Pharmaceutical compositions having analgesic and / or antipruritic functions and their use

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 of related applications This application claims priority to China Patent Application No. 202210147495.5, filed on 17 February 2022, the contents of which are incorporated herein by reference.

[0002] This invention relates to the field of medicinal chemistry, and more specifically to a pharmaceutical composition having analgesic and / or antipruritic functions and its use. [Background technology]

[0003] Pain and itching are clinically important issues, and voltage-gated sodium ion channels (Nav1.7 and Nav1.8) are highly expressed in somatosensory neurons and play a crucial role in the perception of itching, mechanical sensation, and pain. Studies have shown that Nav1.7 and Nav1.8 have different expression patterns in the dorsal root ganglia (DRG). In mice, Nav1.7 is expressed in large, medium, and small neurons, but is more highly expressed in small and medium neurons, while Nav1.8 is mainly expressed in small and medium neurons, and is absent or 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 in humans, and knocking out Nav1.7 also eliminates pain 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 clinical studies have failed to achieve the expected analgesic effect (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.). While there are numerous Nav1.7-selective small molecule inhibitors and Nav1.8-selective small molecule inhibitors, there are currently no reports of clinical studies using combination therapy of Nav1.7 and Nav1.8 inhibitors to treat and / or prevent pain. [Overview of the project]

[0004] The object of the present invention is to overcome the inadequacy of the 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 function and its use.

[0005] The inventors discovered that after nerve injury, downregulation of miR-96 simultaneously upregulates the expression of Nav1.7 and Nav1.8. Furthermore, this may not only increase the number of DRG neurons co-expressing Nav1.7 and Nav1.8, but also suppress their activity. This is presumed to result in higher analgesia, antipruritic, and even anesthetic effects. Therefore, the present invention screened synergistic combination formulations of Nav1.7 inhibitors and Nav1.8 inhibitors using miR-96 knockout mice as an in vivo model.

[0006] To achieve the above objective, a first aspect of the present invention provides a pharmaceutical composition having analgesic and / or antipruritic functions. This 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 the structure represented by formula (1) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (3) or a pharmaceutically acceptable salt thereof. Alternatively, the Nav1.7 inhibitor is a compound having the structure represented by formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (3) or a pharmaceutically acceptable salt thereof. Alternatively, the Nav1.7 inhibitor is a compound having the structure represented by formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (4) or a pharmaceutically acceptable salt thereof. The structures of equations (1), (2), (3), and (4) are as follows. [ka]

[0007] According to a second aspect of the present invention, the use of the pharmaceutical composition in the manufacture of a drug for treating and / or preventing diseases related to voltage-gated sodium ion channels is provided.

[0008] The pharmaceutical composition provided in this invention can significantly relieve pain and itchiness, treat and / or prevent premature ejaculation caused by tactile hypersensitivity, and can also be used as an anesthetic. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1A shows the mechanical threshold of miR-96- / - mice in Example 1. Figures 1B-F show the pain-relieving effects of forced oral administration 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. [Figure 2] Example 1 demonstrates the pain-relieving effect of forced oral administration of gabapentin on miR-96- / - mice. n=8, ***P<0.001, Mann-Whitney test. [Figure 3] Example 2 demonstrates the pain-relieving effect of a pharmaceutical composition containing PF-06305591 and PF-05089771 on miR-96- / - mice administered by forced oral administration. n=8,**P<0.01,***P<0.001, One-way ANOVA. [Figure 4] Example 3 demonstrates the pain-relieving effect of a pharmaceutical composition containing PF-06305591 and PF-06456384 on miR-96- / - mice administered orally. n=8,**P<0.01,***P<0.001,One-way ANOVA; [Figure 5]Example 4 shows the analgesic effect on miR-96- / - mice by forced oral administration of the pharmaceutical composition containing PF-06456384 and PF-04885614. n = 8, *P < 0.05, **P < 0.01, One way ANOVA. [Figure 6] Figures 6A - C show the analgesic effect on miR-96- / - mice by topical administration of the pharmaceutical composition containing PF-06305591 and PF-05089771, the pharmaceutical composition containing PF-06305591 and PF-06456384, and the pharmaceutical composition containing PF-06456384 and PF-04885614 in Example 5, respectively. n = 8, *P < 0.05, **P < 0.01, One way ANOVA. [Figure 7] Example 6 shows the alleviating effect on itch induced by chloroquine by topical application of the pharmaceutical composition containing PF-06305591 and PF-06456384. n = 6, ****P < 0.0001, unpaired t - test. [Figure 8] Example 6 shows the alleviating effect on itch induced by chloroquine by topical application of the pharmaceutical composition containing PF-06305591 and PF-05089771 or the pharmaceutical composition containing PF-06456384 and PF-04885614. n = 6, ****P < 0.0001, unpaired t - test. [Figure 9] The comparative example shows that the analgesic effect on miR-96- / - mice by forced oral administration of the pharmaceutical composition containing CNV1014802 and PF-04885614 is not higher than the analgesic effect by a single CNV1014802 or PF-04885614. n = 8, ***P < 0.00, Mann - Whitney test.

Modes for Carrying Out the Invention

[0010] The ranges and any values disclosed in this specification are not limited to the exact ranges or values, but these ranges or values should be understood to include values approaching such ranges or values. In the case of numerical ranges, the endpoint values of each range, the endpoint values of each range and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges. These numerical ranges shall be regarded as those specifically disclosed in this specification.

[0011] In the present invention, the "pharmaceutically acceptable salt" can be prepared from inorganic acids or organic acids. 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 "pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier" means a compound similar to an amino acid formed by the amino group of the compound and the carboxyl group of the amino acid. For example, compounds similar to amino acids formed with valine, threonine, phenylalanine, etc. can be mentioned.

[0013] "Isomers" include, but are not limited to, stereoisomers, enantiomers, and diastereomers.

[0014] "Solvate" refers to a complex formed by a compound having a structure represented by formula (1) - formula (4) or a derivative thereof binding to a solvent.

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

[0016] "Hydrate" means a compound containing water, in which water can be bound to the moiety represented by formula (1) - formula (4) through a coordination bond or a covalent bond.

[0017] "Polymorphism" refers to different crystalline structures of a crystalline compound. Polymorphisms of compounds can arise from differences in the deposition of crystalline forms (depositional polymorphism) or from differences in the deposition of different conformational isomers of the same molecule (structural polymorphism).

[0018] A "prodrug," also known as a precursor drug, drug precursor, or progenitor, is a compound obtained by chemically modifying the structure of a drug. It is inactive or has low activity in vitro, but in vivo, it undergoes enzymatic or non-enzymatic transformation to release an active drug and exert its therapeutic effect. For example, the amino groups in formulas (1) to (4) form compounds such as amides, amino esters, and amidines after structural modification.

[0019] In a first aspect of the present invention, a pharmaceutical composition having analgesic and / or antipruritic functions is provided. This composition comprises 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), and 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 the following: a structure represented by formula (1) (abbreviated as compound 1) or formula (2) (abbreviated as compound 2) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed on an amino acid as a support, an isomer, a solvide, 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 the following: a structure represented by formula (3) (abbreviated as compound 3) or formula (4) (abbreviated as compound 4) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable amino acid-like compound formed on an amino acid as a support, an isomer, a solvide, 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 the structure represented by formula (1) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (3) or a pharmaceutically 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 the structure represented by formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (3) or a pharmaceutically acceptable salt thereof.

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

[0027] According to some embodiments of the present invention, the Nav1.7 inhibitor is a compound having the structure represented by formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by (4) or a pharmaceutically 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 combinations of Nav1.7 inhibitors and Nav1.8 inhibitors described above, compounds (1)-(4) can also form effective compositions with other Nav1.7 inhibitors or other Nav1.8 inhibitors that are known to those skilled in the art and have inhibitory activity.

[0030] According to some embodiments of the present invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

[0031] Preferably, the pharmaceutically acceptable carrier is one or more selected from solvents, excipients, dispersion media, coating agents, skin permeators, isotonic agents, and absorption retarders.

[0032] More preferably, the pharmaceutically 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, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, Carbopol, polyvinyl alcohol, acrylic resin, 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 relative to the total weight of the pharmaceutical composition is 0.0001-99.9999% by weight.

[0034] A second aspect of the present invention provides the use of the pharmaceutical composition in the manufacture of a drug for treating and / or preventing diseases related to voltage-gated sodium ion channels.

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

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

[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. Examples include at least one of headache, cervical pain, shoulder pain, lower back pain, toothache, chest pain, abdominal pain, leg pain, muscle and skeletal pain, fibromyalgia, glossopharyngeal neuralgia, trigeminal neuralgia, sciatica, multiple sclerosis-related neuralgia, diabetic neuralgia, cancer-related pain, postherpetic neuralgia, HIV-related neuralgia, post-burn pain, arthralgia, menstrual pain, and visceral pain.

[0038] In this invention, inflammatory pain refers to pain caused by the stimulation of sensory nerve endings by various mediators such as prostaglandins, inflammatory factors, chemokines, and adenosine generated by tissue damage. Neuropathic pain refers to pain caused by damage to the central nervous system or peripheral nervous system, or subsequent dysfunction.

[0039] Itching refers to skin itching and the discomfort thereof, and includes itching caused by skin diseases, as well as pruritus, which is skin itching alone and does not involve a primary skin disorder. The itching described in this invention includes at least one selected from histamine-dependent itching, non-histamine-dependent itching, chemical itching, mechanical itching, itching caused by insect bites, and itching caused by chronic kidney disease.

[0040] Furthermore, the present invention relates to a voltage-gated sodium ion channel Na v 1.7 and / or Na vThis also relates to methods for treating diseases related to 1.8. These methods include administering the above-mentioned pharmaceutical composition to a subject. Here, administration can be carried out in a conventional manner. Routes of administration include, but are not limited to, oral, intraoral, injection (e.g., intramuscular, subcutaneous, subarachnoid, epidural, intravenous), respiratory, transdermal (e.g., topical application, skin spray, skin patch), transocular, transnasal mucosa, transrectal, transvaginal, transaural, and dialysis. The subject may be an animal, including mammals (especially primates such as humans), rodents (e.g., rats), livestock, poultry, pets, and laboratory animals. Healthcare professionals can select the dosage according to the subject's physical condition. For example, for adults, the dosage is 0.01-10 mg / kg or 0.01-1 mg / cm³. 2 That's fine.

[0041] According to the present invention, the term "treatment" refers to measures taken to treat, prevent or suppress a disease or medical condition that produce a clinically desirable or beneficial effect (including, but not limited to, the alleviation or reduction of one or more symptoms, or the resolution, delay, or cessation of a disease or disease progression).

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

[0043] Example 1 This example illustrates the test effect of a single drug compound. To screen for analgesics with superior oral efficacy, eight miR-96 cubs aged 3-6 months were used. - / - The analgesic effects of forced oral administration of Nav1.7 inhibitors and Nav1.8 inhibitors were measured using mice (Kunshan Pengji Kaifeng Biotechnology Co., Ltd.).

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

[0045] PF-06456384 (a compound having the 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 = 0.01 nM for hNav1.7) was dissolved in 10% DMSO / saline (V / V), and 1 hour after forced oral administration of 1 mg / kg, 2 mg / kg or 3 mg / kg of PF-0645638 at, miR-96 - / - The mechanical pain threshold of the mouse was measured. As a result, the analgesic effects of the above three doses of PF-06456384 were all significantly higher than those of the solvent control group, and the effect of the 2 mg / kg dose group was the highest (Figure 1C).

[0046] PF-05089771 (a compound having the structure represented by formula (1), 4-[2-(3-amino-1H-pyrazole-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-4-thiazolylbenzenesulfonamide tosylate, IC50 = 11 nM for hNav 1.7) was dissolved in 30% DMSO / physiological saline (V / V), and 2 mg / kg, 4 mg / kg, or 6 mg / kg of PF-05089771 was administered orally, and miR-96 was measured 1 hour later. - / - The mechanical pain threshold was measured in mice. As a result, the analgesic effect of PF-05089771 at doses of 4 mg / kg and 6 mg / kg was significantly higher than that of the solvent control group, and 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 the structure represented by formula (4), 1-methyl-1-[4-(4-trifluoromethoxyphenyl)-1H-imidazole-2-yl]ethylamine, IC50 = 53 nM to hNav 1.8) was dissolved in 10% DMSO / physiological saline (V / V), and PF-04885614 was administered orally at concentrations of 90 μg / kg, 180 μg / kg, or 270 μg / kg. 1 hour after this, miR-96 was measured. - / - The mechanical pain threshold was measured in mice. As a result, the analgesic effect of PF-04885614 at doses of 180 μg / kg and 270 μg / kg was significantly higher than that of the solvent control group, with the 180 μg / kg dose group showing the greatest effect (Figure 1E).

[0048] CNV1014802 (IC50 = 32 μM for hNav 1.7) was dissolved in 30% DMSO / physiological saline (V / V), and 20 mg / kg, 30 mg / kg, or 40 mg / kg of CNV1014802 was forcibly administered orally. One hour later, miR-96 was administered. - / - The mechanical pain threshold was measured in mice. The analgesic effect of all three doses of CNV1014802 was higher than that of the solvent control group, with the 30 mg / kg dose group showing the greatest effect (Figure 1F).

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

[0050] Example 2 This implementation is intended to explain the test effect of a pharmaceutical composition according to one embodiment. This pharmaceutical composition contains PF-06305591 and PF-05089771. Dissolve in 30% DMSO / physiological saline (V / V), and administer 60 μg / kg of PF-06305591 and 4 mg / kg of PF-05089771 orally. One hour after administration, miR-96 - / - The mechanical pain threshold in mice was measured. As a result, the miR-96 was reduced by the combined use of 60 μg / kg PF-06305591 and 4 mg / kg PF-05089771. - / - The alleviating effect on mechanical pain in mice was very high, significantly higher than that of single administration of 60 μg / kg PF-06305591 or 4 mg / kg PF-05089771 (Figure 3). In Figure 3, PF-5591 refers to PF-06305591, and PF-9771 refers to PF-05089771.

[0051] Example 3 This implementation is intended to explain the test effect of a pharmaceutical composition according to one embodiment. This pharmaceutical composition contains PF-06305591 and PF-06456384. Dissolve in 10% DMSO / physiological saline (V / V), and administer 60 μg / kg of PF-06305591 and 2 mg / kg of PF-06456384 orally. One hour after administration, miR-96 - / - The mechanical pain threshold in mice was measured. As a result, the miR-96 was reduced by the combined use of 60 μg / kg PF-06305591 and 2 mg / kg PF-06456384. - / -The alleviating effect on mechanical pain in mice was very high, significantly higher than the effect of 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 implementation is intended to explain the test effect of a pharmaceutical composition according to one embodiment. This pharmaceutical composition contains PF-06456384 and PF-04885614. Dissolve in 10% DMSO / physiological saline (V / V), and administer 2 mg / kg of PF-06456384 and 180 μg / kg of PF-04885614 orally. One hour after administration, miR-96 - / - The mechanical pain threshold in mice was measured. As a result, miR-96 was measured using PF-06456384 at 2 mg / kg and PF-04885614 at 180 μg / kg. - / - The alleviating effect on mechanical pain in mice was very high, significantly higher than the effect of single administration of 180 μg / kg PF-04885614 or 2 mg / kg PF-06456384 (Figure 5). In Figure 5, PF-5614 refers to PF-04885614, and PF-6384 refers to PF-06456384.

[0053] Example 5 This embodiment demonstrates the analgesic effect achieved by applying the substance to the skin. To study the analgesic effects of topical application of Nav1.7 and Nav1.8 inhibitors, miR-96 was treated with 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 / physiological saline (V / V) was applied to the left foot of each mouse. Five minutes after application, the mice were removed from the anesthesia machine and placed under a plexiglass cover on an iron rack, and the mechanical pain threshold of the mice was measured 30 minutes after application.

[0054] As a result, the application of PF-06305591 and PF-05089771 is miR-96 - / - The mechanical pain threshold in mice can be significantly improved (Figure 6A). Here, PF-5591 refers to PF-06305591, and PF-9771 refers to PF-05089771.

[0055] Similarly, after 30 minutes, 10 μl of a composition containing 1 mg / ml PF-06305591 and 10 mg / ml PF-06456384 dissolved in 10% DMSO / physiological saline (V / V) was applied, and miR-96 - / - 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] Similarly, after 30 minutes, 10 μl of a composition containing 10 mg / ml PF-06456384 and 2 mg / ml PF-04885614 dissolved in 10% DMSO / physiological saline (V / V) was applied, and miR-96 - / - The mechanical threshold of the mice was significantly improved (Figure 6C). Here, PF-6384 refers to PF-06456384, and PF-5614 refers to PF-04885614.

[0057] Example 6 This embodiment demonstrates the antipruritic effect achieved by applying the substance to the skin. To study the antipruritic effects of topical Nav1.7 and Nav1.8 inhibitors, six 8-week-old C57 / Bl6 mice were anesthetized with isoflurane. The hair behind the ears and on the neck of the mice was 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 chamber, and 50 μl of 12 mM chloroquine (Chloroquine, Sigma Aldrich, CAS 50-63-5) was injected into the skin of the applied area. Video recording was performed, and the number of times the mice scratched was counted. Statistical analysis showed that topical application of the PF-06305591 and PF-06456384 compositions significantly suppressed chloroquine-induced itching (Figure 7). In Figure 7, PF-6384 refers to PF-06456384, and PF-5591 refers to PF-06305591.

[0058] Similarly, six 8-week-old C57 / Bl6 mice were anesthetized with isoflurane. The hair behind the ears and on the neck of the mice was 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 applied area. Video was recorded, and the number of times the mice scratched was counted. Statistical analysis showed that application of the compositions of PF-06305591 and PF-05089771 significantly suppressed chloroquine-induced itching (Figure 8). In Figure 8, PF-5591 refers to PF-06305591, and PF-9771 refers to PF-05089771.

[0059] Similarly to the above, 50 μl of compositions containing 10 mg / ml PF-06456384 and 2 mg / ml PF-04885614 dissolved in 10% DMSO / saline (V / V) was applied to the surface. 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 applied area. The number of times the mice scratched was counted. As a result, application of the compositions of PF-06456384 and PF-04885614 significantly suppressed chloroquine-induced itching (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 explain the test effect of using CNV1014802 and PF-04885614 in combination. After dissolving CNV1014802 and PF-04885614 in 30% DMSO / saline, 30 mg / kg of CNV1014802 and 180 μg / kg of PF-04885614 were forcibly administered orally, and 1 hour later, miR-96 was administered. - / - The mechanical pain threshold in mice was measured. As a result, the combined effect of 30 mg / kg CNV1014802 and 180 μg / kg PF-04885614 on mechanical pain in miR-96- / - mice was not greater than the effect of monotherapy with either 30 mg / kg CNV1014802 or 180 μg / kg PF-04885614 (Figure 9). In Figure 9, PF-5614 refers to PF-04885614.

[0061] Based on the above, in the present invention, forced oral administration or topical 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 pain. Furthermore, topical 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 relieve itching. In a comparative example, when the Nav1.7 inhibitor CNV1014802 and the Nav1.8 inhibitor PF-04885614 were used in combination for pain relief, the analgesic effect was not higher than that of a single inhibitor. In other words, the formulations of the specific Nav1.7 and Nav1.8 inhibitor compositions provided in the present invention can prevent and / or treat diseases related to Nav1.7 and Nav1.8 activity (including, but not limited to, pain and itching).

Claims

1. A pharmaceutical composition for analgesia and / or antipruritic purposes, 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:(0.01-10). The Nav1.7 inhibitor is a compound having the structure represented by formula (1) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (3) or a pharmaceutically acceptable salt thereof, or The Nav1.7 inhibitor is a compound having the structure represented by formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (3) or a pharmaceutically acceptable salt thereof, or The Nav1.7 inhibitor is a compound having the structure represented by formula (2) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound having the structure represented by formula (4) or a pharmaceutically acceptable salt thereof. The structures of equations (1), (2), (3), and (4) are as follows: 【Chemistry 1】 A pharmaceutical composition characterized by being such.

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

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable carrier is one or more selected from solvents, excipients, dispersion media, coating agents, skin permeators, isotonic agents, and absorption retarders.

5. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable carrier is at least one selected from starch, microcrystalline cellulose, lactose, sucrose, mannitol, inorganic salts including toluenesulfonate and hydrochloride, hydroxypropyl cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, sodium alginate, agar, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, Carbopol, polyvinyl alcohol, acrylic resin, chitosan, beeswax, and stearic acid.

6. The pharmaceutical composition according to claim 3, wherein the total content of the Nav1.7 inhibitor and the Nav1.8 inhibitor is 0.0001-99.9999% by weight of the total weight of the pharmaceutical composition.

7. Use of the pharmaceutical composition according to claim 1 in the manufacture of a drug for treating and / or preventing diseases related to voltage-gated sodium ion channels.

8. The voltage-gated sodium ion channel is Na ｖ 1.7 and / or Na ｖ The use according to claim 7, wherein the ratio is 1.

8.

9. The use according to claim 7, wherein the disease is selected from pain and / or itching.

10. The use according to claim 9, wherein the pain is at least one selected from traumatic pain, intraoperative pain, postoperative pain, inflammatory pain, neuropathic pain, headache, cervical pain, shoulder pain, lower back pain, toothache, chest pain, abdominal pain, leg pain, muscle and skeletal pain, fibromyalgia, glossopharyngeal neuralgia, trigeminal neuralgia, sciatica, neuralgia related to multiple sclerosis, diabetic neuralgia, cancer-related pain, postherpetic neuralgia, HIV-related neuralgia, post-burn pain, arthralgia, menstrual pain, and visceral pain.

11. The use according to claim 9, wherein the itching is one selected from histamine-dependent itching, non-histamine-dependent itching, chemical itch, mechanical itch, itching caused by insect bites, itching caused by liver disease, and itching caused by chronic kidney disease.

12. The use according to claim 7, wherein the pharmaceutical composition is a drug whose route of administration is selected from at least one of the following: oral, intraoral, intramuscular injection, subcutaneous injection, inhalation, topical application to the skin, skin spray, skin patch, transocular, transnasal mucosa, transrectal, transvaginal, transaural, and dialysis.

Images