JP2010159251A - Composition of skin preparation for external use - Google Patents
Composition of skin preparation for external use Download PDFInfo
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- JP2010159251A JP2010159251A JP2009278286A JP2009278286A JP2010159251A JP 2010159251 A JP2010159251 A JP 2010159251A JP 2009278286 A JP2009278286 A JP 2009278286A JP 2009278286 A JP2009278286 A JP 2009278286A JP 2010159251 A JP2010159251 A JP 2010159251A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Description
本発明は、製剤安定性が改善された四級アンモニウム塩とクロルフェニラミンマレイン酸塩を含有する皮膚外用薬組成物に関する。 The present invention relates to a skin external preparation composition containing a quaternary ammonium salt and chlorpheniramine maleate having improved formulation stability.
１９３５年に四級アンモニウム塩に殺菌作用が発見されて以来、現在でも広い分野で殺菌剤として使用されている。四級アンモニウム塩は陽イオン性界面活性剤（逆性石鹸）として分類され、他の界面活性剤と比較して殺菌作用が強力であり、一般的細菌（大腸菌や黄色ブドウ球菌等）について殺菌作用を有する（以上、例えば、非特許文献１参照）。 Since the discovery of bactericidal action on quaternary ammonium salts in 1935, it is still used as a bactericidal agent in a wide range of fields. Quaternary ammonium salts are classified as cationic surfactants (reverse soaps), have a stronger bactericidal action than other surfactants, and bactericidal action for common bacteria (such as Escherichia coli and Staphylococcus aureus) (See, for example, Non-Patent Document 1).
クロルフェニラミンマレイン酸塩は抗ヒスタミン剤として良く知られており、医療用では外用薬はないが、OTC医薬品では局所の痒みを和らげるために、四級アンモニウム塩とともに外用薬に配合されることがある（例えば、非特許文献２参照）。 Chlorpheniramine maleate is well known as an antihistamine, and there is no topical medicine for medical use, but OTC medicines may be combined with topical medicines together with quaternary ammonium salts to relieve local itching ( For example, refer nonpatent literature 2).
これまでに、ベンザルコニウム塩化物とクロルフェニラミンマレイン酸塩を含有する製剤に等張化剤として塩化ナトリウムを添加した点眼剤（例えば、特許文献１の実施例２および実施例３参照）、点鼻薬（例えば、特許文献２の実施例６参照）などの粘膜適用製剤の例が開示されている。 So far, an eye drop in which sodium chloride is added as an isotonic agent to a preparation containing benzalkonium chloride and chlorpheniramine maleate (see, for example, Example 2 and Example 3 of Patent Document 1), Examples of preparations for applying to mucosa such as nasal drops (for example, see Example 6 of Patent Document 2) are disclosed.
しかし、四級アンモニウム塩とクロルフェニラミンマレイン酸塩を含有する製剤に塩化物イオン供給源（塩化ナトリウムなど）を添加した皮膚外用薬は知られておらず、これによって製剤安定性が改善されることを示唆した報告も見当たらない。 However, there is no known external skin preparation in which a chloride ion source (such as sodium chloride) is added to a preparation containing a quaternary ammonium salt and chlorpheniramine maleate, which improves the preparation stability. There are no reports suggesting this.
これまでに、四級アンモニウム塩とクロルフェニラミンマレイン酸塩に配合変化があることは知られていないが、本発明者らは、当該組成物の製剤検討中に、極めて過酷な条件化での保存において、未知の結晶が析出して安定性に影響を及ぼす可能性があることを見出した。さらに、この現象は粘膜適用製剤のような低濃度で四級アンモニウム塩とクロルフェニラミンマレイン酸塩を含有するような場合には発現しないことも見出した。 So far, it has not been known that there is a change in the composition of quaternary ammonium salt and chlorpheniramine maleate, but the present inventors have studied under extremely severe conditions during the formulation study of the composition. During storage, it has been found that unknown crystals may precipitate and affect stability. Furthermore, the present inventors have found that this phenomenon does not occur when the quaternary ammonium salt and chlorpheniramine maleate are contained at a low concentration as in the preparation for mucosa.
すなわち、本発明の課題は、四級アンモニウム塩とクロルフェニラミンマレイン酸塩を含有する皮膚外用薬組成物において、当該結晶の生成を抑制した安定な製剤を実現し提供することである。 That is, the subject of this invention is implement | achieving and providing the stable formulation which suppressed the production | generation of the said crystal | crystallization in the external preparation for skin containing a quaternary ammonium salt and a chlorpheniramine maleate.
本発明者らは、当該結晶がいかなる条件のもとで生成しやすくなるのか、また、どのようにすれば有効に防止できるかを、先ず、ベンゼトニウム塩化物とクロルフェニラミンマレイン酸塩について解明のための研究を鋭意すすめた。 The present inventors first elucidated benzethonium chloride and chlorpheniramine maleate to determine under what conditions the crystals are likely to be formed and how they can be effectively prevented. For the purpose of research.
NMR（核磁気共鳴分析）やMASS（質量分析）による分析研究の結果、析出した結晶がマレイン酸ベンゼトニウムであることを突き止めた。この結果をもとに、何らかの理由で四級アンモニウム塩（ベンゼトニウム塩化物）の塩素が分離し、また、クロルフェニラミンマレイン酸塩のマレイン酸が分離置換して、マレイン酸ベンゼトニウムが生成するのではないかという仮説を立てた。 As a result of analytical studies by NMR (nuclear magnetic resonance analysis) and MASS (mass spectrometry), it was determined that the precipitated crystals were benzethonium maleate. Based on this result, the chlorine of the quaternary ammonium salt (benzethonium chloride) is separated for some reason, and the maleic acid of chlorpheniramine maleate is separated and substituted to produce benzethonium maleate. I hypothesized that there is no such thing.
未だに確固たる発生原因は不明ではあるが、当該仮説を検証するための試験を鋭意行った。その結果、四級アンモニウム塩の塩化物イオンが分離しないように、溶液内の塩化物イオン濃度を上げることによって結晶の析出が防止できることを見出し、本発明を完成するに至った。 Although the cause of the occurrence is still unclear, we conducted diligent tests to verify the hypothesis. As a result, the inventors have found that the precipitation of crystals can be prevented by increasing the chloride ion concentration in the solution so that chloride ions of the quaternary ammonium salt are not separated, and the present invention has been completed.
すなわち、本発明は、
（１）四級アンモニウム塩を0.05〜2重量％、クロルフェニラミンマレイン酸塩を0.1〜4重量％および塩化物イオン供給源を0.01〜10重量％含有することを特徴とする外用薬組成物、
（２）四級アンモニウム塩が、ベンザルコニウム塩化物、ベンゼトニウム塩化物およびセチルピリジニウム塩化物からなる群より選ばれる１種以上である、前記（１）に記載の外用薬組成物、
（３）四級アンモニウム塩がベンゼトニウム塩化物である前記（１）に記載の外用薬組成物、
（４）塩化物イオン供給源が、塩化ナトリウム、塩化カルシウム、塩化カリウム、塩化アルミニウム、塩化アンモニウムおよび塩酸からなる群から選ばれる１種以上である前記（１）〜（３）いずれか１項に記載の外用薬組成物、
（５）塩化物イオン供給源が塩化ナトリウムである前記（１）〜（３）いずれか１項に記載の外用薬組成物、
（６）剤型が液剤である前記（１）〜（５）のいずれか１項に記載の外用薬組成物、
（７）四級アンモニウム塩およびクロルフェニラミンマレイン酸塩を含有する外用薬組成物に塩化物イオン供給源を添加する工程を含む、外用薬組成物の安定化方法、
（８）四級アンモニウム塩が、ベンザルコニウム塩化物、ベンゼトニウム塩化物およびセチルピリジニウム塩化物からなる群より選ばれる１種以上である、前記（７）に記載の方法、
（９）四級アンモニウム塩がベンゼトニウム塩化物である前記（７）に記載の外用薬組成物、
（１０）塩化物イオン供給源が、塩化ナトリウム、塩化カルシウム、塩化カリウム、塩化アルミニウム、塩化アンモニウムおよび塩酸からなる群から選ばれる１種以上である前記（７）〜（９）いずれか１項に記載の方法、ならびに
（１１）塩化物イオン供給源が塩化ナトリウムである前記（７）〜（９）いずれか１項に記載の方法
である。
That is, the present invention
(1) An external pharmaceutical composition comprising 0.05 to 2% by weight of a quaternary ammonium salt, 0.1 to 4% by weight of chlorpheniramine maleate and 0.01 to 10% by weight of a chloride ion source,
(2) The external pharmaceutical composition according to (1), wherein the quaternary ammonium salt is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride,
(3) The external pharmaceutical composition according to (1), wherein the quaternary ammonium salt is benzethonium chloride,
(4) In any one of the above (1) to (3), the chloride ion source is one or more selected from the group consisting of sodium chloride, calcium chloride, potassium chloride, aluminum chloride, ammonium chloride and hydrochloric acid. The externally applied medicinal composition,
(5) The external pharmaceutical composition according to any one of (1) to (3), wherein the chloride ion source is sodium chloride,
(6) The external pharmaceutical composition according to any one of (1) to (5), wherein the dosage form is a liquid agent,
(7) A method for stabilizing an external pharmaceutical composition comprising a step of adding a chloride ion source to an external pharmaceutical composition containing a quaternary ammonium salt and chlorpheniramine maleate,
(8) The method according to (7), wherein the quaternary ammonium salt is one or more selected from the group consisting of benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride.
(9) The external pharmaceutical composition according to (7), wherein the quaternary ammonium salt is benzethonium chloride,
(10) In any one of (7) to (9), the chloride ion source is one or more selected from the group consisting of sodium chloride, calcium chloride, potassium chloride, aluminum chloride, ammonium chloride and hydrochloric acid. (11) The method according to any one of (7) to (9), wherein the chloride ion source is sodium chloride.
本発明により、極めて過酷な条件においても、四級アンモニウム塩とクロルフェニラミンマレイン酸塩を含有する外用薬組成物において、結晶の析出が抑制された安定な外用薬製剤が実現でき有用である。特に、噴射孔面積の小さい噴霧タイプの液剤において、ノズルの閉塞を防止できるため有用な技術となる。 INDUSTRIAL APPLICABILITY According to the present invention, a stable external preparation with suppressed crystal precipitation is useful in an external preparation composition containing a quaternary ammonium salt and chlorpheniramine maleate even under extremely severe conditions. In particular, in a spray type liquid agent having a small injection hole area, the nozzle can be prevented from being blocked, which is a useful technique.
本発明に用いられる四級アンモニウム塩としては、陽イオン性界面活性剤（逆性石鹸）であれば特に限定されないが、例えば、ベンザルコニウム塩化物（塩化ベンザルコニウム）、ベンゼトニウム塩化物（塩化ベンゼトニウム）、セチルピリジニウム塩化物（塩化セチルピリジニウム）などが挙げられ、ベンゼトニウム塩化物が好ましい。ベンザルコニウム塩化物およびベンゼトニウム塩化物は第15改正日本薬局方（以下、単に日局という場合がある）に収載されている。また、セチルピリジニウム塩化物は医薬品添加物規格2003に収載されている。 The quaternary ammonium salt used in the present invention is not particularly limited as long as it is a cationic surfactant (reverse soap). For example, benzalkonium chloride (benzalkonium chloride), benzethonium chloride (chloride) Benzethonium), cetylpyridinium chloride (cetylpyridinium chloride) and the like, and benzethonium chloride is preferred. Benzalkonium chloride and benzethonium chloride are listed in the 15th revised Japanese Pharmacopoeia (hereinafter sometimes simply referred to as “Japan Pharmacopoeia”). Cetylpyridinium chloride is listed in the Pharmaceutical Additives Standard 2003.
本発明の組成物における四級アンモニウム塩の含有量は、本発明の組成物中0.05〜2重量％であり、好ましくは、0.05〜1重量％であり、さらにより好ましくは0.1〜0.5重量％である。 The content of the quaternary ammonium salt in the composition of the present invention is 0.05 to 2% by weight in the composition of the present invention, preferably 0.05 to 1% by weight, and still more preferably 0.1 to 0.5% by weight. is there.
本発明に用いられるクロルフェニラミンマレイン酸塩（マレイン酸クロルフェニラミン）は第一世代の抗ヒスタミン剤として、外用・内服等に汎用されている医薬成分であり、第15改正日本薬局方に収載されている。 Chlorpheniramine maleate (chlorpheniramine maleate) used in the present invention is a first-generation antihistamine agent, a pharmaceutical ingredient that is widely used for topical use, internal use, etc., and is listed in the 15th revised Japanese Pharmacopoeia. Yes.
本発明の組成物におけるクロルフェニラミンマレイン酸塩の含有量は、本発明の組成物中0.1〜4重量％であり、好ましくは、0.1〜2重量％である。より好ましくは、0.2〜1重量％である。 The content of chlorpheniramine maleate in the composition of the present invention is 0.1 to 4% by weight, preferably 0.1 to 2% by weight in the composition of the present invention. More preferably, it is 0.2 to 1% by weight.
本発明に用いられる塩化物イオン供給源としては、上記の四級アンモニウム塩以外の物質であり、かつ、溶液内の塩化物イオン濃度を上げる物質であれば特に限定されないが、例えば、塩化ナトリウム、塩化カルシウム、塩化カリウム、塩化アルミニウム、塩化アンモニウム、塩酸などが挙げられ、塩化ナトリウムが好ましい。塩化ナトリウム、塩化カルシウム、塩化カリウム、塩化アルミニウム、塩化アンモニウムなどは医薬品添加物辞典2000に収載されており、塩酸は日局に収載されている。塩化物イオン供給源は、従来は等張化、pH調整などのために利用できることは知られているが、四級アンモニウム塩とクロルフェニラミンマレイン酸塩とを含有する外用薬組成物の安定化に寄与することは知られていない。 The chloride ion source used in the present invention is not particularly limited as long as it is a substance other than the above quaternary ammonium salt and increases the chloride ion concentration in the solution. For example, sodium chloride, Examples include calcium chloride, potassium chloride, aluminum chloride, ammonium chloride, hydrochloric acid, and sodium chloride is preferred. Sodium chloride, calcium chloride, potassium chloride, aluminum chloride, ammonium chloride and the like are listed in the Pharmaceutical Additives Dictionary 2000, and hydrochloric acid is listed in the Japanese Pharmacopoeia. Although it is known that a chloride ion source can be conventionally used for isotonicity, pH adjustment, etc., stabilization of an external pharmaceutical composition containing a quaternary ammonium salt and chlorpheniramine maleate It is not known to contribute to
本発明の組成物における塩化物イオン供給源の含有量は、本発明の組成物中0.01〜10重量％であり、好ましくは、0.05〜6重量％であり、より好ましくは、0.1〜1重量％である。 The content of the chloride ion source in the composition of the present invention is 0.01 to 10% by weight, preferably 0.05 to 6% by weight, and more preferably 0.1 to 1% by weight in the composition of the present invention. It is.
本発明の外用薬組成物は、必要に応じて、本発明の効果を損なわない範囲内で、アラントイン等の組織修復成分、ジブカインやリドカイン等の局所麻酔成分、ナファゾリン等の血管収縮剤を配合することができる。 The external preparation composition of the present invention contains a tissue repair component such as allantoin, a local anesthetic component such as dibucaine and lidocaine, and a vasoconstrictor such as naphazoline, as necessary, within a range not impairing the effects of the present invention. be able to.
本発明の外用薬組成物としては、液剤、乳化物、軟膏、ゲル剤などが挙げられるが、液剤が好ましい。本発明の外用薬組成物は当該分野で公知の方法、例えば、日局に記載の方法により製造することができる。 Examples of the external pharmaceutical composition of the present invention include liquids, emulsions, ointments, gels, etc., but liquids are preferred. The pharmaceutical composition for external use of the present invention can be produced by a method known in the art, for example, a method described in JP.
本発明の外用薬組成物の適用方法は、通常の外用薬組成物に準じればよく、具体的には、適当量を症状にあわせて一日一回〜数回、患部に一様に噴霧または塗布すればよい。 The application method of the external preparation composition of the present invention may be applied in accordance with a normal external preparation composition. Specifically, an appropriate amount is sprayed uniformly on the affected area once to several times a day according to the symptoms. Or it may be applied.
本発明の実施例を以下に記載するが、これらに限定されるものではない。
（実施例１）液剤
表１に記載の成分および分量をとり、常法により液剤を得る。
Examples of the present invention are described below, but are not limited thereto.
(Example 1) Solution The components and amounts shown in Table 1 are taken to obtain a solution by a conventional method.
表２に記載の成分および分量をとり、常法によりゲル剤を得る。
ベンゼトニウム塩化物とクロルフェニラミンマレイン酸塩の濃度を変えて溶液を調製し、2℃に冷却後、ベンゼトニウムマレイン酸塩の結晶を少量添加し、2℃で24時間保管した後、結晶の状態を観察した結果を表３に示す。
（試験例２）結晶の析出試験
100mL中、ベンゼトニウム塩化物100mgおよびクロルフェニラミンマレイン酸塩200mgを含有する液剤に種々の濃度になるように塩化ナトリウム（NaCl）を添加した後、2℃、24時間保存して、ベンゼトニウムマレイン酸塩の結晶の析出状況を観察した結果を表４に示す。
(Test Example 2) Crystal precipitation test
Sodium chloride (NaCl) is added to a solution containing 100 mg of benzethonium chloride and 200 mg of chlorpheniramine maleate in 100 mL to various concentrations, and then stored at 2 ° C. for 24 hours to obtain benzethonium maleate. Table 4 shows the results of observation of the precipitation of crystals.
本発明により、極めて過酷な条件においても、四級アンモニウム塩とクロルフェニラミンマレイン酸塩を含有する外用薬組成物において、結晶の析出の抑制された安定な外用薬製剤が実現でき有用である。とくに、噴射孔面積の小さい噴霧タイプの液剤において、ノズルの閉塞を防止できるため有用な技術となる。
INDUSTRIAL APPLICABILITY According to the present invention, a stable external pharmaceutical preparation in which precipitation of crystals is suppressed can be realized and useful in an external pharmaceutical composition containing a quaternary ammonium salt and chlorpheniramine maleate even under extremely severe conditions. In particular, the spray type liquid agent having a small injection hole area is useful because it can prevent the nozzle from being blocked.
Claims (11)
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| JP2002114711A (en) * | 2000-10-12 | 2002-04-16 | Lion Corp | External preparation composition |
| JP2003146891A (en) * | 2001-11-07 | 2003-05-21 | Rohto Pharmaceut Co Ltd | Cleaning agent |
| JP2003192589A (en) * | 2001-12-27 | 2003-07-09 | Lion Corp | External preparation composition |
| JP2005126336A (en) * | 2003-10-21 | 2005-05-19 | Sankyo Co Ltd | External antipruritic agent composition and its preparation |
| JP2008143845A (en) * | 2006-12-11 | 2008-06-26 | Hoshienu Seiyaku Kk | Nasal drop composition and nasal drop spraying tool |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06336429A (en) * | 1993-04-01 | 1994-12-06 | Fujisawa Pharmaceut Co Ltd | Topically administrable pharmaceutical |
| JP2002114711A (en) * | 2000-10-12 | 2002-04-16 | Lion Corp | External preparation composition |
| JP2003146891A (en) * | 2001-11-07 | 2003-05-21 | Rohto Pharmaceut Co Ltd | Cleaning agent |
| JP2003192589A (en) * | 2001-12-27 | 2003-07-09 | Lion Corp | External preparation composition |
| JP2005126336A (en) * | 2003-10-21 | 2005-05-19 | Sankyo Co Ltd | External antipruritic agent composition and its preparation |
| JP2008143845A (en) * | 2006-12-11 | 2008-06-26 | Hoshienu Seiyaku Kk | Nasal drop composition and nasal drop spraying tool |
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