Pharmaceutical compositions and their uses

Abstract

The present invention relates to a composition of (S)-3-aminomethyl-5-methylhexanoic acid or a pharma- ceutically acceptable salt thereof and riluzole, which has broad application prospects in the preparation of a medicament for the treatment of neuropathic pain.

Description

[Technical Field]

[0001] (cross reference) This application claims priority from a Chinese patent application entitled "Pharmaceutical Composition and Use Thereof," filed with the State Intellectual Property Office of the People's Republic of China on July 1, 2021, application number 202110742036.7, the entire contents of which are incorporated herein by reference.

[0002] The present invention belongs to the field of pharmaceutical manufacturing and relates to a composition of (S)-3-aminomethyl-5-methylhexanoic acid and riluzole, and its use in preparing a drug for treating neuropathic pain. [Background technology]

[0003] Neuropathic pain (NP) is pain caused by damage or disease to the body's sensory system. It can be divided into peripheral neuropathic pain and central neuropathic pain. Clinically, peripheral neuropathic pain is relatively common. Research data from Europe indicates that the prevalence of neuropathic pain in the general population reaches 8.0%. Neuropathic pain is not a single disease but a syndrome caused by different diseases and injuries. It manifests as a series of symptoms and physical signs, severely impacting patients' quality of life. Postherpetic neuralgia and diabetic peripheral neuropathy are the two most common types of neuropathic pain. Long-term pain not only affects patients' sleep, work, and ability to function, but also increases the incidence of emotional disorders such as depression and anxiety. Studies have shown that the quality of life scores of patients with postherpetic neuralgia are only half that of normal individuals. There is a lack of therapeutic drugs for neuropathic pain, and current clinical treatments mainly involve calcium ion channel modulators, antidepressants, and local anesthetics. However, because the pathogenesis is relatively complex, existing treatments are not satisfactory, and many patients experience insufficient pain relief.

[0004] (S)-3-Aminomethyl-5-methylhexanoic acid (pregabalin) is clinically available for the treatment of adult peripheral neuralgia, including diabetic peripheral neuralgia, fibromyalgia, and postherpetic neuralgia. It is recommended as a first-line treatment for neuropathological pain by multiple international guidelines. Pregabalin's mechanism of action is thought to be through modulation of the α2δ subunit of voltage-gated calcium channels, reducing the release of glutamate, norepinephrine, and substance P. Pregabalin causes side effects, such as dizziness and somnolence, which limit its clinical use to some extent.

[0005] The structural formula of (S)-3-aminomethyl-5-methylhexanoic acid (pregabalin) is: [ka] (The chemical formula is C8H17NO2 and the molecular weight is 159.23.)

[0006] Riluzole (chemical name: 2-amino-6-trifluoromethoxybenzothiazole), developed by Sanofi, is a treatment for amyotrophic lateral sclerosis (ALS). It was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 1996 and has played a crucial role in extending survival, alleviating symptoms, and improving the quality of life of ALS patients. Its mechanism of action is thought to involve inhibition of glutamate release, stabilization of the inactivated state of voltage-gated sodium channels, and interference with intracellular events following neurotransmitter binding to excitatory amino acid receptors. Riluzole has a wide range of pharmacological effects, including modulation of glutamate and its transporters, antidepressant, antianxiety, antiepileptic, analgesic, and neuroprotective effects.

[0007] The structural formula of riluzole is: [ka] (The chemical formula is C8H5F3N2OS and the molecular weight is 234.20.)

[0008] It should be noted that the efficacy of the combination of two different drugs with the same efficacy is very complex and unpredictable, and may result in synergistic, additive, or even antagonistic drug effects. Therefore, without the necessary experimental data, it is difficult for those skilled in the art to simply conclude that riluzole can enhance the analgesic effect of pregabalin simply because riluzole has an analgesic effect. Summary of the Invention

[0009] The present invention provides a pharmaceutical composition comprising (S)-3-aminomethyl-5-methylhexanoic acid and riluzole, which exhibits an unexpected synergistic effect upon use, thereby enhancing the therapeutic effect of anti-neuropathic pain. The present invention provides use of a pharmaceutical composition comprising (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and riluzole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neuropathic pain. In the composition, the mass ratio of (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to Lusol or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 50:1 to 1:20.

[0010] Preferably, the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 20:1 to 1:10. Preferably, the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 20:1 to 1:4. Preferably, the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 10:1 to 1:4.

[0011] Preferably, the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 6:1 to 1:4. Preferably, the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 3:1 to 1:2.

[0012] The pharmaceutical composition of the present invention can be used to prepare a drug for treating neuropathic pain, and the neuropathic pain is preferably peripheral neuropathic pain. More preferably, the peripheral neuropathic pain is post-herpetic neuralgia and diabetic peripheral neuropathy.

[0013] The present invention provides a pharmaceutical composition comprising (S)-3-aminomethyl-5-methylhexanoic acid and riluzole, and the results of animal pharmacodynamic experiments show that the pharmaceutical composition can exert a synergistic effect and enhance the therapeutic effect of anti-peripheral neuropathic pain. DETAILED DESCRIPTION OF THE INVENTION

[0014] The following provides a detailed and complete description of the technical solutions according to the embodiments of the present invention in combination with the embodiments of the present invention, but of course, the described embodiments are only some of the embodiments of the present invention, and are not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without any creative work fall within the scope of protection of the present invention.

[0015] Example 1 Study on the efficacy of a pregabalin and riluzole composition against neuropathic pain 1 1. Materials and Methods 1.1 Experimental animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.

[0016] [ka]

[0017] 1.3 Experimental method 1.3.1 Creation of neuropathic pain animal models A neuropathic pain model was induced by single ligation of the L5 spinal nerve (SNL). Animals were anesthetized with 7% formaldehyde hydrate (420 mg / kg, intraperitoneal administration). The rat's limbs were fixed in a prone position and placed under a dissecting microscope. The back hair was removed and disinfected with alcohol wipes. A long incision approximately 2-3 cm long was made on the right side of the dorsal spine, exposing the two spinal nerves, L4 and L5. The L5 spinal nerve was lightly ligated with 6-0 braided sutures, taking care not to damage adjacent spinal nerves. The incision on the back of the experimental animals was sutured in two layers, disinfected with iodine tincture, and gently placed in a cage where they were allowed to move freely, eat food, and drink water.

[0018] 1.3.2Mechanical pain threshold measurement method The mechanical withdrawal threshold (MWT) of all experimental animals was measured using an automatic mechanical needle. The experimental animals were placed in a transparent organic glass box with a wire bottom and allowed to adapt for 30 minutes. The needle was applied at a constant speed to stimulate the plantar surface of the hind paw of the experimental animals. The reflex threshold (MWT), i.e., the animal's mechanical pain threshold, was recorded when the rat showed a rapid paw withdrawal or paw shaking reaction.

[0019] 1.3.3 Measurement and calculation of animal-based pain thresholds The basal mechanical pain threshold of each experimental animal was measured for two days after the model was established, and the average of the two measurements was used as the basal mechanical pain threshold of the experimental animal.

[0020] 1.4 Animal grouping and experimental procedures The experimental model animals were randomly divided into seven groups: model control group, pregabalin group (25 mg / kg), pregabalin group (0.5 mg / kg), riluzole group (10 mg / kg), riluzole group (0.5 mg / kg), pregabalin-riluzole 50:1 group (pregabalin 25 mg / kg + riluzole 0.5 mg / kg), and pregabalin-riluzole 1:20 group (pregabalin 0.5 mg / kg + riluzole 10 mg / kg). Pregabalin and riluzole were administered intraperitoneally, with 11–12 animals per group. A vehicle blank was administered to the model control group. SD rats of appropriate weight were selected to establish the L5-SNL model, and postoperative mechanical pain thresholds were measured at least 7 days after model establishment. Animals with a significantly lower right hind paw pain threshold than the contralateral hind paw pain threshold were selected for all subsequent pharmacological efficacy studies. Experimental model animals were administered the corresponding drug or vehicle, and their mechanical pain thresholds were measured 0.5 and 3 hours after administration.

[0021] 1.5 Synergistic Analysis of Compositions The synergistic effect of pregabalin and riluzole in the composition was evaluated according to Kim Jeong-gyun's formula: q = E(a + b) / (Ea + Eb - Ea × Eb). In this formula, E(a + b) is the improvement rate with the combined use of drugs, and Ea and Eb are the improvement rates with the single administration of drug A (pregabalin) and drug B (riluzole), respectively. E = (post-administration pain threshold - model value) / (basal value - model value). A q value between 0.85 and 1.15 indicated simple additive effects with the combined use of both drugs; a q value > 1.15 indicated synergy; and a q value < 0.85 indicated antagonistic effects with the combined use of both drugs.

[0022] 1.6 Data Statistics The experimental data were expressed as mean ± standard error (SEM). Differences between groups were analyzed by one-way analysis of variance, and intergroup comparisons were tested by the least significant difference (LSD) method, with a P value of <0.05 defined as significant.

[0023] 2 results The experimental results are shown in Table 1. Compared with the vehicle control group, pregabalin 25 mg / kg, riluzole 10 mg / kg, Composition 50:1, and Composition 1:20 all significantly improved the animals' mechanical pain thresholds at 0.5 h after administration (P = 0.0463, P < 0.0001, P = 0.0458, P < 0.0001). These groups also significantly improved the animals' mechanical pain thresholds at 3 h after administration (P < 0.0001, P = 0.0004, P < 0.0001, P < 0.0001). Synergy calculations showed that Composition 50:1 had q values ​​of 1.073 and 0.919 at 0.5 h and 3 h after administration, respectively, and Composition 1:20 had q values ​​of 0.909 and 0.998 at 0.5 h and 3 h after administration, respectively. [Table 1] Data are expressed as mean ± standard error, *P<0.05, ***P<0.001, ****P<0.0001 compared with the model control group.

[0024] Example 2 Study on the efficacy of pregabalin and riluzole composition against neuropathic pain 2 1. Materials and Methods 1.1 Experimental animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g. 1.2 Test drug Pregabalin and riluzole were the same as in Example 1. 1.3 Experimental method The preparation of the neuropathic pain animal model, the method for measuring the mechanical pain threshold, and the measurement and calculation of the animal's basal pain threshold were carried out in the same manner as in Example 1.

[0025] 1.4 Animal grouping and experimental procedures The experimental model animals were randomly divided into seven groups: model control group, pregabalin group (20 mg / kg), pregabalin group (1 mg / kg), riluzole group (10 mg / kg), riluzole group (1 mg / kg), pregabalin-riluzole composition 20:1 group (pregabalin 20 mg / kg + riluzole 1 mg / kg), and pregabalin-riluzole composition 1:10 group (pregabalin 1 mg / kg + riluzole 10 mg / kg). Pregabalin and riluzole were administered intraperitoneally, with 12 animals per group. A vehicle blank was administered to the model control group. SD rats of appropriate weight were selected to establish the L5-SNL model, and postoperative mechanical pain thresholds were measured at least 7 days after model establishment. Animals with a significantly lower right hind paw pain threshold than the contralateral hind paw pain threshold were selected for all subsequent pharmacological efficacy studies. Experimental model animals were administered the corresponding drug or vehicle, and their mechanical pain thresholds were measured 0.5 and 3 hours after administration. 1.5 Synergistic Analysis of Compositions The synergistic analysis of the compositions was the same as in Example 1. 1.6 Data Statistics Data statistics were the same as in Example 1.

[0026] 2 results The experimental results are shown in Table 2. Compared with the vehicle control group, pregabalin 20 mg / kg, riluzole 10 mg / kg, composition 20:1, and composition 1:10 all significantly improved the animals' mechanical pain thresholds 0.5 hours after administration (P=0.0278, P<0.0001, P=0.0483, P<0.0001), and these groups also significantly improved the animals' mechanical pain thresholds 3 hours after administration (P<0.0001, P<0.0001, P<0.0001, P<0.0001). The results of the synergy calculation were: Composition 20:1 had q values ​​of 1.216 and 1.181 at 0.5 hours and 3 hours after administration, respectively, and Composition 1:10 had q values ​​of 1.206 and 1.213 at 0.5 hours and 3 hours after administration, respectively, indicating that Composition 20:1 and Composition 1:10 both had synergistic effects at 0.5 hours and 3 hours after administration. [Table 2] Data are expressed as mean ± standard error, *P<0.05, ****P<0.0001 compared with the model control group.

[0027] Example 3 Study on the efficacy of pregabalin and riluzole composition against neuropathic pain 3 1. Materials and Methods 1.1 Experimental animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g. 1.2 Test drug Pregabalin and riluzole were the same as in Example 1. 1.3 Experimental method The preparation of the neuropathic pain animal model, the method for measuring the mechanical pain threshold, and the measurement and calculation of the animal-based pain threshold were the same as in Example 1.

[0028] 1.4 Animal grouping and experimental procedures The experimental model animals were randomly divided into nine groups: model control group, pregabalin group (30 mg / kg), pregabalin group (18 mg / kg), pregabalin group (3 mg / kg), riluzole group (12 mg / kg), riluzole group (3 mg / kg), pregabalin-riluzole composition 10:1 group (pregabalin 30 mg / kg + riluzole 3 mg / kg), pregabalin-riluzole composition 1:4 group (pregabalin 3 mg / kg + riluzole 12 mg / kg), and pregabalin-riluzole composition 6:1 group (pregabalin 18 mg / kg + riluzole 3 mg / kg). Pregabalin and riluzole were administered intraperitoneally, with 10–12 animals per group. A vehicle blank was administered to the model control group. SD rats of appropriate weight were selected to establish the L5-SNL model, and postoperative mechanical pain thresholds were measured at least 7 days after model establishment. Animals with a significantly lower right hind paw pain threshold than the contralateral hind paw pain threshold were selected for all subsequent pharmacological efficacy studies. Experimental model animals were administered the corresponding drug or vehicle, and their mechanical pain thresholds were measured 0.5 and 3 hours after administration. 1.5 Synergistic Analysis of Compositions The synergistic analysis of the compositions was the same as in Example 1. 1.6 Data Statistics Data statistics were the same as in Example 1.

[0029] 2 results The experimental results are shown in Table 3. Compared with the vehicle control group, pregabalin 30 mg / kg, riluzole 12 mg / kg, Composition 10:1, Composition 1:4, and Composition 6:1 all significantly improved the animals' mechanical pain thresholds 0.5 h after administration (P=0.0111, P<0.0001, P<0.0001, P<0.0001, P=0.003), and pregabalin 30 mg / kg, pregabalin 18 mg / kg, riluzole 12 mg / kg, Composition 10:1, Composition 1:4, and Composition 6:1 all significantly improved the animals' mechanical pain thresholds 3 h after administration (P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001). The results of the synergy calculation showed that Composition 10:1 had q values ​​of 1.273 and 1.182 at 0.5 hours and 3 hours after administration, Composition 1:4 had q values ​​of 1.210 and 1.211 at 0.5 hours and 3 hours after administration, and Composition 6:1 had q values ​​of 1.222 and 1.269 at 0.5 hours and 3 hours after administration, respectively, indicating that Composition 10:1, Composition 1:4, and Composition 6:1 all had synergistic effects at 0.5 hours and 3 hours after administration. [Table 3] Data are expressed as mean ± standard error, *P<0.05, **P<0.01, ****P<0.0001 compared with the model control group.

[0030] Example 4 Study on the efficacy of pregabalin and riluzole composition against neuropathic pain 4 1. Materials and Methods 1.1 Experimental animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g. 1.2 Test drug Pregabalin and riluzole were the same as in Example 1. 1.3 Experimental method The preparation of the neuropathic pain animal model, the method for measuring the mechanical pain threshold, and the measurement and calculation of the animal's basal pain threshold were carried out in the same manner as in Example 1. 1.4 Animal grouping and experimental procedures The experimental model animals were randomly divided into 11 groups: model control group, pregabalin group (18 mg / kg), pregabalin group (9 mg / kg), pregabalin group (3 mg / kg), riluzole group (12 mg / kg), riluzole group (6 mg / kg), riluzole group (3 mg / kg), pregabalin-riluzole composition 6:1 group (pregabalin 18 mg / kg + riluzole 3 mg / kg), pregabalin-riluzole composition 3:1 group (pregabalin 9 mg / kg + riluzole 3 mg / kg), pregabalin-riluzole composition 1:4 group (pregabalin 3 mg / kg + riluzole 12 mg / kg), and pregabalin-riluzole composition 1:2 group (pregabalin 3 mg / kg + riluzole 6 mg / kg). Pregabalin and riluzole were administered by intraperitoneal injection, with 10 animals per group, and a blank solvent was administered to serve as the model control group. SD rats of appropriate weight were selected to establish the L5-SNL model, and postoperative mechanical pain thresholds were measured at least 7 days after model establishment. Animals with a significantly lower right hind paw pain threshold than the contralateral hind paw pain threshold were selected for all subsequent pharmacological efficacy studies. Experimental model animals were administered the corresponding drug or vehicle, and their mechanical pain thresholds were measured 0.5 and 3 hours after administration.

[0031] 1.5 Synergistic Analysis of Compositions The synergistic analysis of the compositions was the same as in Example 1. 1.6 Data Statistics Data statistics were the same as in Example 1. 2 results The experimental results are shown in Table 4. Compared with the vehicle control group, riluzole 12 mg / kg, riluzole 6 mg / kg, composition 6:1, composition 3:1, composition 1:4, and composition 1:2 all significantly improved the animals' mechanical pain threshold 0.5 hours after administration (P<0.0001, P=0.0031, P=0.0033, P=0.0123, P<0.0001, P<0.0001), while pregabalin 18 mg / kg and pregabalin 18 mg / kg significantly improved the animals' mechanical pain threshold 0.5 hours after administration (P<0.0001, P=0.0031, P=0.0033, P=0.0123, P<0.0001, P<0.0001). Gabalin 9 mg / kg, riluzole 12 mg / kg, riluzole 6 mg / kg, Composition 6:1, Composition 3:1, Composition 1:4, and Composition 1:2 were all able to significantly improve the animals' mechanical pain threshold 3 hours after administration (P<0.0001, P<0.0001, P<0.0001, P=0.0427, P<0.0001, P<0.0001, P<0.0001, P<0.0001). The results of the synergy calculation were as follows: Composition 6:1 had q values ​​of 1.250 and 1.248 at 0.5 h and 3 h after administration, respectively; Composition 3:1 had q values ​​of 1.389 and 1.391 at 0.5 h and 3 h after administration, respectively; Composition 1:4 had q values ​​of 1.235 and 1.294 at 0.5 h and 3 h after administration, respectively; and Composition 1:2 had q values ​​of 1.320 and 1.384 at 0.5 h and 3 h after administration, respectively, indicating that Composition 6:1, Composition 3:1, Composition 1:4, and Composition 1:2 all had synergistic effects at 0.5 h and 3 h after administration. [Table 4] Data are expressed as mean ± standard error, *P<0.05, **P<0.01, ****P<0.0001 compared with the model control group.

[0032] Example 5 Study on the efficacy of pregabalin and riluzole composition against neuropathic pain 5 1. Materials and Methods 1.1 Experimental animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g. 1.2 Test drug Pregabalin and riluzole were the same as in Example 1. 1.3 Experimental method The preparation of the neuropathic pain animal model, the method for measuring the mechanical pain threshold, and the measurement and calculation of the animal's basal pain threshold were carried out in the same manner as in Example 1. 1.4 Animal grouping and experimental procedures The experimental model animals were divided into nine groups: model control group, pregabalin group (9 mg / kg), pregabalin group (6 mg / kg), pregabalin group (3 mg / kg), riluzole group (6 mg / kg), riluzole group (3 mg / kg), pregabalin-riluzole composition 3:1 group (pregabalin 9 mg / kg + riluzole 3 mg / kg), pregabalin-riluzole composition 1:2 group (pregabalin 3 mg / kg + riluzole 6 mg / kg), and pregabalin-riluzole composition 1:1 group (pregabalin 6 mg / kg + riluzole 6 mg / kg). Pregabalin and riluzole were administered intraperitoneally, with 10–11 animals per group. A vehicle blank was administered to the model control group. SD rats of appropriate weight were selected to establish the L5-SNL model, and postoperative mechanical pain thresholds were measured at least 7 days after model establishment. Animals with a significantly lower right hind paw pain threshold than the contralateral hind paw pain threshold were selected for all subsequent pharmacological efficacy studies. Experimental model animals were administered the corresponding drug or vehicle, and their mechanical pain thresholds were measured 0.5 and 3 hours after administration.

[0033] 1.5 Synergistic Analysis of Compositions The synergistic analysis of the compositions was the same as in Example 1. 1.6 Data Statistics Data statistics were the same as in Example 1. 2 results The experimental results are shown in Table 5. Compared with the vehicle control group, riluzole 6 mg / kg, Composition 3:1, Composition 1:2, and Composition 1:1 all significantly improved the animals' mechanical pain thresholds 0.5 h after administration (P = 0.0011, P = 0.0006, P < 0.0001, P < 0.0001), and pregabalin 9 mg / kg, pregabalin 6 mg / kg, riluzole 6 mg / kg, Composition 3:1, Composition 1:2, and Composition 1:1 all significantly improved the animals' mechanical pain thresholds 3 h after administration (P < 0.0001, P = 0.0015, P = 0.0315, P < 0.0001, P < 0.0001, P < 0.0001). The results of the synergy calculation were: Composition 3:1 had q values ​​of 1.362 and 1.384 at 0.5 hours and 3 hours after administration, respectively; Composition 1:2 had q values ​​of 1.330 and 1.361 at 0.5 hours and 3 hours after administration, respectively; and Composition 1:1 had q values ​​of 1.453 and 1.501 at 0.5 hours and 3 hours after administration, respectively, thereby indicating that Composition 3:1, Composition 1:2, and Composition 1:1 all had synergistic effects at 0.5 hours and 3 hours after administration. [Table 5] Data are expressed as mean ± standard error, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared with the model control group.

[0034] Example 6 Study on the efficacy of pregabalin and riluzole composition against neuropathic pain 6 1. Materials and Methods 1.1 Experimental animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g. 1.2 Test drug Pregabalin and riluzole were the same as in Example 1. 1.3 Experimental method The preparation of the neuropathic pain animal model, the method for measuring the mechanical pain threshold, and the measurement and calculation of the animal's basal pain threshold were carried out in the same manner as in Example 1.

[0035] 1.4 Animal grouping and experimental procedures The experimental model animals were divided into a model control group, a pregabalin group (30 mg / kg), a pregabalin group (20 mg / kg), a pregabalin group (6 mg / kg), a riluzole group (10 mg / kg), a riluzole group (7.5 mg / kg), a riluzole group (6 mg / kg), a pregabalin-riluzole composition 1:1 group (pregabalin 6 mg / kg + riluzole 6 mg / kg), a pregabalin-riluzole composition 2:1 group (pregabalin 6 mg / kg + riluzole 6 mg / kg), and a control group (pregabalin 6 mg / kg + riluzole 6 mg / kg). The rats were randomly divided into 11 groups: group 1 (pregabalin 20 mg / kg + riluzole 10 mg / kg), group 2 (pregabalin 30 mg / kg + riluzole 10 mg / kg), group 3 (pregabalin 30 mg / kg + riluzole 10 mg / kg), group 4 (pregabalin 30 mg / kg + riluzole 7.5 mg / kg), and group 5 (pregabalin 30 mg / kg + riluzole 6 mg / kg). Pregabalin and riluzole were administered intragastrically, with 8 to 10 animals per group. A blank vehicle was administered to serve as a model control. SD rats of appropriate weight were selected to establish the L5-SNL model, and postoperative mechanical pain thresholds were measured at least 7 days after model construction. Animals with a significantly lower right hind paw pain threshold than the contralateral hind paw pain threshold were selected for all subsequent pharmacological efficacy studies. Experimental model animals were administered the corresponding drug or vehicle, and their mechanical pain thresholds were measured 0.5, 3, 6, and 8 hours after administration. 1.5 Synergistic Analysis of Compositions The presence or absence of synergistic effects was evaluated at Emax (3 h) after administration of pregabalin and riluzole in the composition according to Kim Jeong-gyun's formula: q = E(a + b) / (Ea + Eb - Ea × Eb). Here, E(a + b) is the improvement rate resulting from the combined use of drugs, and Ea and Eb are the improvement rates resulting from the administration of drug A (pregabalin) and drug B (riluzole) alone, respectively. E = (post-administration pain threshold - model value) / (basal value - model value). A q value between 0.85 and 1.15 indicated simple additive effects when both drugs were used together; a q value > 1.15 indicated a synergistic effect; and a q value < 0.85 indicated antagonistic effects when both drugs were used together. CompuSyn software was used to analyze the overall efficacy of pregabalin and riluzole in the composition from 0 to 8 hours after administration. The formula for calculating the improvement rate for each drug group was (AUC0-8h - model value * 8h) / (basal value * 8h - model value * 8h). The software calculated the combination index (CI) for each composition group. A CI < 1 indicated synergistic activity, a CI = 1 indicated additive activity, and a CI > 1 indicated antagonistic activity when both drugs were used together. 1.6 Data Statistics Data statistics were the same as in Example 1.

[0036] 2 results The experimental results are shown in Table 6. Compared with the vehicle control group, pregabalin 30 mg / kg, riluzole 10 mg / kg, riluzole 7.5 mg / kg, riluzole 6 mg / kg, pregabalin-riluzole composition 1:1, pregabalin-riluzole composition 2:1, pregabalin-riluzole composition 3:1, pregabalin-riluzole composition 4:1, and pregabalin-riluzole composition 5:1 all significantly improved the animals' mechanical pain threshold 0.5 hours after administration (P = 0.018, P < 0.0001). , P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001); pregabalin 30 mg / kg, pregabalin 20 mg / kg, pregabalin 6 mg / kg, riluzole 10 mg / kg, Composition 1:1, Composition 2:1, Composition 3:1, Composition 4:1, and Composition 5:1 all significantly improved the animals' mechanical pain threshold 3 hours after administration (P<0.0001, P<0.0001, P=0.00 08, P=0.023, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001; pregabalin 30 mg / kg, pregabalin 20 mg / kg, pregabalin 6 mg / kg, Composition 1:1, Composition 2:1, Composition 3:1, Composition 4:1, and Composition 5:1 all significantly improved the animals' mechanical pain threshold 6 hours after administration (P<0.0001, P<0.0001, P=0.0007, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001); Pregabalin 30 mg / kg, pregabalin 20 mg / kg, pregabalin 6 mg / kg, Composition 1:1, Composition 2:1, Composition 3:1, Composition 4:1, and Composition 5:1 all significantly improved the animals' mechanical pain threshold 8 hours after administration (P<0.0001, P<0.0001, P=0.0008, P<0.0001, P<0.0001, P<0.0001, P<0.0001, P<0.0001).When the synergistic effect was calculated according to Kim Jeong-gyun's formula, Composition 1:1 had a q value of 1.296 at 3 hours after administration, Composition 2:1 had a q value of 1.258 at 3 hours after administration, Composition 3:1 had a q value of 1.266 at 3 hours after administration, Composition 4:1 had a q value of 1.319 at 3 hours after administration, and Composition 5:1 had a q value of 1.264 at 3 hours after administration. Therefore, Composition 1:1, Composition 2:1, Composition 3:1, Composition 4:1, and Composition 5:1 all had a synergistic effect at 3 hours after administration; CompuSyn Software analysis showed that Composition 1:1 had a CI value of AUC after administration of 0.634, Composition 2:1 had a CI value of AUC after administration of 0.364, Composition 3:1 had a CI value of AUC after administration of 0.349, Composition 4:1 had a CI value of AUC after administration of 0.328, and Composition 5:1 had a CI value of AUC after administration of 0.349, indicating that Composition 1:1, Composition 2:1, Composition 3:1, Composition 4:1, and Composition 5:1 all had a synergistic effect 0 to 8 hours after administration. [Table 6] Data are expressed as mean ± standard error, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared with the model control group. <Additional Notes> The present invention includes the following aspects. <Section 1> A composition for preparing a neuropathic pain treatment drug, comprising (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and riluzole or a pharmaceutically acceptable salt thereof. <Section 2> The composition according to <Item 1>, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 50:1 to 1:20. <Section 3> The composition according to <Item 1>, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 20:1 to 1:10. <Section 4> The composition according to <Item 1>, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 20:1 to 1:4. <Section 5> The composition according to <Item 1>, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 10:1 to 1:4. <Section 6> The composition according to <Item 1>, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 6:1 to 1:4. <Section 7> The composition according to <Item 1>, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 3:1 to 1:2. <Section 8> Use of the composition according to any one of <Item 1> to <Item 7> in the preparation of a drug for treating neuropathic pain. <Section 9> The use according to <Item 8>, wherein the neuropathic pain is peripheral neuropathic pain. <Section 10> The use according to <Item 9>, wherein the peripheral neuropathic pain is postherpetic neuralgia. <Section 11> The use according to <Item 9>, wherein the peripheral neuropathic pain is diabetic peripheral neuropathy.

Claims

1. A composition for preparing a therapeutic agent for neuropathic pain, comprising (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and riluzole or a pharmaceutically acceptable salt thereof, wherein the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 50:1 to 1:

20.

2. The composition according to claim 1, characterized in that the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 20:1 to 1:

10.

3. The composition according to claim 1, characterized in that the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 20:1 to 1:

4.

4. The composition according to claim 1, characterized in that the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 10:1 to 1:

4.

5. The composition according to claim 1, characterized in that the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 6:1 to 1:

4.

6. The composition according to claim 1, characterized in that the mass ratio of the (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof to the riluzole or a pharmaceutically acceptable salt thereof in the form of a free acid or base is 3:1 to 1:

2.

7. Use of the composition according to any one of claims 1 to 6 in the preparation of a medicament for treating neuropathic pain.

8. The use according to claim 7, characterized in that the neuropathic pain is peripheral neuropathic pain.

9. 9. The use according to claim 8, wherein the peripheral neuropathic pain is postherpetic neuralgia.

10. 9. The use according to claim 8, wherein the peripheral neuropathic pain is diabetic peripheral neuropathy.

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