JP2006306739A - Cure for neuropathic pain - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cure for neuropathic pain having superior cure effect to neuropathic pain which is an intractable disease. <P>SOLUTION: The above-mentioned problem is solved by the cure for neuropathic pain containing a medicine (especially, dexamethasone 21-mesylate) having a gulcocorticoid receptor specific antagonistic action as an effective component, a medical composition for curing neuropathic pain, or a curing method of neuropathic pain using these compounds, or the like. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a therapeutic agent for neuropathic pain having an excellent pain-suppressing effect on neuropathic pain, a method for treating neuropathic pain using such a therapeutic agent, and the like.

  Neuropathic pain is pain caused by damage or dysfunction of the peripheral nervous system or central nervous system, and is refractory pain to which opioid receptor agonists such as morphine do not sufficiently respond. Examples of the disease accompanied by neuropathic pain include diseases exhibiting hyperalgesia and allodynia such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, prolonged pain after surgery or trauma.

  As analgesics that have been used in conventional pharmacotherapy, central opioid receptor agonists represented by morphine, nonsteroidal anti-inflammatory drugs (NSAIDs) represented by indomethacin, and the like are known. However, these analgesics are generally less effective against neuropathic pain, and analgesics (especially narcotic analgesics) that are effective for normal nociceptive pain are known to be particularly ineffective. ing. Inadequate analgesic effect of narcotic analgesics on neuropathic pain is a major feature of neuropathic pain. In some cases, neuropathic pain is diagnosed using this feature.

  Various factors are thought to be intricately related to the development of neuropathic pain. So far, neuropathic pain has been treated by nerve block, neurosurgery such as spinal epidural electrical stimulation, tricyclic antidepressant, intrathecal administration of drugs such as baclofen, etc. Are known. However, these treatment methods have problems that a sufficient effect cannot be obtained and there are side effects. In addition, as a topical agent, capsaicin cream has been reported to be effective for postherpetic neuralgia and pain syndrome after mastectomy by depleting pain substance substance P released from nerve terminals and reducing pain. is there. However, there are problems in terms of usefulness and safety, such as the problem of burning pain caused by capsaicin. Thus, neuropathic pain is an intractable disease, and an effective treatment method has not yet been established.

Glucocorticoids, on the other hand, are considered to have the most important role among corticosteroids (steroid hormones), and their pharmacological actions include immunosuppressive and anti-inflammatory effects in addition to sugar, protein and lipid metabolism. Drugs that have glucocorticoid activity, such as action, antiallergic action, and antishock action, are clinically important drugs. In contrast, drugs having anti-glucocorticoid activity have been studied as therapeutic agents for hyperadrenocorticism, and little studies have been conducted on their usefulness. Mifepristone (RU-486: Roussel Uclaf, Paris (US Pat. No. 4,386,085: Patent Document 1)), a progesterone receptor antagonist, has been attracting attention as an anti-progestagen that terminates early pregnancy. Recently, it was reported that mifepristone was effective in neuropathic pain in experiments using model mice (J. Neurosci. 24: 8595-8605 (2004), J. Neurosci. 25: 488-495 (2005): Non-patent document 1).
U.S. Pat.No. 4,386,085 J. Neurosci. 24: 8595-8605 (2004), J. Neurosci. 25: 488-495 (2005)

  As described above, various studies on therapeutic agents for neuropathic pain have been carried out, but at present there are no known drugs effective for neuropathic pain. In such a situation, an object of the present invention is to provide a novel therapeutic agent for neuropathic pain that exhibits an excellent effect on intractable pain called neuropathic pain.

The present inventors have conducted research based on an original idea to achieve the above-mentioned problem, and found that a compound having anti-glucocorticoid activity exhibits a high analgesic effect in an intractable neuropathic pain model. Completed the invention.
That is, the present invention provides the following therapeutic agents for neuropathic pain, pharmaceutical compositions for treating neuropathic pain, methods for treating neuropathic pain, and the like.

(1) A therapeutic agent for neuropathic pain comprising a glucocorticoid receptor-specific antagonist as an active ingredient.
(2) The glucocorticoid receptor-specific antagonist is 1,4-pregnadien-9α-fluoro-16α-methyl-11β, 17,21-triol-3,20-dione 21-methanesulfonate (dexamethasone 21-mesylate) The therapeutic agent for neuropathic pain according to (1) above.
(3) Neuropathic pain is postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, allodynia, post-thoracotomy pain, CRPS, multiple (1) or (2) above, which is one or more symptoms selected from pain due to sclerosis, AIDS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain The therapeutic agent for neuropathic pain as described.
(4) A pharmaceutical composition for treating neuropathic pain comprising a glucocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier.
(5) A method of treating neuropathic pain by administering an effective amount of a glucocorticoid receptor-specific antagonist to a mammal.
(6) Use of a glucocorticoid receptor-specific antagonist for the manufacture of a therapeutic agent for neuropathic pain.

  The therapeutic agent for neuropathic pain of the present invention is post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, allodynia, and other neuropathic pain It is effective for the treatment.

Hereinafter, the present invention will be described in detail.
The present invention relates to a therapeutic agent for neuropathic pain containing a glucocorticoid receptor-specific antagonist as an active ingredient, a glucocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier. And a therapeutic method for neuropathic pain using a glucocorticoid receptor-specific antagonist.
Recently, mifepristone, which has both anti-glucocorticoid activity and anti-progesterone activity in a neuropathic pain model, was reported to have an analgesic effect on neuropathic pain in an experiment using neuropathic pain model mice ( J. Neurosci. 24: 8595-8605 (2004), J. Neurosci. 25: 488-495 (2005)). However, it was unclear as to whether the analgesic action was based on anti-glucocorticoid activity or anti-progesterone activity. The present inventor has found for the first time that an antiglucocorticoid action has an analgesic effect on neuropathic pain by using a glucocorticoid receptor-specific antagonist.

Antiglucocorticoid activity can be confirmed by a known method, for example, the method described in J. Steroid Biochemistry and Molecular Biology, Volume 92, Issue 5, December 2004, Pages 345-356.
The term “treatment” as used herein generally means ameliorating the symptoms of humans and non-human mammals. The term “improvement” means, for example, a case where the degree of the disease is reduced or aggravated as compared with the case where the therapeutic agent of the present invention is not administered, and also includes the meaning of prevention. Furthermore, the term “pharmaceutical composition” means a composition containing an active ingredient (such as dexamethasone 21-mesylate) useful in the present invention and an additive such as a carrier used in the preparation of a medicament.

  The compound having a glucocorticoid receptor-specific antagonistic activity used in the present invention is not particularly limited, but preferably dexamethasone 21-mesylate (1,4-pregnadien-9α-fluoro-16α-methyl-11β, 17,21- Triol-3,20-dione 21-methanesulfonate) and pharmaceutically acceptable salts thereof. All of these are known, and among them, a compound having particularly preferred antiglucocorticoid activity is dexamethasone 21-mesylate. Dexamethasone 21-mesylate is known and is described in Proc. Natl. Acd. Sci. Reference may be made to documents such as USA 100: 7953 (2003). Dexamethasone 21-mesylate is available, for example, from Stellaroid (New Port RI, USA), and its chemical structure, physicochemical properties, etc. can be confirmed on its homepage (http: //www.steraloids.com/products/P/P518.html).

In the present specification, the term “glucocorticoid receptor-specific antagonist” means a compound known as a compound having an antagonistic activity specific to the glucocorticoid receptor and a pharmaceutically acceptable form of the compound ( For example, its salt, ester, amide, hydrated or solvated form, racemic mixture, optically pure form, prodrug, etc.) are used to encompass all use.

    Therefore, the compound as an active ingredient used in the present invention may be a free form or a pharmaceutically acceptable salt. Such “salts” include acid salts and base salts. Examples of the acid salt include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, acetate, lactate, citrate, Acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate , P-toluenesulfonate, 1,1′-methylene-bis- (2-hydroxy-3-naphthoic acid) salt, and the like. Examples of the base salt include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, water-soluble amine addition salts such as ammonium salts and N-methylglucamine salts, and lower alkanols. Mention may be made of ammonium salts, salts derived from other bases of pharmaceutically acceptable organic amines.

  The therapeutic agent and composition for neuropathic pain of the present invention are effective for the treatment of neuropathic pain. Examples of such neuropathic pain include, for example, postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative and posttraumatic prolonged pain, hyperalgesia, allodynia, postthoracotomy pain , CRPS, pain due to multiple sclerosis, AIDS, thalamic pain, paraplegic pain due to spinal disorder, non-sensory pain, neuropathic pain in phantom limb pain, and the like. The therapeutic agent for neuropathic pain of the present invention is particularly effective for the treatment of hyperalgesia and allodynia.

  The administration mode of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and can be administered orally or parenterally. The glucocorticoid receptor-specific antagonist, which is an active ingredient of the therapeutic agent for neuropathic pain of the present invention, may be blended alone, but a pharmaceutically acceptable carrier or formulation additive is blended therewith. It can also be provided in the form of a preparation. In this case, the glucocorticoid receptor-specific antagonist that is the active ingredient of the present invention can be contained, for example, in an amount of 0.1 to 99.9% by weight in the preparation.

  Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrants, disintegration aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilizers, isotonic agents. Agents, pH adjusters, stabilizers and the like can be used.

  Examples of preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, liquids or syrups. For oral administration, various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, glycine are added to starch, preferably corn, potato or tapioca starch, and alginic acid and certain species. It can be used with various disintegrants such as silicate double salts and granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very effective for tablet formation. The same kind of solid composition can also be used by filling gelatin capsules. Suitable substances in this connection include lactose or lactose as well as high molecular weight polyethylene glycols. When an aqueous suspension and / or elixir is desired for oral administration, the active ingredient is used in combination with various sweeteners or flavors, colorants or dyes, and if necessary, an emulsifier and / or suspending agent is also used. And can be used with water, ethanol, propylene glycol, glycerin, and the like, and diluents that combine them.

  Examples of preparations suitable for parenteral administration include injections and suppositories. In the case of parenteral administration, a solution in which the active ingredient of the present invention is dissolved in either sesame oil or peanut oil or dissolved in an aqueous propylene glycol solution can be used. The aqueous solution should be appropriately buffered as necessary (preferably pH 8 or more), and the liquid diluent must first be made isotonic. Such aqueous solutions are suitable for intravenous injection and oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. All these solutions can be prepared aseptically by standard pharmaceutical techniques well known to those skilled in the art. Furthermore, the active ingredient of the present invention can also be administered locally such as on the skin. In this case, topical administration in the form of creams, jellies, pastes, ointments is desirable according to standard pharmaceutical practice.

  The dose of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and is appropriately administered according to various conditions such as the type of pain, the age and symptoms of the patient, the administration route, the purpose of treatment, and the presence or absence of a concomitant drug. It is possible to select the amount. The dosage of the therapeutic agent for neuropathic pain of the present invention is, for example, about 500 to 25000 mg, preferably 900 to 9000 mg per day for an adult (for example, body weight 60 kg). The dose when administered as an injection is, for example, about 100 to 5000 mg, preferably 180 to 1800 mg per day for an adult (for example, body weight 60 kg). These daily doses may be administered in two to four divided doses.

EXAMPLES Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to these examples.

(Experimental materials used and general experimental methods)
(1) Model animal A pain hypersensitivity model prepared by completely ligating the L5 / L6 spinal nerve to a 6-week-old male rat was used as an experimental animal.
(2) Grouping Use the Dynamic Planter Aesthesiometer (37400, Ugo Basil) for the mechanical stimulation test, and the plantar pain stimulation threshold (Planter test 7370, Ugo Basil) for the thermal stimulation test. Each was measured and divided into groups using Preclinical Package Version 5.0 (SAS Institute Japan) so that the pain threshold measured before administration on each experimental day was uniform. For mechanical stimulation, animals with a model animal's foot pain threshold of 8.0 g or more were excluded from the test, and for thermal stimulation, animals with a model foot pain threshold of 10 seconds or more were excluded from the test.
(3) Preparation of the test substance For the test substance, after crushing the raw powder using an agate mortar and pestle, gradually add 0.5w / v% sodium carboxymethylcellulose (CMC-Na) as a medium to make it uniform Suspension. The concentration of the administration solution was adjusted using a measuring cylinder or measuring flask, and all adjustments were made at the time of use.
(4) Administration method The test substance is intended to confirm the direct action on the spinal cord, but since it has been confirmed that it passes through the brain barrier, it was administered intraperitoneally as a simple administration method. Administration was carried out intraperitoneally at a volume of 5 ml / kg using a syringe barrel and a needle.

(Dexamethasone 21-Mesylate / Mechanical stimulation method)
5 male rats (311.7-409.9g) of pain hypersensitivity model are used in 1 group, maximum pressure is 15.0g, maximum pressure before dexamethasone 21-mesylate administration, 30 minutes, 60 minutes and 90 minutes after administration The pain threshold of the left footpad was measured using a stimulator set to 20 seconds. The result is shown in FIG.
As shown in FIG. 1, in the control group administered with 0.5 w / v% sodium carboxymethylcellulose (CMC-Na) aqueous solution, the maximum pain threshold after administration was 5.5 g, whereas dexamethasone 21-mesylate was administered. (A) In the case of 0.3 mg / kg administration, the maximum threshold after administration was 6.3 g, (b) In the case of 3 mg / kg administration, the maximum threshold after administration was 8.7 g, (c) 30 mg / kg administration In this case, the maximum threshold after administration was 10.0 g. Thus, administration of dexamethasone 21-mesylate significantly increased the pain threshold and confirmed the analgesic effect in neuropathic pain. In the above hypersensitivity model, allodynia that causes tactile stimulation that is not usually felt as pain occurs and the pain threshold decreases markedly, but intraperitoneal administration of dexamethasone 21-mesylate depends on the pain threshold in a dose-dependent manner. It was confirmed to improve pain sensitivity.

(Dexamethasone 21-mesylate / thermal stimulation method)
Pain hypersensitivity model male rats (276.6-446.7g) using 5 rats in 1 group, before the dexamethasone 21-mesylate administration, and at the 30, 60 and 90 minutes after administration The pain threshold of the left footpad was measured using a thermal stimulator. The result is shown in FIG.
As shown in FIG. 2, in the control group administered with 0.5 w / v% sodium carboxymethylcellulose (CMC-Na) aqueous solution, the maximum pain threshold after administration was 7.7 seconds, whereas dexamethasone 21-mesylate was administered. (A) In the case of 0.3 mg / kg administration, the maximum threshold after administration is 7.3 seconds, (b) In the case of 3 mg / kg administration, the maximum threshold after administration is 9.9 seconds, (c) 30 mg / kg administration In this case, the maximum threshold after administration was 10.7 seconds.
As a result, as in Example 3, administration of dexamethasone 21-mesylate significantly increased the pain threshold, confirming the analgesic effect in neuropathic pain. In the above hypersensitivity model, allodynia that causes tactile stimulation that is not usually felt as pain occurs and the pain threshold decreases markedly, but intraperitoneal administration of dexamethasone 21-mesylate depends on the pain threshold in a dose-dependent manner. It was confirmed to improve pain sensitivity.

Comparative Example 1

(Mifepristone study and mechanical stimulation method)
Male rats (262.5-315.2 g) of hypersensitivity model were used in one group. The pain threshold of the left footpad was measured using a stimulator set to maximum pressure: 15.0 g, time to reach maximum pressure: 20 seconds before and after mifepristone administration, 30 minutes, 60 minutes and 90 minutes after administration. The result is shown in FIG. In the figure, “**” indicates that there is a dominant difference at P <0.01 by Dunnett's multiple test method, and “*” indicates that there is a dominant difference at P <0.05 by Dunnett's multiple test method (the same applies hereinafter).
As shown in FIG. 3, in the control group administered with a 0.5 w / v% sodium carboxymethylcellulose (CMC-Na) aqueous solution, the maximum pain threshold after administration was 5.2 g, whereas mifepristone was administered. In group (a) 0.3 mg / kg administration, the maximum threshold after administration is 6.0 g, (b) 3 mg / kg administration, the maximum threshold after administration is 9.3 g, (c) 30 mg / kg administration The maximum threshold after administration was 10.3 g. Thus, administration of mifepristone significantly increased the pain threshold with administration of 3 mg and 30 mg, confirming the analgesic effect in neuropathic pain.
Comparative Example 2

(Mifepristone study / thermal stimulation method)
Five male rats (284.2-380.9 g) of a hypersensitivity model were used in one group. The pain threshold of the left footpad was measured before and after mifepristone administration using a plantar thermal stimulator set at thermal stimulation intensity 35 at 30, 60 and 90 minutes after administration. The result is shown in FIG.
As shown in FIG. 4, in the control group administered with 0.5 w / v% sodium carboxymethylcellulose (CMC-Na) aqueous solution, the maximum pain threshold after administration was 7.0 seconds, whereas mifepristone was administered. In the group (a) 0.3 mg / kg administration, the maximum threshold after administration was 7.5 seconds, (b) 3 mg / kg administration, the maximum threshold after administration was 10.6 seconds, (c) 30 mg / kg administration In cases, the maximum threshold after administration was 11.6 seconds. Thus, administration of mifepristone significantly increased the pain threshold with administration of 3 mg and 30 mg, confirming the analgesic effect in neuropathic pain.
(Discussion)
By the said Example, it was clarified that the neuropathic pain therapeutic agent containing the compound which has a glucocorticoid receptor specific antagonist as an active ingredient is effective in the treatment of neuropathic pain.

  As described above, the therapeutic agent for neuropathic pain containing the glucocorticoid receptor-specific antagonist of the present invention has an effect of improving the symptoms of neuropathic pain caused by various causes. It can be used effectively in the treatment of

FIG. 1 is a diagram showing the experimental results of Example 1, and shows the change in the pain threshold for mechanical stimulation when dexamethasone 21-mesylate was intraperitoneally administered to pain-sensitive rats. FIG. 2 is a diagram showing the experimental results of Example 2, and shows the change in pain threshold with respect to thermal stimulation when dexamethasone 21-mesylate was intraperitoneally administered to rats with hypersensitivity. FIG. 3 is a diagram showing the experimental results of Comparative Example 1, and shows changes in the pain threshold for mechanical stimulation when mifepristone was administered intraperitoneally to hypersensitive rats. FIG. 4 is a diagram showing the experimental results of Comparative Example 2, and shows changes in the pain threshold for heat stimulation when mifepristone was administered intraperitoneally to hypersensitive rats.

Claims (6)

  A therapeutic agent for neuropathic pain comprising a glucocorticoid receptor-specific antagonist as an active ingredient.   The nerve according to claim 1, wherein the glucocorticoid receptor-specific antagonist is 1,4-pregnadien-9α-fluoro-16α-methyl-11β, 17,21-triol-3,20-dione 21-methanesulfonate. Agent for the treatment of pathogenic pain.   Neuropathic pain is due to postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, allodynia, post-thoracotomy pain, CRPS, multiple sclerosis The neuropathy according to claim 1 or 2, wherein the neuropathy is one or more symptoms selected from pain, AIDS, thalamic pain, paraplegia due to spinal cord disorder, non-sensory pain, and neuropathic pain in phantom limb pain. Pain treatment agent.   A pharmaceutical composition for treating neuropathic pain comprising a glucocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier.   A method of treating neuropathic pain by administering an effective amount of a glucocorticoid receptor-specific antagonist to a mammal. Use of a glucocorticoid receptor-specific antagonist for the manufacture of a therapeutic agent for neuropathic pain.

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