JP6425767B2 - Pharmaceutical composition containing loxoprofen <弐> - Google Patents
Pharmaceutical composition containing loxoprofen <弐> Download PDFInfo
- Publication number
- JP6425767B2 JP6425767B2 JP2017095262A JP2017095262A JP6425767B2 JP 6425767 B2 JP6425767 B2 JP 6425767B2 JP 2017095262 A JP2017095262 A JP 2017095262A JP 2017095262 A JP2017095262 A JP 2017095262A JP 6425767 B2 JP6425767 B2 JP 6425767B2
- Authority
- JP
- Japan
- Prior art keywords
- oil
- group
- salt
- loxoprofen
- mass
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960002373 loxoprofen Drugs 0.000 title claims description 66
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 41
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims description 87
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims description 59
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 19
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 18
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 16
- 239000000499 gel Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 8
- 239000006071 cream Substances 0.000 claims description 7
- 239000002552 dosage form Substances 0.000 claims description 6
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- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 19
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- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960003779 gefarnate Drugs 0.000 description 1
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- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
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- 235000019410 glycyrrhizin Nutrition 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ロキソニン(登録商標)の有効成分としても知られるロキソプロフェンを含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing loxoprofen, which is also known as the active ingredient of Loxonin®.
ロキソプロフェンは、非ステロイド性消炎鎮痛剤(NSAID)の一種であり(非特許文献1)、変形性関節症、筋肉痛、外傷後の腫脹・疼痛等の疾患並びに症状の消炎・鎮痛を効能効果とするゲル剤、パップ剤やテープ剤等の外用剤の有効成分として用いられている(非特許文献2)。
一方、メントール、ハッカ油等のテルペン類は、冷却感を与える目的で外用消炎鎮痛剤等に配合されており、ロキソプロフェンと共に配合された外用剤も知られている(特許文献1〜3)。
Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID) (Non-patent document 1), and it is effective for the treatment of diseases such as osteoarthritis, myalgia, swelling and pain after trauma, and symptoms and anti-inflammatory and analgesic effects. It is used as an active ingredient of external preparations such as gel agents, cataplasms and tape agents (non-patent document 2).
On the other hand, terpenes such as menthol and peppermint oil are blended in an external anti-inflammatory analgesic for the purpose of giving a feeling of cooling, and external preparations blended with loxoprofen are also known (Patent Documents 1 to 3).
しかしながら、ロキソプロフェン又はその塩と、l−メントールなどを包含するテルペン類との間に、保存安定性に影響を与えるような相互作用が生じるか否かについては、知られていない。
そこで、本発明者らは、まず、ロキソプロフェン又はその塩と種々の成分の保存安定性について検討したところ、ロキソプロフェン又はその塩と、l−メントールなどを包含するテルペン類とを含有する組成物を調製すると、意外にも、これらの成分の間に相互作用が生じ、安定性に問題が生じ得ることを見出した。
However, it is not known whether an interaction that affects storage stability occurs between loxoprofen or a salt thereof and a terpene including l-menthol and the like.
Therefore, the present inventors first examined the storage stability of loxoprofen or a salt thereof and various components, and prepared a composition containing loxoprofen or a salt thereof and terpenes including l-menthol and the like. Then, surprisingly, it has been found that interactions occur between these components, which can cause stability problems.
従って、本発明の課題は、ロキソプロフェン又はその塩と上記テルペン類との間の相互作用が抑制された医薬組成物を提供することである。 Therefore, an object of the present invention is to provide a pharmaceutical composition in which the interaction between loxoprofen or a salt thereof and the terpenes is suppressed.
そこで、本発明者らは、この問題を解決すべくさらに検討したところ、ロキソプロフェン又はその塩及びテルペン類に、さらに下記の(C−1)、(C−2)のうちいずれか: Therefore, the present inventors have further studied to solve this problem, and loxoprofen or a salt thereof and terpenes are further selected from the following (C-1) and (C-2):
(C−1)クロルフェニラミン又はその塩などを包含する、下記一般式(1) (C-1) The following general formula (1) including chlorpheniramine or a salt thereof
[式(1)中、Xは単結合又は酸素原子を示し、Yはメチン基又は窒素原子を示し、R1は水素原子、水酸基又はアルキル基を示し、R2は置換基を有してもよい環状アミノ基、又は置換基を有してもよいアミノアルキル基を示し、R3は水素原子又はハロゲン原子を示す。]
で表される化合物又はその塩
(C−2)多価アルコール
(なお、本明細書において、上記(C−1)及び(C−2)から選ばれる成分の1種以上を「相互作用抑制成分」と称することがある。)
を共存せしめることにより、相互作用を抑制することができることを見出し、本発明を完成した。
[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 may have a substituent] R @ 3 represents a hydrogen atom or a halogen atom. ]
Or a salt thereof (C-2) polyhydric alcohol (in the present specification, one or more of the components selected from the above (C-1) and (C-2) May be referred to as
It was found that the interaction can be suppressed by coexistence of H. Thus, the present invention has been completed.
すなわち、本発明は、次の成分(A)、(B)及び(C):
(A)ロキソプロフェン又はその塩
(B)テルペン類
(C)次の成分(C−1)及び(C−2)からなる群より選ばれる1種以上
(C−1)下記一般式(1)
That is, the present invention provides the following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof (B) terpenes (C) One or more selected from the group consisting of the following components (C-1) and (C-2) (C-1) the following general formula (1)
[式(1)中、Xは単結合又は酸素原子を示し、Yはメチン基又は窒素原子を示し、R1は水素原子、水酸基又はアルキル基を示し、R2は置換基を有してもよい環状アミノ基、又は置換基を有してもよいアミノアルキル基を示し、R3は水素原子又はハロゲン原子を示す。]
で表される化合物又はその塩
(C−2)多価アルコール
を含有する医薬組成物を提供するものである。
[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 may have a substituent] R @ 3 represents a hydrogen atom or a halogen atom. ]
The compound represented by these, or its salt (C-2) provides the pharmaceutical composition containing polyhydric alcohol.
本発明によれば、ロキソプロフェン又はその塩とテルペン類との相互作用を抑制できる。従って、保存安定性が優れた、ロキソプロフェン又はその塩、及びテルペン類を含有する医薬組成物を提供することができる。
また、複雑な工程を経ることなく、簡便かつ安価に、ロキソプロフェン又はその塩、及びテルペン類を含有する、相互作用が抑制された医薬組成物を提供することができる。
According to the present invention, the interaction between loxoprofen or a salt thereof and a terpene can be suppressed. Therefore, it is possible to provide a pharmaceutical composition containing loxoprofen or a salt thereof and terpenes, which is excellent in storage stability.
Moreover, the pharmaceutical composition in which the interaction is suppressed which contains loxoprofen or its salt, and terpenes simply and inexpensively without going through a complicated process can be provided.
<成分(A)>
本発明において、「ロキソプロフェン又はその塩」には、ロキソプロフェンそのもののほか、ロキソプロフェンの薬学上許容される塩、さらにはロキソプロフェンやその薬学上許容される塩と水やアルコール等との溶媒和物も含まれる。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。本発明において、ロキソプロフェン又はその塩としては、ロキソプロフェンナトリウム水和物(化学名: Monosodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate dihydrate)が好ましい。
<Component (A)>
In the present invention, "loxoprofen or a salt thereof" includes loxoprofen itself, pharmaceutically acceptable salts of loxoprofen, and further, loxoprofen or a solvate of the pharmaceutically acceptable salt thereof with water, alcohol and the like. Be These are known compounds and can be produced by known methods, and commercially available ones can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).
本発明の医薬組成物におけるロキソプロフェン又はその塩の含有量は特に限定されず、所望の消炎鎮痛効果に応じて適宜検討すればよい。本発明においては、ロキソプロフェン又はその塩を医薬組成物全質量に対して、ロキソプロフェンナトリウム無水物換算で0.01〜10質量%含有するのが好ましく、0.1〜5質量%含有するのがより好ましく、0.5〜3質量%含有するのが特に好ましい。 The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately examined depending on the desired anti-inflammatory and analgesic effect. In the present invention, loxoprofen or a salt thereof is preferably contained in an amount of 0.01 to 10% by mass in terms of anhydrous loxoprofen, more preferably 0.1 to 5% by mass, based on the total mass of the pharmaceutical composition. Preferably, 0.5 to 3% by mass is particularly preferable.
<成分(B)>
本発明において、「テルペン類」は特に限定されるものでなく、環式又は鎖式の、モノテルペンやセスキテルペン等が挙げられる。
斯様なテルペン類としては、具体的には例えば、イソボルネオール、イロン、オシメン、カルベオール、カルボタナセトン、カルボメントン、カルボン、カレン、カロン、カンフェン、カンフル、ゲラニオール、サビネン、サフラナール、シクロシトラール、シトラール、シトロネラール、シトロネル酸、シトロネロール、シネオール、シメン、シルベストレン、チモール、イソツジョール、ツジョン、テルピネオール、テルピネン、テルピノレン、トリシクレン、ネロール、ピネン、ピノカンフェオール、ピノール、ピペリテノン、フェランドラール、フェランドレン、フェンチェン、フェンチルアルコール、ペリリルアルコール、ペリリルアルデヒド、ボルネオール、ミルセン、メントール、メントン、ヨノール、ヨノン、リナロール、リモネン等が挙げられ、これらを単独で又は2種以上組み合わせて用いることができる。なお、これらのテルペン類が光学異性を有する場合、本発明においてはいずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。
これらの中でも、カンフル、ゲラニオール、シトロネラール、テルピネオール、ボルネオール、メントール、リモネン等が好ましく、d−カンフル、dl−カンフル、チモール、ボルネオール、l−メントール、dl−メントールがより好ましく、l−メントール、dl−カンフルが特に好ましい。
<Component (B)>
In the present invention, "terpenes" are not particularly limited, and cyclic or chained monoterpenes, sesquiterpenes and the like can be mentioned.
As such terpenes, specifically, for example, isoborneol, yrone, ocimene, carveol, carbotanatheton, carbomenton, carvone, carene, caron, camphor, camphor, geraniol, sabinal, saflanal, cyclocitral, citral, citronellal , Citronelic acid, citronellol, cineole, cymene, silvestrene, thymol, isotujool, tsujone, terpineol, terpinene, terpinorene, tricyclene, nerol, pinole, pinocampheol, pinol, piperitenone, felandalle, ferandrene, phenchen, phenen Chil alcohol, perillyl alcohol, perillyl aldehyde, borneol, myrcene, menthol, menthol, yonol, yonon, linalool, Limonene and the like, can be used in combination thereof alone or. In addition, when these terpenes have optical isomerism, in this invention, any optical isomer may also be included, a single optical isomer may be sufficient, and the mixture of various optical isomers may be sufficient.
Among these, camphor, geraniol, citronellal, terpineol, borneol, menthol, limonene and the like are preferable, d-camphor, dl-camphor, thymol, borneol, l-menthol and dl-menthol are more preferable, l-menthol and dl- Camphor is particularly preferred.
また、上記テルペン類を医薬組成物に含有せしめる場合、上述のようなテルペン類を含む精油を用いてもよい。
斯様な精油としては、例えば、アニス油、イランイラン油、イリス油、ウイキョウ油、オレンジ油、カナンガ油、カミツレ油、カヤプト油、カラウェー油、クベブ油、グレープフルーツ油、ケイヒ油、コリアンダー油、サフラン油、サンショウ油、シソ油、シトリオドラ油、シトロネラ油、ショウキョウ油、ショウズク油、樟脳油、ジンジャーグラス油、スペアミント油、セイヨウハッカ油、ゼラニウム油、ダイウイキョウ油、チョウジ油、テレビン油、トウヒ油、ネロリ油、バジル油、ハッカ油、パルマローザ油、ピメント油、プチグレン油、ベイ油、ペニローヤル油、ヘノポジ油、ベルガモット油、ボアドローズ油、ホウショウ油、マジョラン油、マンダリン油、メリッサ油、ユーカリ油、ライム油、ラベンダー油、リナロエ油、レモン油、レモングラス油、ローズ油、ローズマリー油、ローマカミツレ油等が挙げられ、これらを単独で又は2種以上組み合わせて用いてもよい。
これらの中でも、イランイラン油、ウイキョウ油、オレンジ油、カミツレ油、ケイヒ油、シソ油、シトロネラ油、ショウキョウ油、樟脳油、セイヨウハッカ油、ゼラニウム油、チョウジ油、テレビン油、トウヒ油、ネロリ油、ハッカ油、パルマローザ油、ベルガモット油、ユーカリ油、ラベンダー油、リナロエ油、レモン油、ローズ油、ローズマリー油、ローマカミツレ油等が好ましく、樟脳油、セイヨウハッカ油、テレビン油、ハッカ油、ユーカリ油がより好ましく、ハッカ油が特に好ましい。
When the terpenes are contained in a pharmaceutical composition, an essential oil containing the terpenes as described above may be used.
Such essential oils include, for example, anise oil, ylang ylang oil, iris oil, fennel oil, orange oil, cananga oil, camomile oil, cayapt oil, caraway oil, kebbe oil, grapefruit oil, cayenne oil, coriander oil, saffron Oil, Sansho oil, Perilla oil, Citriola oil, Citronella oil, Persimmon oil, Shoal oil, Camphor oil, Gingergrass oil, Spearmint oil, Salixmint oil, Geranium oil, Daisyichone oil, Clove oil, turpentine oil, Spruce oil , Neroli oil, basil oil, peppermint oil, palma rosa oil, pimento oil, petit gren oil, bay oil, peny royal oil, henoposi oil, bergamot oil, boad rose oil, borosho oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime Oil, Lavender oil, linaroe oil, lemon , Lemongrass oil, rose oil, rosemary oil, Roman chamomile oil, and the like, may be used in combination thereof alone or.
Among these, ylang ylang oil, fennel oil, orange oil, chamomile oil, camphor oil, persimmon oil, citronella oil, camphor oil, camphor oil, black pepper oil, geranium oil, clove oil, turpentine oil, spruce oil, neroli oil , Peppermint oil, palma rosa oil, bergamot oil, eucalyptus oil, lavender oil, linaroe oil, lemon oil, rose oil, rosemary oil, rome chamomile oil etc., preferably camphor oil, peppermint oil, turpentine oil, peppermint oil, eucalyptus oil Is more preferred, and peppermint oil is particularly preferred.
本発明の医薬組成物におけるテルペン類の含有量は特に限定されず、適宜検討して決定すればよい。本発明においては、テルペン類を医薬組成物全質量に対して0.01〜15質量%含有するのが好ましく、0.1〜10質量%含有するのがより好ましく、0.5〜7質量%含有するのが特に好ましい。また、上記精油を用いる場合、医薬組成物全質量に対し、精油として、0.1〜40質量%含有するのが好ましく、0.5〜30質量%含有するのがより好ましく、1〜20質量%含有するのが特に好ましい。 The content of terpenes in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined. In the present invention, the terpene is preferably contained in an amount of 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, and most preferably 0.5 to 7% by mass, based on the total mass of the pharmaceutical composition. It is particularly preferred to contain. Moreover, when using the said essential oil, it is preferable to contain 0.1-40 mass% as an essential oil with respect to the pharmaceutical composition total mass, It is more preferable to contain 0.5-30 mass%, and 1-20 mass % Is particularly preferred.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩とテルペン類の含有比は特に限定されず、適宜検討して決定すればよいが、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、テルペン類を、0.01〜15質量部含有するものが好ましく、0.1〜10質量部含有するものがより好ましく、0.5〜7質量部含有するものが特に好ましい。また、上記精油を用いる場合、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、精油を0.1〜40質量部含有するものが好ましく、0.5〜30質量部含有するものがより好ましく、1〜20質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and a terpene contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined, but loxoprofen or a salt thereof is 1 part by mass in terms of loxoprofen sodium anhydride On the other hand, those containing 0.01 to 15 parts by mass of terpenes are preferable, those containing 0.1 to 10 parts by mass are more preferable, and those containing 0.5 to 7 parts by mass are particularly preferable. Moreover, when using the said essential oil, what contains 0.1-40 mass parts of essential oils with respect to 1 mass part of loxoprofen or its salt with respect to loxoprofen sodium anhydride conversion is preferable, and contains 0.5-30 mass parts Is more preferable, and one containing 1 to 20 parts by mass is particularly preferable.
<成分(C−1)>
本発明において、一般式(1)
<Component (C-1)>
In the present invention, the general formula (1)
[式(1)中、Xは単結合又は酸素原子を示し、Yはメチン基又は窒素原子を示し、R1は水素原子、水酸基又はアルキル基を示し、R2は置換基を有してもよい環状アミノ基、又は置換基を有してもよいアミノアルキル基を示し、R3は水素原子又はハロゲン原子を示す。]
で表される化合物又はその塩には、上記一般式(1)で表される化合物そのもののほか、一般式(1)で表される化合物の薬学上許容される塩も含まれる。一般式(1)で表される化合物又はその塩の具体例としては例えば、一般式(1)で表される化合物、一般式(1)で表される化合物の無機酸塩や有機酸塩(例えば、塩酸塩、マレイン酸塩、フマル酸塩、ジフェニルジスルホン酸塩、テオクル酸塩、サリチル酸塩、タンニン酸塩、ベシル酸塩、リン酸塩など)等が挙げられる。また、一般式(1)で表される化合物の化学構造中、不斉炭素が存する場合は、種々の光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。さらに、一般式(1)で表される化合物又はその塩は溶媒和物の状態にあってもよく、一般式(1)で表される化合物やその塩と水やアルコール等との溶媒和物も「一般式(1)で表される化合物又はその塩」に含まれる。
[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R 1 represents a hydrogen atom, a hydroxyl group or an alkyl group, and R 2 may have a substituent] R @ 3 represents a hydrogen atom or a halogen atom. ]
The compound represented by or the salt thereof includes, in addition to the compound itself represented by the above general formula (1), a pharmaceutically acceptable salt of the compound represented by the general formula (1). Specific examples of the compound represented by the general formula (1) or a salt thereof include inorganic acid salts and organic acid salts of compounds represented by the general formula (1) and compounds represented by the general formula (1) For example, hydrochloride, maleate, fumarate, diphenyl disulfonate, theocorbate, salicylate, tannate, besylate, phosphate and the like) and the like can be mentioned. Moreover, in the chemical structure of the compound represented by the general formula (1), when an asymmetric carbon is present, it has various optical isomers, but in the present invention, any optical isomer is included and it is single. Or a mixture of various optical isomers. Furthermore, the compound represented by the general formula (1) or a salt thereof may be in the form of a solvate, and the compound represented by the general formula (1) or a salt thereof and a solvate of water, alcohol and the like Is also included in the “compound represented by the general formula (1) or a salt thereof”.
上記R1において、アルキル基としては、直鎖又は分枝鎖の炭素数1〜3のアルキル基が好ましい。具体的には、メチル基、エチル基、n−プロピル基、イソプロピル基が挙げられるが、メチル基が好ましい。
また、上記R1としては、水素原子、メチル基が好ましい。
In R 1 above, the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group may be mentioned, but a methyl group is preferable.
Moreover, as said R < 1 >, a hydrogen atom and a methyl group are preferable.
上記R2において、置換基を有してもよい環状アミノ基における「環状アミノ基」とは、環構成原子として窒素原子を少なくとも1個、好適には1又は2個有する5〜7員の脂環式基を意味する。
このような環状アミノ基としては、具体的には例えば、ピロリジニル基、ピラゾリジニル基、ピペリジニル基、ピペラジニル基、モルホリニル基、ホモピペリジニル基、ホモピペラジニル基等が挙げられる。中でも、ピペリジニル基、ピペラジニル基、ホモピペラジニル基が好ましく、ピペリジニル基、ピペラジニル基がより好ましい。
In the above R 2 , the “cyclic amino group” in the cyclic amino group which may have a substituent is a 5- to 7-membered oil having at least one, preferably one or two nitrogen atoms as ring-constituting atoms. It means a cyclic group.
Specific examples of such cyclic amino group include pyrrolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperidinyl group, homopiperazinyl group and the like. Among them, piperidinyl group, piperazinyl group, homopiperazinyl group are preferable, and piperidinyl group and piperazinyl group are more preferable.
また、置換基を有してもよい環状アミノ基における「置換基」としては、例えば、アルキルベンゾイル基、1,3−ジヒドロ−2H−ベンゾイミダゾール−2−オン−1−イル基、カルボキシアルコキシ基、カルボキシル基、カルボキシアルキルフェニル基及び水酸基から選ばれる1種以上の基が置換していてもよいアルキル基等が挙げられる。中でも、アルキル基、カルボキシアルコキシアルキル基、カルボキシアルキルフェニル(ヒドロキシ)アルキル基が好ましい。
上記「置換基」の具体例としては、例えば、メチル基、3−(4−tert−ブチルベンゾイル)プロピル基、3−(1,3−ジヒドロ−2H−ベンゾイミダゾール−2−オン−1−イル)プロピル基、2−(カルボキシメトキシ)エチル基、4−[4−(2−カルボキシプロパン−2−イル)フェニル]−4−ヒドロキシブチル基、3−カルボキシプロピル基等が挙げられる。
Moreover, as a "substituent" in the cyclic amino group which may have a substituent, for example, alkyl benzoyl group, 1,3-dihydro-2H-benzoimidazol-2-one-1-yl group, carboxyalkoxy group And an alkyl group which may be substituted by one or more groups selected from a carboxyl group, a carboxyalkylphenyl group and a hydroxyl group. Among them, an alkyl group, a carboxyalkoxyalkyl group and a carboxyalkylphenyl (hydroxy) alkyl group are preferable.
Specific examples of the above-mentioned "substituent" include, for example, methyl group, 3- (4-tert-butylbenzoyl) propyl group, 3- (1,3-dihydro-2H-benzoimidazol-2-one-1-yl) And the like) propyl group, 2- (carboxymethoxy) ethyl group, 4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl group, 3-carboxypropyl group and the like.
上記R2において、「置換基を有してもよい環状アミノ基」としては、1−メチルピペリジン−4−イル基、4−メチルホモピペラジン−1−イル基、1−[3−(4−tert−ブチルベンゾイル)プロピル]ピペリジン−4−イル基、4−[3−(1,3−ジヒドロ−2H−ベンゾイミダゾール−2−オン−1−イル)プロピル]ピペラジン−1−イル基、4−[2−(カルボキシメトキシ)エチル]ピペラジン−1−イル基、1−{4−[4−(2−カルボキシプロパン−2−イル)フェニル]−4−ヒドロキシブチル}ピペリジン−4−イル基、1−(3−カルボキシプロピル)ピペリジン−4−イル基が好ましい。 In the above-mentioned R 2 , examples of the “cyclic amino group which may have a substituent” include 1-methylpiperidin-4-yl group, 4-methylhomopiperazin-1-yl group, 1- [3- (4- (4) tert-Butylbenzoyl) propyl] piperidin-4-yl group, 4- [3- (1,3-dihydro-2H-benzoimidazol-2-one-1-yl) propyl] piperazin-1-yl group, 4- [2- (Carboxymethoxy) ethyl] piperazin-1-yl group, 1- {4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl} piperidin-4-yl group, 1 -(3-Carboxypropyl) piperidin-4-yl is preferred.
上記R2において、置換基を有してもよいアミノアルキル基における「アミノアルキル基」は、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基又は環状アミノ基(当該「環状アミノ基」は、上記した「置換基を有してもよい環状アミノ基」における「環状アミノ基」と同義である。)が置換したアルキル基を意味する。中でも、ジアルキルアミノ基又は環状アミノ基が置換したアルキル基が好ましい。なお、当該環状アミノ基としては、ピロリジニル基が好ましい。
このようなアミノアルキル基としては、具体的には例えば、2−(ジメチルアミノ)エチル基、2−(ピロリジン−2−イル)エチル基、2−[(イソプロピル)(メチル)アミノ]エチル基等が挙げられる。また、置換基を有してもよいアミノアルキル基における「置換基」としては、例えば、水酸基、フェニル基、アルキル基等が挙げられる。
In the above R 2 , the “aminoalkyl group” in the aminoalkyl group which may have a substituent is an amino group, a monoalkylamino group, a dialkylamino group or a cyclic amino group (the “cyclic amino group” is as described above It means an alkyl group substituted by the “cyclic amino group” in the “cyclic amino group optionally having substituent (s)”. Among them, an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferable. In addition, as said cyclic amino group, pyrrolidinyl group is preferable.
As such an aminoalkyl group, specifically, for example, 2- (dimethylamino) ethyl group, 2- (pyrrolidin-2-yl) ethyl group, 2-[(isopropyl) (methyl) amino] ethyl group, etc. Can be mentioned. Moreover, as a "substituent" in the aminoalkyl group which may have a substituent, a hydroxyl group, a phenyl group, an alkyl group etc. are mentioned, for example.
上記R2において、「置換基を有してもよいアミノアルキル基」としては、2−(ジメチルアミノ)エチル基、2−(1−メチルピロリジン−2−イル)エチル基、2−[(メチル)(1−フェニル−1−ヒドロキシプロパン−2−イル)アミノ]エチル基が好ましい。 In the above-mentioned R 2 , examples of “an aminoalkyl group which may have a substituent” include 2- (dimethylamino) ethyl group, 2- (1-methylpyrrolidin-2-yl) ethyl group, 2-[(methyl) ) (1-phenyl-1-hydroxypropan-2-yl) amino] ethyl group is preferred.
なお、上記R2において、「アルキル基」、「アルキルベンゾイル基」、「カルボキシアルキルフェニル基」、「アミノアルキル基」、「モノアルキルアミノ基」、「ジアルキルアミノ基」におけるアルキル基部分としては、炭素数1〜6の直鎖又は分枝鎖のアルキル基が好ましく、具体例としては、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基等が挙げられる。
また、上記R2において、「カルボキシアルコキシ基」におけるアルコキシ基部分としては、炭素数1〜6の直鎖又は分枝鎖のアルコキシ基が好ましく、具体例としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基等が挙げられる。
In R 2 above, the alkyl group in “alkyl group”, “alkyl benzoyl group”, “carboxy alkyl phenyl group”, “amino alkyl group”, “mono alkyl amino group”, “dialkyl amino group” is A linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group and the like.
In the above R 2 , the alkoxy group in the “carboxyalkoxy group” is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group and a propoxy group And butoxy, pentyloxy, hexyloxy and the like.
上記R3において、「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられ、本発明においては、塩素原子が好ましい。また、一般式(1)においてR3のフェニル基上の置換位置は特に限定されないが、4位に置換するのが好ましい。 In the above R 3 , examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferable in the present invention. Moreover, in General formula (1), although the substituted position on the phenyl group of R < 3 > is not specifically limited, It is preferable to substitute at 4-position.
本発明において、一般式(1)で表される化合物又はその塩としては、具体的には例えば、エバスチン又はその塩;オキサトミド又はその塩;カルビノキサミンジフェニルジスルホン酸塩、カルビノキサミンマレイン酸塩等のカルビノキサミン又はその塩;クレマスチンフマル酸塩等のクレマスチン又はその塩;d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩等のクロルフェニラミン又はその塩;ジフェテロール塩酸塩、ジフェテロールリン酸塩等のジフェテロール又はその塩;ジフェニルピラリン塩酸塩、ジフェニルピラリンテオクル酸塩等のジフェニルピラリン又はその塩;ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、ジフェンヒドラミンタンニン酸塩等のジフェンヒドラミン又はその塩;セチリジン塩酸塩等のセチリジン又はその塩;フェキソフェナジン又はその塩;ベポタスチンベシル酸塩等のベポタスチン又はその塩;ホモクロルシクリジン塩酸塩等のホモクロルシクリジン又はその塩等が挙げられる。なお、これらは単独で又は2種以上組み合わせて用いることができる。
上記一般式(1)で表される化合物及びその塩、特に上記した化合物及びその塩は公知であり、公知の方法により製造できるほか、市販のものを用いることができる。
In the present invention, as the compound represented by the general formula (1) or a salt thereof, specifically, ebastine or a salt thereof; oxatomide or a salt thereof; carbinoxamine diphenyl disulfonate, carbinoxamine maleate Carbinoxamine or its salts; clemastine or its salts such as clemastine fumarate; chlorpheniramine or its salts such as d-chlorpheniramine maleate, dl-chlorpheniramine maleate; dipheterol hydrochloride, diphete Dipheterol or its salt such as roll phosphate; Diphenylpyraline or its salt such as diphenylpyraline hydrochloride, diphenylpyraline theocorbate; Diphenhydramine such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate or the like Salts; cetirizines such as cetirizine hydrochloride or salts thereof; fexofenadine or salts thereof; bepotastine such as bepotastine besilates or salts thereof; homochlorcyclidine such as homochlorcyclidine hydrochloride or salts thereof; Be In addition, these can be used individually or in combination of 2 or more types.
The compound represented by the above general formula (1) and a salt thereof, particularly the above-mentioned compound and a salt thereof are known, can be produced by known methods, and commercially available products can be used.
本発明の医薬組成物における一般式(1)で表される化合物又はその塩の合計含有量は特に限定されず、相互作用抑制の観点から適宜検討して決定すればよい。本発明においては、相互作用抑制作用の観点から、一般式(1)で表される化合物又はその塩を医薬組成物全質量に対して0.01〜10質量%含有するのが好ましく、0.05〜5質量%含有するのがより好ましく、0.1〜3質量%含有するのが特に好ましい。 The total content of the compound represented by the general formula (1) or the salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined from the viewpoint of suppressing interaction. In the present invention, the compound represented by the general formula (1) or a salt thereof is preferably contained in an amount of 0.01 to 10% by mass based on the total mass of the pharmaceutical composition, from the viewpoint of the interaction suppressing action. The content is more preferably 05 to 5% by mass, and particularly preferably 0.1 to 3% by mass.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及び一般式(1)で表される化合物又はその塩の含有比は特に限定されず、相互作用抑制の観点から適宜検討して決定すればよいが、相互作用抑制作用の観点から、ロキソプロフェン又はその塩をロキソプロフェン無水物換算で1質量部に対し、一般式(1)で表される化合物又はその塩を合計で0.01〜10質量部含有するものが好ましく、0.05〜5質量部含有するものがより好ましく、0.1〜3質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and the compound represented by the general formula (1) or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined from the viewpoint of suppressing interaction Although it is good, from the viewpoint of the interaction suppressing action, loxoprofen or a salt thereof is 1 part by mass in terms of loxoprofen anhydride, and 0.01 to 10 parts by mass in total of the compound represented by the general formula (1) or a salt thereof Those containing are preferable, those containing 0.05 to 5 parts by mass are more preferable, and those containing 0.1 to 3 parts by mass are particularly preferable.
本発明においては、一般式(1)で表される化合物又はその塩として、「クロルフェニラミン又はその塩」又は「ジフェンヒドラミン又はその塩」を用いるのが好ましく、「クロルフェニラミン又はその塩」が特に好ましい。 In the present invention, “chlorpheniramine or a salt thereof” or “diphenhydramine or a salt thereof” is preferably used as the compound represented by the general formula (1) or a salt thereof, and “chlorpheniramine or a salt thereof” is Particularly preferred.
本発明において、「クロルフェニラミン又はその塩」には、クロルフェニラミンそのもののほか、クロルフェニラミンの薬学上許容される塩も含まれる。なお、クロルフェニラミンは、下記式 In the present invention, "chlorpheniramine or a salt thereof" includes chlorpheniramine itself as well as pharmaceutically acceptable salts of chlorpheniramine. In addition, chlorpheniramine has the following formula
で表される化合物である。
クロルフェニラミンには不斉炭素が存するため、光学異性体を有するが、本発明においては、いずれの光学異性体をも含み、単一の光学異性体でもよく、各種光学異性体の混合物でもよい。これらのうち、本発明においては、d−体、dl−体が好ましい。当該クロルフェニラミン又はその塩の具体例としては例えば、クロルフェニラミン、クロルフェニラミンマレイン酸塩、d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩等が挙げられる。本発明においては、d−クロルフェニラミンマレイン酸塩、dl−クロルフェニラミンマレイン酸塩が好ましく、d−クロルフェニラミンマレイン酸塩が特に好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。
It is a compound represented by
Because chlorpheniramine has an asymmetric carbon, it has an optical isomer, but in the present invention, it may contain any optical isomer, may be a single optical isomer, or may be a mixture of various optical isomers. . Among these, in the present invention, d-isomer and dl-isomer are preferred. Specific examples of chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate and the like. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are preferred, and d-chlorpheniramine maleate is particularly preferred. These are known compounds and can be produced by known methods, and commercially available ones can be used.
本発明の医薬組成物におけるクロルフェニラミン又はその塩の含有量は特に限定されず、相互作用抑制の観点から適宜検討して決定すればよい。本発明においては、相互作用抑制作用の観点から、クロルフェニラミン又はその塩を医薬組成物全質量に対して0.01〜5質量%含有するのが好ましく、0.05〜3質量%含有するのがより好ましく、0.1〜2質量%含有するのが特に好ましい。 The content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined from the viewpoint of suppressing interaction. In the present invention, chlorpheniramine or a salt thereof is preferably contained in an amount of 0.01 to 5% by mass, preferably 0.05 to 3% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of the interaction suppressing action. Is more preferable, and 0.1 to 2% by mass is particularly preferable.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びクロルフェニラミン又はその塩の含有比は特に限定されず、相互作用抑制の観点から適宜検討して決定すればよいが、相互作用抑制作用の観点から、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、クロルフェニラミン又はその塩を0.01〜5質量部含有するものが好ましく、0.05〜3質量部含有するものがより好ましく、0.1〜2質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined from the viewpoint of suppressing interaction, but the interaction suppressing action From the viewpoint of the above, one containing 0.01 to 5 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride equivalent, preferably 0.05 to 3 parts by mass And more preferably 0.1 to 2 parts by mass.
本発明において、「ジフェンヒドラミン又はその塩」には、ジフェンヒドラミンそのもののほか、ジフェンヒドラミンの薬学上許容される塩も含まれる。なお、ジフェンヒドラミンは、下記式 In the present invention, "diphenhydramine or a salt thereof" includes not only diphenhydramine itself but also pharmaceutically acceptable salts of diphenhydramine. In addition, diphenhydramine has the following formula
で表される化合物である。当該ジフェンヒドラミン又はその塩の具体例としては例えば、ジフェンヒドラミン、ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩、ジフェンヒドラミンタンニン酸塩等が挙げられる。本発明においては、ジフェンヒドラミン、ジフェンヒドラミン塩酸塩、ジフェンヒドラミンサリチル酸塩が好ましく、ジフェンヒドラミン、ジフェンヒドラミンサリチル酸塩がより好ましい。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることができる。 It is a compound represented by Specific examples of the diphenhydramine or a salt thereof include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate and the like. In the present invention, diphenhydramine, diphenhydramine hydrochloride and diphenhydramine salicylate are preferred, and diphenhydramine and diphenhydramine salicylate are more preferred. These are known compounds and can be produced by known methods, and commercially available ones can be used.
本発明の医薬組成物におけるジフェンヒドラミン又はその塩の含有量は特に限定されず、相互作用抑制の観点から適宜検討して決定すればよい。本発明においては、相互作用抑制作用の観点から、ジフェンヒドラミン又はその塩を医薬組成物全質量に対して0.05〜10質量%含有するのが好ましく、0.1〜5質量%含有するのがより好ましく、0.3〜3質量%含有するのが特に好ましい。 The content of diphenhydramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined from the viewpoint of suppressing interaction. In the present invention, it is preferable to contain diphenhydramine or a salt thereof in an amount of 0.05 to 10% by mass, preferably 0.1 to 5% by mass, based on the total mass of the pharmaceutical composition, from the viewpoint of the interaction suppressing action. It is more preferable to contain 0.3 to 3% by mass.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びジフェンヒドラミン又はその塩の含有比は特に限定されず、相互作用抑制の観点から適宜検討して決定すればよいが、相互作用抑制作用の観点から、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、ジフェンヒドラミン又はその塩を0.05〜10質量部含有するものが好ましく、0.1〜5質量部含有するものがより好ましく、0.3〜3質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and diphenhydramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined from the viewpoint of interaction suppression, but the interaction suppression action Therefore, those containing 0.05 to 10 parts by mass of diphenhydramine or a salt thereof with respect to 1 part by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride equivalent are preferable, and those containing 0.1 to 5 parts by mass are more preferable. Particularly preferred is one containing 0.3 to 3 parts by mass.
<成分(C−2)>
本発明において、「多価アルコール」とは、同一分子内に水酸基を2個以上有するアルコールを意味し、具体的には例えば、プロピレングリコール、グリセリン、1,3−ブチレングリコール、ソルビトール、マンニトール、ジプロピレングリコール、ポリビニルアルコール、マクロゴール等が挙げられる。多価アルコールとしては、グリセリン、1,3−ブチレングリコール、ソルビトール、マンニトール、ジプロピレングリコール、ポリビニルアルコールが好ましい。
<Component (C-2)>
In the present invention, "polyhydric alcohol" means an alcohol having two or more hydroxyl groups in the same molecule, and specifically, for example, propylene glycol, glycerin, 1,3-butylene glycol, sorbitol, mannitol, di- Propylene glycol, polyvinyl alcohol, macrogol and the like can be mentioned. As polyhydric alcohols, glycerin, 1,3-butylene glycol, sorbitol, mannitol, dipropylene glycol and polyvinyl alcohol are preferable.
本発明の医薬組成物における多価アルコールの合計含有量は特に限定されず、相互作用の抑制の観点から適宜検討して決定すればよい。本発明においては、相互作用抑制作用の観点から、多価アルコールを医薬組成物全質量に対して5〜80質量%含有するのが好ましく、10〜70質量%含有するのがより好ましく、20〜60質量%含有するのが特に好ましい。 The total content of polyhydric alcohols in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined from the viewpoint of suppressing the interaction. In the present invention, from the viewpoint of the interaction suppressing action, the polyhydric alcohol is preferably contained in an amount of 5 to 80% by mass, more preferably 10 to 70% by mass, based on the total mass of the pharmaceutical composition. It is particularly preferable to contain 60% by mass.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及び多価アルコールの含有比は特に限定されず、相互作用の抑制の観点から適宜検討して決定すればよいが、相互作用抑制作用の観点から、ロキソプロフェン又はその塩をロキソプロフェン無水物換算で1質量部に対し、多価アルコールを合計で0.1〜80質量部含有するものが好ましく、0.5〜70質量部含有するものがより好ましく、1〜60質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and a polyhydric alcohol contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined from the viewpoint of suppression of interaction, but from the viewpoint of interaction inhibitory action From the viewpoint of loxoprofen or its salt, it is preferable to contain 0.1 to 80 parts by mass in total of polyhydric alcohol, and more preferably 0.5 to 70 parts by mass, with respect to 1 part by mass of loxoprofen anhydride equivalent. And 1 to 60 parts by mass are particularly preferable.
本発明において、多価アルコールとしては、ポリビニルアルコールが好ましい。「ポリビニルアルコール」は、ポリ酢酸ビニルをけん化して得られる重合物であり、公知の方法で製造することができ、また、市販品を用いることもできる。ポリビニルアルコールの原料となる酢酸ビニルの重合度は適宜調整することができ、また、けん化度も適宜調整することができる。 In the present invention, polyvinyl alcohol is preferred as the polyhydric alcohol. "Polyvinyl alcohol" is a polymer obtained by saponifying polyvinyl acetate, which can be produced by a known method, and a commercially available product can also be used. The degree of polymerization of vinyl acetate, which is a raw material of polyvinyl alcohol, can be appropriately adjusted, and the degree of saponification can be appropriately adjusted.
酢酸ビニルの重合度及びけん化度は、特に限定されるものではなく、適宜検討して決定すればよい。重合度としては、200〜3500程度が好ましく、300〜2200程度が特に好ましい。また、けん化度としては、65mоl%以上が好ましく、78mоl%以上がより好ましい。中でも、けん化度が78〜96mоl%のもの(ポリビニルアルコール(部分けん化物)と称される。)及び97mоl%以上のもの(ポリビニルアルコール(完全けん化物)と称される。)が更に好ましく、78〜96mоl%のものが特に好ましい。 The polymerization degree and the saponification degree of vinyl acetate are not particularly limited, and may be appropriately determined and determined. As a polymerization degree, about 200-3500 are preferable, and about 300-2200 are especially preferable. Moreover, as a saponification degree, 65 mol% or more is preferable, and 78 mol% or more is more preferable. Among them, those having a degree of saponification of 78 to 96 mol% (referred to as polyvinyl alcohol (partial saponification)) and those having 97 mol% or more (referred to as polyvinyl alcohol (complete saponification)) are more preferable, 78 Particular preference is given to 9696 mol%.
本発明の医薬組成物におけるポリビニルアルコールの含有量は特に限定されず、相互作用の抑制の観点から適宜検討して決定すればよい。本発明においては、相互作用抑制作用の観点から、ポリビニルアルコールを医薬組成物全質量に対して0.05〜10質量%含有するのが好ましく、0.1〜7質量%含有するのがより好ましく、0.2〜5質量%含有するのが特に好ましい。 The content of polyvinyl alcohol in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined from the viewpoint of suppression of interaction. In the present invention, from the viewpoint of the interaction suppressing action, polyvinyl alcohol is preferably contained in an amount of 0.05 to 10% by mass, more preferably 0.1 to 7% by mass, based on the total mass of the pharmaceutical composition. And 0.2 to 5% by mass is particularly preferable.
本発明の医薬組成物に含まれるロキソプロフェン又はその塩、及びポリビニルアルコールの含有比は特に限定されず、相互作用の抑制の観点から適宜検討して決定すればよいが、相互作用抑制作用の観点から、ロキソプロフェン又はその塩をロキソプロフェンナトリウム無水物換算で1質量部に対し、ポリビニルアルコールを0.05〜10質量部含有するものが好ましく、0.1〜7質量部含有するものがより好ましく、0.2〜5質量部含有するものが特に好ましい。 The content ratio of loxoprofen or a salt thereof and polyvinyl alcohol contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined from the viewpoint of suppression of interaction, but from the viewpoint of interaction suppressing action Preferably contains 10 to 10 parts by mass of polyvinyl alcohol, more preferably 0.1 to 7 parts by mass, with respect to 1 part by mass of loxoprofen or a salt thereof in terms of loxoprofen sodium anhydride equivalent; Those containing 2 to 5 parts by mass are particularly preferred.
本発明の医薬組成物は、例えば、第十六改正日本薬局方 製剤総則等に記載の公知の方法により製造することができる。また、剤形は、特に限定されるものではなく、固形状、半固形状、液状のいずれの形状であってもよく、その利用目的等に応じて医薬品において通常利用される形状とすることができる。具体的には例えば、経口投与する製剤(錠剤、カプセル剤、顆粒剤、散剤、経口液剤、シロップ剤、経口ゼリー剤等)、膣に適用する製剤(膣錠、膣用坐剤等)、皮膚等に適用する製剤(外用固形剤、外用液剤、スプレー剤、軟膏剤、クリーム剤、ゲル剤、貼付剤等)などの、第十六改正日本薬局方 製剤総則に記載の剤形とすることができる。
本発明においては、半固形状又は液状の製剤であるのが好ましく、特に、経口液剤、シロップ剤、外用液剤、スプレー剤、軟膏剤、クリーム剤、ゲル剤及び貼付剤から選ばれる剤形であるのが好ましく、リニメント剤、ローション剤、外用エアゾール剤、ポンプスプレー剤、軟膏剤、クリーム剤、ゲル剤、テープ剤及びパップ剤から選ばれる剤形であるのが特に好ましい。
The pharmaceutical composition of the present invention can be produced, for example, by a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations and the like. In addition, the dosage form is not particularly limited, and may be any form of solid, semi-solid, and liquid, and it may be in a form generally used in medicine depending on the purpose of use and the like. it can. Specifically, for example, preparations for oral administration (tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), preparations for vaginal application (vaginal tablets, suppositories for vaginal use, etc.), skin The dosage forms described in the General Regulations of the 16th Amended Japanese Pharmacopoeia, such as preparations for external application (solid external solution, external solution liquid, spray, ointment, cream, gel, patch, etc.), etc. it can.
In the present invention, semisolid or liquid preparations are preferable, and in particular, dosage forms selected from oral solutions, syrups, solutions for external use, sprays, ointments, creams, gels and patches. It is particularly preferable that the dosage form is selected from liniment, lotion, external aerosol, pump spray, ointment, cream, gel, tape and patch.
また、別の観点から、本発明の医薬組成物は、半固形又は液状の組成物であるのが好ましく、含水組成物(より詳細には、組成物中に水を1質量%以上、より好ましくは5質量%以上、特に好ましくは10〜80質量%含有する組成物)であるのがより好ましい。後記実施例に具体的に開示の通り、相互作用抑制成分が、溶液中におけるロキソプロフェン又はその塩とテルペン類との間の相互作用を抑制することが確認されている。 From another point of view, the pharmaceutical composition of the present invention is preferably a semisolid or liquid composition, and a water-containing composition (more specifically, 1% by mass or more of water in the composition, more preferably Is more preferably 5% by mass or more, particularly preferably 10 to 80% by mass. As specifically disclosed in the Examples below, it has been confirmed that the interaction suppressing component suppresses the interaction between loxoprofen or a salt thereof and the terpene in the solution.
本発明の医薬組成物の服用経路としては、経口及び経皮、経膣等の非経口が挙げられ、本発明においては、非経口が好ましく、経皮投与が特に好ましい。 The route of administration of the pharmaceutical composition of the present invention includes oral and parenteral routes such as transdermal and vaginal. In the present invention, parenteral is preferred, and transdermal administration is particularly preferred.
本発明の医薬組成物には、医薬成分として、ロキソプロフェン又はその塩、テルペン類、及び相互作用抑制成分以外の薬物、例えば、鎮痛成分、抗炎症成分、抗ヒスタミン成分、殺菌成分、収れん・保護成分、血行促進成分、温感成分、局所麻酔成分、鎮咳剤、ノスカピン類、気管支拡張剤、去痰剤、催眠鎮静剤、ビタミン類、胃粘膜保護剤、制酸剤、抗コリン剤、生薬類、漢方処方等からなる群より選ばれる1種又は2種以上を含んでいてもよい。 The pharmaceutical composition of the present invention comprises, as a pharmaceutical component, loxoprofen or a salt thereof, a terpene, and a drug other than an interaction suppressing component, such as an analgesic component, an anti-inflammatory component, an antihistamine component, a bactericidal component, an astringency / protective component , Blood circulation promoting ingredients, warm feeling ingredients, local anesthetic ingredients, antitussives, noscapines, bronchodilators, expectorants, hypnotic sedatives, vitamins, gastric mucosa protective agents, antacids, anticholinergics, herbal medicines, traditional Chinese medicine prescription And the like, may contain one or more selected from the group consisting of and the like.
鎮痛成分としては、例えば、アスピリン、アスピリンアルミニウム、アセトアミノフェン、イソプロピルアンチピリン、イブプロフェン、エテンザミド、サザピリン、サリチルアミド、サリチル酸、サリチル酸エチレングリコール、サリチル酸グリコール、サリチル酸ナトリウム、サリチル酸メチル、チアラミド塩酸塩、ラクチルフェネチジン等が挙げられる。
抗炎症成分としては、例えば、グアイアズレンスルホン酸ナトリウム、グリチルリチン酸及びその誘導体並びにそれらの塩類(例えば、グリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム等)、グリチルレチン酸、セアプローゼ、セミアルカリプロティナーゼ、セラペプターゼ、プロクターゼ、プロナーゼ、ブロメライン等が挙げられる。
As an analgesic component, for example, aspirin, aspirin aluminum, acetaminophen, isopropyl antipyrine, ibuprofen, ethensamide, sazapyrin, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, tiaramide hydrochloride, lactyl phenetidine Etc.
Examples of the anti-inflammatory component include sodium guaiazulene sulfonate, glycyrrhizinic acid and derivatives thereof and salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, seaprose, semialkaline proteinase, serrapeptase, procutase, Pronase, bromelain and the like can be mentioned.
抗ヒスタミン成分としては、例えば、アゼラスチン塩酸塩、アリメマジン酒石酸塩、イソチペンジル塩酸塩、イプロヘプチン塩酸塩、エピナスチン塩酸塩、エメダスチンフマル酸塩、ケトチフェンフマル酸塩、トリプロリジン塩酸塩、トリペレナミン塩酸塩、トンジルアミン塩酸塩、フェネタジン塩酸塩、プロメタジン塩酸塩、プロメタジンメチレン二サリチル酸塩、メキタジン、メトジラジン塩酸塩、メブヒドロリンナパジシル酸塩等が挙げられる。 As an antihistamine component, for example, azelastine hydrochloride, alimemazine tartrate, isothipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, ketotifen fumarate, triprolidine hydrochloride, triperenamine hydrochloride, tongilamine Hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylic acid, mequitazine, methyzirazine hydrochloride, mebhydrolinnapadisylate, etc. may be mentioned.
殺菌成分としては、例えば、塩化ベンザルコニウム等が挙げられる。収れん・保護成分としては、例えば、酸化亜鉛等が挙げられる。血行促進成分としては、酢酸トコフェロール、ニコチン酸ベンジル、ヘパリン類似物質、ポリエチレンスルホン酸ナトリウム等が挙げられる。温感成分としては、例えば、ノナン酸バニリルアミド、カプサイシン、トウガラシ等が挙げられる。局所麻酔成分としては、例えば、リドカイン、チョウジ油、ベラドンナエキス等が挙げられる。 Examples of the bactericidal component include benzalkonium chloride and the like. Examples of the astringent and protective components include zinc oxide and the like. Examples of the blood circulation promoting component include tocopherol acetate, benzyl nicotinate, heparin analogues, sodium polyethylene sulfonate and the like. Examples of the warm sensation component include nonanoic acid vanillylamide, capsaicin, pepper and the like. Examples of the topical anesthetic component include lidocaine, clove oil, veradonna extract and the like.
鎮咳剤としては、例えば、アロクラミド塩酸塩、エプラジノン塩酸塩、カルベタペンタンクエン酸塩、クロペラスチン塩酸塩、クロペラスチンフェンジゾ酸塩、ジブナートナトリウム、ジメモルファンリン酸塩、チペピジンクエン酸塩、チペピジンヒベンズ酸塩等が挙げられる。 As an antitussive, for example, alloclamide hydrochloride, epraginone hydrochloride, calbetapentane citrate, chlorperastine hydrochloride, chlorperastine phendizoate, dibanato sodium, dimemorphan phosphate, tipepidine citrate, Tipepidine hibenzate and the like can be mentioned.
ノスカピン類としては、例えば、ノスカピン塩酸塩、ノスカピン等が挙げられる。
気管支拡張剤としては、例えば、トリメトキノール塩酸塩、フェニレフリン塩酸塩、メトキシフェナミン塩酸塩等が挙げられる。
Examples of noscapins include noscapine hydrochloride, noscapine and the like.
Examples of bronchodilators include trimetoquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.
去痰剤としては、例えば、アンモニア・ウイキョウ精、塩化アンモニウム等が挙げられる。 As the expectorant, for example, ammonia, fennel, ammonium chloride and the like can be mentioned.
催眠鎮静剤としては、アリルイソプロピルアセチル尿素やブロムワレリル尿素等が挙げられる。
ビタミン類としては、ビタミンB1、ビタミンB2、ビタミンB5、ビタミンB6、ビタミンB12、ビタミンC、ヘスペリジン及びその誘導体並びにそれらの塩類等(例えば、チアミン、チアミン塩化物塩酸塩、チアミン硝化物、ジセチアミン塩酸塩、セトチアミン塩酸塩、フルスルチアミン、フルスルチアミン塩酸塩、オクトチアミン、シコチアミン、チアミンジスルフィド、ビスイブチアミン、ビスベンチアミン、プロスルチアミン、ベンフォチアミン、リボフラビン、リボフラビンリン酸エステル、リボフラビン酪酸エステル、リン酸リボフラビンナトリウム、パンテノール、パンテチン、パントテン酸ナトリウム、ピリドキシン塩酸塩、ピリドキサールリン酸エステル、シアノコバラミン、メコバラミン、アスコルビン酸、アスコルビン酸ナトリウム、アスコルビン酸カルシウム、ヘスペリジン等)が挙げられる。
The hypnotic sedative includes allyl isopropyl acetyl urea and brom valeryl urea.
Examples of vitamins include vitamin B 1 , vitamin B 2 , vitamin B 5 , vitamin B 6 , vitamin B 12 , vitamin C, hesperidin and derivatives thereof, and salts thereof (eg, thiamine, thiamine chloride hydrochloride, thiamine nitrification , Disethiamine Hydrochloride, Cetotiamine Hydrochloride, Flusultiamine Hydrochloride, Flusultiamine Hydrochloride, Octothiamine, Shikotiamine, Thiamine Disulfide, Bisibutiamine, Bisbenchamine, Prosultiamine, Benfotiamine, Riboflavin, Riboflavin Phosphate , Riboflavin butyrate, sodium riboflavin phosphate, panthenol, panthetin, pantothenic acid sodium, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, ascorbic acid Sodium binate, calcium ascorbate, hesperidin and the like).
胃粘膜保護剤としては、ゲファルナート、セトラキサート塩酸塩、ソファルコン、テプレノン、メチルメチオニンスルホニウムクロリド等が挙げられる。
制酸剤としては、アミノ酢酸、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、合成ケイ酸アルミニウム、合成ヒドロタルサイト、酸化マグネシウム、ジヒドロキシアルミニウムアミノアセテート、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、乾燥水酸化アルミニウムゲル、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸水素ナトリウムの共沈生成物、水酸化アルミニウム・炭酸カルシウム・炭酸マグネシウムの共沈生成物、水酸化マグネシウム、水酸化マグネシウム・硫酸アルミニウムカリウムの共沈生成物、炭酸マグネシウム、炭酸水素ナトリウム、沈降炭酸カルシウム、メタケイ酸アルミン酸マグネシウム、無水リン酸水素カルシウム、リン酸水素カルシウム、烏賊骨、石決明、ボレイ等が挙げられる。
As the gastric mucosa protective agent, gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methyl methionine sulfonium chloride and the like can be mentioned.
As an antacid, aminoacetic acid, magnesium aluminum silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxy aluminum amino acetate, magnesium aluminum hydroxide, aluminum hydroxide gel, dry hydroxide Aluminum gel, aluminum hydroxide / magnesium carbonate mixed dry gel, coprecipitated product of aluminum hydroxide / sodium bicarbonate, coprecipitated product of aluminum hydroxide / calcium carbonate / magnesium carbonate, magnesium hydroxide, magnesium hydroxide / sulfuric acid Aluminum coprecipitated with potassium, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, bone bone, stone determination, Rei, and the like.
抗コリン薬としては、オキシフェンサイクリミン塩酸塩、ジサイクロミン塩酸塩、メチキセン塩酸塩、チペピジウム臭化物、メチルベナクチジウム臭化物、ピレンゼピン塩酸塩、ヨウ化イソプロパミド、ヨウ化ジフェニルピペリジノメチルジオキソラン等が挙げられる。 Examples of anticholinergic agents include oxyphencyclimamine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, tipepidium bromide, methylbenactobium bromide, pirenzepine hydrochloride, iodopropyide iodide, diphenylpiperidinomethyl iodide, etc. .
生薬類としては、アカメガシワ(赤芽柏)、アセンヤク(阿仙薬)、アルニカ、インヨウカク(淫羊霍)、ウイキョウ(茴香)、ウコン(鬱金)、エンゴサク(延胡索)、オウゴン(黄岑)、オウセイ(黄精)、オウバク(黄柏)、オウヒ(桜皮)、オウレン(黄連)、オンジ(遠志)、ガジュツ(我朮)、カノコソウ(鹿子草)、カミツレ、カロニン(か楼仁)、キキョウ(桔梗)、キョウニン(杏仁)、クコシ(枸杞子)、クコヨウ(枸杞葉)、ケイガイ(荊芥)、ケイヒ(桂皮)、ケツメイシ(決明子)、ゲンチアナ、ゲンノショウコ(現証拠)、コウカ(紅花)、コウブシ(香附子)、ゴオウ(牛黄)、ゴミシ(五味子)、サイシン(細辛)、サンシシ(山梔子)、サンショウ(山椒)、シオン(紫苑)、ジコッピ(地骨皮)、シコン(紫根)、シャクヤク(芍薬)、ジャコウ(麝香)、シャジン(沙参)、シャゼンシ(車前子)、シャゼンソウ(車前草)、獣胆(ユウタン(熊胆)を含む)、ショウキョウ(生姜)、ジリュウ(地竜)、シンイ(辛夷)、セイヨウトチノキ、セキサン(石蒜)、セネガ、センキュウ(川きゅう)、ゼンコ(前胡)、センブリ(千振)、ソウジュツ(蒼朮)、ソウハクヒ(桑白皮)、ソヨウ(蘇葉)、タイサン(大蒜)、チクセツニンジン(竹節人参)、チンピ(陳皮)、トウキ(当帰)、トコン(吐根)、ナンテンジツ(南天実)、ニンジン(人参)、バイモ(貝母)、バクモンドウ(麦門冬)、ハンゲ(半夏)、バンコウカ(番紅花)、ハンピ(反鼻)、ビャクシ(白し)、ビャクジュツ(白朮)、ブクリョウ(茯苓)、ボタンピ(牡丹皮)、ヨウバイヒ(楊梅皮)、ロクジョウ(鹿茸)等の生薬及びこれらの抽出物(エキス、チンキ、乾燥エキス等)等が挙げられる。 As herbal medicines, red-legged moth (red bud), asenyak (anemochi), arnica, inyoukak (incomparable), fennel (mushroom), turmeric (depressing metal), engosac (bulk), ougon (album), oseui (palm) , Oupaku (ovenus), Oohi (cherry bark), Ouren (黄 ren), Onji (遠), 、 ジ ((朮), カ (シ (朮 子 草), chamomile, caronin (か 仁), 桔 キ ョ (桔), kyounin (Apricot kernel), Kukoshi (Kanko), Kukoyou (Kanoba), Kishi (Kansai), Kishi (Kinnamon), Ketsumeishi (Decisyuko), Gentiana, Gennoshoko (now proof), Kouka (Safflower), Koubushi (Kobushi), Goow (cow yellow), Gojishi (gojiko), Saishin (thin spicy), Sanshishi (Yamashinoko), Sansho (Yamako), Shion (Shion), Zikopi (dichoderma), Shikon (sheep root), Peony (Ginseng), musk (mushroom), shajin (sasan), shazenshi (car ancestry), spinach (carpe grass), animal gall (including yuutang (bear bear)), spinach (germ), jiryu (ground dragon) , Shini (spicy), Aesculus hippocastanum, Sexan (Sekigan), Senega, Senkyu (kawakyu), Zenko (pre-hu), Semburi (sensori), Soju-tu (蒼朮), Soo-ha-kuhi (桑), Soyo (su-ha) ), Taisan (Daimushi), Chixsetsu Carrot (Bamboo Ginseng), Chinpi (Chen peel), Toki (Toki), Tokon (Naked Root), Nantenjitsu (South Tenchi), Carrot (Ginseng), Baimo (Shell Mother), Bacummondo (March gate winter), Hange (half summer), Bankouka (Banka flower), Hampi (anti-nose), Birak (white), Birch (white), Bokuryo (mochi), Betpi (peony skin), Gourd (salmon plum skin) ), Rokujo (茸) and other raw materials And these extracts (extract, tincture, dry extract, etc.) and the like.
漢方処方としては、ケイシトウ(桂枝湯)、コウソサン(香蘇散)、サイコケイシトウ(柴胡桂枝湯)、ショウサイコトウ(小柴胡湯)、バクモンドウトウ(麦門冬湯)、ハンゲコウボクトウ(半夏厚朴湯)等が挙げられる。 Chinese medicine prescriptions include Kishitou (Keishi-to), Kososan (Kasosansu), Pikakei-shitou (Shoko-Keishi-tou), Shosaiko-to (Kosai-ko-to), Bakkomdeo-tou (Borimumunyu-to), Hangekoubokuto (Semi-summer hot spring bath) etc. are mentioned.
本発明の医薬組成物は、NSAIDの一種であるロキソプロフェン又はその塩を含有することから、医療用医薬品やOTC医薬品として用いることができ、具体的には例えば、変形性関節症、筋肉痛及び外傷後の腫脹・疼痛から選ばれる疾患並びに症状の消炎・鎮痛等の効能又は効果を有し、鎮痛・抗炎症剤等として有用である。 Since the pharmaceutical composition of the present invention contains loxoprofen, which is a type of NSAID, or a salt thereof, it can be used as a medical drug or an OTC drug, and specifically, for example, osteoarthritis, myalgia and trauma It has efficacy or effects such as anti-inflammatory and analgesic effects of diseases and symptoms selected from later swelling and pain, and is useful as an analgesic and anti-inflammatory agent and the like.
以下に実施例を挙げて本発明を詳細に説明するが、本発明はこれら実施例に何ら限定されるものではない。
[試験例1]ロキソプロフェンナトリウム水和物とl−メントールの相互作用の検討 その1
ブリトン−ロビンソン広域緩衝液(Buritton Robinson's Buffer)(pH7.0)と無水エタノールを等量混合して得た混液に、表1記載の各成分を同表記載の濃度(w/w%)となるよう溶解せしめた後、希塩酸又は10%水酸化ナトリウム水溶液を用いてpH8.0に調整して、各サンプル溶液を調製した。得られた各サンプル溶液は、それぞれ10mlずつ、ガラス瓶(10K規格瓶)に充填した。
相互作用の有無は、得られた各サンプル溶液の調製直後(調製の1時間後)の外観を目視により評価することで判定した。なお、外観が澄明であったものを○、不溶物の生成が認められたものを×とした。
結果を表1に示す。
EXAMPLES The present invention will be described in detail by way of examples, but the present invention is not limited to these examples.
[Test Example 1] Examination of the interaction between loxoprofen sodium hydrate and l-menthol Part 1
Each component listed in Table 1 is the concentration (w / w%) shown in the same table in a mixture obtained by mixing equal amounts of Buritton Robinson's Buffer (pH 7.0) and absolute ethanol. After dissolution, each sample solution was prepared by adjusting to pH 8.0 using dilute hydrochloric acid or 10% aqueous sodium hydroxide solution. 10 ml of each of the obtained sample solutions was filled in a glass bottle (10 K standard bottle).
The presence or absence of interaction was determined by visually evaluating the appearance of each of the obtained sample solutions immediately after preparation (one hour after preparation). In addition, that whose appearance was clear was made into (circle) and formation of insoluble matter was recognized as (circle).
The results are shown in Table 1.
表1記載の試験結果から明らかな通り、ロキソプロフェンナトリウム水和物、l−メントールそれぞれ単独で含有するサンプル溶液(参考例1及び2)は澄明な外観を呈したにも拘わらず、ロキソプロフェンナトリウム水和物とl−メントールを共に含有するサンプル溶液(比較例1)では不溶物の生成が認められ、両成分の間に相互作用が確認された。
一方、ロキソプロフェンナトリウム水和物、l−メントールに、さらにクロルフェニラミンマレイン酸塩を含有する実施例1のサンプル溶液においては、参考例1、2と同様、澄明な外観を呈することが明らかとなった。なお、実施例1のサンプル溶液を25℃で1週間保存した後も、澄明な外観を維持していた。
以上の試験結果から、クロルフェニラミン又はその塩を包含する上記一般式(1)で表される化合物又はその塩が、ロキソプロフェン又はその塩とテルペン類との相互作用を抑制する作用を有することが明らかとなった。
As is clear from the test results described in Table 1, although loxoprofen sodium hydrate and 1-menthol each contained a single sample solution (Reference Examples 1 and 2), despite having a clear appearance, loxoprofen sodium hydration In the sample solution (comparative example 1) which contains both a substance and 1-menthol, generation | occurrence | production of insolubles was recognized and interaction between both components was confirmed.
On the other hand, in the sample solution of Example 1 which contains loxoprofen sodium hydrate, l-menthol and chlorpheniramine maleate, it becomes clear that it exhibits a clear appearance as in the reference examples 1 and 2. The Even after storing the sample solution of Example 1 at 25 ° C. for one week, the clear appearance was maintained.
From the above test results, it is possible that the compound represented by the above general formula (1) including chlorpheniramine or a salt thereof or the salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and a terpene. It became clear.
[試験例2]ロキソプロフェンナトリウム水和物とl−メントールの相互作用の検討 その2
マレイン酸クロルフェニラミンをポリビニルアルコール(部分けん化物:商品名 ゴーセノールEG−05(日本合成化学工業製))に変更したほかは試験例1と同様の方法により、相互作用を検討した。結果を表2に示す。
[Test Example 2] Examination of the interaction between loxoprofen sodium hydrate and l-menthol Part 2
The interaction was examined in the same manner as in Test Example 1 except that chlorpheniramine maleate was changed to polyvinyl alcohol (partially saponified product: Gohsenol EG-05 (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.)). The results are shown in Table 2.
表2記載の試験結果から明らかな通り、ポリビニルアルコールを含有する実施例2のサンプル溶液も、上記実施例1のサンプル溶液と同様、澄明な外観を呈することが明らかとなった。なお、実施例2のサンプル溶液を25℃で1週間保存した後も、澄明な外観を維持していた。
以上の試験結果から、多価アルコールは、ロキソプロフェン又はその塩とテルペン類との相互作用を抑制する作用を有することが明らかとなった。
As is clear from the test results described in Table 2, it was revealed that the sample solution of Example 2 containing polyvinyl alcohol also exhibits a clear appearance as the sample solution of Example 1 above. Incidentally, even after the sample solution of Example 2 was stored at 25 ° C. for one week, the clear appearance was maintained.
From the above test results, it has become clear that the polyhydric alcohol has an action of suppressing the interaction between loxoprofen or a salt thereof and terpenes.
製造例1(ゲル剤)
常法により、100mg中に以下の成分を含有するゲル剤を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
l−メントール 3mg
クロルフェニラミンマレイン酸塩 0.1mg
ヒドロキシプロピルメチルセルロース 1mg
カルボキシビニルポリマー 1.2mg
1,3−ブチレングリコール 5mg
トリエタノールアミン 1.5mg
エタノール 20mg
精製水 全量100mg
Production Example 1 (gel agent)
In a conventional manner, a gel was prepared which contained the following ingredients in 100 mg.
Loxoprofen sodium hydrate 1.13 mg
l-menthol 3 mg
Chlorpheniramine maleate 0.1 mg
Hydroxypropyl methylcellulose 1 mg
Carboxy vinyl polymer 1.2 mg
1,3-butylene glycol 5 mg
Triethanolamine 1.5 mg
Ethanol 20 mg
100 mg of purified water
製造例2(テープ剤)
常法により、100mg中に以下の成分を含有するテープ剤(プラスター剤)を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
l−メントール 6mg
クロルフェニラミンマレイン酸塩 0.1mg
SIS共重合体 20mg
ポリイソブチレン 7.5mg
水素添加ロジングリセリンエステル 25mg
流動パラフィン 36.77mg
ジブチルヒドロキシトルエン 0.5mg
リン酸 1mg
クロタミトン 2mg
精製水 全量100mg
Production Example 2 (tape agent)
The tape agent (plaster agent) which contains the following ingredients in 100 mg was manufactured by a conventional method.
Loxoprofen sodium hydrate 1.13 mg
l-menthol 6 mg
Chlorpheniramine maleate 0.1 mg
SIS copolymer 20 mg
Polyisobutylene 7.5 mg
Hydrogenated rosin glycerin ester 25 mg
Liquid paraffin 36.77 mg
Dibutylhydroxytoluene 0.5 mg
Phosphoric acid 1 mg
Crotamiton 2 mg
100 mg of purified water
製造例3(ゲル剤)
常法により、100mg中に以下の成分を含有するゲル剤(ゲルクリーム剤)を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
l−メントール 2mg
ポリビニルアルコール 0.2mg
サリチル酸グリコールエステル 2mg
カルボキシビニルポリマー 1mg
グリセリン 10mg
オクチルドデカノール 10mg
モノステアリン酸グリセリン 0.5mg
ステアリン酸ポリオキシル 0.5mg
ミリスチン酸イソプロピル 5mg
ラウロマクロゴール 1.5mg
トリエタノールアミン 1mg
精製水 全量100mg
Production Example 3 (gel agent)
A gel formulation (gel cream formulation) containing the following ingredients in 100 mg was produced by a conventional method.
Loxoprofen sodium hydrate 1.13 mg
l-menthol 2 mg
Polyvinyl alcohol 0.2 mg
Salicylic acid glycol ester 2 mg
Carboxy vinyl polymer 1 mg
10 mg of glycerin
Octyl dodecanol 10 mg
Glycerin monostearate 0.5 mg
Polyoxyl Stearate 0.5 mg
Isopropyl myristate 5 mg
Lauro Macrogol 1.5 mg
Triethanolamine 1 mg
100 mg of purified water
製造例4(パップ剤)
常法により、100mg中に以下の成分を含有するパップ剤を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
l−メントール 3mg
ポリビニルアルコール 0.8mg
ポリアクリル酸部分中和物 7mg
カルメロースナトリウム 5mg
クロタミトン 2mg
濃グリセリン 25mg
ポリソルベート80 0.3mg
水酸化アルミニウムゲル 0.05mg
酸化チタン 1mg
タルク 2mg
酒石酸 0.6mg
エデト酸ナトリウム水和物 0.1mg
カオリン 2.5mg
亜硫酸水素ナトリウム 0.3mg
精製水 全量100mg
Production Example 4 (Papping Agent)
According to a conventional method, a patch having the following ingredients in 100 mg was produced.
Loxoprofen sodium hydrate 1.13 mg
l-menthol 3 mg
Polyvinyl alcohol 0.8 mg
Partially neutralized polyacrylic acid 7 mg
Carmellose sodium 5 mg
Crotamiton 2 mg
Concentrated glycerin 25 mg
Polysorbate 80 0.3 mg
Aluminum hydroxide gel 0.05 mg
Titanium oxide 1 mg
Talc 2 mg
0.6 mg of tartaric acid
Edetate sodium hydrate 0.1 mg
Kaolin 2.5 mg
Sodium bisulfite 0.3 mg
100 mg of purified water
製造例5(ローション剤)
常法により、100mg中に以下の成分を含有するローション剤を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
ハッカ油 6mg
ノナン酸バニリルアミド 0.1mg
クロルフェニラミンマレイン酸塩 0.5mg
アジピン酸ジイソプロピル 5mg
イソプロパノール 40mg
ヒドロキシプロピルメチルセルロース 0.1mg
ポリエチレングリコール 1mg
亜硫酸水素ナトリウム 0.2mg
精製水 全量100mg
Production Example 5 (lotion agent)
The lotion which contains the following ingredients in 100 mg was manufactured by a conventional method.
Loxoprofen sodium hydrate 1.13 mg
Hakka oil 6 mg
Nonanoic acid vanillylamide 0.1 mg
Chlorpheniramine maleate 0.5 mg
Diisopropyl adipate 5 mg
Isopropanol 40 mg
Hydroxypropyl methylcellulose 0.1 mg
Polyethylene glycol 1 mg
Sodium bisulfite 0.2 mg
100 mg of purified water
製造例6(テープ剤)
常法により、100mg中に以下の成分を含有するテープ剤(プラスター剤)を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
l−メントール 1mg
ノナン酸バニリルアミド 0.12mg
クロルフェニラミンマレイン酸塩 0.5mg
SIS共重合体 20mg
ポリイソブチレン 7.5mg
水素添加ロジングリセリンエステル 25mg
流動パラフィン 42.25mg
ジブチルヒドロキシトルエン 0.5mg
リン酸 1mg
クロタミトン 2mg
精製水 全量100mg
Production Example 6 (tape agent)
The tape agent (plaster agent) which contains the following ingredients in 100 mg was manufactured by a conventional method.
Loxoprofen sodium hydrate 1.13 mg
l-menthol 1 mg
Nonanoic acid vanillylamide 0.12 mg
Chlorpheniramine maleate 0.5 mg
SIS copolymer 20 mg
Polyisobutylene 7.5 mg
Hydrogenated rosin glycerin ester 25 mg
Liquid paraffin 42.25 mg
Dibutylhydroxytoluene 0.5 mg
Phosphoric acid 1 mg
Crotamiton 2 mg
100 mg of purified water
製造例7(クリーム剤)
常法により、100mg中に以下の成分を含有するクリーム剤を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
dl−カンフル 4mg
ノナン酸バニリルアミド 0.12mg
ポリビニルアルコール 0.2mg
カルボキシビニルポリマー 0.8mg
エデト酸ナトリウム水溶液 1mg
亜硫酸水素ナトリウム 0.1mg
ミリスチン酸オクチルドデシル 10mg
アジピン酸ジイソプロピル 5mg
モノステアリン酸グリセリン 2mg
モノステアリン酸ソルビタン 0.5mg
モノステアリン酸ポリオキシエチレンソルビタン 1mg
パラベン 0.2mg
モノステアリン酸ポリオキシエチレンソルビタン 0.1mg
水酸化ナトリウム 0.1mg
精製水 全量100mg
Production Example 7 (Cream agent)
In a conventional manner, a cream containing the following ingredients in 100 mg was produced.
Loxoprofen sodium hydrate 1.13 mg
dl-camphor 4 mg
Nonanoic acid vanillylamide 0.12 mg
Polyvinyl alcohol 0.2 mg
Carboxyvinyl polymer 0.8 mg
Edetate sodium solution 1 mg
Sodium bisulfite 0.1 mg
Octyl dodecyl myristate 10 mg
Diisopropyl adipate 5 mg
Glycerin monostearate 2 mg
Sorbitan monostearate 0.5 mg
Polyoxyethylene sorbitan monostearate 1 mg
Paraben 0.2 mg
Polyoxyethylene sorbitan monostearate 0.1 mg
Sodium hydroxide 0.1 mg
100 mg of purified water
製造例8(パップ剤)
常法により、100mg中に以下の成分を含有するパップ剤を製造した。
ロキソプロフェンナトリウム水和物 1.13mg
l−メントール 3mg
ノナン酸バニリルアミド 0.1mg
ポリビニルアルコール 1mg
ポリアクリル酸部分中和物 7mg
カルメロースナトリウム 5mg
クロタミトン 2mg
濃グリセリン 25mg
ポリソルベート80 0.3mg
水酸化アルミニウムゲル 0.05mg
酸化チタン 1mg
タルク 2mg
酒石酸 0.6mg
エデト酸ナトリウム水和物 0.1mg
カオリン 2.5mg
亜硫酸水素ナトリウム 0.3mg
精製水 全量100mg
Production Example 8 (Papping Agent)
According to a conventional method, a patch having the following ingredients in 100 mg was produced.
Loxoprofen sodium hydrate 1.13 mg
l-menthol 3 mg
Nonanoic acid vanillylamide 0.1 mg
Polyvinyl alcohol 1 mg
Partially neutralized polyacrylic acid 7 mg
Carmellose sodium 5 mg
Crotamiton 2 mg
Concentrated glycerin 25 mg
Polysorbate 80 0.3 mg
Aluminum hydroxide gel 0.05 mg
Titanium oxide 1 mg
Talc 2 mg
0.6 mg of tartaric acid
Edetate sodium hydrate 0.1 mg
Kaolin 2.5 mg
Sodium bisulfite 0.3 mg
100 mg of purified water
本発明によれば、ロキソプロフェン又はその塩とテルペン類との相互作用を抑制できる。従って、保存安定性が優れた、ロキソプロフェン又はその塩、及びテルペン類を含む医薬組成物を提供することができる。本発明の医薬組成物は、NSAIDの一種であるロキソプロフェンを含有することから、例えば、変形性関節症、筋肉痛及び外傷後の腫脹・疼痛から選ばれる疾患並びに症状の消炎・鎮痛等に有効な医薬組成物として好適に利用できる。 According to the present invention, the interaction between loxoprofen or a salt thereof and a terpene can be suppressed. Therefore, it is possible to provide a pharmaceutical composition comprising loxoprofen or a salt thereof, and terpenes, which is excellent in storage stability. Since the pharmaceutical composition of the present invention contains loxoprofen, which is a type of NSAID, it is effective, for example, in the treatment of diseases selected from osteoarthritis, myalgia and swelling / pain after trauma, as well as anti-inflammatory and analgesic effects of symptoms. It can be suitably used as a pharmaceutical composition.
Claims (5)
(A)ロキソプロフェン又はその塩
(B)メントール
(C)1,3−ブチレングリコール、ソルビトール、マンニトール、ジプロピレングリコール及びポリビニルアルコールよりなる群から選ばれる1種以上
を含有する、半固形状又は液状の医薬組成物(但し、貼付剤を除く)。 The following components (A), (B) and (C):
(A) Loxoprofen or a salt thereof (B) menthol (C) 1,3-butylene glycol, semi-solid or liquid containing one or more selected from the group consisting of sorbitol, mannitol, dipropylene glycol and polyvinyl alcohol Pharmaceutical composition (except for patches).
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