different doses of JNJ5207852;

[0052] Figure 2The analgesic results of BD1063 and NE100 combined with JNJ5207852 in the acute inflammatory pain model induced by carrageenan, wherein A is the effect of BD1063 combined with JNJ5207852 on the mechanical pain threshold of mice, B is the change of AUC of BD1063 combined with JNJ5207852 at different doses, C is the effect of NE100 combined with JNJ5207852 on the mechanical pain threshold of mice, D is the change of AUC of NE100 combined with JNJ5207852 at different doses, E is the isoradiometric analysis diagram of BD1063 combined with JNJ5207852, and F is the isoradiometric analysis diagram of NE100 combined with JNJ5207852;

[0053] Figure 3 The analgesic effects of BD1063, NE100 and JNJ5207852 in the paclitaxel-induced neuropathic pain model, where A is the effect of BD1063 on the mechanical pain threshold of mice, B is the change of AUC at different doses of BD1063, C is the effect of NE100 on the mechanical pain threshold of mice, D is the change of AUC at different doses of NE100, E is the effect of JNJ5207852 on the mechanical pain threshold of mice, and F is the change of AUC at different doses of JNJ5207852;

[0054] Figure 4 The analgesic effects of BD1063 and NE100 in combination with JNJ5207852 in the paclitaxel-induced neuropathic pain model, wherein A is the effect of BD1063 and JNJ5207852 in combination on the mechanical pain threshold of mice, B is the change of AUC at different doses of BD1063 and JNJ5207852 in combination, C is the effect of NE100 and JNJ5207852 in combination on the mechanical pain threshold of mice, D is the change of AUC at different doses of NE100 and JNJ5207852 in combination, E is the isoradiometric analysis diagram of BD1063 and JNJ5207852 in combination, and F is the isoradiometric analysis diagram of NE100 and JNJ5207852 in combination;

[0055] Figure 5 The analgesic effects of BD1063, NE100 and JNJ5207852 in the visceral pain model induced by acetic acid writhing are shown in Figure 1, where A is the effect of BD1063 on the number of writhing times in mice, B is the effect of NE100 on the number of writhing times in mice, and C is the effect of JNJ5207852 on the number of writhing times in mice;

[0056] Figure 6The analgesic effects of BD1063 and NE100 in combination with JNJ5207852 in the visceral pain model induced by acetic acid writhing are shown in Figure 1, where A is the effect of BD1063 and JNJ5207852 in combination on the number of writhing times in mice, B is the isoradiometric analysis diagram of BD1063 and JNJ5207852 in combination, C is the effect of NE100 and JNJ5207852 in combination on the number of writhing times in mice, and D is the isoradiometric analysis diagram of NE100 and JNJ5207852 in combination;

[0057] Figure 7 The results are for the analgesic effects of S1RA and JNJ5207852 in the acute inflammatory pain model induced by carrageenan;

[0058] Figure 8 The results show the effects of BD1063, NE100 and JNJ5207852 combined on the total distance traveled by mice. DETAILED DESCRIPTION

[0059] The technical solution of the present invention is further described below in conjunction with embodiments.

[0060] In order to verify the synergistic effect of drugs, the present invention adopts isoradiometric analysis, which is the gold standard method for evaluating pharmacological interactions between drugs. Its core criterion is to select an effect level and determine the dosage of drug A alone, drug B alone and the combination (a, b) that produces this effect through experiments. The line connecting the dosages that produce the same effect is called an isobologram, and the drug effect after combination can be represented by a / A+b / B=γ. When γ=1, the interaction between drugs is additive; when γ<1, the interaction between drugs is synergistic; when γ>1, the interaction between drugs is antagonistic.

[0061] Example 1: Evaluation of the synergistic analgesic effect of Sigma-1 receptor antagonist and histamine H3 receptor antagonist / inverse agonist in the carrageenan-induced inflammatory pain model

[0062] (1) Experimental methods

[0063] Experimental animals: ICR mice (22-30 g), female, were housed in an environment with a constant temperature (22±3°C) and a relative humidity of 55±5% and a 12-h light / dark cycle.

[0064] Experimental materials: BD1063; NE100; JNJ5207852; carrageenan.

[0065] Preparation method: BD1063, NE100, and JNJ5207852 use normal saline as the solvent; carrageenan: use normal saline as the solvent to prepare a solution with a mass fraction of 1%.

[0066] Inflammatory pain is one of the most common types of pathological pain in clinical practice. Carrageenan-induced inflammatory pain has a high predictive value in the study of analgesics and is often used to evaluate the anti-inflammatory pain effects of drugs.

[0067] ICR mice were randomly divided into negative control group, model group and compound dose groups, with 6 mice in each group. Before injection of carrageenan or saline, the baseline mechanical withdrawal threshold (MWTs, expressed in g) of each mouse was measured. Mechanical allodynia was assessed using a ZH-ZKL mechanical needle analgesia instrument. Briefly, mice were acclimated to the environment in an elevated metal grid under a transparent plastic chamber (21×27×15 cm) without restraint. When the mice were acclimated for at least 30 min, a progressive force was applied to the left hind paw of the mice, and the analgesia instrument automatically recorded the MWTs of the mice when the mice withdrew their hind paws. Each test was repeated three times (inter-trial interval: 30 s). Three hours after the injection of 20 μL of 1% carrageenan or saline, the drug or saline was administered orally. MWTs were measured at 0, 30, 60, 90 and 120 min after administration. The percentage of maximum possible effect (%MPE) was calculated by the following formula: %MPE = (MWT1-MWT2) / (MWT3-MWT2) × 100%, where MWT1 refers to the maximum threshold after drug treatment, MWT2 refers to the threshold after modeling, and MWT3 refers to the threshold of normal mice before modeling. The degree and duration of analgesia were estimated by the area under the curve (AUC). The AUC describing the change of mechanical withdrawal threshold over time was calculated using GraphPad Prism 9.0 software by the approximate trapezoidal rule.

[0068] The experimental dose grouping settings are shown in Table 1.

[0069] Table 1 Experimental groups of BD1063, NE100 and JNJ5207852 in the carrageenan-induced acute inflammatory pain model

[0070]

[0071]

[0072] (2) Experimental results

[0073] The results are as follows Figure 1As shown, 3 hours after carrageenan injection, the mechanical threshold of mice was significantly reduced. Intraperitoneal administration of high, medium and low doses of Sigma-1 receptor antagonists BD1063, NE100 and histamine H3 receptor antagonist JNJ5207852 can dose-dependently relieve carrageenan-induced inflammatory pain. The analgesic inhibition rates of 4, 8 and 16 mg / kg BD1063 in inflammatory pain were 17.19%, 55.8% and 75.10%, respectively, and the 25% maximum effect concentration (ED 25 ) value was 4.47mg / kg; the analgesic inhibition rates of 16, 32, and 64mg / kg NE100 in inflammatory pain were 15.67%, 51.66%, and 93.45%, respectively. 25 The value was 20.92 mg / kg; the analgesic inhibition rates of JNJ5207852 at 20, 40, 80, and 100 mg / kg in inflammatory pain were 14.97%, 18.88%, 30.47%, and 35.53%, respectively. 25 The value is 54.71 mg / kg.

[0074] like Figure 2 A. Figure 2 B and Figure 2 As shown in E, BD1063 and JNJ5207852 were administered in fixed doses (i.e., 1, 1 / 2, 1 / 4 ED 25 ) co-administration significantly improved carrageenan-induced acute inflammatory pain, and the analgesic effect was dose-dependent. BD1063 and JNJ5207852 were respectively 1, 1 / 2, and 1 / 4 of ED 25 The analgesic inhibition rates of the combined intraperitoneal administration of 1:1 concentration were 6.39%, 37.30% and 77.84%, respectively. 25 Actual value ED 25mix =24.28mg / kg, ED 25 Theoretical value ED 25add =29.6 mg / kg. Isoradiometric analysis showed that the ED of the combination of BD1063 and JNJ5207852 was 25mix Below the predicted additivity line, the interaction index γ(ED 50mix / ED 50add ) was 0.82<1, indicating that the two had a synergistic analgesic effect in the acute inflammatory pain model induced by carrageenan.

[0075] like Figure 2 C. Figure 2 D and Figure 2 As shown in F, NE100 and JNJ5207852 were administered in fixed doses (i.e., 1, 1 / 2, 1 / 4 ED 25) co-administration significantly improved carrageenan-induced acute inflammatory pain, and the analgesic effect was dose-dependent. NE100 and JNJ5207852 were respectively 1, 1 / 2, and 1 / 4 of ED 25 The analgesic inhibition rates of the combined intraperitoneal administration of 1% and 2% were 15.77%, 26.24% and 63.52%, respectively. 25 Actual value ED 25mix =32.45mg / kg, ED 25 Theoretical value ED 25add =37.81 mg / kg. Isoradiometric analysis showed that the ED of the combination of NE100 and JNJ5207852 was 25mix Below the predicted additivity line, the interaction index γ(ED 50mix / ED 50add ) was 0.86<1, indicating that the two had a synergistic analgesic effect in the acute inflammatory pain model induced by carrageenan.

[0076] Example 2: Synergistic analgesic effects of Sigma-1 receptor antagonists and histamine H3 receptor antagonists / inverse agonists in the paclitaxel-induced neuropathic pain model

[0077] (1) Experimental methods

[0078] Experimental animals: Same as Example 1.

[0079] Experimental materials: BD1063, NE100, JNJ5207852, polyoxyethylene castor oil EL, paclitaxel, normal saline, and anhydrous ethanol.

[0080] Preparation method: BD1063, NE100, and JNJ5207852 use normal saline as the solvent; Paclitaxel: dissolved in a solution consisting of 50% polyoxyethylene castor oil EL and 50% anhydrous ethanol at a concentration of 6 mg / mL (stored at -20°C for up to 14 days), and then diluted with normal saline (0.9% NaCl) to a final concentration of 0.2 mg / mL before administration.

[0081] Paclitaxel can induce a peripheral neuropathic pain state characterized by allodynia and hyperalgesia induced by noxious or innocuous stimuli and is widely used to evaluate the anti-chemotherapeutic drug-induced neuropathic pain effects of drugs.

[0082] ICR mice were randomly divided into negative control group, model group and compound dose groups, with 6 mice in each group. MWTs of each mouse were measured before injection of paclitaxel or saline. Mechanical allodynia was assessed using a ZH-ZKL mechanical needle analgesia instrument. Briefly, mice were allowed to adapt to the environment in an elevated metal grid under a transparent plastic chamber (21×27, 15 cm) without restraint. When the mice had adapted for at least 30 minutes, a gradual force was applied to the left hind paw of the mouse, and the analgesia instrument automatically recorded the MWTs of the mouse when the mouse retracted its hind paw. Each test was repeated three times (inter-trial interval: 30 seconds). Paclitaxel stock solution (6.00 mg / mL) was prepared in a mixed solution of 50% polyoxyethylene castor oil and 50% ethanol, and diluted to a concentration of 0.2 mg / ml using saline. 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 (days 1, 2, 3, 4, and 5). On the sixth day, the baseline mechanical threshold of each mouse was assessed, and intraperitoneal administration or saline was given. The mechanical withdrawal threshold of mice in each group was measured at 30, 60, 90, and 120 minutes after administration. The calculation formula of %MPE is as follows: %MPE = (MWT1-MWT2) / (MWT3-MWT2) × 100%, where MWT1 refers to the maximum threshold after drug treatment, MWT2 refers to the threshold after modeling, and MWT3 refers to the threshold of normal mice before modeling. The degree and duration of analgesia were estimated by AUC values. The AUC describing the change of mechanical withdrawal threshold over time was calculated using GraphPad Prism 9.0 software by the approximate trapezoidal rule.

[0083] The experimental dose grouping settings are shown in Table 2.

[0084] Table 2 Experimental groups of BD1063, NE100 and JNJ5207852 in paclitaxel-induced neuropathic pain model

[0085]

[0086] (2) Experimental results

[0087] like Figure 3 As shown in the figure, after five consecutive days of paclitaxel administration, the mechanical pain threshold of mice was significantly lower than the baseline level, indicating that the neuropathic pain model was successfully established. Sigma-1 receptor antagonists BD1063, NE100 and histamine H3 receptor antagonist JNJ5207852 can reverse paclitaxel-induced neuropathic pain in a dose-dependent manner. The analgesic inhibition rates of 16, 32, and 64 mg / kg BD1063 in paclitaxel-induced neuropathic pain were 4.51%, 25.63%, and 81.0%, respectively, and the ED 25The value was 31.49 mg / kg; the analgesic inhibition rates of 16, 32, and 64 mg / kg NE100 in paclitaxel-induced neuropathic pain were 0.347%, 30.07%, and 66.89%, respectively. 25 The value was 30.78 mg / kg; the analgesic inhibition rates of 5, 10, 20, and 40 mg / kg JNJ5207852 in paclitaxel-induced neuropathic pain were 6.89%, 25.34%, 55.04%, and 87.25%, respectively. 25 The value is 10.29mg / kg.

[0088] like Figure 4 A. Figure 4 B and Figure 4 As shown in E, BD1063 and JNJ5207852 were administered in fixed doses (i.e., 1, 1 / 2, 1 / 4 ED 25 ) co-administration significantly improved paclitaxel-induced neuropathic pain, and the analgesic effect was dose-dependent. BD1063 and JNJ5207852 were 1, 1 / 2, and 1 / 4 of ED 25 The analgesic inhibition rates of the combined intraperitoneal administration of 1% and 2% were 18.97%, 33.69%, and 58.76%, respectively. 25 Actual value ED 25mix =14.47mg / kg, ED 25 Theoretical value ED 25 add =20.88 mg / kg. Isoradiometric analysis showed that the actual ED of the drug combination of BD1063 and JNJ5207852 25mix Below the predicted additivity line, the interaction index γ(ED 50mix / ED 50add ) was 0.69<1, indicating that the two have a synergistic analgesic effect in paclitaxel-induced neuropathic pain.

[0089] like Figure 4 C, 4D and Figure 4 As shown in F, NE100 and JNJ5207852 were administered in fixed doses (i.e., 1, 1 / 2, 1 / 4 ED 25 ) co-administration significantly improved paclitaxel-induced neuropathic pain, and the analgesic efficacy was dose-dependent. The analgesic inhibition rates of NE100 and JNJ5207852 at 1, 1 / 2, and 1 / 4 ED25 concentrations were 17.71%, 22.76%, and 51.40%, respectively. 25 Actual value ED 25mix =20.54mg / kg, ED 25 Theoretical value ED 25add=18.40 mg / kg. Isoradiometric analysis showed that the actual ED of the combination of NE100 and JNJ5207852 was 25mix Below the predicted additivity line, the interaction index γ(ED 50mix / ED 50add ) was 0.9<1, indicating that the two have a synergistic analgesic effect in paclitaxel-induced neuropathic pain.

[0090] Example 3: Evaluation of the synergistic analgesic effect of Sigma-1 receptor antagonist and histamine H3 receptor antagonist / inverse agonist in the acetic acid-induced visceral pain model

[0091] (1) Experimental methods

[0092] Experimental animals: Same as Example 1.

[0093] Experimental materials: BD1063, NE100, JNJ5207852, glacial acetic acid, and normal saline.

[0094] Preparation method: BD1063, NE100, and JNJ5207852 use normal saline as the solvent.

[0095] Acetic acid-induced writhing pain is a mature model for evaluating the peripheral analgesic activity of drugs. The analgesic effect of drugs that intervene in writhing pain can be inferred from the reduction in the writhing frequency of mice, which can measure pain qualitatively and quantitatively.

[0096] ICR mice were randomly divided into negative control group, model group and compound dose groups, 6 mice in each group. 30 minutes after intraperitoneal administration of therapeutic drugs or saline, 1% glacial acetic acid was intraperitoneally injected, and the administration volume and glacial acetic acid volume were both 0.1mL / 10g. The number of mouse writhing reactions within 45 minutes after acetic acid injection was observed and recorded, and the inhibition rate of mouse writhing reaction in each administration group was calculated. %MPE = (average number of writhing reactions in the model group - average number of writhing reactions in the administration group) / average number of writhing reactions in the model group × 100%.

[0097] The experimental dose grouping settings are shown in Table 3.

[0098] Table 3 Evaluation of the synergistic analgesic effects of BD1063, NE100 and JNJ5207852 in the acetic acid-induced visceral pain model

[0099]

[0100] (2) Experimental results

[0101] like Figure 5As shown in the results, Sigma-1 receptor antagonists BD1063, NE100 and histamine H3 receptor antagonist JNJ5207852 can reverse glacial acetic acid-induced visceral pain in a dose-dependent manner. The analgesic inhibition rates of 10, 20, and 40 mg / kg BD1063 in acetic acid writhing pain were 10.79%, 27.35%, and 57.55%, respectively. 25 The analgesic inhibition rates of 1, 5, and 15 mg / kg NE100 in acetic acid writhing pain were 4.41%, 35.68%, and 73.56%, respectively. 25 The value was 3.57mg / kg; the analgesic inhibition rates of 10, 20, and 30mg / kg JNJ5207852 in acetic acid writhing pain were 27.77%, 42.21%, and 62.83%, respectively. 25 The value is 9.56mg / kg.

[0102] like Figure 6 A and Figure 6 As shown in B, BD1063 and JNJ5207852 were administered in fixed doses (i.e., 1, 1 / 2, 1 / 4 ED 25 ) co-administration significantly improved glacial acetic acid-induced visceral pain, and the analgesic effect was dose-dependent. BD1063 and JNJ5207852 were respectively 1, 1 / 2, and 1 / 4 of ED 25 The analgesic inhibition rates of the combined intraperitoneal administration of 1:1 concentration were 37.89%, 61.15% and 77.70%, respectively. 25 Actual value ED 25mix =4.26mg / kg, ED 25 Theoretical value ED 25add =13.95 mg / kg. The isoradiometric analysis showed that the actual ED of the drug combination of BD1063 and JNJ5207852 was 25mix Below the predicted additivity line, the interaction index γ(ED 50mix / ED 50add ) was 0.30<1, indicating that the two had a synergistic analgesic effect in the visceral pain model induced by glacial acetic acid.

[0103] like Figure 6 C and Figure 6 As shown in D, NE100 and JNJ5207852 co-administered at fixed doses (i.e., 1, 1 / 2, and 1 / 4) significantly improved glacial acetic acid-induced visceral pain, and the analgesic efficacy was dose-dependent. 25 The analgesic inhibition rates of the combined intraperitoneal administration of 1:1 concentration were 37.76%, 27.59% and 21.08%, respectively. 25 Actual value ED25mix =5.12mg / kg, ED 25 Theoretical value ED 25add =6.57 mg / kg. The isoradiometric analysis showed that the actual ED of the combination of NE100 and JNJ5207852 was 25mix Below the predicted additivity line, the interaction index γ(ED 50mix / ED 50add ) was 0.78<1, indicating that the two had a synergistic analgesic effect in the visceral pain model induced by glacial acetic acid.

[0104] Example 4: Evaluation of the analgesic effect of non-analgesic doses of Sigma-1 receptor antagonists or histamine H3 receptor antagonists / inverse agonists and their combinations in the carrageenan-induced inflammatory pain model

[0105] (1) Experimental methods

[0106] The experimental animals and implementation details are the same as in Example 1.

[0107] Experimental materials: S1RA, JNJ5207852.

[0108] Preparation method: S1RA and JNJ5207852 use physiological saline as solvent; carrageenan: use physiological saline as solvent to prepare a solution with a mass fraction of 1%.

[0109] The experimental dose grouping settings are shown in Table 4.

[0110] Table 4 Experimental groups of S1RA and JNJ5207852 in the carrageenan-induced acute inflammatory pain model

[0111]

[0112] (2) Experimental results

[0113] like Figure 7 As shown in the figure, the low-dose S1RA group and JNJ5207852 group had no analgesic activity in the acute inflammatory pain model induced by carrageenan. The analgesic inhibition rate of the combination of S1RA with no analgesic activity and JNJ5207852 reached 32.60%, and the combination of the two significantly improved the analgesic activity, proving that it has a synergistic analgesic effect in the acute inflammatory pain model induced by carrageenan.

[0114] Example 5: Effects of Sigma-1 receptor antagonists and histamine H3 receptor antagonists / inverse agonists on the total distance traveled by mice

[0115] (1) Experimental methods

[0116] Experimental animals: Same as Example 1.

[0117] Experimental materials: BD1063, NE100, JNJ5207852.

[0118] Preparation method: BD1063, NE100, and JNJ5207852 use normal saline as the solvent.

[0119] The open field test was used to evaluate the effect of the preferred compounds on the total distance traveled by mice.

[0120] The experimental field was a gray opaque organic plastic experimental box (6 cm × 60 cm × 30 cm). Using ANY-maze software, the activity field of each mouse was evenly divided into 16 grids (4 × 4). Every 4 mice were tested together, and the mouse trajectory was tracked and data was collected using a camera system. First, each mouse was gently placed in the open field (the central area of ​​each square floor) to adapt for 30 minutes. After the adaptation, the mouse was intraperitoneally administered or solvent and then placed in the open field and its behavioral trajectory was tracked and collected, and the total activity distance of the mouse was recorded. The test time was 2 hours, and the test box was cleaned in time after each experiment.

[0121] The experimental dose grouping settings are shown in Table 5.

[0122] Table 5 Grouping of BD1063, NE100 and JNJ5207852 in the open field test

[0123]

[0124] (2) Experimental results

[0125] The results are as follows Figure 8 As shown, compared with the vehicle group, the total movement distance of the histamine H3 receptor antagonist JNJ5207852 group and the Sigma-1 receptor antagonist NE100 group was significantly reduced, indicating that JNJ5207852 and NE100 have sedative side effects. The BD1063+JNJ5207852 combination group and the NE100+JNJ5207852 combination group increased the total movement distance, indicating that the pharmaceutical combination of H3 receptor antagonist and Sigma-1 receptor antagonist can reduce the sedative side effects of the drug.

[0126] Example 6: Preparation of a compound tablet containing a Sigma-1 receptor antagonist and an H3 receptor antagonist / inverse agonist

[0127] Table 6 Composition of Sigma-1 receptor antagonist and H3 receptor antagonist / inverse agonist tablets prescription 1

[0128]

[0129] Preparation method:

[0130] (1) Mix the prescribed amount of BD1063, JNJ5207852, powdered sugar, starch, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose, grind them together, and pass through a 100-mesh sieve;

[0131] (2) adding a prescribed amount of ethanol to the mixture obtained in the first step, mixing evenly, granulating, drying and granulating;

[0132] (3) The mixture obtained in the second step is added with a prescribed amount of magnesium stearate and granulated for tableting.

[0133] Table 7 Composition of Sigma-1 Receptor Antagonist and H3 Receptor Antagonist / Inverse Agonist Tablets Prescription 2

[0134]

[0135] Preparation method:

[0136] (1) Mix the prescribed amount of BD1063, JNJ5207852 and micro-powdered silica gel evenly, then add one-half of the prescribed amount of starch, mix evenly, grind together, and pass through a 100-mesh sieve;

[0137] (2) passing microcrystalline cellulose, powdered sugar, hydroxypropyl methylcellulose, magnesium lauryl sulfate, the remaining amount of starch, and magnesium stearate through an 80-mesh sieve respectively;

[0138] (3) uniformly mixing the microcrystalline cellulose obtained in the first step and the sieved amount of the second step, powdered sugar, magnesium lauryl sulfate, and the remaining amount of starch, and then uniformly mixing with the hydroxypropyl methylcellulose in the prescribed amount, and wet granulating with 50% ethanol;

[0139] (4) drying the granules obtained in the third step at 60° C., sieving the granules through a 60-mesh sieve;

[0140] (5) Finally, add the prescribed amount of magnesium stearate and compress into tablets.

[0141] Table 8 Composition of Sigma-1 receptor antagonist and H3 receptor antagonist / inverse agonist tablets prescription 3

[0142]

[0143] Preparation method:

[0144] (1) Weigh the prescribed amount of calcium hydrogen phosphate and sodium carboxymethyl cellulose, crush them, and sieve them separately (100 mesh);

[0145] (2) Weigh the prescribed amount of BD1063 raw material and JNJ5207852 raw material, and mix them evenly with the above excipients by equal amount addition method;

[0146] (3) Using an appropriate amount of 50% ethanol solution as a binder to prepare a soft material, the granules are passed through a 20-mesh sieve to form granules; the wet granules are dried at 60° C. with forced air, and the granules are passed through a 20-mesh sieve to form granules;

[0147] (4) Add the prescribed amount of magnesium stearate and micro-powdered silica gel that have passed through a 100-mesh sieve, mix well, and press into tablets.

Claims

1. A pharmaceutical composition for preventing and / or treating pain, characterized in that: The invention comprises a Sigma-1 receptor antagonist, a histamine H3 receptor antagonist / inverse agonist and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, characterized in that The Sigma-1 receptor antagonist is selected from BD1063, NE100, S1RA, BD1047 or a pharmaceutically acceptable salt thereof, 3. The pharmaceutical composition according to claim 1, characterized in that The H3 receptor antagonist / inverse agonist is selected from JNJ5207852, GSK189254, A-960656 or a pharmaceutically acceptable salt thereof, 4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The Sigma-1 receptor antagonist and the histamine H3 receptor antagonist / inverse agonist have a synergistic analgesic effect and the effect of reducing the effective dose.

5. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of the Sigma-1 receptor antagonist to the histamine H3 receptor antagonist / inverse agonist is 1:(0.2-20).

6. The pharmaceutical composition according to claim 5, characterized in that The weight ratio of the Sigma-1 receptor antagonist to the histamine H3 receptor antagonist / inverse agonist is 1:(0.3-13).

7. The pharmaceutical composition according to claim 1, characterized in that It includes any combination of the following: (1) Combination of BD1063 and JNJ5207852; (2) Combination of NE100 and JNJ5207852; (3) Combination of S1RA and JNJ5207852.

8. The pharmaceutical composition according to claim 7, characterized in that It includes any combination of the following: (1) Combinations of BD1063 and JNJ5207852 in weight ratios of 1:12.2, 1:0.33, 1:0.52, and 1:2.5; (2) combinations of NE100 and JNJ5207852 in weight ratios of 1:2.6, 1:0.33, 1:2.68, and 1:5; (3) A combination of S1RA and JNJ5207852 in a weight ratio of 1.5:

1.

9. The pharmaceutical composition according to claim 1, characterized in that The preparation dosage form is selected from granules, tablets, capsules and powders.

10. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for preventing and / or treating neuropathic pain, inflammatory pain, visceral pain, acute pain, and chronic pain.

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