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

Abstract

A pharmaceutical composition having analgesic and / or antipruritic functions and its use. The composition comprises a Nav1.7 inhibitor and a Nav1.8 inhibitor. The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.001-5000). The composition of the present invention can significantly relieve analgesia and also provide antipruritic effect, and can treat and / or prevent premature ejaculation caused by tactile hypersensitivity, or can be used for anesthesia.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. 202210147495.5, filed on February 17, 2022, the contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of medicinal chemistry, in particular to a pharmaceutical composition having analgesic and / or antipruritic functions and its use. [Background technology]

[0003] Pain and itch are important clinical problems, and voltage-gated sodium ion channels (Nav1.7 and Nav1.8) are highly expressed in somatosensory neurons and play an important role in the perception of itch, mechanosensation, and pain. Studies have shown that Nav1.7 and Nav1.8 have 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 small and medium neurons, whereas Nav1.8 is mainly expressed in small and medium neurons, and not expressed or expressed very low in large neurons. Nav1.7 and Nav1.8 are co-expressed in medium and small DRG neurons. Loss-of-function mutations in Nav1.7 cause congenital pain insensibility in humans, and knocking out Nav1.7 also causes pain insensibility in mice. These findings suggest that pain relief can be achieved simply by inhibiting Nav1.7. PF-05089771 is a highly effective Nav1.7 inhibitor, but failed to achieve the expected analgesic effect in clinical studies (A. McDonnell., et al., Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain. 2018 Aug; 159(8): 1465-1476.). There are many Nav1.7-selective small molecule inhibitors and Nav1.8-selective small molecule inhibitors, but there have been no reports of clinical studies using Nav1.7 and Nav1.8 inhibitors in combination to treat and / or prevent pain. Summary of the Invention

[0004] The object of the present invention is to overcome the lack of therapeutic effect of the prior art targeting a single Nav1.7 or Nav1.8, and to provide a pharmaceutical composition having analgesic and / or antipruritic functions, and use thereof.

[0005] The present inventors have found that after nerve injury, miR-96 is downregulated, which simultaneously upregulates the expression of Nav1.7 and Nav1.8. This may not only increase the number of DRG neurons that co-express Nav1.7 and Nav1.8, but also suppress their activity. This is expected to result in higher analgesic, antipruritic, and even anesthetic effects. Therefore, the present invention screened for a combination formulation of Nav1.7 inhibitors and Nav1.8 inhibitors that have synergistic effects using miR-96 knockout mice as an in vivo model.

[0006] In order to achieve the above object, in a first aspect of the present invention, there is provided a pharmaceutical composition having analgesic and / or antipruritic function, which comprises a Nav1.7 inhibitor and a Nav1.8 inhibitor. The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.001-5000). The Nav1.7 inhibitor is a compound having a structure represented by formula (1) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (3) or a pharma- ceutically acceptable salt thereof. Alternatively, the Nav1.7 inhibitor is a compound having a structure represented by formula (2) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (3) or a pharma- ceutically acceptable salt thereof. Alternatively, the Nav1.7 inhibitor is a compound having a structure represented by formula (2) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (4) or a pharma- ceutically acceptable salt thereof. The structures of formula (1), formula (2), formula (3), and formula (4) are as follows: [ka]

[0007] According to a second aspect of the invention there is provided the use of said pharmaceutical composition in the manufacture of a medicament for the treatment and / or prevention of a disease associated with a voltage-gated sodium ion channel.

[0008] The pharmaceutical composition provided by the present invention can significantly relieve pain and itching, treat and / or prevent premature ejaculation caused by tactile hypersensitivity, and can also be used for anesthesia. [Brief description of the drawings]

[0009] [Figure 1] Figure 1A shows the mechanical threshold of miR-96- / - mice in Example 1. Figure 1B-F shows the pain-relieving effect of oral gavage of PF-06305591, PF-06456384, PF-05089771, PF-04885614, and CNV1014802 on miR-96- / - mice, respectively. n=8, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, One way ANOVA. [Diagram 2] This shows the pain-relieving effect of forced oral administration of Gabapentin on miR-96- / - mice in Example 1. n=8, ***P<0.001, Mann-Whitney test. [Diagram 3] 1 shows the pain-relieving effect on miR-96− / − mice by forced oral administration of a pharmaceutical composition containing PF-06305591 and PF-05089771 in Example 2. n=8, **P<0.01, ***P<0.001, One-way ANOVA. [Figure 4] The pain-relieving effect on miR-96- / - mice by forced oral administration of a pharmaceutical composition containing PF-06305591 and PF-06456384 in Example 3 is shown. n=8, **P<0.01, ***P<0.001, One-way ANOVA; [Diagram 5]This shows the pain-relieving effect on miR-96− / − mice by forced oral administration of a pharmaceutical composition containing PF-06456384 and PF-04885614 in Example 4. n=8, *P<0.05, **P<0.01, One-way ANOVA. [Figure 6] 6A-C show the pain relieving effects in miR-96- / - mice by dermally administering a pharmaceutical composition containing PF-06305591 and PF-05089771, a pharmaceutical composition containing PF-06305591 and PF-06456384, and a pharmaceutical composition containing PF-06456384 and PF-04885614, respectively, in Example 5. n=8, *P<0.05, **P<0.01, One-way ANOVA. [Figure 7] FIG. 6 shows the alleviating effect of chloroquine-induced itching by skin application of a pharmaceutical composition containing PF-06305591 and PF-06456384 in Example 6. n=6, ****P<0.0001, unpaired t-test. [Figure 8] The results show the effect of skin application of a pharmaceutical composition containing PF-06305591 and PF-05089771, or a pharmaceutical composition containing PF-06456384 and PF-04885614 on alleviating chloroquine-induced itching in Example 6. n=6, ****P<0.0001, unpaired t-test. [Figure 9] This shows that the pain-relieving effect of the pharmaceutical composition containing CNV1014802 and PF-04885614 on miR-96- / - mice by forced oral administration in a comparative example was not higher than the analgesic effect of CNV1014802 or PF-04885614 alone. n=8, ***P<0.001, Mann-Whitney test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The ranges and any endpoints of values ​​disclosed herein are not limited to the exact ranges or values, but should be understood to include the values ​​approaching such ranges or values. In the case of numerical ranges, the endpoints of each range, the endpoints of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges. These numerical ranges are to be considered as specifically disclosed herein.

[0011] In the present invention, a "pharmaceutically acceptable salt" can be prepared from an inorganic acid or an organic acid. Salts derived from inorganic acids include hydrochloride, toluenesulfonate, sulfate, hydrobromide, nitrate, phosphate, etc. Salts derived from organic acids include acetate, propionate, glycolate, pyruvate, oxalate, malonate, citrate, maleate, tartrate, pamoate, etc.

[0012] The term "pharmacologically acceptable amino acid-like compound formed using an amino acid as a carrier" refers to a compound similar to an amino acid formed by the amino group of the compound and the carboxyl group of an amino acid, such as compounds similar to amino acids formed with valine, threonine, phenylalanine, etc.

[0013] "Isomer" includes, but is not limited to, stereoisomers, enantiomers, and diastereomers.

[0014] The term "solvate" refers to a complex formed by a compound having a structure represented by any one of formulas (1) to (4) or a derivative thereof binding to a solvent.

[0015] "Isotopic variants" include, but are not limited to, deuterated variants.

[0016] The term "hydrate" refers to a compound containing water, in which water can be bound to the moieties represented by formulae (1) to (4) via a coordinate bond or a covalent bond.

[0017] "Polymorphism" refers to different crystal structures of a crystalline compound. Different polymorphs of a compound can result from differences in the crystal structure of the compound (sequence polymorphism) or between different conformers of the same molecule (structural polymorphism).

[0018] "Prodrug", also called precursor drug, drug precursor, precursor drug, etc., refers to a compound obtained by chemically modifying a drug structure, which has no or little activity in vitro, but releases an active drug through enzymatic or non-enzymatic conversion in vivo to exert its medicinal effect. For example, the amino groups of formulae (1) to (4) form compounds such as amides, amino esters, and amidines after structural modification.

[0019] In a first aspect of the present invention, there is provided a pharmaceutical composition having analgesic and / or antipruritic function, the composition comprising a Nav1.7 inhibitor and a Nav1.8 inhibitor.

[0020] The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.001-50), preferably 1:(0.005-10), more preferably 1:(0.01-2).

[0021] According to a preferred embodiment of the present invention, the Nav1.7 inhibitor is at least one of a structure represented by formula (1) (abbreviation: compound 1) or formula (2) (abbreviation: compound 2) or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable amino acid-like compound formed using an amino acid as a carrier, an isomer, a solvate, an isotopic variant, a hydrate, a crystalline polymorph, or a prodrug. [ka]

[0022] According to a preferred embodiment of the present invention, the Nav1.8 inhibitor is at least one of a structure represented by formula (3) (abbreviation: compound 3) or formula (4) (abbreviation: compound 4) or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable amino acid-like compound formed using an amino acid as a carrier, an isomer, a solvate, an isotopic variant, a hydrate, a crystalline polymorph, or a prodrug. [ka]

[0023] According to some embodiments of the present invention, the Nav1.7 inhibitor is a compound having a structure represented by formula (1) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (3) or a pharma- ceutically acceptable salt thereof.

[0024] And / or, the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.005-0.5).

[0025] According to some embodiments of the present invention, the Nav1.7 inhibitor is a compound having a structure represented by formula (2) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (3) or a pharma- ceutically acceptable salt thereof.

[0026] And / or the weight ratio of Nav1.7 inhibitor to Nav1.8 inhibitor is 1:(0.01-0.1).

[0027] According to some embodiments of the present invention, the Nav1.7 inhibitor is a compound having a structure represented by formula (2) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (4) or a pharma- ceutically acceptable salt thereof.

[0028] And / or, the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.05-2).

[0029] In some specific embodiments of the present invention, in addition to the combination of the Nav1.7 inhibitor and the Nav1.8 inhibitor described above, compounds (1)-(4) can also form effective compositions together with other Nav1.7 inhibitors or other Nav1.8 inhibitors having inhibitory activity known to those skilled in the art.

[0030] According to some embodiments of the invention, the pharmaceutical composition comprises a pharma- ceutically acceptable carrier.

[0031] Preferably, the pharma- ceutically acceptable carrier is one or more selected from solvents, excipients, dispersion media, coatings, skin permeation agents, isotonic agents, and absorption delaying agents.

[0032] More preferably, the pharma- ceutically acceptable carrier is at least one selected from starch, microcrystalline cellulose, lactose, sucrose, mannitol, inorganic salts, hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, sodium alginate, agar, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carbopol, polyvinyl alcohol, acrylic resins, chitosan, beeswax, and stearic acid.

[0033] 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.

[0034] In a second aspect of the invention there is provided the use of said pharmaceutical composition in the manufacture of a medicament for the treatment and / or prevention of a disease associated with a voltage-gated sodium ion channel.

[0035] According to some embodiments of the invention, the voltage-gated sodium ion channel is Na v 1.7 and / or Na v It could be 1.8.

[0036] According to some embodiments of the invention, the disorder may be selected from premature ejaculation due to pain and / or itching or tactile hypersensitivity.

[0037] According to some embodiments of the present invention, the pain is at least one selected from traumatic pain, intraoperative pain, postoperative pain, inflammatory pain, and neuropathic pain, such as at least one of headache, cervical pain, shoulder pain, low back pain, toothache, chest pain, abdominal pain, lower limb pain, musculoskeletal pain, fibromyalgia, glossopharyngeal neuralgia, trigeminal neuralgia, sciatica, multiple sclerosis-related neuralgia, diabetic neuralgia, cancer-related pain, postherpetic neuralgia, HIV-related neuralgia, postburn pain, arthralgia, menstrual pain, and visceral pain.

[0038] In the present invention, inflammatory pain refers to pain caused by various mediators such as prostaglandins, inflammatory factors, chemokines, adenosine, etc., generated by tissue damage, stimulating sensory nerve endings. Neuropathic pain refers to pain caused by damage to the central or peripheral nervous system or dysfunction after damage.

[0039] Itch refers to skin itching and the discomfort associated with it, including itching caused by skin diseases and pruritus that is only skin itching and has no primary skin disorder, and the itch described in the present invention includes at least one selected from histamine-dependent itch, non-histamine-dependent itch, chemical itch, mechanical itch, itch caused by insect bites, and itch caused by chronic kidney disease.

[0040] The present invention also relates to a voltage-dependent sodium ion channel Na v 1.7 and / or Na vThe present invention also relates to a method for treating diseases related to 1.8. The method includes administering the above pharmaceutical composition to a subject. Here, administration can be performed in a conventional manner. The administration route includes, but is not limited to, oral, buccal, injection (e.g., intramuscular injection, subcutaneous injection, subarachnoid injection, epidural injection, intravenous injection, etc.), airway, transdermal (e.g., skin application, skin spray, skin patch, etc.), ocular, nasal mucosa, rectal, vaginal, auricular, dialysis, etc. The subject may be an animal, including a mammal (especially a primate such as a human), a rodent (e.g., a rat), livestock, poultry, pet, laboratory animal, etc. A medical professional can select the dosage according to the physical condition of the subject. For example, for an adult, the dosage is 0.01-10 mg / kg or 0.01-1 mg / cm. 2 may be also possible.

[0041] According to the present invention, the term "treatment" refers to measures to treat and prevent or inhibit a disease or condition that results in a clinically desirable or beneficial effect, including, but not limited to, alleviation or relief of one or more symptoms, elimination, slowing or halting of a disease or disease progression.

[0042] All the following animal experiments were performed in accordance with ethical approval reviewed and approved by the Experimental Animal Ethics Committee of the Suzhou Institute of Biomedical Engineering, Chinese Academy of Sciences.

[0043] Example 1 This example is presented to illustrate the effectiveness of testing a single drug compound. To screen for analgesic drugs with good oral efficacy, eight mice aged 3-6 months were treated with miR-96. - / - The analgesic effects of Nav1.7 inhibitors and Nav1.8 inhibitors were measured by forced oral administration using mice (Kunshan Pengji Kaifeng Biotechnology Co., Ltd.).

[0044] First, miR-96 - / - The mechanical pain thresholds of both paws of the mice were measured. - / -The mice were placed on an iron rack and covered with plexiglass. After 30 minutes, the basal mechanical threshold (paw withdrawal threshold) of the mice was measured using a Von Frey (DanMic Global, CA, USA). The average threshold of the mice was 0.16 g ± 0.07 g, which corresponds to abnormal mechanical allodynia, as shown in Figure 1A. PF-06305591 (a compound having a structure represented by formula (3); (αR, βS)-β-amino-6-(1,1-dimethylethyl)-α-methyl-1H-benzimidazole-2-propanamide dihydrate, Sigma, PZ0297-25MG, IC50 for hNav1.8 = 15 nM) was dissolved in 10% DMSO / saline (V / V), and PF-06305591 was orally administered at 30 μg / kg, 60 μg / kg, or 90 μg / kg for 1 hour. - / - The mechanical pain thresholds of both paws of the mice were measured, and the analgesic effects of PF-063055911 at 60 μg / kg and 90 μg / kg were significantly higher than those of the vehicle control group, with the 60 μg / kg dose group showing the highest effect (Figure 1B).

[0045] PF-06456384 (a compound having a structure represented by formula (2); 3-cyano-4-[[3-[2-[[[2-(4-piperidinyl)ethyl]amino]methyl]-4-pyridinyl]-3'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]oxy]-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide trihydrochloride, Sigma, PZ0386-25MG, IC50 for hNav1.7 = 0.01 nM) was dissolved in 10% DMSO / physiological saline (V / V), and miR-96 was assayed 1 hour after oral administration of 1 mg / kg, 2 mg / kg, or 3 mg / kg of PF-06456384. - / - The mechanical pain threshold of the mice was measured, and the analgesic effects of PF-06456384 at the three doses were significantly higher than those of the vehicle control group, with the 2 mg / kg dose group showing the highest effect (Figure 1C).

[0046] PF-05089771 (a compound having a structure represented by the following formula (1), 4-[2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-4-thiazolylbenzenesulfonamide tosylate, IC50 for hNav1.7 = 11 nM) was dissolved in 30% DMSO / physiological saline (V / V), and PF-05089771 was forcibly orally administered at 2 mg / kg, 4 mg / kg, or 6 mg / kg, and miR-96 was measured 1 hour later. - / - The mechanical pain threshold of the mice was measured. The results showed that the analgesic effects of PF-05089771 at 4 mg / kg and 6 mg / kg were significantly higher than those of the vehicle control group, while the effect of the 6 mg / kg dose group was not higher than that of the 4 mg / kg dose group (Figure 1D).

[0047] PF-04885614 (a compound having a structure represented by formula (4), 1-methyl-1-[4-(4-trifluoromethoxyphenyl)-1H-imidazol-2-yl]-ethylamine, IC50 for hNav1.8 = 53 nM) was dissolved in 10% DMSO / saline (V / V), and PF-04885614 was forcibly orally administered at 90 μg / kg, 180 μg / kg, or 270 μg / kg. One hour later, miR-96 was measured. - / - The mechanical pain threshold of the mice was measured, and the analgesic effects of PF-04885614 at doses of 180 μg / kg and 270 μg / kg were significantly higher than those of the vehicle control group, with the 180 μg / kg dose group showing the highest effect (Figure 1E).

[0048] CNV1014802 (IC50=32μM for hNav1.7) was dissolved in 30% DMSO / physiological saline (V / V), and 20mg / kg, 30mg / kg, or 40mg / kg of CNV1014802 was orally administered by force, and miR-96 was detected 1 hour later. - / - The mechanical pain threshold of the mice was measured. The analgesic effects of the three doses of CNV1014802 were greater than those of the vehicle control group, with the 30 mg / kg dose group showing the highest effect (Figure 1F).

[0049] Gabapentin was dissolved in saline, and 50 mg / kg of gabapentin was orally administered. One hour after administration, miR-96 was increased. - / - The mechanical pain threshold of mice was measured. As a result, 50 mg / kg of Gabapentin can significantly improve the mechanical pain threshold of mice (difference in paw withdrawal threshold was 0.5 g ± 0.09 g) (Figure 2).

[0050] Example 2 This example is intended to illustrate the effectiveness of testing a pharmaceutical composition according to one embodiment. This pharmaceutical composition contains PF-06305591 and PF-05089771. The composition was dissolved in 30% DMSO / physiological saline (V / V), and 60 μg / kg of PF-06305591 and 4 mg / kg of PF-05089771 were orally administered by force, and miR-96 was detected 1 hour later. - / - The mechanical pain threshold of the mice was measured. As a result, the combination of PF-06305591 at 60 μg / kg and PF-05089771 at 4 mg / kg significantly reduced the miR-96 - / - The alleviation effect on mechanical pain in mice was very high and significantly higher than the effect of a single administration of 60 μg / kg PF-06305591 or 4 mg / kg PF-05089771 ( FIG. 3 ). In FIG. 3 , PF-5591 refers to PF-06305591, and PF-9771 refers to PF-05089771.

[0051] Example 3 This example is intended to illustrate the effectiveness of testing a pharmaceutical composition according to one embodiment. This pharmaceutical composition contains PF-06305591 and PF-06456384. The composition was dissolved in 10% DMSO / physiological saline (V / V), and 60 μg / kg of PF-06305591 and 2 mg / kg of PF-06456384 were orally administered by force, and miR-96 was detected 1 hour later. - / - The mechanical pain threshold of the mice was measured. As a result, the combination of PF-06305591 at 60 μg / kg and PF-06456384 at 2 mg / kg significantly reduced the miR-96 - / -The alleviation effect on mechanical pain in mice was very high and significantly higher than the effect of a single administration of 60 μg / kg PF-06305591 or 2 mg / kg PF-06456384 (Figure 4). In Figure 4, PF-5591 refers to PF-06305591, and PF-6384 refers to PF-06456384.

[0052] Example 4 This example is intended to illustrate the effectiveness of testing a pharmaceutical composition according to one embodiment. This pharmaceutical composition contains PF-06456384 and PF-04885614. The composition was dissolved in 10% DMSO / saline (V / V) and PF-06456384 (2 mg / kg) and PF-04885614 (180 μg / kg) were orally administered forcibly, and the miR-96 activity was measured 1 hour after the administration. - / - The mechanical pain threshold of the mice was measured. As a result, the miR-96 - / - The alleviation effect on mechanical pain in mice was very high and significantly higher than the effect of a single administration of 180 μg / kg PF-04885614 or 2 mg / kg PF-06456384 ( FIG. 5 ). In FIG. 5 , PF-5614 refers to PF-04885614, and PF-6384 refers to PF-06456384.

[0053] Example 5 This example demonstrates the analgesic effect of the drug when applied to the skin. To study the analgesic effect of cutaneous application of Nav1.7 and Nav1.8 inhibitors, we induced miR-96 expression by isoflurane. - / - Mice were anesthetized, and 10 μl of a composition of 1 mg / ml PF-06305591 and 20 mg / ml PF-05089771 dissolved in 30% DMSO / saline (V / V) was applied to the left paw of each mouse. Five minutes after application, the mouse was removed from the anesthesia machine and placed under a plexiglass cover on an iron rack. Thirty minutes after application, the mechanical pain threshold of the mouse was measured.

[0054] As a result, application of PF-06305591 and PF-05089771 significantly increased the expression of miR-96 - / - It can significantly improve the mechanical pain threshold of mice (Figure 6A). Here, PF-5591 refers to PF-06305591, and PF-9771 refers to PF-05089771.

[0055] As above, 10 μl of 1 mg / ml PF-06305591 and 10 mg / ml PF-06456384 dissolved in 10% DMSO / saline (V / V) were applied for 30 minutes, and then miR-96 was detected. - / - The mechanical threshold of the mice was significantly improved (Figure 6B). Here, PF-6384 refers to PF-06456384 and PF-5591 refers to PF-06305591.

[0056] As described above, 10 mg / ml PF-06456384 and 2 mg / ml PF-04885614 dissolved in 10% DMSO / saline (V / V) were applied in an amount of 10 μl for 30 minutes, and then miR-96 was detected. - / - The mechanical threshold of the mice was significantly improved (FIG. 6C). Here, PF-6384 refers to PF-06456384 and PF-5614 refers to PF-04885614.

[0057] Example 6 This example demonstrates the antipruritic effect of a skin application method. To study the antipruritic effect of skin application of Nav1.7 and Nav1.8 inhibitors, 8-week-old C57 / Bl6 mice (6 mice) were anesthetized with isoflurane, the hair behind the ears and on the neck of the mice were shaved, and 50 μl of a composition of 1 mg / ml PF-06305591 and 10 mg / ml PF-06456384 dissolved in 10% DMSO / saline (V / V) was applied. Five minutes after application, the mice were removed from the anesthesia machine and 50 μl of 12 mM chloroquine (Chloroquine, Sigma Aldrich, CAS 50-63-5) was injected into the skin of the application area. Videos were recorded and the number of times the mice scratched was counted. Statistical analysis showed that application of the composition of PF-06305591 and PF-06456384 significantly suppressed chloroquine-induced itch (Figure 7). In Figure 7, PF-6384 refers to PF-06456384 and PF-5591 refers to PF-06305591.

[0058] As described above, 8-week-old C57 / Bl6 mice (6 mice) were anesthetized with isoflurane, the hair behind the ears and on the neck of the mice were shaved, and 50 μl of a composition of 1 mg / ml PF-06305591 and 20 mg / ml PF-05089771 dissolved in 30% DMSO / saline (V / V) was applied. Five minutes after application, the mice were removed from the anesthesia machine and 50 μl of 12 mM chloroquine was injected into the skin of the application area. A video was recorded and the number of times the mice scratched was counted. Statistical analysis showed that application of the composition of PF-06305591 and PF-05089771 significantly suppressed chloroquine-induced itch (Figure 8). In Figure 8, PF-5591 refers to PF-06305591, and PF-9771 refers to PF-05089771.

[0059] As above, 50 μl of a composition of 10 mg / ml PF-06456384 and 2 mg / ml PF-04885614 dissolved in 10% DMSO / saline (V / V) was applied, and 5 minutes after application, the mouse was removed from the anesthesia machine and 50 μl of 12 mM chloroquine was injected into the skin of the application area. The number of times the mouse scratched was counted. As a result, application of the composition of PF-06456384 and PF-04885614 can significantly suppress chloroquine-induced itch (Figure 8). In Figure 8, PF-6384 refers to PF-06456384, and PF-5614 refers to PF-04885614.

[0060] Comparative Example This comparative example is intended to illustrate the efficacy of the combined use of CNV1014802 and PF-04885614. CNV1014802 and PF-04885614 were dissolved in 30% DMSO / saline, and then 30 mg / kg of CNV1014802 and 180 μg / kg of PF-04885614 were orally administered by force, and miR-96 was detected 1 hour later. - / - The mechanical pain threshold of the mice was measured. As a result, the effect of combining 30 mg / kg CNV1014802 and 180 μg / kg PF-04885614 on the alleviation of mechanical pain in miR-96- / - mice was not higher than the effect of single administration of 30 mg / kg CNV1014802 or 180 μg / kg PF-04885614 (Figure 9). In Figure 9, PF-5614 refers to PF-04885614.

[0061] From the above, in the present invention, the forced oral administration or skin application of a pharmaceutical composition containing PF-06305591 and PF-05089771, a pharmaceutical composition containing PF-06305591 and PF-06456384, or a pharmaceutical composition containing PF-06456384 and PF-04885614 can significantly relieve analgesia. In addition, the skin application of a pharmaceutical composition containing PF-06305591 and PF-06456384, a composition containing PF-06305591 and PF-05089771, or a pharmaceutical composition containing PF-06456384 and PF-04885614 can also provide antipruritic effects. In a comparative example, when the Nav1.7 inhibitor CNV1014802 and the Nav1.8 inhibitor PF-04885614 were used in combination for analgesia, the analgesic effect was not higher than that of a single inhibitor. Thus, the formulation of certain Nav1.7 inhibitor and Nav1.8 inhibitor compositions provided herein can prevent and / or treat disorders associated with Nav1.7 and Nav1.8 activity (including, but not limited to, pain and itch).

Claims

1. A pharmaceutical composition having analgesic and / or antipruritic function, the pharmaceutical composition comprises a Nav1.7 inhibitor and a Nav1.8 inhibitor; The weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.001-5000); The Nav1.7 inhibitor is a compound having a structure represented by formula (1) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (3) or a pharma- ceutically acceptable salt thereof; or The Nav1.7 inhibitor is a compound having a structure represented by formula (2) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (3) or a pharma- ceutically acceptable salt thereof; or The Nav1.7 inhibitor is a compound having a structure represented by formula (2) or a pharma- ceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having a structure represented by formula (4) or a pharma- ceutically acceptable salt thereof; The structures of formula (1), formula (2), formula (3), and formula (4) are 【Chemistry 1】 2. A pharmaceutical composition comprising:

2. The pharmaceutical composition of claim 1, wherein the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.001-50).

3. The pharmaceutical composition according to claim 1, wherein the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.005-10).

4. The pharmaceutical composition of claim 1, wherein the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.01-2).

5. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition comprises a pharma- ceutically acceptable carrier.

6. 6. The pharmaceutical composition of claim 5, wherein the pharma- ceutically acceptable carrier is one or more selected from solvents, excipients, dispersion media, coating agents, skin permeation agents, isotonic agents, and absorption delaying agents.

7. 6. The pharmaceutical composition of claim 5, wherein the pharma- ceutically acceptable carrier is at least one selected from starch, microcrystalline cellulose, lactose, sucrose, mannitol, inorganic salts including toluenesulfonates and hydrochlorides, hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, sodium alginate, agar, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carbopol, polyvinyl alcohol, acrylic resins, chitosan, beeswax, and stearic acid.

8. The pharmaceutical composition according to claim 5, wherein 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.

9. 10. Use of a pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment and / or prevention of a disease associated with voltage-gated sodium ion channels.

10. The voltage-dependent sodium ion channel is Na ｖ 1.7 and / or Na ｖ 10. The use according to claim 9, wherein the molecular weight is 1.

8.

11. The use according to claim 9 or 10, wherein the disease is selected from pain and / or itch.

12. The use according to claim 11, wherein the pain is at least one selected from traumatic pain, intraoperative pain, postoperative pain, inflammatory pain, neuropathic pain, headache, cervical pain, shoulder pain, low back pain, toothache, chest pain, abdominal pain, lower limb pain, muscular and skeletal pain, fibromyalgia, glossopharyngeal neuralgia, trigeminal neuralgia, sciatica, neuralgia associated with multiple sclerosis, diabetic neuralgia, cancer-related pain, post-herpetic neuralgia, HIV-related neuralgia, post-burn pain, arthralgia, menstrual pain, and visceral pain.

13. The use according to claim 11, wherein the itch is one selected from histamine-dependent itch, non-histamine-dependent itch, chemical itch, mechanical itch, itch caused by insect bites, itch caused by liver disease, and itch caused by chronic kidney disease.

14. The use according to claim 9 or 10, wherein the pharmaceutical composition is administered as a drug via at least one route selected from oral, buccal, intramuscular, subcutaneous injection, inhalation, skin application, skin spray, skin patch, ocular, nasal mucosa, rectal, vaginal, aural, and dialysis.

Images