JP2020019740A - Combination of cox inhibitors with morphinan antagonists - Google Patents
Combination of cox inhibitors with morphinan antagonists Download PDFInfo
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- JP2020019740A JP2020019740A JP2018144160A JP2018144160A JP2020019740A JP 2020019740 A JP2020019740 A JP 2020019740A JP 2018144160 A JP2018144160 A JP 2018144160A JP 2018144160 A JP2018144160 A JP 2018144160A JP 2020019740 A JP2020019740 A JP 2020019740A
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- Prior art keywords
- pain
- flurbiprofen
- analgesic
- acid
- combination
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Images
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
Description
本発明は、疼痛（痛み）、特に慢性痛（例えばがん性疼痛）の軽減又は処置に有用な鎮痛薬に関する。より詳しくは、Ｃｏｘ阻害薬とモルフィナン系麻薬拮抗性鎮痛薬を組み合わせて配合又は併用し、非麻薬性でありながら、がん性疼痛にも効果を示す強力な鎮痛作用を有する鎮痛薬に関する。 The present invention relates to analgesics useful for reducing or treating pain, especially chronic pain (eg, cancer pain). More specifically, the present invention relates to an analgesic having a strong analgesic effect, which is non-narcotic and has an effect on cancer pain, in which a Cox inhibitor and a morphinan-type narcotic antagonistic analgesic are combined or used in combination.
日本人の２〜３人にひとりががんに罹患するといわれる現代において、疼痛によるがん患者のＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ Ｌｉｆｅ）の低下は、大きな社会問題となっている。がんのステージが進むにつれて、患者の疼痛は次第に耐え難いほど激しくなる。中等度〜高度の疼痛がある段階になると、最も強力な鎮痛効果を有する麻薬性の鎮痛薬が用いられる。しかし、麻薬性のオピオイド薬物は耐性の発現、さらには精神的依存および乱用に至る重大な副作用がある。依存性や中毒性を有するイメージから、麻薬性鎮痛薬はがん患者からも忌避され、鎮痛薬をスムーズに切り替えにくい実態がある。軽度の痛みから中等度の痛みを経て高度の痛みに至る過程のそれぞれの段階において、がん患者がストレスなく使用できる鎮痛薬の選択肢が用意されていることは、上記の社会問題を軽減するために求められている。 In today's world, where one in two or three Japanese people suffers from cancer, a decrease in QOL (Quality of Life) of cancer patients due to pain has become a major social problem. As the stage of the cancer progresses, the patient's pain becomes increasingly intolerable. At some stage of moderate to severe pain, narcotic analgesics with the most potent analgesic effect are used. However, narcotic opioid drugs have serious side effects that lead to the development of tolerance, as well as mental dependence and abuse. Due to their image of dependence and addiction, narcotic analgesics are also repelled by cancer patients, making it difficult to switch analgesics smoothly. At each stage of the process, from mild pain to moderate pain to severe pain, cancer patients have a choice of pain-free medications that can be used without stress to reduce the above social problems. Is required.
したがって、軽度の疼痛に対して処方されるＮＳＡＩＤｓやアセトアミノフェンから、高度の疼痛に対して処方されるオピオイド（モルヒネ、フェンタニル等）への過渡期を補う鎮痛薬として、使用実績のある成分の組み合わせで非麻薬性でありながら優れた鎮痛作用を示す鎮痛薬を実現した医薬品は、安全性の確保しやすさの観点からも価値がある。 Therefore, as an analgesic that supplements the transitional period from NSAIDs or acetaminophen prescribed for mild pain to opioids (morphine, fentanyl, etc.) prescribed for severe pain, it has been used as an analgesic. Pharmaceutical products that realize an analgesic that is excellent in analgesic action while being non-narcotic in combination are also valuable from the viewpoint of ensuring safety.
２又は３種類の鎮痛成分を配合した鎮痛薬は、過去に報告及び特許出願された例がある。例えば国際公開ＷＯ９９／１３７９９号公報（［先行技術文献］特許文献１）では、Ｃｏｘ−２阻害薬とオピオイド鎮痛薬の組み合わせが開示されている。ここではモルヒネをはじめとする強オピオイド鎮痛薬が必須の構成要素となっており、最も強いオピオイド鎮痛薬よりさらに５倍程度強い鎮痛作用を発揮することによって強オピオイド鎮痛薬の投与量を低減させることが目的とされている。しかしながら、強オピオイド鎮痛薬の投与量が低減されたとしても、強オピオイド鎮痛薬を含む点で、患者の不安は払拭しにくい。この投与量が低減された強オピオイド鎮痛薬を使用する前の段階の選択肢として、強オピオイド鎮痛薬とは別のニーズがあると考えられる。 Analgesics containing two or three types of analgesic components have been reported in the past and patent applications have been filed. For example, International Publication WO99 / 13799 ([Prior Art Document] Patent Document 1) discloses a combination of a Cox-2 inhibitor and an opioid analgesic. Here, morphine and other strong opioid analgesics are an essential component, and the dosage of strong opioid analgesics is reduced by exerting an analgesic effect about 5 times stronger than the strongest opioid analgesic. Is intended. However, even if the dose of the strong opioid analgesic is reduced, the patient's anxiety is hard to be wiped out in that the strong opioid analgesic is included. It is believed that there is a separate need for strong opioid analgesics as an option before using this reduced dose strong opioid analgesic.
国際公開ＷＯ９７／０４７８０号公報（［先行技術文献］特許文献２）も強オピオイド鎮痛薬を必須とする点が特許文献１と共通し、鎮静剤、骨格筋弛緩剤及び非オピオイドタイプの第二の鎮痛剤からなる群から選ばれる第二の成分、並びに第三の成分としてデキストロオルファン、デキストロメトルファンに代表される非毒性Ｎ−メチル−Ｄ−アスパルテート受容体拮抗剤の３成分の組み合わせが開示されている。国際公開ＷＯ９９／４５９６３号公報（［先行技術文献］特許文献３）も同様の３成分の組み合わせが開示されている。
International Publication WO97 / 04780 ([Prior Art Documents] Patent Document 2) also shares the point of requiring a strong opioid analgesic with
特開２００６−３２７９９３（［先行技術文献］特許文献４）は、プロピオン酸誘導体系非ステロイド性抗炎症薬、非ピリン系解熱鎮痛薬及びオピオイド系鎮痛薬を含有する医薬製剤を発明の構成としている。それぞれ多数の薬物が明細書中に列挙されているが、実施例にはプロピオン酸誘導体系非ステロイド性抗炎症薬としてイブプロフェン、非ピリン系解熱鎮痛薬としてアセトアミノフェン、オピオイド系鎮痛薬としてリン酸ジヒドロコデインとリン酸コデインの２種から選ばれる１種からなる組み合わせしか開示していない。机上の論理では膨大な組み合わせを包含する明細書の記載ぶりであるが、実施例に開示された組み合わせ以外の具体的な組み合わせを導き出す示唆は何も開示されていない。 Japanese Patent Application Laid-Open No. 2006-327993 ([Prior Art Document] Patent Document 4) discloses a pharmaceutical formulation containing a propionic acid derivative-based non-steroidal anti-inflammatory drug, a non-pyrine antipyretic analgesic, and an opioid analgesic. Although a number of drugs are listed in the specification, examples include ibuprofen as a propionic acid derivative non-steroidal anti-inflammatory drug, acetaminophen as a non-pyrine antipyretic analgesic, and dihydrocodeine phosphate as an opioid analgesic. And only one combination selected from two of codeine phosphate. Although the description of the specification includes an enormous number of combinations according to the theoretical logic, no suggestion for deriving a specific combination other than the combinations disclosed in the examples is disclosed.
以上の通り、分子構造や作用機序が異なり、分類が異なる鎮痛薬を２乃至３種類組み合わせて鎮痛作用の増強を意図した発明は過去に特許出願されている。しかし、多少なりとも鎮痛作用の増強が認められたとしても、当業者の予想を超えるほどの鎮痛作用の増強を明確に実証している特許文献および非特許文献は一握りであるし、そこで実証された組み合わせは極めて限定された具体的な数通りに過ぎない。しかも、オピオイド系鎮痛薬の中でもモルヒネ等の強オピオイド薬は法規制の観点から厳重な管理が必要で、中毒の恐れから一般の患者から忌避される等の実用性の面で障害がある。したがって、先行技術文献の記載から机上で想定される膨大な数の組み合わせの中には、産業的に利用価値が高いにもかかわらず見出されないままになっている未知の組み合わせが存在する。 As described above, inventions intended to enhance the analgesic effect by combining two or three types of analgesics having different molecular structures and action mechanisms and different classifications have been applied for patents in the past. However, even if the analgesic effect is enhanced to some extent, only a handful of patent documents and non-patent documents clearly demonstrate the enhancement of analgesic effect more than expected by those skilled in the art. The combinations made are only a few very specific examples. Moreover, among the opioid analgesics, strong opioid drugs such as morphine require strict management from the viewpoint of legal regulations, and there is an obstacle in practicality such as being repelled by general patients due to fear of poisoning. Therefore, among the vast number of combinations assumed on the desk from the description of the prior art documents, there are unknown combinations that remain undiscovered despite their high industrial value.
従って、本発明の目的は、上記の通り机上の論理で想定しうる膨大な数の組み合わせの集合の中から、実際のところ疼痛、例えば慢性痛（特にがん性疼痛）の軽減又は処置に有用な医薬製剤を提供することにある。 Therefore, an object of the present invention is to reduce or treat pain, for example, chronic pain (particularly, cancerous pain), in fact, from a huge number of combinations that can be assumed by desk logic as described above. To provide a novel pharmaceutical preparation.
さらに具体的には、神経因性疼痛に起因する疾患（例えば、がん性疼痛、帯状疱疹後神経痛、開胸術後痛、三叉神経痛、幻肢痛、カウザルギー、糖尿病性神経因性疼痛、四肢の
外傷・切断など）の軽減又は処置に有用な医薬を提供することにある。
More specifically, diseases caused by neuropathic pain (eg, cancer pain, postherpetic neuralgia, post-thoracotomy pain, trigeminal neuralgia, phantom limb pain, causalgia, diabetic neuropathic pain, limbs The present invention provides a medicament useful for reducing or treating trauma, amputation, etc.
本発明者は、既存の有効成分の組み合わせで、従来の非オピオイド鎮痛薬が処方されるステージから麻薬性鎮痛薬が処方されるステージまでをつなぐ医薬、もしくは麻薬拮抗性でありながら鎮痛作用が麻薬に匹敵する医薬の開発に鋭意注力してきた。その結果、Ｃｏｘ阻害薬であるフルルビプロフェンとモルフィナン系麻薬拮抗鎮痛薬であるブトルファノールの組み合わせが相乗的に増強された鎮痛作用を発現することを見出した。 The present inventor has proposed a combination of existing active ingredients, a drug that connects a stage where a conventional non-opioid analgesic is prescribed to a stage where a narcotic analgesic is prescribed, or a drug that has an analgesic effect while being a narcotic antagonist. Has been dedicated to the development of pharmaceuticals comparable to. As a result, they found that a combination of flurbiprofen, a Cox inhibitor, and butorphanol, a morphinan-type antagonistic analgesic, exhibited a synergistically enhanced analgesic effect.
すなわち、本発明の態様は、以下の通りである。
（１）Ｓ−フルルビプロフェン若しくはその薬学的に許容される塩又はそれらの水和物と、ブトルファノール若しくはその薬学的に許容される塩又はそれらの水和物との組み合わせを特徴とする医薬。
（２）疼痛の軽減又は処置用である（１）に記載の医薬。
（３）疼痛が慢性痛である（１）又は（２）に記載の医薬。
（４）疼痛ががん性疼痛である（１）〜（３）のいずれか１項に記載の医薬。
（５）患者の疼痛を軽減又は処置するための方法であって、Ｓ−フルルビプロフェン若しくはその薬学的に許容される塩又はそれらの水和物と、ブトルファノール若しくはその薬学的に許容される塩又はそれらの水和物とを同時または時間差をおいて患者に投与することを含む方法。
（６）疼痛が慢性痛である（５）に記載の方法。
（７）疼痛ががん性疼痛である（５）又は（６）に記載の方法。
That is, aspects of the present invention are as follows.
(1) A drug characterized by a combination of S-flurbiprofen or a pharmaceutically acceptable salt thereof or a hydrate thereof, and butorphanol or a pharmaceutically acceptable salt thereof or a hydrate thereof. .
(2) The medicament according to (1), which is used for reducing or treating pain.
(3) The medicament according to (1) or (2), wherein the pain is chronic pain.
(4) The medicament according to any one of (1) to (3), wherein the pain is cancer pain.
(5) A method for reducing or treating pain in a patient, comprising S-flurbiprofen or a pharmaceutically acceptable salt or hydrate thereof, and butorphanol or a pharmaceutically acceptable salt thereof. A method comprising administering a salt or a hydrate thereof to a patient simultaneously or at an interval.
(6) The method according to (5), wherein the pain is chronic pain.
(7) The method according to (5) or (6), wherein the pain is cancer pain.
本発明は、Ｃｏｘ阻害薬とモルフィナン系麻薬拮抗鎮痛薬のそれぞれが有する鎮痛作用を組み合わせ、具体的にはＳ−フルルビプロフェンと酒石酸ブトルファノールの組み合わせによって鎮痛作用を相乗的に増強し、患者の痛み（疼痛）、例えば慢性的な痛み、特にがん性疼痛を予想外に軽減または治療できる医薬を提供する。さらに、本発明の医薬は、神経因性疼痛に起因する疾患である帯状疱疹後神経痛、開胸術後痛、三叉神経痛、幻肢痛、カウザルギー、糖尿病性神経因性疼痛、四肢の外傷・切断などの治療にも適応し得ることが想定される。 The present invention combines the analgesic action of each of a Cox inhibitor and a morphinan narcotics antagonist analgesic, specifically synergistically enhances the analgesic action by a combination of S-flurbiprofen and butorphanol tartrate, Provided is a medicament capable of unexpectedly reducing or treating pain (pain), for example, chronic pain, particularly cancer pain. Furthermore, the medicament of the present invention is useful for treating post-herpetic neuralgia, post-thoracotomy pain, trigeminal neuralgia, phantom limb pain, causalgia, diabetic neuropathic pain, limb trauma or amputation, which are diseases caused by neuropathic pain. It is assumed that it can be applied to such treatments.
本発明における用語の意義は以下の通りである。 The meanings of the terms in the present invention are as follows.
「Ｃｏｘ阻害薬」のうち好ましいのは、フルルビプロフェン（ｆｌｕｒｂｉｐｒｏｆｅｎ）である。さらに好ましくは光学異性体のＳ−フルルビプロフェン（Ｓ−ｆｌｕｒｂｉｐｒｏｆｅｎ）である。フルルビプロフェンは、（２ＲＳ）−２−（２−フルオロビフェニル−４−イル）プロピオン酸、Ｓ−フルルビプロフェンは２Ｓ−２−（２−フルオロビフェニル−４−イル）プロピオン酸の化学名を有する物質である。 Preferred among the "Cox inhibitors" is flurbiprofen. Even more preferably, it is the optical isomer S-flurbiprofen. Flurbiprofen is the chemistry of (2RS) -2- (2-fluorobiphenyl-4-yl) propionic acid, and S-flurbiprofen is the chemistry of 2S-2- (2-fluorobiphenyl-4-yl) propionic acid. It is a substance with a name.
「モルフィナン系麻薬拮抗鎮痛薬」のうち、好ましいのはブトルファノールである。ブトルファノールは、モルフィナン構造を有し、化学名は１７−（シクロブチルメチル）−モルフィナン−３，１４−ジオールである。麻薬拮抗性鎮痛薬とは、オピオイド作動薬が存在しない状況では作動薬として作用するが、オピオイド作動薬の存在下ではその作用に拮抗する作用をもつ鎮痛薬をいう。フリー体として、又は、好ましくは酒石酸のような弱い有機酸の薬学的に許容しうる塩として使用し得る。 Of the "morphinan narcotics antagonist analgesics", preferred is butorphanol. Butorphanol has a morphinan structure and its chemical name is 17- (cyclobutylmethyl) -morphinan-3,14-diol. The narcotic antagonistic analgesic refers to an analgesic that acts as an agonist in the absence of an opioid agonist, but has an action to antagonize the action in the presence of an opioid agonist. It can be used in free form or, preferably, as a pharmaceutically acceptable salt of a weak organic acid such as tartaric acid.
前記薬効成分（Ｃｏｘ阻害薬及びモルフィナン系麻薬拮抗鎮痛薬）の塩としては、生理学的または薬学的に許容される種々の塩が利用でき、塩を形成する酸または塩基は、これらの薬効成分の種類に応じて選択できる。これらの塩としては、例えば、硫酸、塩酸、臭化水素酸、リン酸、硝酸などの無機酸との塩、酢酸、シュウ酸、乳酸、酒石酸、フマル酸、マレイン酸、クエン酸、ベンゼンスルホン酸、メタンスルホン酸、ｐ−トルエンスルホン酸、安息香酸、カンファースルホン酸、エタンスルホン酸、グルコヘプトン酸、グルコン酸、グルタミン酸、グリコール酸、リンゴ酸、マロン酸、マンデル酸、ガラクタル酸、ナフタレン−２−スルホン酸などの有機酸との塩、リチウムイオン、ナトリウムイオン、カリウムイオン、カルシウムイオン、マグネシウムイオン、亜鉛イオン、アルミニウムイオンなどの１種又は複数の金属イオンとの塩、アンモニア、アルギニン、リシン、ピペラジン、コリン、ジエチルアミン、４−フェニルシクロヘキシルアミン、２−アミノエタノール、ベンザチンなどのアミンなどが挙げられる。特にブトルファノールは酒石酸塩が好ましい。 As salts of the medicinal ingredients (Cox inhibitors and morphinan narcotics antagonistic analgesics), various physiologically or pharmaceutically acceptable salts can be used. Can be selected according to the type. These salts include, for example, salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid , Methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactic acid, naphthalene-2-sulfone Salts with organic acids such as acids, lithium ions, sodium ions, potassium ions, calcium ions, magnesium ions, zinc ions, salts with one or more metal ions such as aluminum ions, ammonia, arginine, lysine, piperazine, Choline, diethylamine, 4-phenylcyclohexylamine, - aminoethanol, and the like amines such as benzathine. Particularly, butorphanol is preferably a tartrate salt.
また、Ｃｏｘ阻害薬及びモルフィナン系麻薬拮抗鎮痛薬には薬学的に許容される塩のほか各種溶媒和物であってもよく、水付加物（水和物）も含まれる。さらに、エナンチオマー、ジアステレオマー、平衡化合物、これらの任意の割合の混合物、ラセミ体等を全て含む。 The Cox inhibitor and the morphinan narcotics antagonist may be various solvates in addition to pharmaceutically acceptable salts, and include water adducts (hydrates). Furthermore, all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like are included.
本発明の医薬の投与量は、投与対象、投与方法等により適切に設定されうる。また、本発明のフルルビプロフェン若しくはその薬学的に許容される塩又はそれらの水和物と、ブトルファノール若しくはその薬学的に許容される塩又はそれらの水和物の適した比は、投与対象、投与方法等により異なるが、フルルビプロフェンと酒石酸ブトルファノールの組み合わせの場合、酒石酸ブトルファノールの割合は、フルルビプロフェン１００重量部に対して、２〜２０００重量部の範囲から選択すればよく、通常２０〜１８０重量部、好ましくは４０〜１４０重量部、さらに好ましくは５０〜１２０重量部、特に好ましくは６０〜１００重量部程度である。 The dose of the medicament of the present invention can be appropriately set depending on the administration subject, administration method and the like. Further, the appropriate ratio of flurbiprofen or a pharmaceutically acceptable salt thereof or a hydrate thereof to butorphanol or a pharmaceutically acceptable salt thereof or a hydrate thereof according to the present invention depends on the administration subject. Depending on the administration method, etc., in the case of a combination of flurbiprofen and butorphanol tartrate, the ratio of butorphanol tartrate may be selected from a range of 2 to 2,000 parts by weight with respect to 100 parts by weight of flurbiprofen, Usually, it is about 20 to 180 parts by weight, preferably about 40 to 140 parts by weight, more preferably about 50 to 120 parts by weight, particularly preferably about 60 to 100 parts by weight.
上記割合は、フルルビプロフェン及びブトルファノールが光学分割されていない状態（ラセミ体）で換算した割合である。このため、薬学的に活性な光学異性体を使用する場合には、上記割合を調整する必要がある。Ｓ−フルルビプロフェンを使用する場合、Ｓ−フルルビプロフェンに対する酒石酸ブトルファノールの割合は、上記範囲の２倍程度の量に相当する。 The above ratio is a ratio calculated in a state where flurbiprofen and butorphanol are not optically resolved (racemic form). Therefore, when a pharmaceutically active optical isomer is used, the above ratio must be adjusted. When S-flurbiprofen is used, the ratio of butorphanol tartrate to S-flurbiprofen corresponds to about twice the amount in the above range.
Ｓ−フルルビプロフェンと酒石酸ブトルファノールの組み合わせの場合、酒石酸ブトルファノールの割合は、Ｓ−フルルビプロフェン１００重量部に対して、１〜１０００重量部の範囲から選択すればよく、通常１０〜９０重量部、好ましくは２０〜７０重量部、さらに好ましくは２５〜６０重量部、特に好ましくは３０〜５０重量部程度である。 In the case of a combination of S-flurbiprofen and butorphanol tartrate, the ratio of butorphanol tartrate may be selected from the range of 1 to 1000 parts by weight with respect to 100 parts by weight of S-flurbiprofen, and is usually 10 to 90 parts by weight. Parts by weight, preferably 20 to 70 parts by weight, more preferably 25 to 60 parts by weight, particularly preferably about 30 to 50 parts by weight.
Ｓ−フルルビプロフェンと酒石酸ブトルファノールの組み合わせの場合、それらの割合を効力で表すと、Ｓ−フルルビプロフェンの効力１に対して、酒石酸ブトルファノールの効力は０．１〜１０の範囲から選択すればよく、通常は０．３〜３、好ましくは０．４〜２．５、さらに好ましくは０．５〜２、特に好ましくは０．７〜１．５程度である。
In the case of a combination of S-flurbiprofen and butorphanol tartrate, when the ratio is expressed by potency, the potency of butorphanol tartrate is selected from the range of 0.1 to 10 with respect to
フルルビプロフェン若しくはその薬学的に許容される塩又はそれらの水和物とブトルファノール若しくはその薬学的に許容される塩又はそれらの水和物それぞれの投与時期は限定されず、これらを投与対象に対し同時に投与してもよいし、時間差をおいて投与してもよい。さらに、これらは、それぞれ異なる製剤として投与されてもよいし、両方を含む単一の製剤として投与されてもよい。これらの比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。 The administration timing of flurbiprofen or a pharmaceutically acceptable salt thereof or a hydrate thereof and butorphanol or a pharmaceutically acceptable salt thereof or a hydrate thereof is not limited. On the other hand, they may be administered at the same time, or may be administered with a time lag. Furthermore, they may be administered as different formulations or as a single formulation containing both. These ratios can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like.
本発明の医薬製剤には、フルルビプロフェン若しくはその薬学的に許容される塩又はそれらの水和物とブトルファノール若しくはその薬学的に許容される塩又はそれらの水和物のほかに、鎮痛薬に配合可能な他の薬効成分を適宜配合することができる。当該配合可能な薬効成分としては、本発明の医薬製剤の鎮痛活性および安全性に悪影響を及ぼさない薬効成分であればよい。 Pharmaceutical preparations of the present invention include, in addition to flurbiprofen or a pharmaceutically acceptable salt thereof or a hydrate thereof and butorphanol or a pharmaceutically acceptable salt thereof or a hydrate thereof, an analgesic Other medicinal ingredients that can be blended with the above can be appropriately blended. The medicinal ingredient that can be blended may be any medicinal ingredient that does not adversely affect the analgesic activity and safety of the pharmaceutical preparation of the present invention.
そのほかに、例えば、ビタミン類（ビタミンＡ、Ｄ、Ｅ、Ｋ、Ｕなど脂溶性ビタミン類及びビタミンＢ、Ｃ、Ｐなど水溶性ビタミン類）、解熱・鎮痛・抗炎症薬（スルピリンなどのピリン系解熱鎮痛薬、サリチル酸ナトリウムなどのサリチル酸系薬剤、フルフェナム酸、メフェナム酸などのフェナム酸系薬剤、ジクロフェナクナトリウム、インドメタシンなどのアリール酢酸系薬剤、フェニルブタゾン、オキシフェニルブタゾンなどのピラゾリジン系薬剤、ブコロームなどのピリミジン系薬剤、ピロキシカムなどのオキシカム系薬剤、イソプロピルアンチピリンなど）、抗ヒスタミン薬（フマル酸クレマスチン、塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミンなど）、鎮咳去痰薬（クロペラスチン、デキストロメトルファン、ベンゾナテートなどの鎮咳薬、去痰薬、例えば、塩酸ブロムヘキシン、塩酸Ｌ−システイン、塩酸Ｌ−メチルシステイン、アセチルシステインなどの粘膜溶解液、カルボシステインなどの粘液修復薬、塩酸アンブロキソールなどの粘液潤滑薬など）、気管支拡張薬又は喘息治療薬（シュードエフェドリン、塩酸エフェドリン、塩酸メチルエフェドリン、塩酸テルブタリン、イソプロテレノール、サルブタモール、テルブタリンなどのβ2−アドレナリン受容体刺激薬、テオフィリン、アミノフィリン、プロキシフィリンなどのキサンチン系薬剤、クロモグリク酸など）、局所麻酔薬（例えば、塩酸テトラカイン、塩酸プロカインなどのアミノ安息香酸アルカミンエステル系薬剤、塩酸ジブカインなどのジブカイン系薬剤；塩酸ブピバカイン、塩酸メピバカイン、塩酸リドカイン、塩酸ロピバカインなどのキシリジン系薬剤）、カフェイン類、制酸剤、アミノ酸類、生薬などが例示できる。これらの薬効成分は単独で又は二種以上組み合わせて使用できる。 In addition, for example, vitamins (fat-soluble vitamins such as vitamins A, D, E, K and U and water-soluble vitamins such as vitamins B, C and P), antipyretic / analgesic / anti-inflammatory drugs (pyrine antipyretics such as sulpyrine) Analgesics, salicylic acid drugs such as sodium salicylate, fenamic acid drugs such as flufenamic acid and mefenamic acid, arylacetic acid drugs such as diclofenac sodium and indomethacin, pyrazolidine drugs such as phenylbutazone and oxyphenylbutazone, bucolome, etc. Pyrimidine drugs, oxicam drugs such as piroxicam, isopropylantipyrine, etc., antihistamines (clemastine fumarate, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), antitussive expectorants (cloperastine, dextromethorphan, ben) Antitussives such as natate, expectorants, for example, mucosal lysates such as bromhexine hydrochloride, L-cysteine hydrochloride, L-methylcysteine hydrochloride, acetylcysteine, mucous repairing agents such as carbocysteine, mucous lubricants such as ambroxol hydrochloride ), Bronchodilators or asthma treatments (pseudoephedrine, ephedrine hydrochloride, methylephedrine hydrochloride, terbutaline hydrochloride, isoproterenol, salbutamol, terbutaline, etc., β2-adrenoceptor stimulants, xanthine such as theophylline, aminophylline, proxyphylline) Drugs, cromoglycic acid, etc.), local anesthetics (eg, aminobenzoic acid alkamine ester drugs such as tetracaine hydrochloride and procaine hydrochloride, dibucaine drugs such as dibucaine hydrochloride; bupivacaine hydrochloride, Bakain, lidocaine hydrochloride, xylidine drugs such as hydrochloric ropivacaine), caffeine, antacids, amino acids, such as crude drugs can be exemplified. These active ingredients can be used alone or in combination of two or more.
本発明の医薬製剤は、疼痛に苦しむ患者に合わせて、経口又は非経口（例えば、経皮、静脈内、筋肉内など）投与することができる。例えば、慢性痛、特にがん性疼痛を患っている患者に対して経口投与する場合、経口投与に適した製剤としては、固形製剤（例えば、錠剤、丸剤、細粒剤、顆粒剤、散剤、硬カプセル剤、軟カプセル剤、トローチ剤、ドライシロップ剤など）であってもよく、非固形製剤（例えば、シロップ剤、液剤および懸濁剤など）であってもよい。また、非経口投与する場合、非経口投与に適した製剤としては、テープ剤（プラスター剤ともいう）、パップ剤、軟膏剤、クリーム剤、ローション剤などの外用製剤又は注射剤（点滴を含む）であってもよい。外用製剤の好ましい剤形は非水系外用製剤、例えばテープ剤、軟膏剤などであり、特に好ましいのはテープ剤である。なお、医薬製剤には、薬効成分の放出性をコントロールした製剤（例えば、速放性製剤、徐放性製剤など）も含まれる。 The pharmaceutical preparation of the present invention can be administered orally or parenterally (for example, transdermally, intravenously, intramuscularly, etc.) according to the patient suffering from pain. For example, in the case of oral administration to a patient suffering from chronic pain, particularly cancer pain, a formulation suitable for oral administration includes solid preparations (eg, tablets, pills, fine granules, granules, powders) , Hard capsules, soft capsules, troches, dry syrups and the like, and non-solid preparations (eg, syrups, solutions and suspensions). In the case of parenteral administration, preparations suitable for parenteral administration include external preparations such as tapes (also called plasters), cataplasms, ointments, creams, and lotions or injections (including infusions). It may be. Preferred dosage forms for external preparations are non-aqueous external preparations, such as tapes, ointments and the like, with tapes being particularly preferred. Pharmaceutical preparations also include preparations with controlled release of medicinal components (eg, immediate release preparations, sustained release preparations, etc.).
本発明の医薬は、前記Ｃｏｘ阻害薬及びモルフィナン系麻薬拮抗鎮痛薬を担体（医薬製剤に適した製剤添加物）と組み合わせ、慣用の方法で製剤化し得る。すなわち、本発明の医薬は、例えば、日本薬局方に記載の錠剤、顆粒剤、散剤、硬カプセル剤、軟カプセル剤、トローチ剤、ドライシロップ剤、シロップ剤、液剤、懸濁剤などの製造法に従って製造することができる。外用剤は、テープ剤（プラスター剤ともいう）、パップ剤、軟膏剤、クリーム剤、ローション剤などの各種剤形を常法により製造することができる。これら製剤は各剤形に適した添加剤や基剤を適宜使用し、日本薬局方などに記載される通常の方法に従って製造できる。液剤は、剤形に応じて、薬効成分と液体担体成分（水など）と必要により添加剤（乳化剤、分散剤や懸濁剤、保存剤、安定剤、矯味剤、ｐＨ調整剤や緩衝剤など）を混合して調製でき、必要により滅菌処理して製造することができる。 The medicament of the present invention can be formulated by a conventional method by combining the above-mentioned Cox inhibitor and morphinan narcotic antagonist analgesic with a carrier (formulation additive suitable for pharmaceutical preparation). That is, the medicament of the present invention is, for example, according to the manufacturing method of tablets, granules, powders, hard capsules, soft capsules, troches, dry syrups, syrups, solutions, suspensions and the like described in the Japanese Pharmacopoeia. Can be manufactured. As the external preparation, various dosage forms such as a tape (also referred to as a plaster), a poultice, an ointment, a cream, a lotion and the like can be produced by a conventional method. These preparations can be produced according to a usual method described in the Japanese Pharmacopoeia or the like, by appropriately using additives and bases suitable for each dosage form. Liquid preparations contain, depending on the dosage form, a pharmaceutically active ingredient, a liquid carrier component (eg, water) and, if necessary, additives (emulsifiers, dispersants and suspending agents, preservatives, stabilizers, flavoring agents, pH adjusters, buffers, etc. ) Can be prepared by mixing, and if necessary, sterilized.
前記担体（製剤添加物）としては、前記剤型の医薬品を製造する上で通常使用される添加剤が挙げられ、例えば、「第１７改正日本薬局方」および「医薬品添加物事典2016」（薬事日報社刊）に収載されている賦形剤、結合剤、崩壊剤、滑沢剤、コーティング剤、溶剤、乳化剤、分散剤や懸濁剤、保存剤、安定剤、矯味剤、ｐＨ調整剤や緩衝剤などが利用できる。 Examples of the carrier (formulation additive) include additives that are commonly used in the manufacture of pharmaceuticals of the above-described dosage form, and include, for example, “17th Revised Japanese Pharmacopoeia” and “Pharmaceutical Additives Dictionary 2016” Excipients, binders, disintegrants, lubricants, coatings, solvents, emulsifiers, dispersants and suspending agents, preservatives, stabilizers, flavoring agents, pH adjusters Buffers and the like can be used.
テープ剤の膏体基剤としては、スチレン・イソプレン・スチレンブロック共重合体（ＳＩＳ）、スチレン・ブタジエン・スチレンブロック共重合体（ＳＢＳ）、スチレン・エチレン・ブチレン・スチレンブロック共重合体（ＳＥＢＳ）又はスチレン・エチレン・プロピレン・スチレンブロック共重合体（ＳＥＰＳ）等が挙げられる。 Examples of the base of the tape preparation include styrene / isoprene / styrene block copolymer (SIS), styrene / butadiene / styrene block copolymer (SBS), and styrene / ethylene / butylene / styrene block copolymer (SEBS). Alternatively, a styrene-ethylene-propylene-styrene block copolymer (SEPS) may be used.
粘着付与剤としては、ロジンエステル樹脂、ポリテルペン樹脂、テルペンフェノール樹脂、石油樹脂等が挙げられる。 Examples of the tackifier include a rosin ester resin, a polyterpene resin, a terpene phenol resin, and a petroleum resin.
膏体基剤には、さらに、軟化剤、抗酸化剤、ゴムの老化防止剤等を任意に配合できる。ゴムの老化防止剤としては、例えば、ｐ，ｐ’−ジアミノジフェニルメタン、アルドール−α−ナフチルアミン、フェニル−α−ナフチルアミン、フェニル−β−ナフチルアミン、Ｎ，Ｎ’−ジフェニル−ｐ−フェニレンアミン、Ｎ，Ｎ’−ジ−β−ナフチル−ｐ−フェニレンジアミン、１，２−ジヒドロ−２，２，４−トリメチルキノリン、２，６−ジ第三ブチル−ｐ−クレゾール、２，５−ジ第三ブチル−ハイドロキノン、ハイドロキノン−モノベンジルエーテル、４，４’−ジヒドロキシ-ジフェニルシクロヘキサノンなどを１種以上配合することができる。 The plaster base may optionally further contain a softener, an antioxidant, an antioxidant for rubber and the like. Examples of the rubber antioxidant include p, p'-diaminodiphenylmethane, aldol-α-naphthylamine, phenyl-α-naphthylamine, phenyl-β-naphthylamine, N, N′-diphenyl-p-phenyleneamine, N′-di-β-naphthyl-p-phenylenediamine, 1,2-dihydro-2,2,4-trimethylquinoline, 2,6-di-tert-butyl-p-cresol, 2,5-di-tert-butyl -One or more kinds of hydroquinone, hydroquinone-monobenzyl ether, 4,4'-dihydroxy-diphenylcyclohexanone and the like can be blended.
以下に、試験例に基づいて本発明をさらに詳細に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail based on test examples, but the present invention is not limited thereto.
［試験例１］ラットイースト誘発疼痛モデルＳ−フルルビプロフェン及び酒石酸ブトルファノール併用投与の鎮痛作用における相加／相乗効果の検討
＜単独投与による作用＞
[Test Example 1] Investigation of additive / synergistic effect on analgesic effect of combined administration of rat yeast-induced pain model S-flurbiprofen and butorphanol tartrate <action by single administration>
Ｓ−フルルビプロフェン及び酒石酸ブトルファノールの併用時の鎮痛作用を評価する前段階として、まず、Ｓ−フルルビプロフェン及び酒石酸ブトルファノールの単独投与時の鎮痛作用を、ラットを用いたＲａｎｄａｌｌ ＆ Ｓｅｌｉｔｔｏ法にて評価し、それぞれのＥＤ５０を算出した。 Before evaluating the analgesic effect of the combined use of S-flurbiprofen and butorphanol tartrate, first, the analgesic effect of the single administration of S-flurbiprofen and butorphanol tartrate was determined using the Randall & Selitto method using rats. Was evaluated, and each ED 50 was calculated.
すなわち、４週齢ラットの右側後肢足蹠皮下に１０％ビール酵母を用いて起炎し、起炎前、起炎後１、２、３、４及び５時間の疼痛閾値をＲａｎｄａｌｌ ＆ Ｓｅｌｉｔｔｏ法にて測定した。 That is, 4-week-old rats were inflamed using 10% brewer's yeast subcutaneously in the right hind footpad, and the pain thresholds before, 1, 2, 3, 4 and 5 hours after the inflammation were determined by the Randall & Selitto method. Measured.
Ｓ−フルルビプロフェンは１、３及び１０ｍｇ／ｋｇを起炎前１時間に経口投与し、酒石酸ブトルファノールは０．０３、０．３及び３ｍｇ／ｋｇを起炎直後と起炎後３時間の計２回、皮下投与した。対照群として起炎対照群を設けた。
S-flurbiprofen was orally administered at 1, 3 and 10 mg /
初回測定時の疼痛閾値をもとに算出した疼痛閾値比を経時的にプロットし、その曲線下面積（ＡＵＣ０−５ｈｒ）を算出した。Ｓ−フルルビプロフェン及び酒石酸ブトルファノール各投与量におけるＡＵＣ０−５ｈｒからそれぞれのＥＤ５０を算出した（表１）。各投与量におけるＡＵＣ０−５ｈｒから市販統計ソフトＳＡＳ９．２（ＳＡＳ Ｉｎｓｔｉｔｕｔｅ Ｊａｐａｎ株式会社）を用いてそれぞれのＥＤ５０を算出した The pain threshold ratio calculated based on the pain threshold at the time of the first measurement was plotted with time, and the area under the curve (AUC 0-5 hr ) was calculated. The ED 50 of each of S-flurbiprofen and butorphanol tartrate was calculated from AUC 0-5 hr at each dose (Table 1). Each ED 50 was calculated from AUC 0-5 hr at each dose using commercially available statistical software SAS 9.2 (SAS Institute Japan).
＜併用投与による作用＞
<Effect of combined administration>
単剤で算出したＥＤ５０の１０倍量を参考に、Ｓ−フルルビプロフェン１０ｍｇ／ｋｇ及び酒石酸ブトルファノール３ｍｇ／ｋｇを基準にして、効力比として１：３（投与量：２．５／２．２５ｍｇ／ｋｇ）、１：１（投与量：５／１．５ｍｇ／ｋｇ）、３：１（投与量：７．５／０．７５ｍｇ／ｋｇ）となるように設定し、それぞれの比について、Ｓ−フルルビプロフェンは公比１０、酒石酸ブトルファノールは公比１０で低用量に設定し、各重量比で３用量、合計９用量を設定した。
With reference to 10 times the ED 50 calculated with a single agent, the efficacy ratio was 1: 3 (dose: 2.5 / 2 based on S-flurbiprofen 10 mg / kg and
その９用量において初回測定時の疼痛閾値をもとに算出した疼痛閾値比を経時的にプロットし、その曲線下面積（ＡＵＣ０−５ｈｒ）を算出した結果を図２、４及び６に示す。さらに各用量のＡＵＣ０−５ｈｒとＳ−フルルビプロフェンまたは酒石酸ブトルファノールそれぞれの用量からＥＤ５０を算出した（表２）。単独投与と同様に、各投与量におけるＡＵＣ０−５ｈｒから市販統計ソフトＳＡＳ９．２（ＳＡＳ Ｉｎｓｔｉｔｕｔｅ Ｊａｐａｎ株式会社）を用いてそれぞれのＥＤ５０を算出した。表２において、「実測値」は併用投与試験の測定値から算出したＥＤ５０、「計算値」は上記の単独投与試験の測定値から算出したそれぞれのＥＤ５０に併用投与した効力比の比率（例えば効力比１：３のとき、Ｓ−フルルビプロフェンは１／４、酒石酸ブトルファノールは３／４）を乗じた値である。 The pain threshold ratio calculated based on the pain threshold at the time of the first measurement in the 9 doses was plotted with time, and the area under the curve (AUC 0-5 hr ) was calculated. The results are shown in FIGS. Further, the ED 50 was calculated from each dose of AUC 0-5 hr and each dose of S-flurbiprofen or butorphanol tartrate (Table 2). As in the case of single administration, each ED 50 was calculated from AUC 0-5 hr at each dose using commercially available statistical software SAS 9.2 (SAS Institute Japan). In Table 2, “actual value” is the ED 50 calculated from the measured value of the combined administration test, and “calculated value” is the ratio of the efficacy ratio of the combined administration to each ED 50 calculated from the measured value of the above-described single administration test ( For example, when the efficacy ratio is 1: 3, the value is obtained by multiplying S-flurbiprofen by 1/4 and butorphanol tartrate by 3/4).
＜Ｃｏｍｂｉｎａｔｉｏｎ Ｉｎｄｅｘ（ＣＩ）の算出＞
<Calculation of Combination Index (CI)>
単独投与試験のＥＤ５０及び併用投与試験のＥＤ５０（実測値）を用いて第１式よりＣＩを算出した（表３）。
ＣＩ＝（ＤＳ／Ｄ５０，Ｓ）＋（ＤＢ／Ｄ５０，Ｂ） ・・・ 第１式
ＤＳ：併用投与でのＳ−フルルビプロフェンのＥＤ５０（実測値）
ＤＢ：併用投与での酒石酸ブトルファノールのＥＤ５０（実測値）
Ｄ５０，Ｓ：Ｓ−フルルビプロフェン単独投与でのＥＤ５０
Ｄ５０，Ｂ：酒石酸ブトルファノール単独投与でのＥＤ５０
Using the ED 50 of the single administration test and the ED 50 (actually measured value) of the combined administration test, CI was calculated from the first formula (Table 3).
CI = (D S / D 50 , S) + (D B /
D S: in combination administration S- flurbiprofen ED 50 (actually measured value)
D B: ED 50 of butorphanol tartrate in the combined administration (found)
D 50, S : ED 50 of S-flurbiprofen administered alone
D 50, B : ED 50 when butorphanol tartrate is administered alone
表３のとおり、効力比（重量比）が１：１（１０：３）の時にＣＩ＜１となり、鎮痛作用の相乗効果が認められた。 As shown in Table 3, when the efficacy ratio (weight ratio) was 1: 1 (10: 3), CI <1 and a synergistic effect of analgesic action was recognized.
［試験例２］ラットイースト誘発疼痛モデルＳ−フルルビプロフェン及び酒石酸ブトルファノール併用投与時の血中濃度の測定
＜単独投与及び併用投与時の血中濃度曲線下面積ＡＵＣ＞
[Test Example 2] Measurement of blood concentration in rat yeast-induced pain model S-flurbiprofen and butorphanol tartrate in combination <AUC under blood concentration curve in single and combined administration>
Ｓ−フルルビプロフェン及び酒石酸ブトルファノール併用による相乗効果が認められた効力比（重量比）１：１（１０：３）の投与時の血中濃度を最高用量であるＳ−フルルビプロフェン５ｍｇ／ｋｇ：酒石酸ブトルファノール１．５ｍｇ／ｋｇで検討した。 The synergistic effect of S-flurbiprofen and butorphanol tartrate was recognized. The blood concentration at the time of administration of an efficacy ratio (weight ratio) of 1: 1 (10: 3) was 5 mg, the highest dose, S-flurbiprofen. / Kg: 1.5 mg / kg of butorphanol tartrate was examined.
まず、正常ラットにＳ−フルルビプロフェン及び酒石酸ブトルファノールを単独で投与し、投与１、２及び３時間後に尾静脈から採血を行い、血中濃度を測定した。次に併用効果検討時と同条件（Ｓ−フルルビプロフェン経口投与１時間後に酒石酸ブトルファノールを皮下投与）で投与を行い、酒石酸ブトルファノール投与時を０時間として投与１、２及び３時間後に尾静脈から採血を行い、それぞれの血中濃度を測定した。
First, S-flurbiprofen and butorphanol tartrate alone were administered to normal rats, and blood was collected from the
Ｓ−フルルビプロフェンの単独投与時および併用投与時の血中濃度推移を図７に示す。さらに、その曲線下面積（ＡＵＣ０−３ｈｒ）を算出した結果を表４に示す。 FIG. 7 shows changes in blood concentration when S-flurbiprofen is administered alone and in combination. Table 4 shows the results of calculating the area under the curve (AUC 0-3hr ).
図７及び表４の通りＳ−フルルビプロフェンの血中濃度は、単独投与と併用投与において違いはなかった。 As shown in FIG. 7 and Table 4, the blood concentration of S-flurbiprofen did not differ between the single administration and the combined administration.
酒石酸ブトルファノールの単独投与時および併用投与時の血中濃度推移を図８に示す。さらに、その曲線下面積（ＡＵＣ０−３ｈｒ）を算出した結果を表５に示す。 FIG. 8 shows the change in blood concentration when butorphanol tartrate is administered alone and in combination. Table 5 shows the results of calculating the area under the curve (AUC 0-3hr ).
図８及び表５の通り酒石酸ブトルファノールの血中濃度は、単独投与と併用投与において違いはなかった。 As shown in FIG. 8 and Table 5, the blood concentration of butorphanol tartrate did not differ between the single administration and the combined administration.
これらの血中濃度の結果より、併用による血中濃度の変化がなかったことから、Ｓ−フルルビプロフェン及び酒石酸ブトルファノール併用による鎮痛効果の増強は、併用による相乗効果であることが示された。 From the results of these blood concentrations, since there was no change in blood concentration due to the combination, it was shown that the enhancement of the analgesic effect by the combination of S-flurbiprofen and butorphanol tartrate was a synergistic effect of the combination. .
本発明の医薬は、疼痛、特に慢性痛（例えばがん性疼痛）の軽減又は処置に使用することができる。特に神経因性疼痛に起因する疾患（がん性疼痛、帯状疱疹後神経痛、開胸術後痛、三叉神経痛、幻肢痛、カウザルギー、糖尿病性神経因性疼痛、四肢の外傷・切断など）の軽減又は処置に有用である。 The medicament of the present invention can be used for reducing or treating pain, especially chronic pain (eg, cancer pain). Especially for diseases caused by neuropathic pain (cancer pain, postherpetic neuralgia, post-thoracotomy pain, trigeminal neuralgia, phantom limb pain, causalgia, diabetic neuropathic pain, limb trauma / amputation, etc.) Useful for alleviation or treatment.
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