Pharmaceutical composition with analgesic and / or antipruritic function and use thereof

Abstract

The present application relates to the technical field of pharmaceutical chemistry, and discloses a pharmaceutical composition with analgesic and / or antipruritic functions and application thereof.The composition contains Nav1.7 inhibitors and Nav1.8 inhibitors; and the composition satisfies (1) or (2): (1) at least one of the Nav1.8 inhibitors has a half-inhibitory concentration IC50 of Nav1.8 on Hek293 cells overexpressing human Nav1.8 ≤ 10 μM under manual patch clamp test conditions; (2) at least one of the Nav1.7 inhibitors has a half-inhibitory concentration IC50 of Nav1.7 on Hek293 cells overexpressing human Nav1.7 ≤ 1 μM under manual patch clamp test conditions; and the weight ratio of the Nav1.7 inhibitors and the Nav1.8 inhibitors is 1:(0.001-5000). The composition can significantly relieve pain, and also can relieve itching, and can treat and / or prevent premature ejaculation with tactile sensitivity or be used for anesthesia.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a pharmaceutical composition having analgesic and / or antipruritic functions and its application. Background Technology

[0002] Pain and itching are clinical challenges. Voltage-gated sodium channels (Nav) Nav1.7 and Nav1.8 are highly expressed in somatic sensory neurons and play important roles in the perception of itch, mechanosensory sensation, and pain. Studies have shown that Nav1.7 and Nav1.8 exhibit different expression patterns in the dorsal root ganglion (DRG). In mice, Nav1.7 is expressed in large, medium, and small neurons, with higher expression in medium and small neurons, while Nav1.8 is mainly expressed in medium and small neurons, and not expressed or expressed at very low levels in large neurons. Both Nav1.7 and Nav1.8 are expressed in small and medium DRG neurons. Functional loss-of-function mutations in Nav1.7 result in congenital analgesia in humans, and knockout of Nav1.7 also results in analgesia in mice. These findings suggest that inhibiting Nav1.7 alone may provide analgesia. PF-05089771 is a potent Nav1.7 inhibitor, but its analgesic effect in clinical studies has been poor (A. McDonnell, et al., Efficacy of the Nav1.7 blocker PF-05089771 in arandomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain. 2018 Aug; 159(8):1465-1476.). Although there are many selective small molecule inhibitors of Nav1.7 and Nav1.8, there are currently no reports of clinical studies on the combined use of Nav1.7 and Nav1.8 inhibitors for the treatment and / or prevention of pain. Summary of the Invention

[0003] The purpose of this invention is to overcome the technical problem of poor therapeutic effect of single-target Nav1.7 or Nav1.8 in the prior art, and to provide a pharmaceutical composition with analgesic and / or antipruritic functions and its application.

[0004] Based on in-depth research and speculation, the inventors of this invention have determined that downregulation of miR-96 after nerve injury not only simultaneously upregulates the expression of Nav1.7 and Nav1.8, but may also increase the number of DRG neurons that co-express Nav1.7 and Nav1.8. Furthermore, inhibiting the activity of Nav1.7 and Nav1.8 may achieve better analgesic, antipruritic, and even anesthetic effects. Therefore, this invention uses miR-96 knockout mice as an in vivo model to screen for synergistic Nav1.7 and Nav1.8 inhibitor formulations.

[0005] To achieve the above objectives, a first aspect of the present invention provides a pharmaceutical composition having analgesic and / or antipruritic functions, the composition comprising a Nav1.7 inhibitor and a Nav1.8 inhibitor; and the composition satisfies (1) or (2):

[0006] (1) At least one of the Nav1.8 inhibitors, under manual patch-clamp testing conditions, has an IC50 ≤ 10 μM for inhibiting Nav1.8 on Hek293 cells overexpressing human Nav1.8;

[0007] (2) At least one of the Nav1.7 inhibitors, under manual patch-clamp testing conditions, has an IC50 ≤ 1 μM for inhibiting Nav1.7 on Hek293 cells overexpressing human Nav1.7;

[0008] The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.001-5000).

[0009] A second aspect of the present invention provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing conditions related to voltage-gated sodium ion channels.

[0010] The pharmaceutical composition provided by this invention can significantly relieve pain and itching, and can also treat and / or prevent tactilely sensitive premature ejaculation or be used for anesthesia. Attached Figure Description

[0011] Figure 1 In Example 1, A represents miR-96. - / - The mechanical threshold of mice; Figure 1 B, C, D, E, and F are respectively PF-06305591, PF-06456384, PF-05089771, PF-04885614, and CNV1014802 administered via gavage to relieve miR-96. - / - Effect of pain on mice. n=8, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, One-way ANOVA;

[0012] Figure 2 In Example 1, gavage administration of Gabapentin was used to relieve miR-96. - / - Effect of pain on mice. n=8, ***P<0.001, Mann-Whitney test;

[0013] Figure 3 The drug composition containing PF-06305591 and PF-05089771 administered by gavage in Example 2 was used to relieve miR-96. - / - Effect of pain on mice. n=8, **P<0.01, ***P<0.001, One-way ANOVA;

[0014] Figure 4 The oral administration of the drug composition containing PF-06305591 and PF-06456384 in Example 3 was used to relieve miR-96. - / - Effect of pain on mice. n=8, **P<0.01, ***P<0.001, One-way ANOVA;

[0015] Figure 5 The drug composition containing PF-06456384 and PF-04885614 administered by gavage in Example 4 was used to relieve miR-96. - / - Effect of pain on mice. n=8, *P<0.05, **P<0.01, One-way ANOVA;

[0016] Figure 6 In Example 5, A, B, and C represent the topical drug compositions containing PF-06305591 and PF-05089771, PF-06305591 and PF-06456384, and PF-06456384 and PF-04885614, respectively, used to relieve miR-96. - / - The effect of pain on mice. n=8, *P<0.05, **P<0.01, One-way ANOVA;

[0017] Figure 7 The efficacy of the topical drug composition containing PF-06305591 and PF-05089771 in Example 6 for relieving chloroquine-induced itching was demonstrated. n=6, ****P<0.0001, T-test;

[0018] Figure 8 In a comparative study, a drug composition containing CNV1014802 and PF-04885614 was administered by gavage for the relief of miR-96. - / -The analgesic effect in mice was not superior to that of CNV1014802 or PF-04885614 alone. n=8, ***P<0.001, Mann-Whitney test. Detailed Implementation

[0019] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0020] In this invention, the "pharmaceutically acceptable salt" can be prepared from inorganic or organic acids. Salts derived from inorganic acids include hydrochloric acid, toluenesulfonate, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, citric acid, maleic acid, tartaric acid, dihydroxynaphthyl salt, etc.

[0021] "Pharmaceutically acceptable amino acid-like compounds formed by amino acids as carriers" refers to compounds formed by the amino group on the compound and the carboxyl group on the amino acid, such as compounds formed by valine, threonine, phenylalanine, etc.

[0022] "Isomers" include, but are not limited to: stereoisomers, enantiomers and diastereomers.

[0023] "Solvates" refer to complexes formed by the combination of compounds or their derivatives represented by formulas (1)-(4) and solvents.

[0024] "Isotope variants" include, but are not limited to, deuterated variants.

[0025] "Hydrate" refers to a compound containing water, in which water can be linked by coordinate bonds to the parts shown in formulas (1)-(4) or by covalent bonds.

[0026] "Polymorphic compounds" refer to different crystal structures of crystalline compounds. Different polymorphic compounds may be due to differences in crystal form stacking (packing polymorphism) or differences in stacking between different conformational isomers of the same molecule (conformation polymorphism).

[0027] "Prodrugs," also known as precursor drugs, drug precursors, or predrugs, refer to compounds obtained by modifying the chemical structure of a drug. These compounds are inactive or have low activity in vitro, but release their active drug effect in vivo through enzymatic or non-enzymatic transformation. For example, the amine groups in formulas (1) to (4) can be modified to form compounds such as amides, amino esters, and amidines.

[0028] A first aspect of the present invention provides a pharmaceutical composition having analgesic and / or antipruritic functions, the composition comprising a Nav1.7 inhibitor and a Nav1.8 inhibitor; and the composition satisfies (1) or (2):

[0029] (1) At least one of the Nav1.8 inhibitors, under manual patch-clamp testing conditions, has an IC50 ≤ 10 μM (e.g., 10 μM, 1 μM, 100 nM, 53 nM, 15 nM, 10 nM, etc.) for the inhibition of Nav1.8 on Hek293 cells overexpressing human Nav1.8.

[0030] (2) At least one of the Nav1.7 inhibitors, under manual patch-clamp testing conditions, has an IC50 ≤ 1 μM for the inhibition of Nav1.7 on Hek293 cells overexpressing human Nav1.7 (e.g., 1 μM, 100 nM, 75 nM, 50 nM, 11 nM, 0.01 nM, etc.);

[0031] The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor can be 1:(0.001-5000), such as 1:0.001, 1:0.002, 1:0.004, 1:0.006, 1:0.008, 1:0.01, 1:0.02, 1:0.04, 1:0.06, 1:0.08, 1:0.1, 1:0.15, 1:0.2, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:20, 1:50, 1:100, 1:200, 1:300, 1:400, 1:500, 1:1000, 1:5000, etc.

[0032] The IC50 test can be performed following standard procedures and will not be elaborated here.

[0033] According to some embodiments of the present invention, the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor can be 1:(0.001-50), preferably 1:(0.005-10), and more preferably 1:(0.01-2).

[0034] According to a preferred embodiment of the present invention, the Nav1.7 inhibitor may be at least one of the following having the structure shown in formula (1) (hereinafter referred to as compound 1) or formula (2) (hereinafter referred to as compound 2) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug.

[0035]

[0036] According to a preferred embodiment of the present invention, the Nav1.8 inhibitor is at least one of the following: a compound having the structure shown in formula (3) (hereinafter referred to as compound 3) or formula (4) (hereinafter referred to as compound 4), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug.

[0037]

[0038] According to some embodiments of the present invention, the Nav1.7 inhibitor is at least one of a compound having the structure shown in formula (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug; and the Nav1.8 inhibitor is at least one of a compound having the structure shown in formula (3) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug.

[0039] And / or, the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.005-0.5).

[0040] According to some embodiments of the present invention, the Nav1.7 inhibitor is at least one of the following: a compound having the structure shown in formula (2) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug; and the Nav1.8 inhibitor is at least one of the following: a compound having the structure shown in formula (3) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug.

[0041] And / or, the weight ratio of Nav1.7 inhibitor to Nav1.8 inhibitor is 1:(0.01-0.1).

[0042] According to some embodiments of the present invention, the Nav1.7 inhibitor is at least one of the following: a compound having the structure shown in formula (2) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug; and the Nav1.8 inhibitor is at least one of the following: a compound having the structure shown in formula (4) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed with an amino acid carrier, an isomer, a solvate, an isotope variant, a hydrate, a polymorph, or a prodrug.

[0043] And / or, the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.05-2).

[0044] In some specific embodiments of the present invention, in addition to the combination of Nav1.7 inhibitor and Nav1.8 inhibitor mentioned above, compounds (1)-(4) can also form effective composition schemes with other Nav1.7 inhibitors or other Nav1.8 inhibitors with inhibitory activity that can be conceived by those skilled in the art.

[0045] According to some embodiments of the present invention, the pharmaceutical composition includes a pharmaceutically acceptable carrier.

[0046] Preferably, the pharmaceutically acceptable carrier is selected from one or more of solvents, excipients, dispersion media, coatings, transdermal agents, isotonic agents, and absorption delay agents.

[0047] More preferably, the pharmaceutically acceptable carrier is at least one of starch, microcrystalline cellulose, lactose, sucrose, mannitol, inorganic salts, hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose, sodium alginate, agar, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, carboplatin, polyvinyl alcohol, acrylic resin, chitosan, beeswax, and stearic acid.

[0048] According to some embodiments of the present invention, the total content of the Nav1.7 inhibitor and the Nav1.8 inhibitor is 0.0001-99.9999% by weight, based on the total weight of the pharmaceutical composition.

[0049] A second aspect of the present invention provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing conditions related to voltage-gated sodium ion channels.

[0050] According to some embodiments of the present invention, the voltage-gated sodium ion channel can be Na v 1.7 and / or Na v 1.8.

[0051] According to some embodiments of the present invention, the disease may be selected from premature ejaculation caused by pain and / or itching or tactile sensitivity.

[0052] According to some embodiments of the present invention, the pain is selected from at least one of traumatic pain, intraoperative pain, postoperative pain, inflammatory pain, and neuropathic pain. Examples include headache, cervical spondylosis, shoulder pain, lower back pain, toothache, chest pain, abdominal pain, lower limb pain, muscle and bone pain, fibromyalgia, glossopharyngeal neuralgia, trigeminal neuralgia, sciatica, multiple sclerosis-related neuralgia, diabetic neuralgia, cancer-related pain, postherpetic neuralgia, HIV-related neuralgia, post-burn pain, arthritis pain, dysmenorrhea, and visceral pain.

[0053] In this invention, inflammatory pain refers to pain caused by various mediators produced by tissue damage, such as prostaglandins, inflammatory factors, chemokines, and adenosine, stimulating sensory nerve endings. Neuropathic pain, on the other hand, is pain caused by damage to the central or peripheral nervous system or functional disorders following such damage.

[0054] Itching refers to the discomfort of itchy skin, including itching caused by skin diseases, as well as pruritus with only itching without primary skin lesions. The pruritus described in this invention can be selected from at least one of histamine-dependent pruritus, non-histamine-dependent pruritus, chemical pruritus, mechanical pruritus, pruritus caused by insect bites, and pruritus caused by chronic kidney disease.

[0055] In addition, the present invention also relates to the treatment of voltage-gated sodium ion channels Na v 1.7 and / or Na v 1.8 Methods for treating related conditions, comprising administering the above-described pharmaceutical composition to a subject. Administration may be carried out in a conventional manner, including but not limited to: oral, oral, injection (e.g., intramuscular, subcutaneous, intrathecal, epidural, intravenous), respiratory, skin (e.g., topical application, spray, poultice), ocular, nasal mucosa, rectal, vaginal, ear, dialysis, etc. The subject may be an animal, including mammals (especially primates, such as humans), rodents (e.g., rats), livestock, poultry, pets, and laboratory animals. Medical personnel can select the dosage based on the subject's physical condition; for example, in adults, the dosage may be 0.01-10 mg / kg or 0.01-1 mg / cm³. 2 .

[0056] According to the present invention, the term "treatment" means: therapeutic, preventive or inhibitory measures for a disease or condition that result in any clinically desired or beneficial effect (including, but not limited to, relief or reduction of one or more symptoms; regression, slowing or cessation of the progression of the disease or condition).

[0057] The present invention will be described in detail below through examples. All animal experiments were conducted in accordance with the ethical guidelines reviewed and approved by the Laboratory Animal Ethics Committee of the Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences.

[0058] Example 1

[0059] This example illustrates the testing effect of a single drug compound.

[0060] To screen for oral analgesics with good efficacy, eight miR-96 mice aged 3-6 months were used. - / - The analgesic effects of oral administration of Nav1.7 inhibitors and Nav1.8 inhibitors were tested in mice (Kunshan Pengji Kaifeng Biotechnology Co., Ltd.).

[0061] First, measure miR-96 - / - Mechanical pain threshold in the feet of mice. Eight miR-96 mice were used. - / - Mice were placed on an iron rack and covered with an acrylic glass cover. After 30 minutes, the mice's baseline mechanical threshold (paw withdrawal threshold) was measured using a Von Frey (DanMic Global, CA, USA) microscope. The mean threshold for the mice was 0.16g ± 0.07g. (See [link to relevant documentation]). Figure 1 In the middle A, it belongs to mechanical allodynia. PF-06305591 (a compound with the structure shown in formula (3), (αR,βS)-β-Amino-6-(1,1-dimethylethyl)-α-methyl-1H-benzimidazole-2-propana midedihydrate, Sigma, PZ0297-25MG, IC50 of hNav1.8 = 15 nM) was dissolved in 10% DMSO / physiological saline (V / V). After gavage administration of 30 μg / kg, 60 μg / kg or 90 μg / kg of PF-06305591 for one hour, miR-96 was measured. - / - The mechanical pain threshold of the two feet of mice was tested. The results showed that the analgesic effects of PF-063055911 at 60 μg / kg and 90 μg / kg were significantly better than those of the solvent control group, and the 60 μg / kg dose group had the best effect. Figure 1 B.

[0062] PF-06456384 (a compound with the structure shown in formula (2), 3-Cyano-4-[[3-[2-[[[2-(4-piperidinyl)ethyl]amino]methyl]-4-pyridinyl]-

[0063] 3′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]oxy]-

[0064] N-1,2,4-thiadiazol-5-yl-benzenesulfonamide trihydrochloride, Sigma, PZ0386-25 mg (IC50 = 0.01 nM against hNav 1.7) was dissolved in 10% DMSO / physiological saline (v / v) and administered by gavage at 1 mg / kg, 2 mg / kg, or 3 mg / kg of PF-06456384. One hour later, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that the analgesic effect of all three doses of PF-06456384 was significantly better than that of the solvent control group, with the 2 mg / kg dose group showing the best effect. Figure 1 C.

[0065] PF-05089771 (a compound with the structure shown in formula (1), 4-[2-(3-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-4-thiazolylbenzenesulfonamide tosylate, IC50 = 11 nM against hNav1.7) was dissolved in 30% DMSO / physiological saline (V / V). After gavage administration of 2 mg / kg, 4 mg / kg, or 6 mg / kg of PF-05089771 for one hour, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that the analgesic effects of PF-05089771 at 4 mg / kg and 6 mg / kg were significantly better than those in the solvent control group. Furthermore, the 6 mg / kg dose group did not show a significantly better effect than the 4 mg / kg dose group. (See [link to relevant documentation]). Figure 1 D.

[0066] PF-04885614 (a compound with the structure shown in formula (4), 1-Methyl-1-[4-(4-trifluoromethoxy-phenyl)-1H-imidazol-2-yl]-ethylamine, IC50 = 53 nM against hNav1.8) was dissolved in 10% DMSO / physiological saline (V / V). After gavage administration of 90 μg / kg, 180 μg / kg, or 270 μg / kg of PF-04885614 for one hour, miR-96 was measured. - / -The mechanical pain threshold in mice was tested, and the results showed that PF-04885614 at doses of 180 μg / kg and 270 μg / kg had significantly better analgesic effects than the solvent control group, with the 180 μg / kg dose group showing the best effect. (See [link to relevant documentation]). Figure 1 E in Chinese.

[0067] CNV1014802 (IC50 = 32 μM against hNav1.7) was dissolved in 30% DMSO / physiological saline (v / v). After gavage administration of 20 mg / kg, 30 mg / kg, or 40 mg / kg of CNV1014802 for one hour, miR-96 was measured. - / - The mechanical pain threshold in mice was assessed, and it was found that the analgesic effect of all three doses of CNV1014802 was significantly better than that of the solvent control group, with the 30 mg / kg dose group showing the best effect. (See [link to study]). Figure 1 Middle F.

[0068] Gabapentin was dissolved in physiological saline. One hour after oral administration of 50 mg / kg of gabapentin, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that 50 mg / kg of Gabapentin significantly increased the mechanical pain threshold in mice (difference in claw withdrawal threshold was 0.5 g ± 0.09 g). (See [link to relevant documentation]). Figure 2 .

[0069] Example 2

[0070] This embodiment is used to illustrate the test effect of a pharmaceutical composition according to a specific implementation.

[0071] The drug composition comprises PF-06305591 and PF-05089771, dissolved in 30% DMSO / physiological saline (v / v). One hour after oral administration of 60 μg / kg of PF-06305591 and 4 mg / kg of PF-05089771, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that 60 μg / kg of PF-06305591 and 4 mg / kg of PF-05089771 together were effective in relieving miR-96. - / - The mechanical pain response in mice was excellent and significantly superior to that of PF-06305591 alone at 60 μg / kg or PF-05089771 alone at 4 mg / kg. (See attached image) Figure 3 ( Figure 3 (where "PF-5591" refers to "PF-06305591" and "PF-9771" refers to "PF-05089771").

[0072] Example 3

[0073] This embodiment is used to illustrate the test effect of a pharmaceutical composition according to a specific implementation.

[0074] The drug composition comprises PF-06305591 and PF-06456384, dissolved in 10% DMSO / physiological saline (v / v). One hour after oral administration of 60 μg / kg of PF-06305591 and 2 mg / kg of PF-06456384, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that 60 μg / kg of PF-06305591 and 2 mg / kg of PF-06456384 together were effective in relieving miR-96. - / - The mechanical pain response in mice was excellent and significantly superior to that of PF-06305591 alone (60 μg / kg) or PF-06456384 alone (2 mg / kg). (See attached image.) Figure 4 ( Figure 4 (where "PF-5591" refers to "PF-06305591" and "PF-6384" refers to "PF-06456384").

[0075] Example 4

[0076] This embodiment is used to illustrate the test effect of a pharmaceutical composition according to a specific implementation.

[0077] The drug composition comprises PF-06456384 and PF-04885614, dissolved in 10% DMSO / physiological saline (v / v). One hour after oral administration of 2 mg / kg of PF-06456384 and 180 μg / kg of PF-04885614, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that PF-06456384 at 2 mg / kg and PF-04885614 at 180 μg / kg alleviated miR-96. - / - The mechanical pain response in mice was excellent and significantly superior to that of PF-04885614 alone at 180 μg / kg or PF-06456384 alone at 2 mg / kg. (See attached image) Figure 5 ( Figure 5 (where "PF-5614" refers to "PF-04885614" and "PF-6384" refers to "PF-06456384").

[0078] Example 5

[0079] This example illustrates the analgesic effect of topical application to the skin.

[0080] To test the analgesic effects of topical Nav1.7 and Nav1.8 inhibitors, miR-96 was anesthetized with isoflurane.- / - Mice were treated with 10 μl of a combination of 1 mg / ml PF-06305591 and 20 mg / ml PF-05089771 dissolved in 30% DMSO / physiological saline (V / V). Five minutes after application, the mice were removed from the anesthesia machine and placed under an immersion glass dome on an iron frame. Thirty minutes after application, the mechanical pain threshold of the mice was measured.

[0081] Test results showed that applying PF-06305591 and PF-05089771 significantly improved miR-96. - / - The mechanical pain threshold in mice is shown in [reference needed]. Figure 6 China A (where “PF-5591” refers to “PF-06305591” and “PF-9771” refers to “PF-05089771”).

[0082] As above, after applying 10 μl of a combination of 1 mg / ml PF-06305591 and 10 mg / ml PF-06456384 dissolved in 10% DMSO / physiological saline (v / v) for 30 minutes, miR-96 - / - The mechanical threshold of mice was significantly increased, see Figure 6 In the case of "PF-6384", "PF-06456384" and "PF-5591" refers to "PF-06305591".

[0083] As above, after applying 10 μl of a combination of 10 mg / ml PF-06456384 and 2 mg / ml PF-04885614 dissolved in 10% DMSO / physiological saline (v / v) for 30 minutes, miR-96 - / - The mechanical threshold of mice was significantly increased, see Figure 6 In the middle C (where “PF-6384” refers to “PF-06456384” and “PF-5614” refers to “PF-04885614”).

[0084] Example 6

[0085] This example illustrates the effectiveness of topical application for relieving itching.

[0086] To test the antipruritic effect of topical Nav1.7 and Nav1.8 inhibitors, six 8-week-old C57 / Bl6 mice were anesthetized with isoflurane. The hair on the back of the ears and neck of the mice was shaved, and 50 μl of a combination of 1 mg / ml PF-06305591 and 10 mg / ml PF-06456384 dissolved in 10% DMSO / physiological saline (v / v) was applied. Five minutes after application, the mice were removed from the anesthesia machine, and 50 μl of 12 mM chloroquine (Sigma Aldrich, CAS50-63-5) was injected subcutaneously into the treated area. Video recordings were made, and the number of scratches by the mice was counted. Statistical analysis showed that the combination of PF-06305591 and PF-06456384 significantly inhibited chloroquine-induced itching. (See below) Figure 7 ( Figure 7 , "PF-6384" refers to "PF-06456384", "PF-5591" refers to "PF-06305591").

[0087] Comparative Example

[0088] This comparative example is used to illustrate the test results of using CNV1014802 and PF-04885614 together.

[0089] CNV1014802 and PF-04885614 were dissolved in 30% DMSO / physiological saline. One hour after gavage administration of 30 mg / kg CNV1014802 and 180 μg / kg PF-04885614, miR-96 was measured. - / - The mechanical pain threshold in mice was tested, and the results showed that 30 mg / kg CNV1014802 and 180 μg / kg PF-04885614 together were effective in relieving miR-96. - / - The mechanical pain response in mice was not superior to that of CNV1014802 alone (30 mg / kg) or PF-04885614 alone (180 μg / kg). (See [reference needed]) Figure 8 ( Figure 8 (where “PF-5614” refers to “PF-04885614”).

[0090] In summary, the present invention utilizes a pharmaceutical composition containing PF-06305591 and PF-05089771, or a pharmaceutical composition containing PF-06305591 and PF-06456384, or a pharmaceutical composition containing PF-06456384 and PF-04885614, which can significantly relieve pain. Furthermore, the pharmaceutical composition containing PF-06305591 and PF-05089771, when applied topically, can also relieve itching. Similarly, it is hypothesized that pharmaceutical compositions containing PF-06305591 and PF-06456384, or PF-06456384 and PF-04885614, can also relieve itching. However, in the comparative example, the combined use of the Nav1.7 inhibitor CNV1014802 and the Nav1.8 inhibitor PF-04885614 for analgesia did not demonstrate superior analgesic effects compared to using a single inhibitor. Therefore, the specific Nav1.7 inhibitor and Nav1.8 inhibitor composition formulations provided by the present invention can prevent and / or treat diseases involving Nav1.7 and Nav1.8 activity, including but not limited to pain and itching.

[0091] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for oral or topical use, characterized in that, The pharmaceutical composition contains Nav1.7 inhibitors and Nav1.8 inhibitors; The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.01-2). The Nav1.7 inhibitor is a compound having the structure shown in formula (1) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure shown in formula (3) or a pharmaceutically acceptable salt thereof; Alternatively, the Nav1.7 inhibitor is a compound having the structure shown in formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure shown in (3) or a pharmaceutically acceptable salt thereof; Alternatively, the Nav1.7 inhibitor is a compound having the structure shown in formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure shown in (4) or a pharmaceutically acceptable salt thereof; The structures of equations (1), (2), (3), and (4) are shown below: 。 2. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition includes a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, wherein, The pharmaceutically acceptable carrier is selected from at least one of starch, microcrystalline cellulose, lactose, sucrose, mannitol, hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose, sodium alginate, agar, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, carboplatin, polyvinyl alcohol, acrylic resin, chitosan, beeswax, and stearic acid.

4. The pharmaceutical composition according to claim 2, wherein, Based on the total weight of the pharmaceutical composition, the total content of the Nav1.7 inhibitor and the Nav1.8 inhibitor is 0.0001-99.9999 by weight.

5. The use of the pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for treating and / or preventing conditions associated with voltage-gated sodium ion channels Nav1.7 and / or Nav1.8, wherein the condition is selected from pain; the pain is selected from at least one of traumatic pain, intraoperative pain, postoperative pain, inflammatory pain, neuropathic pain, headache, cervical spondylosis, shoulder pain, low back pain, toothache, chest pain, abdominal pain, lower extremity pain, musculoskeletal pain, fibromyalgia, glossopharyngeal neuralgia, trigeminal neuralgia, sciatica, multiple sclerosis-related neuralgia, diabetic neuralgia, cancer-related pain, postherpetic neuralgia, HIV-related neuralgia, post-burn pain, arthritis pain, dysmenorrhea, and visceral pain.

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