WO2021024855A1 - Therapeutic agent or prophylactic agent for fibromyalgia - Google Patents

Therapeutic agent or prophylactic agent for fibromyalgia Download PDF

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WO2021024855A1
WO2021024855A1 PCT/JP2020/028858 JP2020028858W WO2021024855A1 WO 2021024855 A1 WO2021024855 A1 WO 2021024855A1 JP 2020028858 W JP2020028858 W JP 2020028858W WO 2021024855 A1 WO2021024855 A1 WO 2021024855A1
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drug
fibromyalgia
oxytocin
acid addition
addition salt
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French (fr)
Japanese (ja)
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洋之 高橋
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帝人ファーマ株式会社
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a drug which is a therapeutic agent or a preventive agent for fibromyalgia, and particularly to a therapeutic agent or a preventive agent for fibromyalgia, which contains oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient.
  • Oxytocin is a peptide hormone consisting of 9 amino acids. It is synthesized in the paraventricular nucleus of the hypothalamus of the brain, secreted into the blood from the posterior pituitary gland, and acts on uterine contractions and lactation. It is also secreted into the brain from dendrites, etc., and is said to have a function involved in social interaction.
  • a nasal drop (product name: syntocinone) containing oxytocin as an active ingredient is already known. Indications such as induction of labor have been approved, but clinical trials are also underway for indications such as autism spectrum disorders.
  • Fibromyalgia is mainly symptom of chronic pain and stiffness in the musculoskeletal system of a wide range of parts of the body, and is abnormal in objective findings and general clinical laboratory findings other than tenderness in anatomically clear areas. It is a rheumatic disease of unknown cause that occurs frequently in middle-aged and older women with various physical, psychological and neurological symptoms such as fatigue, sleep disorders and depressed mood.
  • the pain of fibromyalgia is not nociceptive, but is considered to be neuropathic or central pain with an unspecified site, and is one of the central sensitization syndromes in which so-called central sensitization of pain is established.
  • Non-drug treatments include aerobic exercise and cognitive behavioral therapy.
  • Patent Document 1 Japanese Patent Laid-Open No. 2001-527537 filed in 1998
  • administration of an oxytocin nasal agent gives a VAS score for pain and fatigue in some patients.
  • it is difficult to judge the effect because the number of patients is small.
  • Non-Patent Document 1 it is reported that even if oxytocin was administered to a patient, no improving effect was observed in the VAS scale evaluation. Therefore, at present, the relationship between oxytocin and fibromyalgia is unclear.
  • Special Table 2001-527537 Mameli S et al. Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int. 2014 Aug; 34 (8): 1047-52.
  • An object of the present invention is to provide a therapeutic agent or a preventive agent capable of sufficiently relieving the pain of fibromyalgia.
  • the present invention is as follows.
  • a drug containing oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient which is a therapeutic or preventive drug for fibromyalgia.
  • the medicament according to (1), wherein the dose of oxytocin or an acid addition salt thereof or a derivative thereof is 1 to 500 U / Body.
  • the drug according to (1) or (2), wherein the drug containing oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient is a drug for nasal mucosal administration.
  • the daily dose of pregabalin or its acid addition salt is 25 to 450 mg, the daily dose of mirogabalin or its acid addition salt is 2.5 to 30 mg, or the daily dose of gabapentin or its acid addition salt is 25 to 30 mg.
  • the drug of the present invention By administration of the drug of the present invention, a therapeutic or preventive effect on fibromyalgia can be obtained.
  • the medicament of the present invention has an excellent effect as a pharmaceutical product.
  • Oxytocin-Containing Medicine Oxytocin is a peptide hormone consisting of 9 amino acids. Its composition is Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
  • the oxytocin in the present invention may be an acid addition salt thereof.
  • Typical acid addition salts include, but are not limited to, acetates.
  • Examples of the oxytocin derivative include, but are not limited to, demoxytocin, carbetocin, nacartocin, and acid addition salts thereof, and derivatives in which a polysaccharide or polyethylene glycol is added as a linker to them.
  • oxytocins in the present specification, it is described as including not only oxytocin but also oxytocin or an acid addition salt thereof or a derivative thereof.
  • the dose of oxytocins alone in the present invention is an effective amount for the treatment or prevention of fibromyalgia of the present invention, and the age, weight, frequency of treatment, desired type of effect, or administration method of the patient. It can be determined according to the above, but 1 to 500 U / Body is preferable. 2.
  • Fibromyalgia The definition of fibromyalgia is as described in the section "6. Diagnosis" of "1-2 Disease Explanation” of "Fibromyalgia Clinical Practice Guideline 2017" (Issue date: October 20, 2017, Publisher: Nippon Medical Shinposha).
  • the American College of Rheumatology (ACR) criteria are used internationally as a classification criterion for fibromyalgia, and in addition to a wide range of physical pain (3 months or longer), an anatomically defined body. It consists of confirming tender points at 11 or more of the 18 sites.
  • the diagnostic criteria for fibromyalgia (2010 criteria) proposed by the 2010 ACR actively incorporate clinical signs characteristic of fibromyalgia other than pain, and were created for primary care physicians as well. It has been used as a product that can be used over time based on the symptom severity (SS) of fibromyalgia. 3. 3.
  • Pregabalin is (S) -3- (aminomethyl) -5-methylhexanoic acid (IUPAC name), which is a drug used for neuropathic pain.
  • Pregabalin exerts an analgesic effect by binding to the ⁇ 2 ⁇ subunit of calcium (Ca 2+ ) channels at presynaptic synapses, reducing the influx of Ca 2+ and suppressing the release of excitatory neurotransmitters.
  • Ligsins that bind to the ⁇ 2 ⁇ subunit include, but are not limited to, mirogabalin, gabapentin, and acid addition salts thereof.
  • the term "pregabalin” is used to mean not only pregabalin but also a ligand that binds to the ⁇ 2 ⁇ subunit and a drug having an analgesic effect such as an acid addition salt thereof.
  • Pregabalins already have indications for fibromyalgia. Therefore, it was found that administration of pregabalins alone also has an effect of improving fibromyalgia, but administration of oxytocins in combination further improves the effect.
  • administration of oxytocins when used in combination, when oxytocins alone are used, the effect of improving fibromyalgia is low or even at a low dose, which is surprisingly used in combination with pregabalins. As a result, the effect of improving fibromyalgia was obtained as compared with that of pregabalins alone.
  • the dose of pregabalin can be reduced by using in combination with the oxytocins of the present invention.
  • the side effect due to pregabalin administration can be reduced.
  • further administration of oxytocin can be expected to have a further effect of improving symptoms. Since oxytocins are peptides that are already present in the body, they have low toxicity and are easy to use safely.
  • the dose of oxytocins when used in combination with pregabalins is not limited as long as it is an effective amount for the treatment or prevention of fibromyalgia of the present invention as in the case of administration of oxytocins alone, but is 1 to 400 U / Body. Is preferable.
  • the dose of oxytocins when used in combination with pregabalins may be such that the oxytocins alone have a low or no effect of improving fibromyalgia.
  • the dose of pregabalin when used in combination with oxytocin is an effective amount for the treatment or prevention of fibromyalgia of the present invention, and the age, weight, type of combination therapy, frequency of treatment, desired It can be determined according to the type of effect to be obtained, the administration method, and the like.
  • the initial dose of pain associated with fibromyalgia with pregabalin or its acid addition salt alone is 150 mg orally administered twice daily, followed by a daily dose over a week or longer. After gradually increasing to 300 mg, maintain at 300 to 450 mg.
  • the dose of pregabalin or its acid addition salt may be reduced to less than the dosage and administration of these single agents.
  • pregabalin or its acid addition salt when used in combination with oxytocins is preferably 25 mg or more and 450 mg or less, and can be determined according to the symptoms. It is also possible to change the upper limit of the combined use according to the change in the maximum dose of pregabalin or an acid addition salt thereof.
  • the daily dose of mirogabalin or its acid addition salt is preferably 2.5 to 30 mg, or the daily dose of gabapentin or its acid addition salt is preferably 200 to 2400 mg.
  • oxytocins and pregabalins of the present invention means that both oxytocins and pregabalins are administered to the same patient, and both active ingredients can be mixed and administered at the same time.
  • the pharmaceutical objects containing the active ingredient may be administered separately, and may be administered simultaneously or sequentially in time, or separately at intervals. When the administration times are not simultaneous, for example, both active ingredients may be administered alternately to each other, or one active ingredient may be continuously administered and then the other active ingredient may be administered. 4.
  • the drug (preparation) in the present invention can be administered orally or parenterally as a pharmaceutical composition without any particular limitation on the route of administration.
  • the dosage form is not particularly limited, and as an orally administered preparation, for example, tablets, capsules, granules, powders, fine granules, syrups, emulsions, suspensions, etc., as parenteral preparations, for example, injections, external preparations, etc. (Nasal agents, transdermal agents, ointments, etc.), suppositories, etc. These can be produced by methods commonly used in the formulation process.
  • the preparation containing oxytocins in the present invention is not particularly limited, but is preferably a nasal preparation, that is, a preparation for administration of nasal mucosa.
  • the therapeutic or prophylactic agent in which oxytocins and pregabalins of the present invention are used in combination may be composed of a combination drug containing both active ingredients, or may be composed of independent single agents.
  • the combination drug in the present invention refers to a mixture of the active ingredients of oxytocins and pregabalins in one preparation
  • the single agent in the present invention means that one of the oxytocins and pregabalins is effective in one preparation. Refers to those containing ingredients.
  • both active ingredients in the present invention are single agents
  • the single agents that can be used individually are used in combination. Therefore, the drugs containing both active ingredients may have different dosage forms.
  • the form of each agent may be solid or liquid, solid and liquid, and is not particularly limited.
  • each administration route may be the same or different. Since pregabalins have already been marketed as oral tablets, they can be used as tablets.
  • oxytocins are preferably nasal agents. Therefore, it is preferable to administer pregabalins as oral tablets and oxytocins as nasal agents in combination.
  • both active ingredients are single agents, they may be in the form of a kit in which both agents are prepared as a set.
  • combination drug examples include dosage forms such as tablets, granules, powders, capsules, liquids, nasal drops, and injections containing the active amounts of both active ingredients.
  • the combination drug in the present invention is a drug having a mode in which both drugs are combined in order to use the oxytocins and pregabalins of the present invention in combination.
  • the mode of the combination drug and the kit can be mentioned, but the present invention is not limited to these.
  • the preparation containing the active ingredient of the present invention is prepared using the additives usually used for formulation.
  • these additives include lactose, sucrose, glucose, corn starch, potato starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate and the like.
  • binders such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and polyvinylpyrrolidone
  • disintegrants such as starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, and carboxymethyl starchina trim
  • Lubricants such as talc and stearic acids
  • coating agents such as hydroxymethylpropyl cellulose, hydroxypropylmethylcellulose phthalate, and ethylcellulose
  • colorants bases such as white vaseline in the case of semi-solid preparations, ethanol in the case of liquid preparations
  • Solvents such as ethanol, solubilizers such as ethanol, preservatives such as paraoxybenzoic acid esters, tonicity agents such as glucose, buffers such as citrates, antioxidants such as L-ascorbic acid, chelates such as EDTA
  • agents include agents, suspending agents and emulsifiers such as polysorbate 80, and
  • the number of administrations when both active ingredients are single agents may be the same or different. Further, when both agents are single agents, the number of times each is usually administered may be combined.
  • the pain-suppressing effect of oxytocin was examined using a repetitive cold stress-loaded rat (strain: Crl: CD (SD), male, 5 weeks old at the time of arrival, Charles River Laboratories, Inc.), which is a model of fibromyalgia.
  • the breeding cages were laid with wire mesh floor nets, and 6 animals were housed in each group and 3 animals in 1 cage (2 cages in each group). Animals are housed in a programmed incubator (CDB-41A, Daiwa Cold Machinery Co., Ltd.) with a warm temperature of 23 ° C and a cold temperature of -3 ° C for 120 hours (5 days) to reduce the load of cold stress. Gave. Three unloaded Sham animals were housed in a breeding cage lined with a wire mesh floor net and bred normally. The setting of cold stress was repeated 5 times a day (20 hours in total) in the warm period (23 ° C: 2 hours) and the cold period (-3 ° C: 2 hours), and maintained at -3 ° C for the remaining 4 hours. ..
  • the degree of pain in the hind limbs is used as an index, and the 50% pain threshold is calculated using Dixon's Up-Down method based on the pain response by mechanical stimulation using von Frey filament, and evaluated as evaluation points.
  • the item was the sum of the pain thresholds of the left and right hind limbs 1 and 3 hours after administration of the test substance.
  • the pain threshold decreased due to the onset of the pathological condition, and the normal value was defined as the pain threshold of the hind limbs of 6.0 g or more on both the left and right sides.
  • oxytocin preparation manufactured by Teijin Pharma Limited
  • the administration solution was weighed with a micropipette and administered into the right nasal cavity at doses of 0.0125, 0.125 and 1.25 U / Body (dose volume: 25 ⁇ L / Body).
  • Pregabalin manufactured by Haoyuan ChemExpress Co., Ltd.
  • the combined use of oxytocin and pregabalin was 0.125 U / Body of oxytocin and 10 mg / kg of pregabalin, and each usage was according to single administration.
  • the results are shown in Fig. 1.
  • the symbols "*" and “**” in FIG. 1 indicate that the significant differences from the control group to which the cold stress load was applied are P ⁇ 0.05 and P ⁇ 0.01 (Dunnett's test or Steel test), respectively. Means.
  • the symbol “++” means that the significant difference from the Control group is P ⁇ 0.01 (Student's t-test or Aspin Welch's t-test).
  • the symbol "##” means that the significant difference from the pregabalin-administered group is P ⁇ 0.01 (Student's t-test).
  • the graph shows the mean value + standard error (6 animals per group).
  • the 50% pain threshold 1 and 3 hours after administration of the oxytocin 1.25U / Body administration group was significantly higher than that of the Control group, and the pain-relieving effect of oxytocin was observed.
  • the 50% pain threshold 1 and 3 hours after administration of the pregabalin 10 mg / kg group was significantly higher than that of the Control group.
  • the combined use of oxytocin 0.125 U / Body and pregabalin 10 mg / kg significantly increased the 50% pain threshold 3 hours after administration as compared with pregabalin alone, confirming the synergistic effect of pain relief by the combined use.
  • the administration of oxytocin 0.125 U / Body did not show a significant difference as compared with the Control group, but it was unexpected that the effect appeared and the degree was remarkable when used in combination with pregabalin.
  • the therapeutic or prophylactic agent of the present invention can be used as a therapeutic or prophylactic agent for fibromyalgia, or as a therapeutic or prophylactic method for fibromyalgia.

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Abstract

The purpose of the present invention is to provide a therapeutic or prophylactic agent for fibromyalgia, which contains oxytocin as an active ingredient. Provided by the present invention is a therapeutic or prophylactic agent that is for fibromyalgia and that contains oxytocin as an active ingredient. Administration of 1-500 U/body of oxytocin alone or in combination with pregabalin provides a therapeutic or prophylactic effect against fibromyalgia.

Description

線維筋痛症の治療薬又は予防薬Treatment or prevention of fibromyalgia
　本発明は、線維筋痛症の治療薬又は予防薬である医薬に関し、特にオキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する、線維筋痛症の治療薬又は予防薬に関する。 The present invention relates to a drug which is a therapeutic agent or a preventive agent for fibromyalgia, and particularly to a therapeutic agent or a preventive agent for fibromyalgia, which contains oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient.
　オキシトシンは９個のアミノ酸からなるペプチドホルモンである。脳の視床下部室傍核等で合成され、下垂体後葉から血中へ分泌され、子宮収縮や乳汁分泌に作用する。樹状突起等から脳内へも分泌され、社会的相互作用に関与する働きがあると言われている。 Oxytocin is a peptide hormone consisting of 9 amino acids. It is synthesized in the paraventricular nucleus of the hypothalamus of the brain, secreted into the blood from the posterior pituitary gland, and acts on uterine contractions and lactation. It is also secreted into the brain from dendrites, etc., and is said to have a function involved in social interaction.
　オキシトシンを有効成分とする点鼻剤（製品名：シントシノン）が既に知られている。分娩誘発等の適応症が承認されているが、自閉スペクトラム症等の適応症についても臨床試験中である。 A nasal drop (product name: syntocinone) containing oxytocin as an active ingredient is already known. Indications such as induction of labor have been approved, but clinical trials are also underway for indications such as autism spectrum disorders.
　線維筋痛症は身体の広範な部位の筋骨格系における慢性の疼痛とこわばりを主症状とし、解剖学的に明確な部位に圧痛を認める以外、他覚的所見並びに一般的臨床検査所見に異常がなく、疲労感、睡眠障害や抑うつ気分等の多彩な身体及び精神・神経症状を伴い、中年以降の女性に好発する原因不明のリウマチ性疾患である。線維筋痛症の疼痛は侵害受容性ではなく、部位の特定されない神経障害性ないし中枢性疼痛とされており、いわゆる疼痛の中枢性感作が成立する中枢性感作症候群の一つである。 Fibromyalgia is mainly symptom of chronic pain and stiffness in the musculoskeletal system of a wide range of parts of the body, and is abnormal in objective findings and general clinical laboratory findings other than tenderness in anatomically clear areas. It is a rheumatic disease of unknown cause that occurs frequently in middle-aged and older women with various physical, psychological and neurological symptoms such as fatigue, sleep disorders and depressed mood. The pain of fibromyalgia is not nociceptive, but is considered to be neuropathic or central pain with an unspecified site, and is one of the central sensitization syndromes in which so-called central sensitization of pain is established.
　現在の治療法は、薬物治療と非薬物治療とがある。薬物治療では、神経障害性疼痛緩和薬のプレガバリンや、抗うつ薬のデュロキセチン等が使用される。非薬物治療では、有酸素運動や認知行動療法等が挙げられる。 Current treatment methods include drug treatment and non-drug treatment. In drug treatment, pregabalin, a neuropathic pain reliever, and duloxetine, an antidepressant, are used. Non-drug treatments include aerobic exercise and cognitive behavioral therapy.
　しかしながら、それらの治療によっても、痛みを十分に和らげることができない場合が多い。薬物治療においては、推奨薬物（プレガバリン、デュロキセチン等）に抵抗性を示す例も多く、またこれらの薬剤は浮動性めまい、傾眠、体重増加、又は、末梢性浮腫等の副作用が高頻度に発生するため、新たな治療法が望まれている。 However, even with these treatments, it is often not possible to sufficiently relieve the pain. In drug treatment, there are many cases of resistance to recommended drugs (pregabalin, duloxetine, etc.), and these drugs frequently cause side effects such as floating dizziness, dizziness, weight gain, or peripheral edema. Therefore, a new treatment method is desired.
　オキシトシンと線維筋痛症に関しては、１９９８年出願の特許文献１（特表２００１－５２７５３７号公報）において、オキシトシン経鼻剤（シントシノン）の投与が、一部の患者の痛み及び疲労感のＶＡＳスコアにおいて改善の効果があったことが報告されているが、患者数が少数であって、効果の判定は難しい。最近の２０１４年の非特許文献１においては、患者にオキシトシンを投与しても、ＶＡＳスケール評価で改善作用が認められなかったことが報告されている。従って、現在のところ、オキシトシンと線維筋痛症との関係は不明確である。
特表２００１－５２７５３７号公報 Mameli S等、Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int. 2014 Aug;34(8):1047-52. Regarding oxytocin and fibromyalgia, in Patent Document 1 (Japanese Patent Laid-Open No. 2001-527537) filed in 1998, administration of an oxytocin nasal agent (sintocinone) gives a VAS score for pain and fatigue in some patients. However, it is difficult to judge the effect because the number of patients is small. In the recent 2014 Non-Patent Document 1, it is reported that even if oxytocin was administered to a patient, no improving effect was observed in the VAS scale evaluation. Therefore, at present, the relationship between oxytocin and fibromyalgia is unclear.
Special Table 2001-527537 Mameli S et al., Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int. 2014 Aug; 34 (8): 1047-52.
　本発明の目的は、線維筋痛症の痛みを十分に和らげることができる治療薬又は予防薬を提供することである。 An object of the present invention is to provide a therapeutic agent or a preventive agent capable of sufficiently relieving the pain of fibromyalgia.
　本発明者らは、上記の課題を達成するために鋭意研究した結果、オキシトシンの単独投与、又はオキシトシンとプレガバリンの併用投与により、線維筋痛症の治療又は予防効果があることを見出し、本発明を完成するに至った。 As a result of diligent research to achieve the above problems, the present inventors have found that administration of oxytocin alone or a combination of oxytocin and pregabalin has a therapeutic or preventive effect on fibromyalgia, and the present invention Has been completed.
　すなわち本発明は、以下である。
（１）オキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する、線維筋痛症の治療薬又は予防薬である医薬。
（２）オキシトシンもしくはその酸付加塩又はその誘導体の投与量が、１～５００Ｕ／Ｂｏｄｙである、（１）に記載の医薬。
（３）オキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する医薬が、鼻粘膜投与用医薬である、（１）又は（２）に記載の医薬。
（４）プレガバリン、ミロガバリン、ガバペンチン、又はそれらの酸付加塩を有効成分として含有する医薬と併用するための（１）から（３）のいずれかに記載の医薬。
（５）オキシトシンもしくはその酸付加塩又はその誘導体の投与量が、1～４００Ｕ／Ｂｏｄｙである、（４）に記載の医薬。
（６）（ａ）と（ｂ）との組み合わせ医薬であって、線維筋痛症の治療薬又は予防薬である医薬。
（ａ）（１）～（５）のいずれかに記載のオキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する医薬。
（ｂ）プレガバリン、ミロガバリン、ガバペンチン、又はそれらの酸付加塩を有効成分として含有する医薬。
（７）（ａ）と（ｂ）の配合剤であることを特徴とする、（６）に記載の医薬。
（８）（ａ）と（ｂ）のキットであることを特徴とする、（６）に記載の医薬。
（９）プレガバリン又はその酸付加塩の1日投与量が２５～４５０ｍｇ、ミロガバリン又はその酸付加塩の１日投与量が２．５～３０ｍｇ、あるいはガバペンチン又はその酸付加塩の１日投与量が２００～２４００ｍｇである、（４）～（８）のいずれかに記載の医薬。 That is, the present invention is as follows.
(1) A drug containing oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient, which is a therapeutic or preventive drug for fibromyalgia.
(2) The medicament according to (1), wherein the dose of oxytocin or an acid addition salt thereof or a derivative thereof is 1 to 500 U / Body.
(3) The drug according to (1) or (2), wherein the drug containing oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient is a drug for nasal mucosal administration.
(4) The drug according to any one of (1) to (3) for use in combination with a drug containing pregabalin, mirogabalin, gabapentin, or an acid addition salt thereof as an active ingredient.
(5) The medicament according to (4), wherein the dose of oxytocin or an acid addition salt thereof or a derivative thereof is 1 to 400 U / Body.
(6) A drug that is a combination drug of (a) and (b) and is a therapeutic or preventive drug for fibromyalgia.
(A) A drug containing the oxytocin according to any one of (1) to (5), an acid addition salt thereof, or a derivative thereof as an active ingredient.
(B) A drug containing pregabalin, mirogabalin, gabapentin, or an acid addition salt thereof as an active ingredient.
(7) The medicament according to (6), which is a combination drug of (a) and (b).
(8) The medicament according to (6), which is the kit of (a) and (b).
(9) The daily dose of pregabalin or its acid addition salt is 25 to 450 mg, the daily dose of mirogabalin or its acid addition salt is 2.5 to 30 mg, or the daily dose of gabapentin or its acid addition salt is 25 to 30 mg. The medicament according to any one of (4) to (8), which is 200 to 2400 mg.
　本発明の薬剤の投与により、線維筋痛症の治療又は予防効果を得ることができる。また、本発明の医薬は医薬品として優れた効果を有する。 By administration of the drug of the present invention, a therapeutic or preventive effect on fibromyalgia can be obtained. In addition, the medicament of the present invention has an excellent effect as a pharmaceutical product.
繰り返し寒冷ストレス負荷ラットにおけるオキシトシン、プレガバリン、オキシトシンとプレガバリンとの併用の、各投与の際の疼痛抑制作用を示すグラフである。It is a graph which shows the pain-suppressing effect at each administration of oxytocin, pregabalin, and the combined use of oxytocin and pregabalin in a rat with repeated cold stress.
１．オキシトシン含有医薬
　オキシトシンは、９個のアミノ酸からなるペプチドホルモンである。その構成は、Ｃｙｓ－Ｔｙｒ－Ｉｌｅ－Ｇｌｎ－Ａｓｎ－Ｃｙｓ－Ｐｒｏ－Ｌｅｕ－Ｇｌｙである。 1. 1. Oxytocin-Containing Medicine Oxytocin is a peptide hormone consisting of 9 amino acids. Its composition is Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
　本発明におけるオキシトシンは、その酸付加塩でもよい。代表的な酸付加塩としては、酢酸塩を挙げることができるが、これに限定されない。オキシトシン誘導体としては、デモキシトシン、カルベトシン、ナカルトシン、及びそれらの酸付加塩、並びにそれらにリンカーとして多糖やポリエチレングリコールを付加した誘導体等が挙げられるが、これらに限定されない。本明細書において「オキシトシン類」と記載するときには、オキシトシンのみならず、オキシトシンもしくはその酸付加塩又はその誘導体も含む意味として記載する。 The oxytocin in the present invention may be an acid addition salt thereof. Typical acid addition salts include, but are not limited to, acetates. Examples of the oxytocin derivative include, but are not limited to, demoxytocin, carbetocin, nacartocin, and acid addition salts thereof, and derivatives in which a polysaccharide or polyethylene glycol is added as a linker to them. When referring to "oxytocins" in the present specification, it is described as including not only oxytocin but also oxytocin or an acid addition salt thereof or a derivative thereof.
　本発明におけるオキシトシン類単独での用量は、本発明の線維筋痛症の治療又は予防に有効な量であり、かつ、患者の年齢、体重、治療の頻度、望まれる効果の種類、あるいは投与法等に応じて定めることができるが、１～５００Ｕ／Ｂｏｄｙが好ましい。
２．線維筋痛症
　線維筋痛症の定義は、「繊維筋痛症診療ガイドライン２０１７」の「１－２　疾患の解説」の「６．診断」の項に記載されているとおりである（発行日：２０１７年１０月２０日、発行所：日本医事新報社）。すなわち、線維筋痛症の分類基準として米国リウマチ学会（ＡＣＲ）の基準が国際的に用いられており、身体の広範囲の疼痛（３カ月以上）に加えて、解剖学的に定義化された身体の部位１８箇所のうち１１箇所以上に圧痛点を確認することからなる。２０１０年ＡＣＲから提案された線維筋痛症の診断基準（２０１０年基準）は、疼痛以外の線維筋痛症に特徴的な臨床徴候を積極的に取り入れており、プライマリケア医をも対象として作成され、線維筋痛症の徴候重症度（symptom severity: SS）を基に、経時的に使用できるものとして用いられている。
３．オキシトシン類とプレガバリン類の併用
　プレガバリンとは、（Ｓ）－３－（ａｍｉｎｏｍｅｔｈｙｌ）－５－ｍｅｔｈｙｌｈｅｘａｎｏｉｃ　ａｃｉｄ（ＩＵＰＡＣ名）であって、神経障害性疼痛に用いられる医薬品である。プレガバリンは、神経前シナプスにおけるカルシウム（Ｃａ２＋）チャネルのα２δサブユニットに結合してＣａ２＋の流入を低下させ、興奮性神経伝達物質の放出を抑制することで鎮痛効果を発揮する。α２δサブユニットに結合するリガンドとしては、ミロガバリン、ガバペンチン、及びそれらの酸付加塩等が挙げられるが、これらに限定されない。本明細書において「プレガバリン類」と記載するときは、プレガバリンのみならず、α２δサブユニットに結合するリガンド、及びその酸付加塩等の鎮痛作用を有する薬も含む意味として記載する。 The dose of oxytocins alone in the present invention is an effective amount for the treatment or prevention of fibromyalgia of the present invention, and the age, weight, frequency of treatment, desired type of effect, or administration method of the patient. It can be determined according to the above, but 1 to 500 U / Body is preferable.
2. 2. Fibromyalgia The definition of fibromyalgia is as described in the section "6. Diagnosis" of "1-2 Disease Explanation" of "Fibromyalgia Clinical Practice Guideline 2017" (Issue date: October 20, 2017, Publisher: Nippon Medical Shinposha). That is, the American College of Rheumatology (ACR) criteria are used internationally as a classification criterion for fibromyalgia, and in addition to a wide range of physical pain (3 months or longer), an anatomically defined body. It consists of confirming tender points at 11 or more of the 18 sites. The diagnostic criteria for fibromyalgia (2010 criteria) proposed by the 2010 ACR actively incorporate clinical signs characteristic of fibromyalgia other than pain, and were created for primary care physicians as well. It has been used as a product that can be used over time based on the symptom severity (SS) of fibromyalgia.
3. 3. Combination of Oxytocins and Pregabalins Pregabalin is (S) -3- (aminomethyl) -5-methylhexanoic acid (IUPAC name), which is a drug used for neuropathic pain. Pregabalin exerts an analgesic effect by binding to the α 2 δ subunit of calcium (Ca 2+ ) channels at presynaptic synapses, reducing the influx of Ca 2+ and suppressing the release of excitatory neurotransmitters. Ligsins that bind to the α 2 δ subunit include, but are not limited to, mirogabalin, gabapentin, and acid addition salts thereof. In the present specification, the term "pregabalin" is used to mean not only pregabalin but also a ligand that binds to the α 2 δ subunit and a drug having an analgesic effect such as an acid addition salt thereof.
　プレガバリン類は、既に線維筋痛症の適応も有する。従って、プレガバリン類単独投与でも、線維筋痛症の改善効果が得られるが、オキシトシン類を併用して投与すると、より改善効果が上がることがわかった。また併用する場合のオキシトシン類の投与量は、オキシトシン類単独である場合は、線維筋痛症の改善効果が低いか、無い程度の低用量であっても、驚くべきことにプレガバリン類と併用することによって、線維筋痛症の改善効果がプレガバリン類単独よりも増強するという効果が得られた。 Pregabalins already have indications for fibromyalgia. Therefore, it was found that administration of pregabalins alone also has an effect of improving fibromyalgia, but administration of oxytocins in combination further improves the effect. In addition, when the dose of oxytocins is used in combination, when oxytocins alone are used, the effect of improving fibromyalgia is low or even at a low dose, which is surprisingly used in combination with pregabalins. As a result, the effect of improving fibromyalgia was obtained as compared with that of pregabalins alone.
　プレガバリン類単独のときと同程度の線維筋痛症の改善効果を望むときに、本発明のオキシトシン類との併用によって、プレガバリン類の投与量を減らすことができる。特にプレガバリン類の服用で副作用の発現が高い、又は高用量投与でも効果が認められにくいプレガバリン類に抵抗性のある患者にとっては、プレガバリン類投与による副作用を減らすことができる優位な効果となる。また、プレガバリン類の用量に上限を有する患者において、さらにオキシトシン類を投与することによって、より症状の改善効果を期待できる。オキシトシン類は既に体内にも備わるペプチドであるため、毒性が低く、安全に用いることが容易である。 When the same level of improvement effect on fibromyalgia as that of pregabalin alone is desired, the dose of pregabalin can be reduced by using in combination with the oxytocins of the present invention. In particular, for patients who are resistant to pregabalin and whose side effects are high when taking pregabalin or whose effect is difficult to be observed even when administered at a high dose, the side effect due to pregabalin administration can be reduced. In addition, in patients who have an upper limit on the dose of pregabalin, further administration of oxytocin can be expected to have a further effect of improving symptoms. Since oxytocins are peptides that are already present in the body, they have low toxicity and are easy to use safely.
　プレガバリン類と併用するときのオキシトシン類の投与量は、オキシトシン類単独投与のときと同様に本発明の線維筋痛症の治療又は予防に有効な量であれば限定されないが、１～４００Ｕ／Ｂｏｄｙが好ましい。特に、プレガバリン類と併用するときのオキシトシン類は、オキシトシン類単独では線維筋痛症の改善効果が低いか、無い程度の用量であっても良い。 The dose of oxytocins when used in combination with pregabalins is not limited as long as it is an effective amount for the treatment or prevention of fibromyalgia of the present invention as in the case of administration of oxytocins alone, but is 1 to 400 U / Body. Is preferable. In particular, the dose of oxytocins when used in combination with pregabalins may be such that the oxytocins alone have a low or no effect of improving fibromyalgia.
　オキシトシン類と併用するときのプレガバリン類の投与量は、本発明の線維筋痛症の治療又は予防に有効な量であり、かつ、患者の年齢、体重、併用療法の種類、治療の頻度、望まれる効果の種類、あるいは投与法等に応じて定めることができる。プレガバリン又はその酸付加塩単剤での線維筋痛症に伴う疼痛の用法・用量は、初期用量として１日１５０ｍｇを１日２回に分けて経口投与し、その後１週間以上かけて１日用量として３００ｍｇまで漸増した後、３００～４５０ｍｇで維持する。オキシトシン類との併用により、プレガバリン又はその酸付加塩の投与量はこれら単剤での用法・用量未満に減薬できる場合がある。あるいは、プレガバリン又はその酸付加塩の上限を有する患者にとって、さらにオキシトシン類と併用することによって、より改善する効果を期待できる。オキシトシン類と併用する際の、プレガバリン又はその酸付加塩の用量は、２５ｍｇ以上から４５０ｍｇ以下が好ましく、症状によって決めることが可能である。また、プレガバリン又はその酸付加塩の最大用量の変化に併せて、併用するときの上限値を変動させることも可能である。 The dose of pregabalin when used in combination with oxytocin is an effective amount for the treatment or prevention of fibromyalgia of the present invention, and the age, weight, type of combination therapy, frequency of treatment, desired It can be determined according to the type of effect to be obtained, the administration method, and the like. The initial dose of pain associated with fibromyalgia with pregabalin or its acid addition salt alone is 150 mg orally administered twice daily, followed by a daily dose over a week or longer. After gradually increasing to 300 mg, maintain at 300 to 450 mg. When used in combination with oxytocins, the dose of pregabalin or its acid addition salt may be reduced to less than the dosage and administration of these single agents. Alternatively, for patients with an upper limit of pregabalin or an acid addition salt thereof, a further improving effect can be expected by further using it in combination with oxytocins. The dose of pregabalin or its acid addition salt when used in combination with oxytocins is preferably 25 mg or more and 450 mg or less, and can be determined according to the symptoms. It is also possible to change the upper limit of the combined use according to the change in the maximum dose of pregabalin or an acid addition salt thereof.
　オキシトシン類と併用するときの、プレガバリン以外のプレガバリン類の投与量は同様に検討することが可能である。それにより、ミロガバリン又はその酸付加塩の１日投与量は２．５～３０ｍｇ、あるいはガバペンチン又はその酸付加塩の１日投与量は２００～２４００ｍｇが好ましい。 The dose of pregabalin other than pregabalin when used in combination with oxytocin can be examined in the same way. Therefore, the daily dose of mirogabalin or its acid addition salt is preferably 2.5 to 30 mg, or the daily dose of gabapentin or its acid addition salt is preferably 200 to 2400 mg.
　本発明のオキシトシン類とプレガバリン類を併用するとは、オキシトシン類及びプレガバリン類のいずれもが同一の患者に投与されることであり、両有効成分は混合して同時に投与することもできるが、それぞれの有効成分を含有する医薬の物体としては別々であって、時間的に同時又は逐次的に、あるいは時間をおいて別々に投与することも挙げられる。投与時が同時でない場合は、例えば、両有効成分を互いに交互に投与してもよいし、一方の有効成分を続けて投与した後に、他方の有効成分を投与してもよい。
４．製剤
　本発明における薬剤（製剤）は、医薬組成物として投与経路は特に限定なく、経口又は非経口的に投与することができる。剤形も特に限定なく、経口投与製剤として、例えば錠剤、カプセル剤、顆粒剤、散剤、細粒剤、シロップ剤、エマルジョン剤、懸濁剤等、非経口投与製剤として、例えば注射剤、外用剤（経鼻剤、経皮剤、軟膏剤等）、坐剤が挙げられる。これらは、製剤化工程で通常一般に用いられる方法により製造できる。 The combined use of oxytocins and pregabalins of the present invention means that both oxytocins and pregabalins are administered to the same patient, and both active ingredients can be mixed and administered at the same time. The pharmaceutical objects containing the active ingredient may be administered separately, and may be administered simultaneously or sequentially in time, or separately at intervals. When the administration times are not simultaneous, for example, both active ingredients may be administered alternately to each other, or one active ingredient may be continuously administered and then the other active ingredient may be administered.
4. Preparation The drug (preparation) in the present invention can be administered orally or parenterally as a pharmaceutical composition without any particular limitation on the route of administration. The dosage form is not particularly limited, and as an orally administered preparation, for example, tablets, capsules, granules, powders, fine granules, syrups, emulsions, suspensions, etc., as parenteral preparations, for example, injections, external preparations, etc. (Nasal agents, transdermal agents, ointments, etc.), suppositories, etc. These can be produced by methods commonly used in the formulation process.
　本発明におけるオキシトシン類を含有する製剤は、特に限定しないが、経鼻剤すなわち鼻粘膜投与用製剤であることが好ましい。 The preparation containing oxytocins in the present invention is not particularly limited, but is preferably a nasal preparation, that is, a preparation for administration of nasal mucosa.
　本発明のオキシトシン類とプレガバリン類を併用する治療薬又は予防薬は、両有効成分を含む配合剤の構成であっても良いし、それぞれ独立した単剤の構成であっても良い。ここで本発明における配合剤とは一つの製剤にオキシトシン類とプレガバリン類の有効成分を配合したものを指し、本発明における単剤とは一つの製剤にオキシトシン類かプレガバリン類のいずれか一つの有効成分を含むものを指す。 The therapeutic or prophylactic agent in which oxytocins and pregabalins of the present invention are used in combination may be composed of a combination drug containing both active ingredients, or may be composed of independent single agents. Here, the combination drug in the present invention refers to a mixture of the active ingredients of oxytocins and pregabalins in one preparation, and the single agent in the present invention means that one of the oxytocins and pregabalins is effective in one preparation. Refers to those containing ingredients.
　本発明における両有効成分が単剤である場合は、それぞれ単一に利用できる単剤を、組み合わせて利用する。したがって、両有効成分を含む薬剤がそれぞれ異なる剤型であっても構わない。例えば、それぞれの剤の形態は、固体又は液体同士でもよいし、固体と液体でも良いし、特に限定されない。また、それぞれの投与経路は同一であっても、異なっていてもよい。プレガバリン類は既に経口の錠剤として上市されているため、錠剤として使用することが可能である。一方で、オキシトシン類は経鼻剤が好ましい。よって、プレガバリン類を経口錠剤として、オキシトシン類を経鼻剤として併用投与することが一態様として好ましい。両有効成分が単剤の場合は、両剤を一式として揃えた状態である、キットの形態にしてもよい。 When both active ingredients in the present invention are single agents, the single agents that can be used individually are used in combination. Therefore, the drugs containing both active ingredients may have different dosage forms. For example, the form of each agent may be solid or liquid, solid and liquid, and is not particularly limited. In addition, each administration route may be the same or different. Since pregabalins have already been marketed as oral tablets, they can be used as tablets. On the other hand, oxytocins are preferably nasal agents. Therefore, it is preferable to administer pregabalins as oral tablets and oxytocins as nasal agents in combination. When both active ingredients are single agents, they may be in the form of a kit in which both agents are prepared as a set.
　配合剤としては、例えば、両有効成分の有効量を含む、錠剤、顆粒剤、散剤、カプセル剤、液剤、点鼻剤、注射剤等の剤形が挙げられる。 Examples of the combination drug include dosage forms such as tablets, granules, powders, capsules, liquids, nasal drops, and injections containing the active amounts of both active ingredients.
　本発明における組み合わせ医薬とは、本発明のオキシトシン類とプレガバリン類を併用するために、両医薬が組み合わされた態様を有する医薬である。例えば、配合剤やキットの態様が挙げられるが、これらに限られない。 The combination drug in the present invention is a drug having a mode in which both drugs are combined in order to use the oxytocins and pregabalins of the present invention in combination. For example, the mode of the combination drug and the kit can be mentioned, but the present invention is not limited to these.
　本発明の有効成分を含有する製剤は、通常製剤化に用いられる添加剤を用いて調製される。それら添加剤としては、固形製剤の場合、乳糖、白糖、ブドウ糖、トウモロコシデンプン、バレイショデンプン、結晶セルロース、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、及びリン酸水素カルシウム等の賦形剤；結晶セルロース、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、及びポリビニルピロリドン等の結合剤；デンプン、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、及びカルボキシメチルスターチナトリム等の崩壊剤；タルク、及びステアリン酸類等の滑沢剤；ヒドロキシメチルプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート、及びエチルセルロース等のコーティング剤；着色剤；半固形製剤の場合、白色ワセリン等の基剤、液状製剤の場合、エタノール等の溶剤、エタノール等の溶解補助剤、パラオキシ安息香酸エステル類等の保存剤、ブドウ糖等の等張化剤、クエン酸類等の緩衝剤、Ｌ－アスコルビン酸等の抗酸化剤、ＥＤＴＡ等のキレート剤、及びポリソルベート８０等の懸濁化剤・乳化剤、等を挙げることができる。
５．投与回数
　本発明の医薬は、特に限定されないが、連日投与、又は間歇的、あるいは頓服で投与しても良く、一日当たりの投与回数は、１回又は２～３回に分けて行うことができる。 The preparation containing the active ingredient of the present invention is prepared using the additives usually used for formulation. In the case of solid preparations, these additives include lactose, sucrose, glucose, corn starch, potato starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate and the like. Excipients; binders such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and polyvinylpyrrolidone; disintegrants such as starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, and carboxymethyl starchina trim; Lubricants such as talc and stearic acids; coating agents such as hydroxymethylpropyl cellulose, hydroxypropylmethylcellulose phthalate, and ethylcellulose; colorants; bases such as white vaseline in the case of semi-solid preparations, ethanol in the case of liquid preparations Solvents such as ethanol, solubilizers such as ethanol, preservatives such as paraoxybenzoic acid esters, tonicity agents such as glucose, buffers such as citrates, antioxidants such as L-ascorbic acid, chelates such as EDTA Examples thereof include agents, suspending agents and emulsifiers such as polysorbate 80, and the like.
5. Number of administrations The medicament of the present invention is not particularly limited, but may be administered daily, intermittently, or in a single dose, and the number of administrations per day can be divided into 1 or 2 to 3 times. ..
　オキシトシン類とプレガバリン類とを併用する場合で、両有効成分がそれぞれ単剤である場合の投与回数は、同じ回数としても良いし、異なった回数とすることもできる。また、両剤が単剤であるときに、それぞれが通常投与される回数を組み合わせることでもよい。 When oxytocins and pregabalins are used in combination, the number of administrations when both active ingredients are single agents may be the same or different. Further, when both agents are single agents, the number of times each is usually administered may be combined.
　以下に本発明を実施例により説明するが、本発明はこれらによって限定されるものではない。 The present invention will be described below with reference to examples, but the present invention is not limited thereto.
　線維筋痛症モデルである繰り返し寒冷ストレス負荷ラット（系統：Ｃｒｌ：ＣＤ（ＳＤ）、雄、入荷時５週齢、日本チャールス・リバー株式会社）を用いて、オキシトシンの疼痛抑制作用を検討した。 The pain-suppressing effect of oxytocin was examined using a repetitive cold stress-loaded rat (strain: Crl: CD (SD), male, 5 weeks old at the time of arrival, Charles River Laboratories, Inc.), which is a model of fibromyalgia.
　寒冷ストレスを負荷する期間は、飼育ケージには金網製の床網を敷いて、動物を各群６匹、1ケージに３匹（各群２ケージ）となるように収容して飼育した。暖期温度を２３℃、寒期温度を－３℃に設定したプログラム付きインキュベータ（ＣＤＢ－４１Ａ、大和冷機工業株式会社）に、動物を１２０時間（５日間）収容して、寒冷ストレスの負荷を与えた。負荷を与えないＳｈａｍ動物は、金網製の床網を敷いた飼育ケージに３匹収容して通常の飼育を行った。寒冷ストレスの設定は、暖期（２３℃：２時間）と寒期（－３℃：２時間）の１日５回（合計２０時間）繰り返し、残りの４時間は－３℃で維持とした。 During the period when cold stress was applied, the breeding cages were laid with wire mesh floor nets, and 6 animals were housed in each group and 3 animals in 1 cage (2 cages in each group). Animals are housed in a programmed incubator (CDB-41A, Daiwa Cold Machinery Co., Ltd.) with a warm temperature of 23 ° C and a cold temperature of -3 ° C for 120 hours (5 days) to reduce the load of cold stress. Gave. Three unloaded Sham animals were housed in a breeding cage lined with a wire mesh floor net and bred normally. The setting of cold stress was repeated 5 times a day (20 hours in total) in the warm period (23 ° C: 2 hours) and the cold period (-3 ° C: 2 hours), and maintained at -3 ° C for the remaining 4 hours. ..
　疼痛の評価は、後肢の疼痛の程度を指標とし、ｖｏｎ　Ｆｒｅｙフィラメントを用いた機械刺激による疼痛反応を基に、ＤｉｘｏｎのＵｐ－Ｄｏｗｎ法を用いて５０％疼痛閾値を算出し、評価ポイントと評価項目は被験物質投与１及び３時間後の左右後肢の疼痛閾値の合計とした。病態発症により疼痛閾値が低下し、正常値は後肢の疼痛閾値が左右いずれも６.０g以上と定義した。 For the evaluation of pain, the degree of pain in the hind limbs is used as an index, and the 50% pain threshold is calculated using Dixon's Up-Down method based on the pain response by mechanical stimulation using von Frey filament, and evaluated as evaluation points. The item was the sum of the pain thresholds of the left and right hind limbs 1 and 3 hours after administration of the test substance. The pain threshold decreased due to the onset of the pathological condition, and the normal value was defined as the pain threshold of the hind limbs of 6.0 g or more on both the left and right sides.
　オキシトシン製剤（帝人ファーマ株式会社製）は、投与液をマイクロピペットで量りとり、０．０１２５、０．１２５及び１．２５Ｕ／Ｂｏｄｙ（投与容量：２５μＬ／Ｂｏｄｙ）の用量で右側鼻腔内に投与した。プレガバリン（Haoyuan ChemExpress Co., Ltd.製）は、フレキシブル経口ゾンデを用いて、１０ｍｇ／ｋｇの用量で胃内に強制的に投与した。オキシトシンとプレガバリンの併用は、オキシトシン０．１２５Ｕ／Ｂｏｄｙ及びプレガバリン１０ｍｇ／ｋｇとし、各用法は単独投与に従った。 For the oxytocin preparation (manufactured by Teijin Pharma Limited), the administration solution was weighed with a micropipette and administered into the right nasal cavity at doses of 0.0125, 0.125 and 1.25 U / Body (dose volume: 25 μL / Body). .. Pregabalin (manufactured by Haoyuan ChemExpress Co., Ltd.) was forcibly administered intragastrically at a dose of 10 mg / kg using a flexible oral sonde. The combined use of oxytocin and pregabalin was 0.125 U / Body of oxytocin and 10 mg / kg of pregabalin, and each usage was according to single administration.
　その結果を図１に示す。図１の記号「＊」及び「＊＊」は、寒冷ストレスの負荷を与えたＣｏｎｔｒｏｌ群に対する有意差が、それぞれＰ＜０．０５、Ｐ＜０．０１（ダネット検定又はスティール検定）であることを意味する。記号「＋＋」は、Ｃｏｎｔｒｏｌ群に対する有意差が、Ｐ＜０．０１（スチューデントのｔ検定又はアスピン・ウエルチのｔ検定）であることを意味する。記号「＃＃」は、プレガバリン投与群に対する有意差が、Ｐ＜０．０１（スチューデントのｔ検定）であることを意味する。グラフは平均値＋標準誤差（１群６匹）で示している。 The results are shown in Fig. 1. The symbols "*" and "**" in FIG. 1 indicate that the significant differences from the control group to which the cold stress load was applied are P <0.05 and P <0.01 (Dunnett's test or Steel test), respectively. Means. The symbol "++" means that the significant difference from the Control group is P <0.01 (Student's t-test or Aspin Welch's t-test). The symbol "##" means that the significant difference from the pregabalin-administered group is P <0.01 (Student's t-test). The graph shows the mean value + standard error (6 animals per group).
　オキシトシン１．２５Ｕ／Ｂｏｄｙ投与群の投与から１及び３時間後の５０％疼痛閾値はＣｏｎｔｒｏｌ群と比較して有意に上昇し、オキシトシンの疼痛軽減作用が認められた。 The 50 % pain threshold 1 and 3 hours after administration of the oxytocin 1.25U / Body administration group was significantly higher than that of the Control group, and the pain-relieving effect of oxytocin was observed.
　プレガバリン１０ｍｇ／ｋｇ投与群の投与から１及び３時間後の５０％疼痛閾値はＣｏｎｔｒｏｌ群と比較して有意に上昇した。オキシトシン０．１２５Ｕ／Ｂｏｄｙ及びプレガバリン１０ｍｇ／ｋｇ併用により、プレガバリン単独投与と比較して投与から３時間後の５０％疼痛閾値が有意に上昇し、併用による疼痛軽減の相乗効果を確認した。オキシトシン０．１２５Ｕ／Ｂｏｄｙの投与では、Ｃｏｎｔｒｏｌ群と比べて有意差が認められなかったが、プレガバリンとの併用によって効果が出現し、かつその程度が顕著なことは予想外であった。 The 50 % pain threshold 1 and 3 hours after administration of the pregabalin 10 mg / kg group was significantly higher than that of the Control group. The combined use of oxytocin 0.125 U / Body and pregabalin 10 mg / kg significantly increased the 50% pain threshold 3 hours after administration as compared with pregabalin alone, confirming the synergistic effect of pain relief by the combined use. The administration of oxytocin 0.125 U / Body did not show a significant difference as compared with the Control group, but it was unexpected that the effect appeared and the degree was remarkable when used in combination with pregabalin.
　本発明の治療薬又は予防薬は、線維筋痛症の治療薬又は予防薬として、あるいは線維筋痛症の治療方法又は予防方法として使用可能である。 The therapeutic or prophylactic agent of the present invention can be used as a therapeutic or prophylactic agent for fibromyalgia, or as a therapeutic or prophylactic method for fibromyalgia.

Claims (9)

  1. 　オキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する、線維筋痛症の治療薬又は予防薬である医薬。 A drug containing oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient, which is a therapeutic or preventive drug for fibromyalgia.
  2. 　オキシトシンもしくはその酸付加塩又はその誘導体の投与量が、1～５００Ｕ／Ｂｏｄｙである、請求項１に記載の医薬。 The medicament according to claim 1, wherein the dose of oxytocin or an acid addition salt thereof or a derivative thereof is 1 to 500 U / Body.
  3. 　オキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する医薬が、鼻粘膜投与用医薬である、請求項１又は２に記載の医薬。 The drug according to claim 1 or 2, wherein the drug containing oxytocin or an acid addition salt thereof or a derivative thereof as an active ingredient is a drug for nasal mucosal administration.
  4. 　プレガバリン、ミロガバリン、ガバペンチン、又はそれらの酸付加塩を有効成分として含有する医薬と併用するための請求項１から３のいずれかに記載の医薬。 The drug according to any one of claims 1 to 3 for use in combination with a drug containing pregabalin, mirogabalin, gabapentin, or an acid addition salt thereof as an active ingredient.
  5. 　オキシトシンもしくはその酸付加塩又はその誘導体の投与量が、1～４００Ｕ／Ｂｏｄｙである、請求項４に記載の医薬。 The medicament according to claim 4, wherein the dose of oxytocin or an acid addition salt thereof or a derivative thereof is 1 to 400 U / Body.
  6. 　（ａ）と（ｂ）との組み合わせ医薬であって、線維筋痛症の治療薬又は予防薬である医薬。
    （ａ）請求項１～５のいずれかに記載のオキシトシンもしくはその酸付加塩又はその誘導体を有効成分として含有する医薬。
    （ｂ）プレガバリン、ミロガバリン、ガバペンチン、又はそれらの酸付加塩を有効成分として含有する医薬。     A drug that is a combination drug of (a) and (b) and is a therapeutic or preventive drug for fibromyalgia.
    (A) A medicament containing the oxytocin according to any one of claims 1 to 5 or an acid addition salt thereof or a derivative thereof as an active ingredient.
    (B) A drug containing pregabalin, mirogabalin, gabapentin, or an acid addition salt thereof as an active ingredient.
  7. 　（ａ）と（ｂ）の配合剤であることを特徴とする、請求項６に記載の医薬。 The medicament according to claim 6, which is a combination drug of (a) and (b).
  8. 　（ａ）と（ｂ）のキットであることを特徴とする、請求項６に記載の医薬。 The medicament according to claim 6, which is a kit of (a) and (b).
  9. 　プレガバリン又はその酸付加塩の1日投与量が２５～４５０ｍｇ、ミロガバリン又はその酸付加塩の１日投与量が２．５～３０ｍｇ、あるいはガバペンチン又はその酸付加塩の１日投与量が２００～２４００ｍｇである、請求項４～８のいずれかに記載の医薬。
    　     The daily dose of pregabalin or its acid addition salt is 25 to 450 mg, the daily dose of mirogabalin or its acid addition salt is 2.5 to 30 mg, or the daily dose of gabapentin or its acid addition salt is 200 to 2400 mg. The medicament according to any one of claims 4 to 8.
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Citations (1)

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