JP2018052839A - Chronic pain therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide chronic pain therapeutic agents for alleviating chronic pain effectively.SOLUTION: Chronic pain is alleviated by a REV-ERB agonist. Chronic pain is involved in hyperexcitability of spinal cord glia cells, and a drug which controls the activity of a clock gene REV-ERB present in spinal cord glia cells serves as an analgesic. A REV-ERB agonist is e.g. SR9009. When the REV-ERB agonist SR 9009 was administered to the spinal of a neuropathic pain model intrathecally, an effect of alleviating the pain in a dose-dependent manner was observed after 3 hours. Even if SR9009 was administered to the control group, the threshold value of the pain was not affected.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a therapeutic agent for chronic pain.

  Pain types are classified as acute pain with tissue damage and chronic pain without tissue damage. In acute pain, heat, chemical stimulation, mechanical shock, etc. are applied to the skin, joints, muscles, or internal organs, and various chemical substances called pain substances are locally produced and released, which are the primary sensory nerves. Pain is caused by excitement. In this case, the excited sensory nerve transmits the information to the spinal cord, and further passes through the upper center (medulla oblongata, midbrain, thalamus), and is finally recognized as pain in the cerebral cortex perception area.

  Chronic pain is pain that persists over a long period of time after tissue damage or lesions have healed, and there is a state where sensitivity to pain has increased and even tactile stimulation that is not originally felt as pain. Appears as a feature. In chronic pain states, it is presumed that the sensitivity to stimulation has increased due to plastic changes in any of the pain transmission pathways described above (especially spinal cord / brain). The mechanism is not clear.

  Recently, it has been found that the protein REV-ERB, which is regarded as a nuclear receptor, is involved in various physiological processes such as regulation of metabolism and immunity (Non-patent Document 1), and examples thereof include diabetes and dyslipidemia. It has been found that the inflammation that is the basis of the pathological condition is suppressed when SR9009 or GSK4112, which is a REV-ERB agonist, is administered as a synthetic ligand.

  Therefore, there is a finding that inflammatory reactions in pain transmission pathways such as the brain and spinal cord are one of the onset mechanisms that cause chronic pain. However, in reality, it is currently used for chronic pain. Typical non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and loxoprofen, which are typical analgesics, have not been effective enough to treat chronic pain immediately. It does not mean that it is beneficial.

  At present, attempts have been made to use or propose various drugs for reducing chronic pain, but they are not always satisfactory in terms of analgesic effect (Patent Documents 1, 2, and 3). The above NSAIDs bring about an analgesic action by suppressing cyclooxygenase, an enzyme that produces the analgesic prostaglandin, but in order to effectively reduce chronic pain, a mechanism completely different from the existing mechanism A chronic pain therapeutic agent is desired.

Japanese Patent Laying-Open No. 2015-214586 JP 2015-129160 A JP 2009-242360 A

Biochem. Biophys. Res. Commun., 2016

  This invention is made | formed in view of this problem, Comprising: It aims at providing the chronic pain therapeutic agent which reduces chronic pain effectively.

  The therapeutic agent for chronic pain according to the present invention has a pharmacological action as a REV-ERB agonist.

  According to the present invention, it is possible to effectively suppress chronic pain that is not successful with existing analgesics. The number of patients with chronic pain in Japan is reported to be about 14% to 23% of the population, but the proportion of patients who are satisfied with the treatment is only about 1/4 of those with chronic pain. However, according to the present invention, the quality of life (QOL) and activities of daily living (ADL) of these chronic pain patients can be improved, and the social benefit of the present invention cannot be achieved.

The analgesic effect of REV-ERB agonist SR9009 with respect to a neuropathic pain model is shown. The analgesic effect of REV-ERB agonist SR9009 and GSK4112 with respect to an inflammatory pain model is shown. The analgesic effect of REV-ERB agonist SR9009 with respect to an inflammatory pain model is shown.

  Hereinafter, embodiments of the present invention will be specifically described with reference to the accompanying drawings. However, the embodiments are for facilitating understanding of the principle of the present invention, and the scope of the present invention is as follows. The present invention is not limited to the embodiments, and other embodiments in which those skilled in the art appropriately replace the configurations of the following embodiments are also included in the scope of the present invention.

  The therapeutic agent for chronic pain according to this embodiment has a REV-ERB agonist.

  The present inventor found that chronic pain involves abnormal excitation of spinal glia cells (microglia astrocytes), and a drug that controls the activity of the clock gene REV-ERB present in spinal glia cells is a new analgesic. It was found as a new finding. That is, the present invention was completed based on a new mechanism that a potent synthetic REV-ERB agonist for nuclear receptor REV-ERB becomes an analgesic for chronic pain. The nuclear receptor REV-ERB plays a role in integrating the expression of clock proteins that regulate behavioral and metabolic rhythms.

  The REV-ERB agonist is not particularly limited, and is, for example, SR9009, GSK4112, SR9011, or SR8278.

  SR9009 is represented by the following formula.

  GSK4112 is represented by the following formula.

  SR9011 is represented by the following formula.

  SR8278 is represented by the following formula.

  Chronic pain is pain that persists or recurs for more than 3 months, persists for more than 1 month after recovery from acute tissue damage, or is accompanied by a lesion that does not heal. Causes include chronic diseases (cancer, arthritis, diabetes, etc.) and injuries (disc herniation, ligament tears, etc.).

  Chronic pain includes neuropathic pain or inflammatory pain. Neuropathic pain is pain caused by damage or dysfunction in the peripheral or central nervous system rather than stimulation of pain receptors. Specific examples include postherpetic neuralgia, pain / numbness associated with diabetic neuropathy, sciatica, trigeminal neuralgia, post-stroke pain, pain after spinal cord injury, and the like. Inflammatory pain is pain caused by bradykinin produced at the site of inflammation as a result of tissue destruction, an analgesic substance such as ATP or proton, and a sensitizing substance such as prostaglandin (PG). A specific example is rheumatoid arthralgia.

  The REV-ERB agonist according to this embodiment includes, for example, preparations for oral administration such as tablets, granules, fine granules, capsules and the like, various liquid preparations suitable for oral administration, or injections and suppositories. Such a preparation for parenteral administration can be obtained.

  In the case of a preparation for oral administration, it is obtained by formulating a fine powder of REV-ERB agonist and a dispersant and / or a dissolution improving agent together with a preparation carrier in the form of tablets, granules, fine granules, capsules and the like.

  As the pharmaceutical carrier, excipients, binders, disintegrants, lubricants, plasticizers and the like can be used. As the excipient, for example, sucrose, sodium chloride, mannitol, lactose, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, silicate, etc. can be used. . As the binder, for example, water, ethanol, propanol, glucose solution, starch solution, gelatin solution, sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like can be used. As the disintegrant, for example, carboxymethylcellulose calcium, dry starch, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, stearic acid monoglyceride, starch, sodium carboxymethyl starch, croscarmellose sodium and the like can be used. As the lubricant, for example, purified talc, stearate, boric acid powder, polyethylene glycol, colloidal silicic acid, hydrogenated oil and the like can be used. As the plasticizer, for example, glycerin fatty acid ester, dioctyl phthalate, dibutyl phthalate, triacetin, triethyl citrate, castor oil and the like can be used.

  As the dispersant and / or dissolution improver, a water-soluble polymer, a surfactant, and the like can be used. As the water-soluble polymer, for example, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose, polyacrylic acid and the like can be used. Examples of the surfactant include alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; polyoxyethylene such as polyoxyethylene sorbitan monooleate Sorbitan fatty acid ester; Polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; Polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; Polyoxyethylene castor oil such as polyoxyethylene hydrogenated castor oil and hydrogenated castor oil; Sucrose Sucrose fatty acid esters such as stearic acid ester and sucrose barmitic acid ester can be used.

  In order to prepare a tablet, REV-ERB agonist powder is formed into a tablet by a conventional method using the above-mentioned pharmaceutical carrier. Granules or fine granules can be granulated by adding the above formulation carrier to REV-ERB agonist powder and fluidized bed granulation, high speed agitation granulation, agitated fluidized bed granulation, centrifugal fluidized granulation, extrusion granulation, etc. Can be prepared. Capsules are prepared by mixing with an inert pharmaceutical filler or diluent and packed into hard gelatin capsules or soft capsules.

  An oral liquid preparation is prepared by mixing a REV-ERB agonist with a sweetener (eg, sucrose), a preservative (eg, methylparaben, propylparaben), a coloring agent, a flavoring agent, and the like.

  Among preparations for parenteral administration, preparations for injection are prepared, for example, in the form of solutions, emulsions or suspensions, and are made isotonic with blood. Formulations in the form of liquids, emulsions or suspensions are prepared using, for example, an aqueous medium, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester . Examples of the aqueous medium include water or a medium containing water. As water, sterilized water is used. Examples of the medium containing water include physiological saline, PBS (phosphate buffered physiological saline), lactic acid-containing Ringer's solution, and the like.

  In the preparation for injection, additives usually used in the art can be appropriately used. Examples of the additive include isotonic agents, stabilizers, buffers, preservatives, chelating agents, antioxidants, and solubilizing agents. Examples of the isotonic agent include sugars such as glucose, sorbitol and mannitol, sodium chloride, glycerin, propylene glycol, polyethylene glycol and the like. Examples of the stabilizer include sodium sulfite. Examples of the buffer include borate buffer, phosphate buffer, citrate buffer, tartaric acid buffer, and acetate buffer. Examples of the preservative include paraoxybenzoic acid ester, benzyl alcohol, chlorocresol, phenethyl alcohol, benzethonium chloride and the like. Examples of chelating agents include sodium edetate and sodium citrate. Examples of the antioxidant include sodium sulfite, sodium hydrogen sulfite, sodium ascorbate, sodium thiosulfate and the like. Examples of the solubilizer include dextran, polyvinylpyrrolidone, sodium benzoate, ethylenediamine, salicylic acid amide, nicotinic acid amide, polyoxyethylene hydrogenated castor oil derivative, and the like.

  The dose of the REV-ERB agonist in the therapeutic agent for chronic pain according to the present embodiment is not particularly limited, and can be appropriately set according to the age, sex, weight, symptoms, etc. of the chronic pain patient, For example, it is possible to administer 10 to 500 mg, preferably 100 to 200 mg per day for an adult (body weight 50 kg) once or in two to several times.

(1) Preparation of pain model Male mice (ddy strain, 5 weeks old) were used as experimental animals. The neuropathic pain model was prepared by exposing the sciatic nerve by skin incision of the hind limb and partially ligating and damaging the sciatic nerve with silk thread (partial sciatic nerve ligation group; PSNL group). On the other hand, similarly, a mouse that only exposed the sciatic nerve but did not damage the nerve was used as a control group (sham operation group). Inflammatory pain models were prepared by administering lipopolysaccharide (LPS, 0.1 μg), an inflammation-inducing substance, into the subarachnoid space of the spinal cord and Complete Freund adjuvant (CFA) into the hindlimb footpad. Saline was administered to the control group. In addition, the receptor TLR2 / 4 is continuously activated during chronic pain, but LPS acts on the receptor TLR2 / 4 to cause pain and model a chronic pain state. In addition, administration of CFA to anesthetized animals causes systemic inflammation as well as arthritis, but pathologically resembles human rheumatoid arthritis.
(2) Measurement of pain The effect on the pain caused by the drug (SR9009) was measured 14 days after the operation for the neuropathic pain model and 7 days after the administration for the inflammatory pain model by CFA. LPS was administered 1 hour after administration of the drug (GSK4112 & SR9009) for the inflammatory pain model by LPS, and then the effect on pain up to 24 hours was examined.

  The pain threshold was measured using a von Frey filament. von Frey filament is widely used as a mechanical stimulator. Some of these differ in the thickness of the filament (strength is categorized in g). Stimulate the sole of the hind limb of the mouse in order from the thin (low strength) filament (when pressing the filament against the sole) The value indicating the weight (g) corresponding force was added as a stimulus) and the value indicating escape behavior (lifting a leg, licking, etc.) was measured to be a pain threshold (g). That is, the smaller the value causing escape behavior, the more sensitive the pain is to the stimulus (the pain threshold is lower). Synthetic REV-ERB agonist (SR9009, GSK4112) was administered into the spinal subarachnoid space. At that time, the same dose of solvent (dimethyl sulfoxide (DMSO) and physiological saline (saline)) was administered as a control for the drug.

  FIG. 1 shows the analgesic effect of the REV-ERB agonist SR9009 on a neuropathic pain model. The vertical axis of the graph indicates the intensity of pain, and the smaller the value, the stronger the pain. The horizontal axis shows the time since SR9009 was administered into the spinal subarachnoid space. As described above, neuropathic pain model mice were prepared, and pain was measured after 14 days. In contrast to the control group (□), the neuropathy group (PSNL group, (1)) shows intense pain. When SR9009 was administered to the PSNL group, the effect of pain relief was observed after 3 hours (◇ <● <▲). Administration of SR9009 to the control group did not affect the pain threshold (◯). In both the control group and the PSNL group, administration of SR9009, DMSO, did not affect the pain threshold (□, ■).

  FIG. 2 shows the analgesic effect of REV-ERB agonists SR9009 and GSK4112 on the inflammatory pain model. The vertical axis of the graph represents the intensity of pain, and the horizontal axis represents the time since LPS was administered into the spinal subarachnoid space. As described above, a mouse model of inflammatory pain was prepared by administering LPS into the spinal cord subarachnoid space of the mouse, and SR9009 and GSK4112 were administered into the spinal cord subarachnoid space of the mouse. It was administered intrathecally. The administration of SR9009 (○ <▲) and GSK4112 (●) improved the pain caused by LPS (■).

  FIG. 3 shows the analgesic effect of the REV-ERB agonist SR9009 on the inflammatory pain model. The vertical axis of the graph indicates the intensity of pain, and the horizontal axis indicates the time since SR9009 was administered into the subarachnoid space. As described above, CFA was administered to the sole of the hind limb of the mouse to prepare an inflammatory pain model mouse, and pain was measured after 7 days. In contrast to the control group (saline administration group, □), the CFA administration group (■) shows intense pain. When SR9009 was administered to the CFA group, the effect of pain relief was observed after 1 hour (● <▲). Administration of SR9009 to the control group did not affect the pain threshold (◯). In both the control group and the PSNL group, administration of SR9009, DMSO, did not affect the pain threshold (□, ■).

  It can be used to treat chronic pain.

Claims (4)

  A therapeutic agent for chronic pain, comprising a REV-ERB agonist.   The therapeutic agent for chronic pain according to claim 1, wherein the REV-ERB agonist is SR9009.   The therapeutic agent for chronic pain according to claim 1, wherein the REV-ERB agonist is GSK4112.   The chronic pain therapeutic agent according to any one of claims 1 to 3, wherein the chronic pain is neuropathic pain or inflammatory pain.