WO2023155837A1 - 具有镇痛和/或止痒功能的药物组合物及其用途 - Google Patents

具有镇痛和/或止痒功能的药物组合物及其用途 Download PDF

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WO2023155837A1
WO2023155837A1 PCT/CN2023/076481 CN2023076481W WO2023155837A1 WO 2023155837 A1 WO2023155837 A1 WO 2023155837A1 CN 2023076481 W CN2023076481 W CN 2023076481W WO 2023155837 A1 WO2023155837 A1 WO 2023155837A1
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inhibitor
pain
pharmaceutical composition
formula
pharmaceutically acceptable
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French (fr)
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刘健平
彭晓梅
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昆山彭济凯丰生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a pharmaceutical composition with analgesic and/or antipruritic functions and its application.
  • Voltage-gated sodium channel Voltage-gated sodium channel
  • Nav1.8 Voltage-gated sodium channel
  • DRG dorsal root ganglion
  • PF-05089771 is a highly potent Nav1.7 inhibitor, but the analgesic effect in clinical studies is poor (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.). Although there are many Nav1.7 selective small molecule inhibitors and many Nav1.8 selective small molecule inhibitors, there is no clinical trial of combining Nav1.7 inhibitors and Nav1.8 inhibitors to treat and/or prevent pain. research reports.
  • the purpose of the present invention is to provide a pharmaceutical composition with analgesic and/or antipruritic functions and its use in order to overcome the technical problem of poor curative effect of single targeting Nav1.7 or Nav1.8 existing in the prior art .
  • the inventors of the present invention have conducted in-depth studies and speculated that the downregulation of miR-96 not only upregulates the expression of Nav1.7 and Nav1.8 after nerve injury, but also may increase the number of DRG neurons that co-express Nav1.7 and Nav1.8, Simultaneously inhibiting the activity of Nav1.7 and Nav1.8 may achieve better analgesic, antipruritic and even anesthetic effects. Therefore, the present invention uses miR-96 knockout mice as an in vivo model to screen the Nav1.7 inhibitor and Nav1.8 inhibitor prescriptions with synergistic effect.
  • the first aspect of the present invention provides a pharmaceutical composition with analgesic and/or antipruritic functions, the composition contains 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 represented by formula (1) or a pharmaceutically acceptable salt thereof, and the Nav1.8 inhibitor is a compound represented by formula (3) or a pharmaceutically acceptable salt thereof Salt;
  • the Nav1.7 inhibitor is a compound represented by formula (2) or a pharmaceutically acceptable salt thereof
  • the Nav1.8 inhibitor is a compound represented by formula (3) or a pharmaceutically acceptable salt thereof. accepted salt
  • the Nav1.7 inhibitor is a compound represented by formula (2) or a pharmaceutically acceptable salt thereof
  • the Nav1.8 inhibitor is a compound represented by formula (4) or a pharmaceutically acceptable salt thereof. accepted salt
  • the second aspect of the present invention provides the application of the aforementioned pharmaceutical composition in the preparation of medicines for treating and/or preventing diseases related to voltage-gated sodium ion channels Nav1.7 and Nav1.8.
  • the pharmaceutical composition provided by the invention can significantly relieve pain and relieve itching, and can also treat and/or prevent touch-sensitive premature ejaculation or be used for anesthesia.
  • a in Fig. 1 is the mechanical threshold value of miR-96 -/- mice in Example 1;
  • B, C, D, E, F in Fig. 1 are gavage PF-06305591, PF-06456384, PF-05089771, PF respectively -04885614, CNV1014802 are used to relieve pain in miR-96 -/- mice.
  • Fig. 2 is the effect of intragastric administration of Gabapentin (gabapentin) for alleviating pain in miR-96 -/- mice in Example 1.
  • n 8, ***P ⁇ 0.001, Mann-Whitney test;
  • Fig. 3 is the effect of intragastric administration of the pharmaceutical composition containing PF-06305591 and PF-05089771 in Example 2 for relieving pain in miR-96 -/- mice.
  • Fig. 5 is the effect of intragastric administration of the pharmaceutical composition containing PF-06456384 and PF-04885614 in Example 4 for alleviating pain in miR-96 -/- mice.
  • A, B, and C in Fig. 6 are the pharmaceutical compositions containing PF-06305591 and PF-05089771 for external application on the skin in Example 5, the pharmaceutical compositions containing PF-06305591 and PF-06456384, and the pharmaceutical compositions containing PF-06456384 and PF-04885614
  • the effect of the pharmaceutical composition for alleviating the pain of miR-96 -/- mice. n 8, *P ⁇ 0.05, **P ⁇ 0.01, One way ANOVA;
  • Fig. 7 is the effect of external application of the pharmaceutical composition containing PF-06305591 and PF-06456384 on the skin in Example 6 for alleviating chloroquine-induced itching.
  • n 6, ****P ⁇ 0.0001, unpaired t-test;
  • Figure 8 is the effect of externally applying the pharmaceutical composition containing PF-06305591 and PF-05089771 on the skin in Example 6, or externally applying the pharmaceutical composition containing PF-06456384 and PF-04885614 for alleviating chloroquine-induced itching.
  • n 6, ****P ⁇ 0.0001, unpaired t-test;
  • Figure 9 shows that in the comparative example, the effect of intragastric administration of the pharmaceutical composition containing CNV1014802 and PF-04885614 for alleviating pain in miR-96 -/- mice was no better than the analgesic effect of CNV1014802 or PF-04885614 alone.
  • salts derived from inorganic acids include hydrochloric, tosylate, sulfuric, hydrobromic, nitric, phosphoric, and the like.
  • Salts derived from organic acids include acetic, propionic, glycolic, pyruvic, oxalic, malonic, citric, maleic, tartaric, pamoate, and the like.
  • a pharmaceutically acceptable amino acid-like compound formed with an amino acid as a carrier refers to a compound that is similar to an amino acid formed by the amino group on the compound and the carboxyl group on the amino acid, such as valine, threonine, phenylalanine, etc. Compounds similar to amino acids are formed.
  • Solvate refers to a complex formed by combining a compound represented by formula (1) to formula (4) or a derivative thereof with a solvent.
  • Immunotopic variants include, but are not limited to, deuterated variants.
  • “Hydrate” refers to a compound containing water, wherein the water can be connected to the moiety represented by formula (1)-formula (4) through a coordination bond, or can be combined with a covalent bond.
  • Polymorphs refer to different crystal structures of a crystalline compound. Different polymorphic forms of compounds may be due to differences in packing of crystal forms (packing polymorphism) or packing differences between different conformers of the same molecule (conformational polymorphism).
  • Prodrugs are also called prodrugs, drug precursors, prodrugs, etc., and refer to drugs that are inactive or less active in vitro after chemical structure modification, and release active drugs through enzymatic or non-enzymatic conversion in vivo.
  • Compounds that exert medicinal effects For example, the amine groups in formula (1) to formula (4) are structurally modified to form amides, amino esters, amidines and other compounds.
  • the first aspect of the present invention provides a pharmaceutical composition with analgesic and/or antipruritic functions, the composition contains a Nav1.7 inhibitor and a Nav1.8 inhibitor;
  • the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor may be 1:(0.001-50), preferably 1:(0.005-10), more preferably 1:(0.01-2).
  • the Nav1.7 inhibitor may have a structure represented by formula (1) (compound 1 for short) or formula (2) (compound 2 for short) or a pharmaceutically acceptable salt thereof, At least one of pharmaceutically acceptable amino acid compounds, isomers, solvates, isotopic variants, hydrates, polymorphs or prodrugs formed with amino acids as carriers,
  • the Nav1.8 inhibitor is a compound having a structure represented by formula (3) (compound 3 for short) or formula (4) (compound 4 for short) or a pharmaceutically acceptable salt thereof , at least one of pharmaceutically acceptable amino acid compounds, isomers, solvates, isotopic variants, hydrates, polymorphs or prodrugs formed with amino acids as carriers,
  • the Nav1.7 inhibitor is a compound represented by formula (1) or a pharmaceutically acceptable salt thereof
  • the Nav1.8 inhibitor is a compound having a structure represented by (3).
  • the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.005-0.5).
  • the Nav1.7 inhibitor is a compound represented by formula (2) or a pharmaceutically acceptable salt thereof
  • the Nav1.8 inhibitor is a compound having a structure represented by (3).
  • the weight ratio of Nav1.7 inhibitor to Nav1.8 inhibitor is 1:(0.01-0.1).
  • the Nav1.7 inhibitor is a compound represented by formula (2) or a pharmaceutically acceptable salt thereof
  • the Nav1.8 inhibitor is a compound having a structure represented by (4).
  • the weight ratio of the Nav1.7 inhibitor to the Nav1.8 inhibitor is 1:(0.05-2).
  • compounds (1)-(4) in addition to the combination of Nav1.7 inhibitors and Nav1.8 inhibitors mentioned above, compounds (1)-(4) can also be combined with those that can be imagined by those skilled in the art Other Nav1.7 inhibitors or other Nav1.8 inhibitors that inhibit activity form an effective combination regimen.
  • the pharmaceutical composition includes a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is selected from one or more of solvents, excipients, dispersion media, coatings, transdermal agents, isotonic agents, and absorption delaying agents.
  • the pharmaceutically acceptable carrier starch microcrystalline cellulose, lactose, sucrose, dew alcohol, inorganic salts, hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, sodium alginate , agar, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carbopol, polyvinyl alcohol, acrylic resin, chitosan, beeswax and stearic acid at least one.
  • the total content of the Nav1.7 inhibitor and the Nav1.8 inhibitor is 0.0001-99.9999% by weight.
  • the second aspect of the present invention provides the application of the aforementioned pharmaceutical composition in the preparation of medicines for treating and/or preventing diseases related to voltage-gated sodium ion channels.
  • the voltage-gated sodium ion channel may be Na v 1.7 and/or Na v 1.8.
  • the disease may be selected from pain and/or itching or premature ejaculation due to tactile sensitivity.
  • the pain is at least one selected from traumatic pain, intraoperative pain, postoperative pain, inflammatory pain, and neuropathic pain.
  • traumatic pain intraoperative pain, postoperative pain, inflammatory pain, and neuropathic pain.
  • inflammatory pain refers to the pain caused by stimulation of sensory nerve endings by various mediators such as prostaglandins, inflammatory factors, chemokines, adenosine, etc. produced by tissue damage, while neuropathic pain is caused by central nervous system or peripheral nervous system pain. Pain caused by injury or post-injury dysfunction.
  • Pruritus refers to skin itching and discomfort, including pruritus caused by skin diseases, and pruritus with only skin pruritus without primary skin damage.
  • the pruritus mentioned in the present invention can be selected from histamine-dependent itching, non-histamine At least one of dependent itch, chemical itch, mechanical itch, mosquito bite itch, liver disease itch, and chronic kidney disease itch.
  • the present invention also relates to a method for treating voltage-gated sodium ion channel Na v 1.7 and/or Na v 1.8 related diseases, the method comprising: administering the above pharmaceutical composition to a subject.
  • the route of administration can include but not limited to: oral, oral, injection (such as intramuscular injection, subcutaneous injection, intrathecal injection, epidural injection, intravenous injection, etc.), respiratory tract (aerosol), skin (such as skin rubbing, skin spraying, skin external application, etc.), eyes, nasal mucosa, rectum, vagina, ear, dialysis, etc.
  • the subject can be an animal, including mammals (especially primates, such as humans), rodents (such as mice), livestock, poultry, pets and experimental animals.
  • the medical personnel can choose the dosage according to the physical condition of the subject. Taking an adult as an example, the dosage can be 0.01-10 mg/kg or 0.01-1 mg/cm 2 .
  • treatment is meant to include any clinically desired or beneficial effect (including but not limited to relief or alleviation of one or more symptoms; regression, slowing or cessation of progression of a disease or condition). Therapeutic as well as preventive or suppressive measures for a disease or condition.
  • the mechanical pain threshold in the feet of miR-96 -/- mice was measured. Put 8 miR-96 -/- mice on the iron rack, cover them with plexiglass, and measure the basic mechanical threshold (paw withdrawal threshold, Paw withdrawal threshold), the average threshold of mice is 0.16g ⁇ 0.07g, see A in Figure 1, which belongs to abnormal mechanical pain (mechanical allodynia).
  • V/V 10% DMSO/normal saline
  • 30 ⁇ g/kg or 60 ⁇ g/kg or 90 ⁇ g/kg of PF-06305591 was administered for one hour to measure miR
  • the mechanical pain threshold of the feet of -96 -/- mice, the test results showed that the analgesic effect of 60 ⁇ g/kg and 90 ⁇ g/kg PF-063055911 was significantly better than that of the solvent control group, and the
  • Gabapentin was dissolved in normal saline, and after gavage of 50mg/kg Gabapentin for one hour, the mechanical pain threshold of miR-96 -/- mice was measured. The test results showed that 50mg/kg Gabapentin could significantly improve the mechanical pain threshold of mice (reduced The paw threshold difference is 0.5g ⁇ 0.09g), see Figure 2.
  • the pharmaceutical composition including PF-06305591 and PF-05089771 was dissolved with 30% DMSO/normal saline (V/V), and after gavage of 60 ⁇ g/kg of PF-06305591 and 4 mg/kg of PF-05089771 for one hour, miR-96 -/-
  • V/V DMSO/normal saline
  • the test results show that 60 ⁇ g/kg of PF-06305591 and 4mg/kg of PF-05089771 are used together to relieve the mechanical pain of miR-96 -/- mice very well and significantly It is better than the effect of 60 ⁇ g/kg PF-06305591 or 4mg/kg PF-05089771 alone, see Figure 3 ("PF-5591" in Figure 3 refers to "PF-06305591", "PF-9771” refers to "PF-05089771").
  • the pharmaceutical composition includes PF-06305591 and PF-06456384, dissolved with 10% DMSO/normal saline (V/V), and after gavage of 60 ⁇ g/kg of PF-06305591 and 2 mg/kg of PF-06456384 for one hour, miR was measured
  • V/V DMSO/normal saline
  • the pharmaceutical composition includes PF-06456384 and PF-04885614, dissolved with 10% DMSO/normal saline (V/V), and after gavage of 2 mg/kg of PF-06456384 and 180 ⁇ g/kg of PF-04885614 for one hour, miR was measured
  • V/V DMSO/normal saline
  • mice were anesthetized with isoflurane, and 10 ⁇ l of Nav1.
  • the composition of 1mg/ml PF-06305591 and 20mg/ml PF-05089771 of/normal saline (V/V) remove the mice from the anesthesia machine after 5 minutes and open under the machine glass cover on the iron frame, wipe The mechanical pain threshold of mice was measured 30 minutes after drug administration.
  • test results show that smearing PF-06305591 and PF-05089771 can significantly improve the mechanical pain threshold of miR-96 -/- mice, see A in Figure 6 (wherein, “PF-5591” refers to “PF-06305591”, “PF- 9771” refers to “PF-05089771”).
  • mice 8-week-old C57/Bl6 mice (6 mice) were anesthetized with isoflurane, and the hair on the neck behind the ears of the mice was shaved.
  • mice anesthetize 8-week-old C57/Bl6 mice (6 mice) with isoflurane, shave off the hair on the back and neck of the mice, and smear 50 ⁇ l of the solution dissolved in 30% DMSO/normal saline (V/V)
  • V/V DMSO/normal saline
  • the present invention adopts the pharmaceutical composition containing PF-06305591 and PF-05089771, or the pharmaceutical composition containing PF-06305591 and PF-06456384, or the pharmaceutical composition containing PF-06456384 and PF-04885614 by intragastric administration or external application on the skin It can significantly relieve pain; in addition, the composition containing PF-06305591 and PF-06456384, or the composition of PF-06305591 and PF-05089771 or the pharmaceutical composition of PF-06456384 and PF-04885614 can also relieve itching.
  • the specific Nav1.7 inhibitor and Nav1.8 inhibitor composition formulation 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.

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Abstract

具有镇痛和/或止痒功能的药物组合物及其用途。该组合物含Nav1.7抑制剂和Nav1.8抑制剂，所述Nav1.7抑制剂和Nav1.8抑制剂的重量比为1：(0.001-5000)。本发明的组合物能显著镇痛，同时也能止痒，且还能治疗和/或预防触觉敏感的早泄或用于麻醉。

Description

具有镇痛和/或止痒功能的药物组合物及其用途
相关申请的交叉引用
本申请要求2022年02月17日提交的中国专利申请202210147495.5的权益，该申请的内容通过引用被合并于本文。
技术领域
本发明涉及医药化学技术领域，具体涉及一种具有镇痛和/或止痒功能的药物组合物及其用途。
背景技术
疼痛和瘙痒是临床难题。电压门控钠离子通道(Voltage-gated sodium channel，Nav)Nav1.7和Nav1.8在躯体感觉神经元中高表达，在痒觉、机械感觉和痛觉的感知中起重要作用。研究表明Nav1.7和Nav1.8在背根神经节中(DRG)中表达模式不同，小鼠中Nav1.7在大中小神经元中都表达，且在中小神经元中表达更高，而Nav1.8主要在中小神经元中表达，在大神经元中不表达或表达非常低；中小DRG神经元中共表达Nav1.7和Nav1.8。Nav1.7的功能性缺失突变致使人先天无痛，敲除Nav1.7也使得小鼠无痛，这些研究结果表明可能单抑制Nav1.7就能止痛。PF-05089771是高效力的Nav1.7抑制剂，但在临床研究中的镇痛效果不佳(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.)。虽然已有很多Nav1.7选择性小分子抑制剂和很多Nav1.8选择性小分子抑制剂，但目前还没有联用Nav1.7抑制剂和Nav1.8抑制剂治疗和/或预防疼痛的临床研究的报道。
发明内容
本发明的目的是为了克服现有技术存在的单靶向Nav1.7或Nav1.8的治病效果差的技术问题，提供一种具有镇痛和/或止痒功能的药物组合物及其用途。
本发明的发明人经深入研究并推测，在神经损伤后miR-96下调不仅同时上调Nav1.7和Nav1.8的表达，而且可能使共同表达Nav1.7和Nav1.8的DRG神经元增多， 同时抑制Nav1.7和Nav1.8的活性可能取得更佳的镇痛、止痒、甚至是麻醉的效果。因此，本发明利用miR-96敲除小鼠为体内模型筛选了具有协同作用的Nav1.7抑制剂和Nav1.8抑制剂组方。
为了实现上述目的，本发明第一方面提供了一种具有镇痛和/或止痒功能的药物组合物，该组合物含有Nav1.7抑制剂和Nav1.8抑制剂；
所述Nav1.7抑制剂和Nav1.8抑制剂的重量比为1：(0.001-5000)；
所述Nav1.7抑制剂为具有式(1)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(3)所示结构的化合物或其药学上可接受的盐；
或者，所述Nav1.7抑制剂为具有式(2)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(3)所示结构的化合物或其药学上可接受的盐；
或者，所述Nav1.7抑制剂为具有式(2)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(4)所示结构的化合物或其药学上可接受的盐；
式(1)、式(2)、式(3)、式(4)的结构如下所示：
本发明第二方面提供了一种前述药物组合物在制备用于治疗和/或预防电压门控钠离子通道Nav1.7和Nav1.8相关的病症的药物中的应用。
本发明提供的药物组合物能够显著镇痛，同时也能止痒，并且还能够治疗和/或预防触觉敏感的早泄或用于麻醉。
附图说明
图1中A为实施例1中miR-96-/-小鼠的机械阈值；图1中B、C、D、E、F分别为灌胃PF-06305591、PF-06456384、PF-05089771、PF-04885614、CNV1014802用于缓解miR-96-/-小鼠疼痛的效果。n＝8，*P<0.05，**P<0.01，***P<0.001，****P<0.0001，One way ANOVA；
图2为实施例1中灌胃Gabapentin(加巴喷丁)用于缓解miR-96-/-小鼠疼痛的效果。n＝8，***P<0.001，Mann-Whitney test；
图3为实施例2中灌胃含PF-06305591和PF-05089771的药物组合物用于缓解miR-96-/-小鼠疼痛的效果。n＝8，**P<0.01，***P<0.001，One way ANOVA；
图4为实施例3中灌胃含PF-06305591和PF-06456384药物组合物用于缓解miR-96-/-小鼠疼痛的效果。n＝8，**P<0.01，***P<0.001，One way ANOVA；
图5为实施例4中灌胃含PF-06456384和PF-04885614的药物组合物用于缓解miR-96-/-小鼠疼痛的效果。n＝8，*P<0.05，**P<0.01，One way ANOVA；
图6中A、B、C分别为实施例5中皮肤外抹含PF-06305591和PF-05089771的药物组合物，含PF-06305591和PF-06456384药物组合物，含PF-06456384和PF-04885614的药物组合物用于缓解miR-96-/-小鼠的疼痛的效果。n＝8，*P<0.05，**P<0.01，One way ANOVA；
图7为实施例6中皮肤外抹含PF-06305591和PF-06456384的药物组合物用于缓解氯喹诱导的痒的效果。n＝6，****P<0.0001，unpaired t-test；
图8为实施例6中皮肤外抹含PF-06305591和PF-05089771的药物组合物，或外抹含PF-06456384和PF-04885614的药物组合物用于缓解氯喹诱导的痒的效果。n＝6，****P<0.0001，unpaired t-test；
图9为对比例中灌胃含CNV1014802和PF-04885614的药物组合物用于缓解miR-96-/-小鼠疼痛的效果没有优于单用CNV1014802或PF-04885614的镇痛效果。n＝8，***P<0.001，Mann-Whitney test。
具体实施方式
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、 各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
本发明中，“药学上可接受的盐”可由无机酸或有机酸制备。衍生自无机酸的盐包括盐酸、甲苯磺酸盐、硫酸、氢溴酸、硝酸、磷酸等。衍生自有机酸的盐包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、丙二酸、枸橼酸、马来酸、酒石酸、双羟萘酸盐等。
“药学上可接受的以氨基酸为载体形成的类似氨基酸化合物”是指化合物上的胺基与氨基酸上的羧基形成类似于氨基酸的化合物，如与缬氨酸、苏氨酸、苯丙氨酸等形成类似于氨基酸的化合物。
“异构体”包括但不限于：立体异构体、对映异构体和非对映异构体。
“溶剂化物”是指式(1)-式(4)所示的化合物或其衍生物和溶剂结合形成的络合物。
“同位素变体”包括但不限于氘代变体。
“水合物”是指含有水的化合物，其中水可以以配位键与式(1)-式(4)所示的部分相连，也可以以共价键相结合。
“多晶型物”是指结晶化合物的不同晶体结构。不同的多晶型化合物可能是由于晶型堆积的不同(堆积多态性)或同一分子的不同构象异构体之间的堆积不同(构象多态性)引起的。
“前药”也称前体药物、药物前体、前驱药物等，是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。如式(1)-式(4)中的胺基经结构修饰后形成酰胺类、氨基酯类、脒类等化合物。
本发明第一方面提供了一种具有镇痛和/或止痒功能的药物组合物，该组合物含有Nav1.7抑制剂和Nav1.8抑制剂；
所述Nav1.7抑制剂和Nav1.8抑制剂的重量比可以为1：(0.001-50)，优选为1：(0.005-10)，更优选为1：(0.01-2)。
根据本发明优选的实施方式，所述Nav1.7抑制剂可以为具有式(1)(简称化合物1)或式(2)(简称化合物2)所示的结构或其药学上可接受的盐、药学上可接受的以氨基酸为载体形成的类似氨基酸化合物、异构体、溶剂化物、同位素变体、水合物、多晶型物或前药中的至少一种，
根据本发明优选的实施方式，所述Nav1.8抑制剂为具有式(3)(简称化合物3)或式(4)(简称化合物4)所示的结构的化合物或其药学上可接受的盐、药学上可接受的以氨基酸为载体形成的类似氨基酸化合物、异构体、溶剂化物、同位素变体、水合物、多晶型物或前药中的至少一种，
根据本发明的一些实施方式，所述Nav1.7抑制剂为具有式(1)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(3)所示结构的化合物或其药学上可接受的盐；
和/或，所述Nav1.7抑制剂与Nav1.8抑制剂的重量比为1：(0.005-0.5)。
根据本发明的一些实施方式，所述Nav1.7抑制剂为具有式(2)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(3)所示结构的化合物或其药学上可接受的盐；
和/或，Nav1.7抑制剂与Nav1.8抑制剂的重量比为1：(0.01-0.1)。
根据本发明的一些实施方式，所述Nav1.7抑制剂为具有式(2)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(4)所示结构的化合物或其药学上可接受的盐；
和/或，所述Nav1.7抑制剂与Nav1.8抑制剂的重量比为1：(0.05-2)。
本发明中，在一些具体实施方式中，除了上述提到的Nav1.7抑制剂与Nav1.8抑制剂组合的方案，化合物(1)-(4)还可以与本领域技术人员能够想到的具有抑制活性的其它Nav1.7抑制剂或其它Nav1.8抑制剂形成有效的组合物方案。
根据本发明的一些实施方式，所述药物组合物包括药学上可接受的载体。
优选地，所述药学上可接受的载体选自溶剂、赋形剂、分散介质、包衣、透皮剂、等渗剂、吸收延迟剂中的一种或多种。
更优选地，所述药学上可接受的载体淀粉、微晶纤维素、乳糖、蔗糖、露醇、无机盐、羟丙基纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、海藻酸钠、琼脂、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、卡波普、聚乙烯醇、丙烯酸树脂、壳聚糖、蜂蜡和硬脂酸中的至少一种。
根据本发明的一些实施方式，以所述药物组合物的总重量为基准，所述Nav1.7抑制剂与Nav1.8抑制剂的总含量为0.0001-99.9999重量％。
本发明第二方面提供了一种前述药物组合物在制备用于治疗和/或预防电压门控钠离子通道相关的病症的药物中的应用。
根据本发明的一些实施方式，所述电压门控钠离子通道可以为Nav1.7和/或Nav1.8。
根据本发明的一些实施方式，所述疾病可以选自疼痛和/或瘙痒或因触觉敏感导致的早泄。
根据本发明的一些实施方式，所述疼痛选自创伤性疼痛、术中疼痛、术后疼痛、炎症性疼痛、神经病理性疼痛中的至少一种。如头痛、颈椎痛、肩痛、腰背痛、牙痛、胸痛、腹痛、下肢痛、肌肉与骨骼疼痛、纤维性肌痛、舌咽神经痛、三叉神经痛、坐骨神经痛、多发性硬化相关的神经痛糖尿病神经痛、癌症相关疼痛、带状疱疹后神经痛、HIV相关神经痛、烧伤后疼痛、关节炎痛、痛经、内脏疼痛中的至少一种。
本发明中，炎症疼痛是指组织损伤产生的各种介质如前列腺素、炎症因子、趋化因子、腺苷等刺激感觉神经末梢引起的疼痛，而神经性疼痛是由于中枢神经系统或周围神经系统损伤或损伤后功能紊乱所引起的疼痛。
瘙痒是指皮肤发痒难受，包括皮肤病引起的瘙痒，也包括仅有皮肤瘙痒而无原发性皮肤损害的瘙痒病，本发明述及的瘙痒可以选自组胺依赖的痒、非组胺依赖的痒、化学痒、机械痒、蚊虫叮咬的痒、肝病引起的瘙痒、慢性肾病的瘙痒中的至少一种。
另外，本发明还涉及治疗电压门控钠离子通道Nav1.7和/或Nav1.8相关的病症的方法，该方法包括：将如上药物组合物给药至受试者。其中，可以通过常规的方式进行给药，给药的途径可以包括但不限于：口服、口腔内、注射(如肌肉注射、皮下注射、鞘内注射、硬膜外注射、静脉注射等)、呼吸道(气雾剂)、皮肤(如皮肤外抹、皮肤外喷、皮肤外敷等)、眼部、鼻粘膜、直肠、阴道、耳部、透析等。所述受试者可以为动物，包括哺乳动物(特别是灵长类，如人)、啮齿类动物(如鼠)、家畜、家禽、宠物 和实验动物等。医务人员能够根据受试者的身体状况对给药剂量进行选择，以成人为例，给药剂量可以为0.01-10mg/kg或0.01-1mg/cm2。
根据本发明，术语“治疗”意指：包含引起任何临床上期望或有益的效果(包含但不限于一种或多种症状的缓解或减轻；疾病或病症进展的消退、减缓或停止)的用于疾病或病症的治疗性以及预防性或抑制性措施。
以下将通过实施例对本发明进行详细描述。以下所有动物实验遵照中国科学院苏州生物医学工程技术研究所实验动物伦理委员会审查和批准的伦理许可执行。
实施例1
本实施例用于说明单个药物化合物的测试效果
为了筛选到口服效果好的镇痛药物，利用8只3-6个月的miR-96-/-小鼠(昆山彭济凯丰生物科技有限公司)测试灌胃Nav1.7抑制剂和Nav1.8抑制剂的镇痛效果。
首先测量miR-96-/-小鼠双脚的机械疼痛阈值。把8只miR-96-/-小鼠置于铁架上，用有机玻璃罩住，30分钟后用Von Frey(DanMic Global,CA,USA)测量小鼠的基础机械阈值(缩足阈值，Paw withdrawal threshold)，小鼠的平均阈值为0.16g±0.07g，见图1中A，属异常机械疼痛(mechanical allodynia)。
PF-06305591(如式(3)所示结构的化合物，(αR,βS)-β-Amino-6-(1,1-dimethylethyl)-α-methyl-1H-benzimidazole-2-propanamide dihydrate，Sigma,PZ0297-25MG，对hNav1.8的IC50＝15nM)用10％DMSO/生理盐水(V/V)溶解，灌胃30μg/kg或60μg/kg或90μg/kg的PF-06305591一个小时后，测量miR-96-/-小鼠的双脚的机械疼痛阈值，测试结果显示60μg/kg和90μg/kg的PF-063055911的镇痛效果显著优于溶剂对照组，且60μg/kg剂量组的效果最佳，见图1中B。
PF-06456384(如式(2)所示结构的化合物，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，对hNav1.7的IC50＝0.01nM)用10％DMSO/生理盐水(V/V)溶解，灌胃1mg/kg或2mg/kg或3mg/kg的PF-06456384一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示上述三个剂量的PF-06456384的镇痛 效果都显著优于溶剂对照组，且2mg/kg剂量组的效果最佳，见图1中C。
PF-05089771(如式(1)所示结构的化合物，4-[2-(3-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-4-thiazolylbenzenes ulfonamide tosylate，对hNav1.7的IC50＝11nM)用30％DMSO/生理盐水(V/V)溶解，灌胃2mg/kg或4mg/kg或6mg/kg的PF-05089771一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示4mg/kg和6mg/kg的PF-05089771的镇痛效果显著优于溶剂对照组，且6mg/kg剂量组的效果没有比4mg/kg剂量组更好，见图1中D。
PF-04885614(如式(4)所示结构的化合物，1-Methyl-1-[4-(4-trifluoromethoxy-phenyl)-1H-imidazol-2-yl]-ethylamine，对hNav1.8的IC50＝53nM)用10％DMSO/生理盐水(V/V)溶解，灌胃90μg/kg或180μg/kg或270μg/kg的PF-04885614一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示180μg/kg和270μg/kg的PF-04885614的镇痛效果显著优于溶剂对照组，且180μg/kg剂量组的效果最佳，见图1中E。
CNV1014802(对hNav1.7的IC50＝32μM)用30％DMSO/生理盐水(V/V)溶解，灌胃20mg/kg或30mg/kg或40mg/kg的CNV1014802一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，发现三个剂量的CNV1014802的镇痛效果都显著优于溶剂对照组，且30mg/kg剂量组的效果最佳，见图1中F。
Gabapentin用生理盐水溶解，灌胃50mg/kg的Gabapentin一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示50mg/kg的Gabapentin能够显著提升小鼠的机械疼痛阈值(缩爪阈值差值0.5g±0.09g)，见图2。
实施例2
本实施例用于说明一种具体实施方式的药物组合物的测试效果
该药物组合物包括PF-06305591和PF-05089771，用30％DMSO/生理盐水(V/V)溶解，灌胃60μg/kg的PF-06305591和4mg/kgPF-05089771一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示60μg/kg的PF-06305591和4mg/kg的PF-05089771一起用于缓解miR-96-/-小鼠的机械疼痛的效果非常好，且显著优于单用60μg/kg的PF-06305591或单用4mg/kg的PF-05089771的效果，见图3(图3中“PF-5591”指“PF-06305591”，“PF-9771”指“PF-05089771”)。
实施例3
本实施例用于说明一种具体实施方式的药物组合物的测试效果
该药物组合物包括PF-06305591和PF-06456384，用10％DMSO/生理盐水(V/V)溶解，灌胃60μg/kg的PF-06305591和2mg/kg的PF-06456384一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示60μg/kg的PF-06305591和2mg/kg的PF-06456384一起用于缓解miR-96-/-小鼠的机械疼痛的效果非常好，且显著优于单用60μg/kg的PF-06305591或单用2mg/kg的PF-06456384的效果，见图4(图4中“PF-5591”指“PF-06305591”，“PF-6384”指“PF-06456384”)。
实施例4
本实施例用于说明一种具体实施方式的药物组合物的测试效果
该药物组合物包括PF-06456384和PF-04885614，用10％DMSO/生理盐水(V/V)溶解，灌胃2mg/kg的PF-06456384和180μg/kg的PF-04885614一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示2mg/kg的PF-06456384和180μg/kg的PF-04885614缓解miR-96-/-小鼠的机械疼痛的效果非常好，且显著优于单用180μg/kg的PF-04885614或单用2mg/kg的PF-06456384的效果，见图5(图5中“PF-5614”指“PF-04885614”，“PF-6384”指“PF-06456384”)。
实施例5
本实施例用于说明采用皮肤外抹的方式对于镇痛的效果
为测试皮肤外抹Nav1.7抑制剂和Nav1.8抑制剂的镇痛效果，用异氟烷麻醉miR-96-/-小鼠，在小鼠的左脚上涂抹10μl的溶于30％DMSO/生理盐水(V/V)的1mg/ml PF-06305591和20mg/ml PF-05089771的组合物，抹药5分钟后把小鼠从麻醉机上移开放在铁架上的机玻璃罩下，抹药30分钟后测量小鼠机械疼痛阈值。
测试结果显示涂抹PF-06305591和PF-05089771可显著提高miR-96-/-小鼠的机械疼痛阈值，见图6中A(其中，“PF-5591”指“PF-06305591”，“PF-9771”指“PF-05089771”)。
同上，涂抹10μl的溶于10％DMSO/生理盐水(V/V)的1mg/ml PF-06305591和10mg/ml PF-06456384的组合物30分钟后，miR-96-/-小鼠的机械阈值显著提升，见图6中B(其中，“PF-6384”指“PF-06456384”，“PF-5591”指“PF-06305591”)。
同上，涂抹10μl的溶于10％DMSO/生理盐水(V/V)的10mg/ml PF-06456384和 2mg/ml PF-04885614的组合物30分钟后，miR-96-/-小鼠的机械阈值显著提升，见图6中C(其中，“PF-6384”指“PF-06456384”，“PF-5614”指“PF-04885614”)。
实施例6
本实施例用于说明采用皮肤外抹的方式对于止痒的效果
为测试皮肤外抹Nav1.7抑制剂和Nav1.8抑制剂的止痒效果，用异氟烷麻醉8周龄的C57/Bl6小鼠(6只)，把小鼠耳后颈部的毛发剃掉，涂抹50μl溶于10％DMSO/生理盐水(V/V)的1mg/ml PF-06305591和10mg/ml PF-06456384的组合物，抹药5分钟后，把小鼠从麻醉机上移开，在抹药区域的皮肤下注射50μl的12mM氯喹(Chloroquine，Sigma Aldrich，CAS 50-63-5)，录制视频并计数小鼠抓挠次数。统计分析显示涂抹PF-06305591和PF-06456384的组合物能够显著抑制氯喹诱导的痒，见图7(图7中，“PF-6384”指“PF-06456384”，“PF-5591”指“PF-06305591”)。
同上，用异氟烷麻醉8周龄的C57/Bl6小鼠(6只)，把小鼠耳后颈部的毛发剃掉，涂抹50μl的溶于30％DMSO/生理盐水(V/V)的1mg/ml PF-06305591和20mg/ml PF-05089771的组合物，抹药5分钟后，把小鼠从麻醉机上移开，在抹药区域的皮肤下注射50μl的12mM氯喹，录制视频并计数小鼠抓挠次数。统计分析显示涂抹PF-06305591和PF-05089771的组合物能够显著抑制氯喹诱导的痒，见图8(其中，“PF-5591”指“PF-06305591”，“PF-9771”指“PF-05089771”)。
同上，涂抹50μl的溶于10％DMSO/生理盐水(V/V)的10mg/ml PF-06456384和2mg/ml PF-04885614的组合物，抹药5分钟后，把小鼠从麻醉机上移开，在抹药区域的皮肤下注射50μl的12mM氯喹，计数小鼠抓挠次数，结果显示涂抹PF-06456384和PF-04885614的组合物能够显著抑制氯喹诱导的痒，见图8(其中，“PF-6384”指“PF-06456384”，“PF-5614”指“PF-04885614”)。
对比例
本对比例用于说明CNV1014802和PF-04885614一起联用的测试效果
用30％DMSO/生理盐水溶解CNV1014802和PF-04885614后，灌胃30mg/kg CNV1014802和180μg/kg PF-04885614一个小时后，测量miR-96-/-小鼠的机械疼痛阈值，测试结果显示30mg/kg的CNV1014802和180μg/kg的PF-04885614一起用于缓解miR-96-/-小鼠的机械疼痛的效果并没有优于单用30mg/kg的CNV1014802或单用180 μg/kg的PF-04885614的效果，见图9(图9中“PF-5614”指“PF-04885614”)。
综上，本发明采用灌胃或皮肤外抹含PF-06305591和PF-05089771的药物组合物，或含PF-06305591和PF-06456384药物组合物，或含PF-06456384和PF-04885614药物组合物能够显著镇痛；另外，皮肤外抹含PF-06305591和PF-06456384组合物，或PF-06305591和PF-05089771组合物或PF-06456384和PF-04885614药物组合物还能止痒。而对比例中，Nav1.7抑制剂CNV1014802和Nav1.8抑制剂PF-04885614一起用于镇痛时，没有优于单一抑制剂的镇痛效果。可见，本发明提供的特定的Nav1.7抑制剂和Nav1.8抑制剂组合物配方能够预防和/或治疗涉及Nav1.7和Nav1.8活性的疾病，包括但不限于疼痛和瘙痒。

Claims (14)

  1. 一种具有镇痛和/或止痒功能的药物组合物，其特征在于，该组合物含有Nav1.7抑制剂和Nav1.8抑制剂；
    所述Nav1.7抑制剂和Nav1.8抑制剂的重量比为1：(0.001-5000)；
    所述Nav1.7抑制剂为具有式(1)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(3)所示结构的化合物或其药学上可接受的盐；
    或者，所述Nav1.7抑制剂为具有式(2)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(3)所示结构的化合物或其药学上可接受的盐；
    或者，所述Nav1.7抑制剂为具有式(2)所示的化合物或其药学上可接受的盐，所述Nav1.8抑制剂为具有(4)所示结构的化合物或其药学上可接受的盐；
    式(1)、式(2)、式(3)、式(4)的结构如下所示：
  2. 根据权利要求1所述的药物组合物，其中，所述Nav1.7抑制剂和Nav1.8抑制剂的重量比为1：(0.001-50)。
  3. 根据权利要求1所述的药物组合物，其中，所述Nav1.7抑制剂和Nav1.8抑制剂的重量比为1：(0.005-10)。
  4. 根据权利要求1所述的药物组合物，其中，所述Nav1.7抑制剂和Nav1.8抑制剂的重量比为1：(0.01-2)。
  5. 根据权利要求1或2所述的药物组合物，其中，所述药物组合物包括药学上可接受的载体。
  6. 根据权利要求5所述的药物组合物，其中，所述药学上可接受的载体选自溶剂、赋形剂、分散介质、包衣、透皮剂、等渗剂、吸收延迟剂中的一种或多种。
  7. 根据权利要求5所述的药物组合物，其中，所述药学上可接受的载体淀粉、微晶纤维素、乳糖、蔗糖、露醇、无机盐诸如甲苯磺酸盐、盐酸盐、羟丙基纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、海藻酸钠、琼脂、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、卡波普、聚乙烯醇、丙烯酸树脂、壳聚糖、蜂蜡和硬脂酸中的至少一种。
  8. 根据权利要求5所述的药物组合物，其中，以所述药物组合物的总重量为基准，所述Nav1.7抑制剂与Nav1.8抑制剂的总含量为0.0001-99.9999重量％。
  9. 权利要求1-8中的任意一项所述的药物组合物在制备用于治疗和/或预防电压门控钠离子通道相关的病症的药物中的应用。
  10. 根据权利要求9所述的应用，其中，所述电压门控钠离子通道为Nav1.7和/或Nav1.8。
  11. 根据权利要求9或10所述的应用，其中，所述疾病选自疼痛和/或瘙痒。
  12. 根据权利要求11所述的应用，其中，所述疼痛选自创伤性疼痛、术中疼痛、术后疼痛、炎症性疼痛、神经病理性疼痛、头痛、颈椎痛、肩痛、腰背痛、牙痛、胸痛、腹痛、下肢痛、肌肉与骨骼疼痛、纤维性肌痛、舌咽神经痛、三叉神经痛、坐骨神经痛、多发性硬化相关的神经痛、糖尿病神经痛、癌症相关疼痛、带状疱疹后神经痛、HIV相 关神经痛、烧伤后疼痛、关节炎痛、痛经、内脏疼痛中的至少一种。
  13. 根据权利要求11所述的应用，其中，所述瘙痒选自组胺依赖的痒、非组胺依赖的痒、化学痒、机械痒、蚊虫叮咬的痒、肝病引起的瘙痒、慢性肾病的瘙痒中的一种。
  14. 根据权利要求9或10所述的应用，其中，所述药物组合物作为药物，其给药的途径选自：口服、口腔内、肌肉注射、皮下注射、吸入、皮肤外抹、皮肤外喷、皮肤外敷、眼部、鼻粘膜、直肠、阴道、耳部、透析中的至少一种。
PCT/CN2023/076481 2022-02-17 2023-02-16 具有镇痛和/或止痒功能的药物组合物及其用途 WO2023155837A1 (zh)

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