WO2006115304A1 - Agent servant à traiter la douleur neuropathique - Google Patents

Agent servant à traiter la douleur neuropathique Download PDF

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Publication number
WO2006115304A1
WO2006115304A1 PCT/JP2006/309190 JP2006309190W WO2006115304A1 WO 2006115304 A1 WO2006115304 A1 WO 2006115304A1 JP 2006309190 W JP2006309190 W JP 2006309190W WO 2006115304 A1 WO2006115304 A1 WO 2006115304A1
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WIPO (PCT)
Prior art keywords
pain
neuropathic pain
administration
specific antagonist
therapeutic agent
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PCT/JP2006/309190
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English (en)
Japanese (ja)
Inventor
Tsutomu Tanabe
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Japan Science And Technology Agency
Tokyo Medical And Dental University
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Publication of WO2006115304A1 publication Critical patent/WO2006115304A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • a therapeutic agent for neuropathic pain is provided.
  • the present invention relates to a therapeutic agent for neuropathic pain having an excellent action for suppressing 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 post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, prolonged pain after surgery and post-traumatic pain, and other diseases exhibiting symptoms of Alodynia.
  • central opioid receptor agonists such as morphine and non-steroidal anti-inflammatory agents (NSAIDS) such as indomethacin.
  • NSAIDS non-steroidal anti-inflammatory agents
  • these analgesics are generally less effective against neuropathic pain, and analgesics (especially narcotic analgesics) that are effective for normal nociceptive pain may be less effective.
  • narcotic analgesics especially narcotic analgesics
  • Inadequate analgesic effect of narcotic analgesics on neuropathic pain is a major feature of neuropathic pain. In some cases, this feature is used to diagnose neuropathic pain. .
  • neuropathic pain has been treated by nerve block, neurosurgical treatment such as spinal epidural electrical stimulation, lumbar intrathecal administration of drugs such as tricyclic antidepressants and baclofen.
  • neurosurgical treatment such as spinal epidural electrical stimulation
  • lumbar intrathecal administration of drugs such as tricyclic antidepressants and baclofen.
  • drugs such as tricyclic antidepressants and baclofen.
  • these treatments have the problem that they are not fully effective and have side effects.
  • force psaicin cream is effective for postherpetic neuralgia and pain syndrome after mastectomy by depleting pain substance substance P released from nerve terminals and reducing pain.
  • the burning pain caused by kabusaicin There are problems in terms of usability and safety, such as accompanying problems.
  • neuropathic pain is an intractable disease, and no effective treatment has yet been established.
  • darcocorticoids are considered to be the most important function of corticosteroids (sterolide hormones), and their pharmacological actions include immunosuppression in addition to their effects on sugar, protein, and lipid metabolism. Drugs with darcocorticoid activity that are effective, anti-inflammatory, antiallergic, antishock, etc. are clinically important drugs. In contrast, drugs with anti-darcocorticoid activity have been studied as therapeutic agents for hyperadrenocorticism, and their usefulness has not been studied.
  • Patent Document 1 4,386,085: Patent Document 1
  • Mif Pristone has been reported to be 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). Disclosure of the invention
  • an object of the present invention is to provide a novel therapeutic agent for neuropathic pain that exhibits an excellent effect on intractable pain such as neurogenic 3 ⁇ 4: 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-darcocorticoid activity exhibits a high analgesic effect in an intractable neuropathic pain model.
  • the present invention has been completed.
  • the present invention provides the following therapeutic agent for neuropathic pain, a pharmaceutical composition for treating neuropathic pain, a method for treating neuropathic pain, and the like.
  • a therapeutic agent for neuropathic pain comprising a darcocorticoid receptor-specific antagonist as an active ingredient.
  • the darcocorticoid receptor-specific antagonist is 1,4 one predanagen — 9 ⁇ -funoleolone 1 6 ⁇ -methinole 1 l 'j3, 1 7, 2 1-triol 1,
  • the therapeutic agent for neuropathic pain according to the above (1) which is 2O-dione 2 1-methanesulfonate (dexamethasone 2 1-mesylate).
  • Neuropathic pain is postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, alodynia, postthoracotomy 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.
  • a pharmaceutical composition for treating neuropathic pain comprising a darcocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier. ..
  • a method of treating neuropathic pain by administering an effective amount of a darcocorticoid receptor-specific antagonist to a mammal.
  • the therapeutic agent for neuropathic pain of the present invention is a neurogenic factor exhibiting symptoms such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, and alodynia. It is effective in the treatment of sexual pain.
  • Fig. 1 shows the experimental results of Example 1, in which dexamethasone 21-mesylate was administered intraperitoneally to rats that had undergone neuropathic pain due to nerve injury, and the change in pain threshold for mechanical stimulation was shown. It is a figure.
  • FIG. 2 is a diagram showing the experimental results of Example 2, in which dexamethasone 21-mesylate was intraperitoneally administered to rats that had undergone neuropathic pain due to nerve injury, and changes in pain threshold for thermal stimulation were observed.
  • FIG. 2 is a diagram showing the experimental results of Example 2, in which dexamethasone 21-mesylate was intraperitoneally administered to rats that had undergone neuropathic pain due to nerve injury, and changes in pain threshold for thermal stimulation were observed.
  • FIG. 3 is a diagram showing the experimental results of Comparative Example 1, which showed changes in the pain threshold for mechanical stimulation after intraperitoneal administration of mifibriston to rats that had caused neuropathic pain due to nerve damage.
  • FIG. 3 is a diagram showing the experimental results of Comparative Example 1, which showed changes in the pain threshold for mechanical stimulation after intraperitoneal administration of mifibriston to rats that had caused neuropathic pain due to nerve damage.
  • FIG. 4 is a diagram showing the experimental results of Comparative Example 2, in which mifibriston was administered intraperitoneally to rats that developed neuropathic pain due to nerve injury, and It is the figure which showed the change of a pain threshold.
  • the present invention relates to a therapeutic agent for neuropathic pain comprising a darcocorticoid receptor-specific antagonist as an active ingredient, a darcocorticoid receptor-specific antagonist and a pharmaceutically acceptable carrier. And a method for treating neuropathic pain using a darcocorticoid receptor-specific antagonist.
  • Anti-darcocorticoid 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” 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.
  • the term “pharmaceutical composition” means a composition containing an active ingredient useful in the present invention (dexamethasone 21-mesylate, etc.) and an additive such as a carrier used in the preparation of a medicament.
  • the compound is not particularly limited, but preferably dexamethasone 2 1-mesylate (1, 4 1 predanagen 9 c 1 fluoro 1 6 ⁇ -methino U ⁇ — 1 1 j3, 1 7, 21—trio 1 20 dione 21-methanesulfonate) and pharmaceutically acceptable salts thereof. All of these are known, and among them, a particularly preferred compound having anti-darcocorticoid activity is dexamethasone 21-mesylate. Dexamethasone 21-mesylate is known, and references such as Proc. Natl. Acd. Sci. USA 100: 7953 (2003) can be referred to.
  • Dexamethasone 21-mesylate can be obtained from, for example, Stellaroid (New Port RI, USA), and its chemical structure, physicochemical properties, etc. can be confirmed on the company's website. can force (http:... // ww steraloids com / products / P / P518 html) 0 in the present specification, the term "Darko glucocorticoid receptor-specific antagonist", Dar here Norre Chico I de receptor A compound known as a compound having a specific antagonistic action on the body and a pharmaceutically acceptable form of this compound (eg, its salt, ester, amide, hydrated or solvated form, racemic mixture, optically In pure form, prodrug, etc.).
  • 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.
  • acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, acetate, lactate, and kenate.
  • the base salt examples include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, water-soluble amine addition salts such as ammonium salt and N-methyl darcamamine salt, Examples include lucanolamine salts and salts derived from other pharmaceutically acceptable bases of organic amines.
  • the therapeutic agent and composition for neuropathic pain of the present invention are effective for the treatment of neuropathic pain.
  • neuropathic pain examples include, for example, postherpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, cancer pain, postoperative or posttraumatic prolonged pain, hyperalgesia, oral dinia, thoracotomy
  • post-pain CRPS
  • pain due to multiple sclerosis AIDS
  • thalamic pain paraplegia due to spinal cord injury
  • sensory pain neuropathic pain in phantom limb pain
  • the therapeutic agent for neuropathic pain of the present invention is particularly effective for the treatment of hyperalgesia and alodynia.
  • the administration form of the therapeutic agent for neuropathic pain of the present invention is not particularly limited, and can be administered orally or parenterally.
  • the darcocorticoid receptor-specific antagonist which is an active ingredient of the therapeutic agent for neuropathic pain of the present invention, may be formulated alone, but it is formulated with a pharmaceutically acceptable carrier or formulation additive. It can also be provided in the form of a preparation.
  • the darcocorticoid receptor-specific antagonist as the active ingredient of the present invention can be contained, for example, in an amount of 0.1 to 99.9% by weight.
  • Examples of pharmaceutically acceptable carriers or additives include excipients, disintegrants, disintegration aids, binders, lubricants, coating agents, dyes, diluents, solubilizers, solubilizers, isotonicity.
  • An agent, pH adjuster, stabilizer and the like can be used.
  • preparations suitable for oral administration include powders, tablets, capsules, fine granules, granules, solutions or syrups.
  • various excipients such as microcrystalline cellulose, sodium guanate, calcium carbonate, dipotassium phosphate, glycine, starch, preferably corn, starch or tapio-powered starch ,
  • various disintegrants such as alginic acid and certain kainate double salts, and granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic.
  • lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very effective for tablet formation.
  • a solid composition of the same kind can also be used in a gelatin capsule.
  • suitable substances in this connection include lactose or lactose, as well as high molecular weight polyethylene dallicol. If you want to use aqueous suspensions and Z or elixirs for oral administration, use the active ingredient in various sweeteners. In addition to flavoring, coloring, or dye, use with emulsifier and Z or suspending agent if necessary, and use with water, ethanol, propylene glycol, glycerin, etc., and diluents that combine them. be able to.
  • preparations suitable for parenteral administration include injections and suppositories.
  • the active ingredient of the present invention can be dissolved in either sesame oil or peanut oil, or a solution dissolved in an aqueous propylene dallicol solution can be used.
  • the aqueous solution should be buffered as appropriate (preferably pH 8 or higher), 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 of these solutions can be readily prepared by standard pharmaceutical techniques well known to those skilled in the art to produce aseptic conditions.
  • the active ingredient of the present invention can be administered locally such as on the skin. In this case, topical administration in the form of creams, jellies, pastes or 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 it is appropriately administered depending on 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 6 O kg). When administered as an injection, the dosage is, for example, about 100 to .5000 mg, preferably 180 to 1800 mg per day for an adult (for example, body weight 6 O kg). These daily doses may be administered in two to four divided doses.
  • Example 1 Example 1
  • the mechanical stimulation test was measured using the Dynamic Planter Aesthesiometer (37400, Ugobasil), and the thermal stimulation test was measured using the plantar thermal stimulation device (Planter test 7370, Ugobasil) to measure the pain threshold of the model animal's foot.
  • the mechanical stimulation test was measured using the Dynamic Planter Aesthesiometer (37400, Ugobasil), and the thermal stimulation test was measured using the plantar thermal stimulation device (Planter test 7370, Ugobasil) to measure the pain threshold of the model animal's foot.
  • Plant test 7370, Ugobasil Plant test 7370, Ugobasil
  • test substance is intended to confirm the direct action on the spinal cord, but it has been confirmed that it passes through the brain barrier. It was administered intraperitoneally at a volume of 5 ml / kg using a syringe and a needle.
  • CMCNa sodium carboxymethylcellulose
  • the control group administered with 0.5 w / v% sodium carboxymethylcellulose (CMCNa) aqueous solution showed a maximum pain threshold of 5.5 g after administration, whereas dexamethasone 21-mesylate was administered.
  • the administered group (a) 0.In the case of 3 mg / kg administration, the maximum threshold after administration is 6.3 g, (b) In the case of 3 mg / kg administration, the maximum threshold after administration is 8.7 g, (c) In the case of 30 mg / kg administration The later maximum threshold was 10.0 g.
  • administration of dexamethasone 21-mesilei® significantly increased the pain threshold, confirming the analgesic effect in neuropathic pain.
  • Example 1 As a result, as in Example 1, administration of dexamethasone 21-mesylate significantly increased the pain threshold, confirming the analgesic effect in neuropathic pain. Comparative Example 1
  • neuropathic pain model Five male rats (284.2-380.9 g) of neuropathic pain model were used in one group.
  • the pain threshold of the left footpad was measured using a plantar thermal stimulator set at 35, 60, and 90 minutes before and after administration of mifeverstone. The results are shown in Fig. 4.
  • the maximum pain threshold after administration was 7.0 seconds
  • the maximum threshold after administration is 7.5 seconds
  • the maximum threshold after administration is 10.6 seconds
  • the maximum threshold after administration was 11.6 seconds.
  • administration of mifepristone significantly increased the pain threshold at 3 mg and 30 mg, confirming the analgesic effect in neuropathic pain.
  • the therapeutic agent for neuropathic pain containing the darcocorticoid receptor-specific antagonist of the present invention has the action of improving the symptoms of neuropathic pain caused by various causes. It can be effectively used for the treatment of sexual pain.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention a pour objet un agent servant à traiter la douleur neuropathique lequel a un excellent effet thérapeutique sur la douleur neuropathique, laquelle est une maladie réfractaire. Plus particulièrement, l'invention a pour objet un agent servant à traiter la douleur neuropathique contenant un médicament présentant un antagonisme spécifique vis-à-vis des récepteurs des glucocorticoïdes (en particulier du 21-mésylate de dexaméthasone) comme ingrédient actif, une composition pharmaceutique servant à traiter la douleur neuropathique, un procédé de traitement de la douleur neuropathique utilisant un tel composé et similaire.
PCT/JP2006/309190 2005-04-26 2006-04-26 Agent servant à traiter la douleur neuropathique WO2006115304A1 (fr)

Applications Claiming Priority (2)

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JP2005128032A JP2006306739A (ja) 2005-04-26 2005-04-26 神経因性疼痛治療剤
JP2005-128032 2005-04-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2288353A2 (fr) * 2008-04-18 2011-03-02 Warsaw Orthopedic, Inc. Méthode permettant de traiter une douleur aiguë au moyen d'une forme retard d'une préparation combinée avec une préparation liquide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092306A1 (fr) * 2004-03-11 2005-10-06 The General Hospital Corporation Procedes et compositions pour moduler la tolerance aux opioides et la douleur chronique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092306A1 (fr) * 2004-03-11 2005-10-06 The General Hospital Corporation Procedes et compositions pour moduler la tolerance aux opioides et la douleur chronique

Non-Patent Citations (8)

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Title
CAPASSO A. ET AL.: "Central Interaction of Dexamethasone and RU-38486 on Morphine Antinociception in Mice", LIFE SCIENCE, vol. 51, no. 14, 1992, pages PL139 - PL143, XP009049342 *
CAPASSO A. ET AL.: "Clonidine-Induced Antinociception and Locomoter Hypoactivity are Reduced by Dexamethasone in Mice", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 53, no. 3, 2001, pages 351 - 360, XP003003075 *
KUROKAWA R. ET AL.: "Nonactivated and Activated Glucocorticoid Receptor Complexes from Human Salivary Gland Adenocarcinoma Cell Line", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 970, no. 3, 1988, pages 292 - 304, XP003003076 *
PIERETTI S. ET AL.: "The Interaction of Peripherally and Centrally Administered Dexamethasone and RU 38486 on Morphine Analgesia in Mice", GENERAL PHARMACOLOGY, vol. 22, no. 5, 1991, pages 929 - 933, XP009049277 *
RICHARD-FOY H. ET AL.: "Mechanisms of Dexamethasone 21-Mesylate Antiglucocorticoid Action: II. Receptor-Antiglucocorticoid Complexes Do Not Interact Productively With Mouse Mammary TUmor Virus Long Terminal Repeat Chromatin", MOLECULAR ENDOCRINOLOGY, vol. 1, no. 9, 1987, pages 659 - 665, XP003003078 *
SCHEIBLE P.P. ET AL.: "Analysis of the Glucocorticoid Antagonist Action of Dexamethasone 21-Mesylate in HeLa S3 Cells", JOURNAL OF STEROID BIOCHEMISTRY, vol. 26, no. 2, 1987, pages 181 - 187, XP003003077 *
WANG S. ET AL.: "Central Glucocorticoid Receptors Modulate the Expression and Function of Spinal NMDA Receptors after Peripheral Nerve Injury", JOURNAL OF NEUROSCIENCE, vol. 25, no. 2, January 2005 (2005-01-01), pages 488 - 495, XP003003074 *
WANG S. ET AL.: "Expression of Central Glucocorticoid Receptors after Peripheral Nerve Injury Contributes to Neuropathic Pain Behaviors in Rats", JOURNAL OF NEUROSCIENCE, vol. 24, no. 39, 2004, pages 8595 - 8605, XP003003073 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2288353A2 (fr) * 2008-04-18 2011-03-02 Warsaw Orthopedic, Inc. Méthode permettant de traiter une douleur aiguë au moyen d'une forme retard d'une préparation combinée avec une préparation liquide
EP2288353A4 (fr) * 2008-04-18 2011-03-02 Warsaw Orthopedic Inc Méthode permettant de traiter une douleur aiguë au moyen d'une forme retard d'une préparation combinée avec une préparation liquide

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