JP6684327B2 - Method for producing external medicine exhibiting foam when used - Google Patents
Method for producing external medicine exhibiting foam when used Download PDFInfo
- Publication number
- JP6684327B2 JP6684327B2 JP2018160897A JP2018160897A JP6684327B2 JP 6684327 B2 JP6684327 B2 JP 6684327B2 JP 2018160897 A JP2018160897 A JP 2018160897A JP 2018160897 A JP2018160897 A JP 2018160897A JP 6684327 B2 JP6684327 B2 JP 6684327B2
- Authority
- JP
- Japan
- Prior art keywords
- external
- pharmaceutical composition
- polyoxyethylene
- fatty acid
- foam
- 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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Landscapes
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Description
本発明は、外用医薬の製造方法に関し、さらに詳細には、使用時に泡状を呈する外用医薬の製造方法に関する。 TECHNICAL FIELD The present invention relates to a method for producing an external medicine, and more particularly, to a method for producing an external medicine that is foamy when used.
外用医薬用の製剤は大きく分類して、ローション製剤、軟膏製剤、クリーム製剤、噴霧エアゾル製剤、泡沫エアゾルの5種の製剤が存在する。この内、噴霧エアゾル製剤、泡沫エアゾル製剤等の使用時に泡状を呈する剤形は、投与時に大きな表面積を稼ぐことができ、微細な部分にまで組成物を送達することが可能であるため、均一且つ広域に患部へ物埋的刺激を低減した形で薬剤を投与できることから注目を浴びている(例えば、特許文献1を参照)。この様な使用時に泡状を呈する剤形としては、液化ガスの様な噴射剤を用い気泡を形成するエアゾール剤形に加え(例えば、特許文献2を参照)、噴射剤を用いることなくポンプフォーマーやスクイズフォーマー等のノンエアゾールフォーマー容器を使用し空気を取り込むことにより気泡を形成するノンエアゾール剤形が知られている。エアゾール剤形は、エアゾルの噴出用のガス組成物自体に皮膚に刺激を与える可能性が高いことに加え、近年の環境問題への意識の高まりから揮発性ガスを使用しない剤形への転換が進められており、発泡用のガスを充填せずに、ポンプ式フォーマーで泡沫などを形成する手段であるノンエアゾール剤形の製剤への関心が高まっている。しかしながら、気化圧力と、ガス自体の物理化学的性質が発泡に大きく寄与するエアゾール発泡に比して、ノンエアゾールでは界面活性剤の物理化学的特性が大きく影響し、アニオン性界面活性剤やカチオン性界面活性剤を用いる、洗い流し使用のものがほとんどである。即ち、化粧品分野においては、毛髪化粧料、洗浄料等を中心にノンエアゾール剤形における泡質・使用感等を改善する検討が行われ、界面活性剤及び高分子化合物を含有するノンエアゾール型泡状化粧料組成物(例えば、特許文献3を参照)、水溶性アルコールと非イオン性界面活性剤とN−アルキルピロリドンを含有する泡沫状化粧料(例えば、特許文献4を参照)等が報告されている。しかしながら、該泡沫状化粧料においては、N−アルキルピロリドンのアルキル鎖長は、炭素数8〜18が好適であり、アルキル鎖長が短い場合には起泡性が悪くなることが知られていた。 Topical pharmaceutical formulations are roughly classified into five types: lotion formulations, ointment formulations, cream formulations, spray aerosol formulations, and foam aerosols. Among them, a dosage form that exhibits a foamy shape when used, such as a spray aerosol formulation or a foam aerosol formulation, can obtain a large surface area during administration and can deliver the composition to a fine portion, so that the composition is uniform. In addition, it has attracted attention because it is possible to administer a drug in a wide area to the affected area with a reduced amount of embedded stimulation (see, for example, Patent Document 1). Examples of such a dosage form that exhibits a foamy shape during use include an aerosol dosage form that forms bubbles using a propellant such as liquefied gas (see, for example, Patent Document 2), and a pump foam without using a propellant. Non-aerosol dosage forms are known which form bubbles by taking in air using a non-aerosol former container such as a mer or squeeze foamer. The aerosol dosage form has a high possibility of irritating the skin to the gas composition itself for ejecting the aerosol, and due to the heightened awareness of environmental problems in recent years, it is possible to switch to a dosage form that does not use volatile gas. There is a growing interest in non-aerosol dosage forms, which is a means of forming foam and the like with a pump-former without being filled with a gas for foaming. However, as compared with aerosol foaming, in which the vaporization pressure and the physicochemical properties of the gas itself contribute greatly to foaming, the non-aerosol is greatly affected by the physicochemical properties of the surfactant, and the anionic surfactant and cationic Most of them are rinsed and used with a surfactant. That is, in the field of cosmetics, studies have been conducted to improve the foam quality and feeling in non-aerosol dosage forms centering on hair cosmetics, detergents, etc., and non-aerosol foam containing a surfactant and a polymer compound. Cosmetic compositions (for example, refer to Patent Document 3), foamy cosmetics containing a water-soluble alcohol, a nonionic surfactant and N-alkylpyrrolidone (for example, refer to Patent Document 4), etc. have been reported. ing. However, in the foamy cosmetic, the alkyl chain length of N-alkylpyrrolidone preferably has 8 to 18 carbon atoms, and it has been known that when the alkyl chain length is short, the foamability deteriorates. .
一方、医薬品分野におけるノンエアゾール剤形の製剤の検討はあまり行われておらず、水溶性の薬剤に適用可能な防腐剤としてパラベンを含有してなる鎮痒剤組成物において、界面活性剤として、脂肪酸アルキロールアミド及び炭素数が11〜18の脂肪族基を有し、かつ、ポリオキシアルキレンの繰り返し単位数が7〜40であるポリオキシアルキレン脂肪族エーテルを配合したことを特徴とするフォーム剤用組成物(例えば、特許文献5を参照)、さらには、水難溶解性の薬剤を安定に可溶化可能な水系の非エアゾール式フォーム剤用組成物が報告されている(例えば、特許文献6を参照)。しかしながら、水溶性又は水難溶解性の薬剤を可溶化するために使用する溶媒は、薬剤の化学構造等に大きく影響を受けるため、薬剤が異なるとそれに伴い使用可能な溶媒も大きく変わってくる。さらに、薬剤を可溶化するために必要となる溶媒量は必ずしも少なくなく、可溶化溶媒の種類及び使用量により、非エアゾール式フォーム剤組成物において好ましい特性を発揮する界面活性剤も非常に限られたものとなる。 On the other hand, studies on non-aerosol dosage forms in the pharmaceutical field have not been conducted much, and in an antipruritic composition containing paraben as a preservative applicable to a water-soluble drug, a fatty acid is used as a surfactant. A foaming agent characterized by being blended with an alkylolamide and a polyoxyalkylene aliphatic ether having an aliphatic group having 11 to 18 carbon atoms and having 7 to 40 repeating units of polyoxyalkylene. A composition (for example, refer to Patent Document 5) and a water-based composition for non-aerosol type foam agent capable of stably solubilizing a poorly water-soluble drug have been reported (for example, refer to Patent Document 6). ). However, the solvent used to solubilize a water-soluble or sparingly water-soluble drug is greatly affected by the chemical structure of the drug, etc. Therefore, when the drug is different, the usable solvent also greatly changes. Furthermore, the amount of solvent required to solubilize the drug is not necessarily small, and the surfactants that exert preferable properties in the non-aerosol foam composition are also very limited depending on the type and amount of the solubilizing solvent used. It becomes a thing.
本願発明は、水難溶性溶媒(極性溶媒)を含有するノンエアゾール剤形の外用医薬組成物において、水難溶性の有効成分を十分に溶解することができる溶媒量を含有しながらも、泡沫形成性、使用時の泡のきめ細かさ等の泡質・持続性、べたつき、つっぱり感などの使用感、目詰まりによる吐出不良、液ダレ(泡ダレ)の発生、皮膚刺激などの安全性に関する副作用等の剤形上の課題を解決することを目的とした外用医薬組成物に関するものである。 The present invention is a non-aerosol externally applied pharmaceutical composition containing a poorly water-soluble solvent (polar solvent), while containing a solvent amount capable of sufficiently dissolving a poorly water-soluble active ingredient, foam forming property, Agents such as foam quality / sustainability such as fineness of foam during use, feeling of use such as stickiness and tightness, discharge failure due to clogging, occurrence of liquid dripping (foam dripping), side effects related to safety such as skin irritation, etc. The present invention relates to a topical pharmaceutical composition for the purpose of solving the problems in form.
本発明は、このような状況下為されたものであり、水難溶解性の薬剤を可溶化するのに十分な量の極性溶媒を含有し、使用時に泡状を呈する外用医薬組成物において、極性溶剤と界面活性剤との関係において生じる課題を解決するものであり、泡沫形成性、泡のきめ細かさ等の泡質・持続性、べたつき、つっぱり感などの使用感、目詰まりによる吐出不良、液ダレ(泡ダレ)の発生等の使用時の不具合、皮膚刺激などの安全性に関する副作用等の剤形上の問題を解決することを課題とする。 The present invention has been made under such circumstances, in an external pharmaceutical composition containing a polar solvent in an amount sufficient to solubilize a poorly water-soluble drug, and exhibiting a foamy state at the time of use. It solves the problems that occur in the relationship between the solvent and the surfactant, and has foam forming properties, foam quality and sustainability such as fineness of the foam, stickiness, feeling of use such as tightness, poor discharge due to clogging, liquid It is an object to solve the problems in the dosage form such as the occurrence of sagging (foam sagging) and the like during use, and the side effects on safety such as skin irritation.
この様な状況に鑑みて、本発明者らは、使用時に泡状であることを特徴とする外用医薬組成物において、極性溶剤と界面活性剤との関係において生じる課題、とりわけ、泡沫形成性及び持続性、使用感、皮膚刺激等に関する課題を解決する手段を求めて、鋭意研究努力を重ねた結果、1)極性溶剤と、2)非イオン性界面活性剤とを含有し、使用時に泡状を呈する外用医薬組成物に、かかる特性を見出し、発明を完成させるに至った。即ち、本発明は、以下に示す外用医薬組成物の製造方法に関するものである。
<1> 1)極性溶剤と、2)非イオン性界面活性剤とを含有する外用医薬組成物であって、使用時に泡状であることを特徴とする外用医薬組成物。
<2> 前記極性溶剤が、炭素数1〜4のアルキル鎖を有するN−アルキル−2−ピロリドン、炭酸ジエステル、クロタミトン、多価アルコールのアシル化物及びエーテル化物より選択される1種又は2種以上であることを特徴とする、<1>に記載の外用医薬組成物。
<3> 前記非イオン性界面活性剤は、ポリオキシエチレンが付加されていても良い脂肪酸モノグリセリド、ポリグリセリンの脂肪酸エステル、ポリオキシエチレンが付加されていても良いソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンのアルキル乃至はアルケニルエーテル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、脂肪酸ジエタノールアミド及び水素添加されていても良いポリオキシエチレンヒマシ油から選択されるものであることを特徴とする、<1>又は<2>に記載の外用医薬組成物。
<4> 更に、アニオン性界面活性剤を含有することを特徴とする、<1>〜<3>何れかに記載の外用医薬組成物。
<5> 使用時に形成される泡は、ポンプ式フォーマーによるものであることを特徴とする、<1>〜<4>何れかに記載の外用医薬組成物。
In view of such a situation, the present inventors, in the pharmaceutical composition for external use characterized by being foamy at the time of use, the problems that occur in the relationship between the polar solvent and the surfactant, especially the foam-forming property and As a result of earnest research efforts in search of means for solving problems relating to persistence, feeling of use, skin irritation, etc., 1) a polar solvent and 2) a nonionic surfactant are contained, and they are foamy when used. The present invention has been completed by finding such characteristics in a pharmaceutical composition for external use that exhibits That is, the present invention relates to the following method for producing a pharmaceutical composition for external use.
<1> An external pharmaceutical composition containing 1) a polar solvent and 2) a nonionic surfactant, which is in the form of foam when used.
<2> The polar solvent is one or more selected from N-alkyl-2-pyrrolidone having an alkyl chain having 1 to 4 carbon atoms, carbonic acid diester, crotamiton, acylated product and etherified product of polyhydric alcohol. The external pharmaceutical composition according to <1>, which is
<3> The nonionic surfactant is a fatty acid monoglyceride to which polyoxyethylene may be added, a fatty acid ester of polyglycerin, a sorbitan fatty acid ester to which polyoxyethylene may be added, a polyoxyethylene fatty acid ester. , An alkyl or alkenyl ether of polyoxyethylene, a polyoxyethylene polyoxypropylene alkyl ether, a fatty acid diethanolamide, and a polyoxyethylene castor oil which may be hydrogenated, <1> or the external pharmaceutical composition described in <2>.
<4> The external pharmaceutical composition according to any one of <1> to <3>, which further contains an anionic surfactant.
<5> The external pharmaceutical composition according to any one of <1> to <4>, wherein the foam formed during use is due to a pump former.
本発明によれば、使用時に泡状を呈する外用医薬組成物、取り分け、ポンプ式フォーマー用の外用医薬組成物において、極性溶剤と、非イオン性界面活性剤との関係において生じる課題を解決する手段を提供することが出来る。 ADVANTAGE OF THE INVENTION According to this invention, in the external pharmaceutical composition which shows a foamy state at the time of use, especially, the external pharmaceutical composition for pump type | formula, the means which solves the problem which arises in the relationship between a polar solvent and a nonionic surfactant. Can be provided.
<1>本発明の外用医薬組成物の必須成分である極性溶剤
本発明の使用時に泡状を呈する外用医薬組成物は、1)極性溶剤と、2)非イオン性界面活性剤とを含有する外用医薬組成物であることを特徴とする。本発明の極性溶剤としては、使用時に泡状を呈する外用医薬組成物に含有することができる薬剤、取り分け、水難溶性の薬剤を可溶化するのに十分な量の極性溶媒であれば特段の限定なく適用することができ、具体的には、炭素数1〜4のアルキル鎖を有するN−アルキル−2−ピロリドン、炭酸ジエステル、クロタミトン、多価アルコールのアシル化物及びエーテル化物等が好適に例示でき、かかる極性溶剤から選択される1種又は2種以上の溶剤を選択し含有させることが好ましい。これらの極性溶剤は、後述する非イオン性界面活性剤と共に外用医薬組成物に含有することにより、水難溶解性の薬剤を可溶化するための極性溶剤を含有しながら、泡沫形成性及び持続性、使用感、皮膚刺激等に優れる外用医薬組成物を提供することができる。本発明の極性溶剤が、前記作用を発現するためには、極性溶剤が外用医薬組成物全量に対して、全量で0.1〜12質量%含有されることが好ましく、0.5〜10質量%含有されることがより好ましい。これは少なすぎると薬剤を十分に可溶化することが困難であり、多すぎると起泡性及び持続性、使用感が損なわれる場合が存するためである。本発明のN−アルキル−2−ピロリドンとしては、炭素数1〜4のアルキル基を有するN−アルキル−2−ピロリドンが好適に例示でき、特に、N−メチル−2−ピロリドン、N−エチル−2−ピロリドンが好適に例示できる。N−メチル−2−ピロリドンは、優れた特性を有する極性溶剤であり、ほとんどの有機溶剤、水と混合することができ、医薬添加物として使用されている実績がある。本発明の炭酸ジエステルとしては、環状構造を有する炭酸アルキレン、直鎖又は分岐の炭化水素基が2つ結合した炭酸ジアルキル等が好適に例示でき、特に、炭酸プロピレンが好ましい。本発明の極性溶剤であるクロタミトンは、優れた溶解性を有する極性溶剤であり、ステロイド、ビタミン類などの有効成分の分解を抑制し安定性を向上させることができる。本発明の多価アルコールのアシル化物としては、短鎖もしくは中鎖脂肪酸のトリグリセリド又は短鎖乃至は長鎖の脂肪酸と(ポリ)エチレングリコールのエステルが好適に例示でき、より好ましくは、トリアセチン、トリカプリリン、トリオクタン酸グリセリン及びトリ(カプリル・カプリン酸)グリセリン、(ポリ)エチレングリコールモノアセテート、ポリエチレングリコールモノラウレート及びポリエチレングリコールモノオレートが挙げられる。本発明の多価アルコールのエーテル化物としては、ポリエチレングリコールアルキルエーテル、ポリオキチエチレンアルキルエーテル及びポリオキシエチレン・ポリオキシプロピレンアルキルエーテルが好適に例示でき、さらに好ましいものとしては、ジエチレングリコールモノエチルエーテル、ジエチレングリコールモノベンジルエーテル、ジエチレングリコールジエチルエーテル、トリエチレングリコールジメチルエーテル、ポリオキシエチレンラウリルエーテル、ポリオキチエチレンセチルエーテルが挙げられる。
<1> Polar solvent which is an essential component of the pharmaceutical composition for external use of the present invention The pharmaceutical composition for external use which is foamy when used in the present invention contains 1) a polar solvent and 2) a nonionic surfactant. It is characterized by being a pharmaceutical composition for external use. The polar solvent of the present invention is not particularly limited as long as it is a drug that can be contained in a pharmaceutical composition for external use that is foamy at the time of use, in particular, a polar solvent in an amount sufficient to solubilize a poorly water-soluble drug. Suitable examples include N-alkyl-2-pyrrolidone having an alkyl chain having 1 to 4 carbon atoms, carbonic acid diester, crotamiton, acylated products and etherified products of polyhydric alcohols, and the like. It is preferable to select and contain one or more solvents selected from such polar solvents. These polar solvents, by containing the nonionic surfactant described below in the pharmaceutical composition for external use, while containing a polar solvent for solubilizing a poorly water-soluble drug, foam formation and sustainability, It is possible to provide a pharmaceutical composition for external use which is excellent in usability and skin irritation. In order for the polar solvent of the present invention to exhibit the above-mentioned action, the polar solvent is preferably contained in a total amount of 0.1 to 12 mass% with respect to the total amount of the pharmaceutical composition for external use, and 0.5 to 10 mass. % Is more preferable. This is because if the amount is too small, it is difficult to sufficiently solubilize the drug, and if the amount is too large, the foaming property, sustainability, and usability may be impaired. Suitable examples of the N-alkyl-2-pyrrolidone of the present invention include N-alkyl-2-pyrrolidone having an alkyl group having 1 to 4 carbon atoms, and particularly N-methyl-2-pyrrolidone and N-ethyl- 2-pyrrolidone can be preferably exemplified. N-methyl-2-pyrrolidone is a polar solvent having excellent properties, can be mixed with most organic solvents and water, and has a track record of being used as a pharmaceutical additive. Suitable examples of the carbonic acid diester of the present invention include alkylene carbonate having a cyclic structure, dialkyl carbonate having two linear or branched hydrocarbon groups bonded to each other, and propylene carbonate is particularly preferable. Crotamiton, which is the polar solvent of the present invention, is a polar solvent having excellent solubility and can suppress the decomposition of active ingredients such as steroids and vitamins and improve the stability. As the acylated product of the polyhydric alcohol of the present invention, triglycerides of short-chain or medium-chain fatty acids or esters of short-chain or long-chain fatty acids and (poly) ethylene glycol can be preferably exemplified, and more preferably triacetin and trica Examples thereof include prillin, glycerin trioctanoate and glycerin tri (caprylic / capric acid), (poly) ethylene glycol monoacetate, polyethylene glycol monolaurate and polyethylene glycol monooleate. As the etherified product of the polyhydric alcohol of the present invention, polyethylene glycol alkyl ether, polyoctyethylene alkyl ether and polyoxyethylene / polyoxypropylene alkyl ether can be preferably exemplified, and more preferable ones are diethylene glycol monoethyl ether and diethylene glycol. Examples include monobenzyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, polyoxyethylene lauryl ether, and polyoctyethylene cetyl ether.
<2>本発明の外用医薬組成物の必須成分である非イオン性界面活性剤
本発明の外用医薬組成物は、非イオン性界面活性剤を必須成分として含有することを特徴とする。本発明の非イオン性界面活性剤としては、ポリオキシエチレンが付加されていても良い脂肪酸モノグリセリド、ポリグリセリンの脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンが付加されていても良いソルビタン脂肪酸エステル、ポリオキシエチレンのアルキル乃至はアルケニルエーテル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、脂肪酸ジエタノールアミド及び水素添加されていても良いポリオキシエチレンヒマシ油等の非イオン界面活性から選択される1種又2種以上を選択し本発明の外用医薬組成物に含有させることが好ましい。ここで、ポリオキシエチレン又はポリオキシプロピレンの平均付加モル数は2〜90が好ましい。また、脂肪酸エステルを構成する脂肪酸の炭素数は平均で6〜24が好ましく、より好ましくは、6〜22である。アルキル基、アルケニル基の平均炭素数は10〜22が好ましい。脂肪酸ジエタノールアミドを構成する脂肪酸としては炭素数10〜18のものが好ましく、10〜14のものが特に好ましい。さらに、本発明における非イオン性界面活性剤の特に好ましい態様は、ポリオキシエチレン(平均付加モル数6〜10)脂肪酸(平均炭素数6〜14)グリセリル又は脂肪酸ジエタノールアミドと、ポリオキシエチレン(平均付加モル数2〜50)アルキル乃至はアルケニルエーテル及び/又はポリオキシエチレン(平均付加モル数30〜90)硬化ヒマシ油を含有する形態、ポリオキシエチレン(平均付加モル数2〜50)アルキル乃至はアルケニルエーテルに加え、ポリオキシエチレンが付加されていても良い脂肪酸モノグリセリド、ポリグリセリンの脂肪酸エステル、ポリオキシエチレン(平均付加モル数5〜70)脂肪酸エステル、ポリオキシエチレン(平均付加モル数10〜50)が付加されていても良いソルビタン脂肪酸(炭素数12〜18)エステル、ポリオキシエチレン(平均付加モル数2〜50)ポリオキシプロピレン(平均付加モル数2〜50)アルキルエーテル、水素添加されていても良いポリオキシエチレン(平均付加モル数30〜90)ヒマシ油から選択される1種又2種以上を選択し含有させる形態が好ましい。前記の好ましい形態において、ポリオキシエチレン脂肪酸グリセリル又は脂肪酸ジエタノールアミドと、ポリオキシエチレンアルキル乃至はアルケニルエーテル及び/又は水素添加されていても良いポリオキシエチレンの質量比は、1:4〜4:1が可溶化系を安定化させる意味で特に好ましい。さらに、前記の好ましい形態において、ポリオキシエチレン(平均付加モル数2〜50)アルキル乃至はアルケニルエーテルと、ポリオキシエチレンが付加されていても良い脂肪酸モノグリセリド、ポリグリセリンの脂肪酸エステル、ポリオキシエチレン(平均付加モル数5〜70)脂肪酸エステル、ポリオキシエチレン(平均付加モル数10〜50)が付加されていても良いソルビタン脂肪酸(炭素数12〜18)エステル、ポリオキシエチレン(平均付加モル数2〜50)ポリオキシプロピレン(平均付加モル数2〜50)アルキルエーテル、水素添加されていても良いポリオキシエチレン(平均付加モル数30〜90)ヒマシ油より選択される1種又は2種以上の非イオン性界面活性剤の質量比は、1:4〜4:1が可溶化系を安定化させる意味で好ましい。また、本発明の非イオン性界面活性剤は、1種類の非イオン界面活性剤を単独で使用することも出来るが、良質な泡質となりにくいため2種類以上の非イオン性界面活性剤を組み合わせて用いることが好ましい。尚、本発明の外用医薬組成物は、損傷されている可能性のある皮膚に投与され、洗浄行為を伴わない態様で使用される可能性も存することから、非イオン性界面活性剤のみを含有させることが好ましい。本発明の外用医薬組成物における、非イオン性界面活性剤の好ましい含有量は、医薬組成物全量に対して、0.5〜10質量%であり、より好ましくは1〜8質量%である。
<2> Nonionic surfactant which is an essential component of the external pharmaceutical composition of the present invention The external pharmaceutical composition of the present invention is characterized by containing a nonionic surfactant as an essential component. Examples of the nonionic surfactant of the present invention include fatty acid monoglyceride to which polyoxyethylene may be added, fatty acid ester of polyglycerin, polyoxyethylene fatty acid ester, and sorbitan fatty acid ester to which polyoxyethylene may be added. , 1 or 2 selected from nonionic surface active agents such as polyoxyethylene alkyl or alkenyl ether, polyoxyethylene polyoxypropylene alkyl ether, fatty acid diethanolamide and optionally hydrogenated polyoxyethylene castor oil. It is preferable to select one or more species to be contained in the external pharmaceutical composition of the present invention. Here, the average addition mole number of polyoxyethylene or polyoxypropylene is preferably 2 to 90. The average number of carbon atoms of the fatty acid constituting the fatty acid ester is preferably 6 to 24, more preferably 6 to 22. The alkyl group and the alkenyl group preferably have an average carbon number of 10 to 22. The fatty acid constituting the fatty acid diethanolamide preferably has 10 to 18 carbon atoms, and particularly preferably 10 to 14 carbon atoms. Furthermore, a particularly preferred embodiment of the nonionic surfactant in the present invention is polyoxyethylene (average addition mole number 6 to 10) fatty acid (average carbon number 6 to 14) glyceryl or fatty acid diethanolamide, and polyoxyethylene (average Addition mole number 2 to 50) Alkyl or alkenyl ether and / or polyoxyethylene (average addition mole number 30 to 90) Hardened castor oil-containing form, polyoxyethylene (average addition mole number 2 to 50) alkyl or In addition to alkenyl ether, fatty acid monoglyceride to which polyoxyethylene may be added, polyglycerin fatty acid ester, polyoxyethylene (average addition mole number: 5 to 70) fatty acid ester, polyoxyethylene (average addition mole number: 10 to 50) ) May be added to sorbitan fatty acid (carbon 12-18) ester, polyoxyethylene (average addition mole number 2-50) polyoxypropylene (average addition mole number 2-50) alkyl ether, optionally hydrogenated polyoxyethylene (average addition mole number 30- 90) A form in which one or more selected from castor oil is selected and contained is preferable. In the above preferred embodiment, the mass ratio of polyoxyethylene fatty acid glyceryl or fatty acid diethanolamide to polyoxyethylene alkyl or alkenyl ether and / or polyoxyethylene which may be hydrogenated is 1: 4 to 4: 1. Is particularly preferable in the sense of stabilizing the solubilization system. Furthermore, in the above preferred embodiment, polyoxyethylene (average addition mole number 2 to 50) alkyl or alkenyl ether, fatty acid monoglyceride to which polyoxyethylene may be added, fatty acid ester of polyglycerin, polyoxyethylene ( Fatty acid ester having an average addition mole number of 5 to 70), sorbitan fatty acid (having a carbon number of 12 to 18) ester to which polyoxyethylene (average addition mole number of 10 to 50) may be added, polyoxyethylene (average addition mole number of 2) To 50) polyoxypropylene (average addition mole number 2 to 50) alkyl ether, polyoxyethylene which may be hydrogenated (average addition mole number 30 to 90), one or more selected from castor oil. A mass ratio of nonionic surfactants of 1: 4 to 4: 1 stabilizes the solubilized system. Preferred in the sense that. Further, the nonionic surfactant of the present invention may be used alone as one type of nonionic surfactant, but since it is difficult to obtain a good foam quality, two or more types of nonionic surfactants are combined. It is preferable to use. The external pharmaceutical composition of the present invention contains only a nonionic surfactant because it may be used in a mode that does not involve a washing action when it is administered to skin that may be damaged. Preferably. The content of the nonionic surfactant in the external pharmaceutical composition of the present invention is preferably 0.5 to 10% by mass, more preferably 1 to 8% by mass, based on the total amount of the pharmaceutical composition.
さらに、本発明の外用医薬組成物においては、前記非イオン界面活性剤にアニオン性界面活性剤を加える形態も好ましい。アニオン性界面活性剤は、唯1種を選択し外用医薬組成物に含有することも出来るし、複数の界面活性剤を選択し含有させることも出来る。本発明の外用医薬組成物においては、非イオン性界面活性剤にアニオン性界面活性剤を加えることにより、有効成分と製剤成分との好ましい状態を作り出すことが出来る。一方、カチオン性界面活性剤及び両性界面活性剤は実質的に含有しないことが好ましい。 Furthermore, in the external pharmaceutical composition of the present invention, a form in which an anionic surfactant is added to the nonionic surfactant is also preferable. Only one anionic surfactant can be selected and contained in the external pharmaceutical composition, or a plurality of surfactants can be selected and contained. In the external pharmaceutical composition of the present invention, a preferable state of the active ingredient and the formulation ingredient can be created by adding an anionic surfactant to the nonionic surfactant. On the other hand, it is preferable that the cationic surfactant and the amphoteric surfactant are not substantially contained.
<3>本発明の外用医薬組成物のアニオン性界面活性剤
本発明の外用医薬組成物は、前記必須成分に加えアニオン性界面活性剤を含有することが好ましい。かかるアニオン性界面活性剤としては、例えば、ラウリン酸ナトリウム、パルミチン酸カリウム、ステアリン酸アルギニン等の炭素数12〜24の脂肪酸塩;ラウリル硫酸ナトリウム、ラウリル硫酸カリウム、セチル硫酸ナトリウム等のアルキル硫酸エステル塩;ポリオキシエチレンラウリル硫酸トリエタノールアミン等のアルキルエーテル硫酸エステル塩;ラウロイルサルコシンナトリウム等のN−アシルサルコシン塩;N−ステアロイル−N−メチルタウリンナトリウム、N−ミリストイル−N−メチルタウリンナトリウム等の脂肪酸アミドスルホン酸塩;モノステアリルリン酸ナトリウム等のアルキルリン酸塩;ポリオキシエチレンオレイルエーテルリン酸ナトリウム、ポリオキシエチレンステアリルエーテルリン酸ナトリウム、ポリオキシエチレンセチルエーテルリン酸ナトリウム等のポリオキシエチレンアルキルエーテルリン酸塩;ジ−2−エチルヘキシルスルホコハク酸ナトリウム等の長鎖スルホコハク酸塩;N−ラウロイルグルタミン酸モノナトリウム、N−ステアロイル−L−グルタミン酸ナトリウム、N−ステアロイル−L−グルタミン酸アルギニン、N−ステアロイルグルタミン酸ナトリウム、N−ミリストイル−L−グルタミン酸ナトリウム等の長鎖N−アシルグルタミン酸塩などが挙げられる。かかるアニオン性界面活性剤は、非イオン性界面活性剤と共に本発明の外用医薬組成物に含有させることにより、極性溶剤と界面活性剤との関係において生じる課題、中でも、泡の細かさ等の泡質、持続性、使用感等の課題を解決することができる。本発明の外用医薬組成物における、アニオン性界面活性剤の好ましい含有量は、医薬組成物全量に対して、0.001〜5質量%であり、より好ましくは0.01〜3質量%である。これは、アニオン界面活性剤の含有量が低すぎても、高すぎても、好ましい特性の泡質、使用感が得られず、特に高い場合には、皮膚刺激性等の作用が生じるためである。
<3> Anionic Surfactant of External Pharmaceutical Composition of the Present Invention The external pharmaceutical composition of the present invention preferably contains an anionic surfactant in addition to the above essential components. Examples of the anionic surfactant include fatty acid salts having 12 to 24 carbon atoms such as sodium laurate, potassium palmitate and arginine stearate; alkyl sulfate ester salts such as sodium lauryl sulfate, potassium lauryl sulfate and sodium cetyl sulfate. Alkyl ether sulfates such as polyoxyethylene lauryl sulfate triethanolamine; N-acyl sarcosine salts such as lauroyl sarcosine sodium; fatty acids such as N-stearoyl-N-methyl taurine sodium, N-myristoyl-N-methyl taurine sodium Amidosulfonates; alkyl phosphates such as sodium monostearyl phosphate; sodium polyoxyethylene oleyl ether phosphate, sodium polyoxyethylene stearyl ether phosphate, poly Polyoxyethylene alkyl ether phosphates such as sodium xyethylene cetyl ether phosphate; long-chain sulfosuccinates such as sodium di-2-ethylhexyl sulfosuccinate; monosodium N-lauroyl glutamate, sodium N-stearoyl-L-glutamate, Examples include long-chain N-acylglutamates such as arginine N-stearoyl-L-glutamate, sodium N-stearoylglutamate, and sodium N-myristoyl-L-glutamate. Such an anionic surfactant, by containing the nonionic surfactant in the pharmaceutical composition for external use of the present invention, the problems that occur in the relationship between the polar solvent and the surfactant, among them, foam such as fineness of foam. It is possible to solve problems such as quality, sustainability, and feeling of use. The preferable content of the anionic surfactant in the external pharmaceutical composition of the present invention is 0.001 to 5% by mass, more preferably 0.01 to 3% by mass, based on the total amount of the pharmaceutical composition. . This is because, if the content of the anionic surfactant is too low or too high, the foam properties and the feeling of use with favorable characteristics cannot be obtained, and particularly when it is high, the action such as skin irritation occurs. is there.
<4>本発明の外用医薬組成物に含有することが可能な薬剤
本発明の外用医薬組成物は、前記極性溶剤に可溶化することができる薬剤、取り分け、水難溶性の薬剤を含有することが出来る。かかる水難溶性の薬剤としては、前記極性溶剤に可溶化することが出来る薬剤であれば特段の限定なく適用することができ、ステロイド類、ビタミン類、ヘパリン類似物質等が好適に例示出来る。前記ステロイド類としては、例えば、ステロイド骨格を有するものであれば特段の限定はなく、性ホルモン、糖質コルチコイド(グルココルチコイド)、鉱質コルチコイド等が好適に例示でき、特に、糖質コルチコイドが好ましい。前記糖質コルチコイドとしては、例えば、コルチゾン、ハイドロコルチゾン、酢酸フルドロコルチゾン等のコルチゾン類、プレドニゾロン、メチルプレドニゾロン等のプレドニゾロン類、デキサメタゾン及びその誘導体、ベタメタゾン及びその誘導体、クロベタゾール及びその誘導体が好適に例示でき、その誘導体としては、リン酸エステル、吉草酸エステル、酪酸エステル、プロピロン酸エステルなどが好ましく例示できる。前記ビタミン類としては、ビタミンA又はその誘導体、ビタミンB又はその誘導体、油溶性ビタミンC又はその誘導体、ビタミンD又はその誘導体、ビタミンE又はその誘導体、ビタミンK又はその誘導体が好適に例示できる。ヘパリン類似物質としては、ムコ多糖を硫酸化して得られる物質を意味し、例えば、ヘパリン、コンドロイチン硫酸D、コンドロイチン硫酸Eのようなコンドロイチン硫酸が好適に例示できる。その他の薬剤としては、例えば、テルビナフィン、ブテナフィン等の抗真菌剤、スプロフェン、ケトチフェン、ケトプロフェン、インドメタシン等の抗炎症剤、アジスロマイシン等の抗生剤、タクロリムス、シクロホスファミド等の免疫抑制剤、ナルフラフィンなどの鎮痒剤等が好適に例示出来る。本発明の使用時に泡状を呈する外用医薬組成物は、前記の水難溶性の薬剤を極性溶剤に可溶化し、非イオン性界面活性剤とともに外用医薬組成物に含有させることにより優れた泡特性、使用感、皮膚安全性等を有する外用医薬組成物を提供することができる。
<4> Drug that can be contained in the external pharmaceutical composition of the present invention The external pharmaceutical composition of the present invention may contain a drug that can be solubilized in the polar solvent, in particular, a poorly water-soluble drug. I can. As the poorly water-soluble drug, any drug that can be solubilized in the polar solvent can be applied without particular limitation, and steroids, vitamins, heparin-like substances and the like can be preferably exemplified. The steroids are not particularly limited as long as they have a steroid skeleton, and sex hormones, glucocorticoids (glucocorticoids), mineralocorticoids and the like can be preferably exemplified, and glucocorticoids are particularly preferable. . Examples of the glucocorticoid include cortisone, hydrocortisone, cortisone such as fludrocortisone acetate, prednisolone, prednisolone such as methylprednisolone, dexamethasone and its derivative, betamethasone and its derivative, clobetasol and its derivative. Examples thereof include phosphoric acid ester, valeric acid ester, butyric acid ester, and propyroic acid ester. Suitable examples of the vitamins include vitamin A or its derivative, vitamin B or its derivative, oil-soluble vitamin C or its derivative, vitamin D or its derivative, vitamin E or its derivative, vitamin K or its derivative. The heparin-like substance means a substance obtained by sulfating a mucopolysaccharide, and preferred examples thereof include chondroitin sulfates such as heparin, chondroitin sulfate D, and chondroitin sulfate E. Other drugs include, for example, antifungal agents such as terbinafine and butenafine, anti-inflammatory agents such as suprofen, ketotifen, ketoprofen and indomethacin, antibiotic agents such as azithromycin, immunosuppressive agents such as tacrolimus and cyclophosphamide, and nalfurafine. The antipruritic agent and the like can be preferably exemplified. A topical pharmaceutical composition which exhibits a foamy state when used in the present invention has excellent foam properties by solubilizing the poorly water-soluble drug in a polar solvent and incorporating it into a topical pharmaceutical composition together with a nonionic surfactant, It is possible to provide a pharmaceutical composition for external use having a feeling of use, skin safety and the like.
<5>本発明の外用医薬組成物
本発明の外用医薬組成物は、1)極性溶剤と、2)非イオン性界面活性剤を必須成分として含有する、使用時に泡状を呈する外用医薬組成物である。本発明の外用医薬組成物においては、前記必須成分以外に、通常医薬組成物に用いられる製剤化のための任意の成分を含有することができる。このような成分としては、例えば、マカデミアナッツ油、アボガド油、トウモロコシ油、オリーブ油、ナタネ油、ゴマ油、ヒマシ油、サフラワー油、綿実油、ホホバ油、ヤシ油、パーム油、液状ラノリン、硬化ヤシ油、硬化油、モクロウ、硬化ヒマシ油、ミツロウ、キャンデリラロウ、カルナウバロウ、イボタロウ、ラノリン、還元ラノリン、硬質ラノリン、ホホバロウ等のオイル、ワックス類;流動パラフィン、スクワラン、プリスタン、オゾケライト、パラフィン、セレシン、ワセリン、マイクロクリスタリンワックス等の炭化水素類;オレイン酸、イソステアリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ベヘン酸、ウンデシレン酸等の高級脂肪酸類;セチルアルコール、ステアリルアルコール、イソステアリルアルコール、ベヘニルアルコール、オクチルドデカノール、ミリスチルアルコール、セトステアリルアルコール等の高級アルコール等;イソオクタン酸セチル、ミリスチン酸イソプロピル、イソステアリン酸ヘキシルデシル、ジ−2−エチルヘキサン酸エチレングリコール、ジカプリン酸ネオペンチルグリコール、ジ−2−ヘプチルウンデカン酸グリセリン、トリ−2−エチルヘキサン酸グリセリン、トリ−2−エチルヘキサン酸トリメチロールプロパン、トリイソステアリン酸トリメチロールプロパン、テトラ−2−エチルヘキサン酸ペンタンエリトリット等の合成エステル油類;ジメチルポリシロキサン、メチルフェニルポリシロキサン、ジフェニルポリシロキサン等の鎖状ポリシロキサン;オクタメチルシクロテトラシロキサン、デカメチルシクロペンタシロキサン、ドデカメチルシクロヘキサンシロキサン等の環状ポリシロキサン;アミノ変性ポリシロキサン、アルキル変性ポリシロキサン、フッ素変性ポリシロキサン等の変性ポリシロキサン等のシリコーン油等の油剤類;ポリエチレングリコール、グリセリン、1,3−ブチレングリコール、エリスリトール、ソルビトール、キシリトール、マルチトール、プロピレングリコール、ジプロピレングリコール、ジグリセリン、イソプレングリコール、1,2−ペンタンジオール、2,4−ヘキサンジオール、1,2−ヘキサンジオール、1,2−オクタンジオール等の多価アルコール類;乳酸、乳酸ナトリウム等の保湿成分類;表面を処理されていても良い、マイカ、タルク、カオリン、合成雲母、炭酸カルシウム、炭酸マグネシウム、無水ケイ酸(シリカ)、酸化アルミニウム、硫酸バリウム等の粉体類、;表面を処理されていても良い、ベンガラ、黄酸化鉄、黒酸化鉄、酸化コバルト、群青、紺青、酸化チタン、酸化亜鉛の無機顔料類;表面を処理されていても良い、雲母チタン、魚燐箔、オキシ塩化ビスマス等のパール剤類;レーキ化されていても良い赤色202号、赤色228号、赤色226号、黄色4号、青色404号、黄色5号、赤色505号、赤色230号、赤色223号、橙色201号、赤色213号、黄色204号、黄色203号、青色1号、緑色201号、紫色201号、赤色204号等の有機色素類;ポリエチレン末、ポリメタクリル酸メチル、ナイロン粉末、オルガノポリシロキサンエラストマー等の有機粉体類;パラアミノ安息香酸系紫外線吸収剤;アントラニル酸系紫外線吸収剤;サリチル酸系紫外線吸収剤、;桂皮酸系紫外線吸収剤、;ベンゾフェノン系紫外線吸収剤;糖系紫外線吸収剤;2−(2’−ヒドロキシ−5’−t−オクチルフェニル)ベンゾトリアゾール、4−メトキシ−4’−t−ブチルジベンゾイルメタン等の紫外線吸収剤類;エタノール、イソプロパノール等の低級アルコール類;フェノキシエタノール等の抗菌剤などが好ましく例示できる。さらに、前記極性溶剤以外の溶剤としては多価アルコールが好ましく例示でき、多価アルコールは、単独で使用することも出来るし、複数の多価アルコールを組み合わせ医薬組成物に含有させることも出来る。前記多価アルコールとしては1,3−ブチレングリコール、プロピレングリコール、1,2−ペンタンジオールなどが好適に例示でき、特に、1,3−ブチレングリコールが好ましい。多価アルコールの含有量は5〜40質量%、より好ましくは、8〜35質量%が好ましい。これらを用いて、常法に従って、可溶化形態の医薬組成物に加工し、使用時に泡状を呈する外用医薬組成物、取り分け、ポンプ式フォーマーに充填することによりノンエアゾール剤形の外用医薬に加工することができる。また、本発明の使用時に泡状を呈する外用医薬組成物は、使用時に泡状を呈する医薬外用剤であれば特段の限定なく適用することができ、例えば、ガス充填タイプのフォーマ容器に充填する外用医薬組成物、ノンガスタイプのフォーマー容器に充填する外用医薬組成物が好適に例示でき、特に、ノンガスタイプのフォーマー容器に充填するタイプの外用医薬組成物が好ましい。これは、ノンガスタイプのポンプフォーマー容器に充填するタイプの外用剤が、使用時における泡質、均一性に優れるためである。
<5> External pharmaceutical composition of the present invention The external pharmaceutical composition of the present invention contains 1) a polar solvent and 2) a nonionic surfactant as essential components, and exhibits a foamy external pharmaceutical composition when used. Is. The topical pharmaceutical composition of the present invention may contain, in addition to the above-mentioned essential components, any components for formulation which are usually used in pharmaceutical compositions. Such components include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid lanolin, hardened palm oil, Oils, waxes such as hydrogenated oil, mokuro, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, carrot wax, lanolin, reduced lanolin, hard lanolin, jojoba wax; liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, vaseline, Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as rucol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; etc .; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, di Synthetic ester oils such as glycerin-2-heptylundecanoate, glyceryl tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate and pentane erythritol tetra-2-ethylhexanoate Chains; chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane; octamethylcyclotetrasiloxane, deca Cyclic polysiloxanes such as tylcyclopentasiloxane and dodecamethylcyclohexanesiloxane; Oil agents such as silicone oil such as amino-modified polysiloxane, alkyl-modified polysiloxane, modified polysiloxane such as fluorine-modified polysiloxane; polyethylene glycol, glycerin, 1, 3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1, Polyhydric alcohols such as 2-octanediol; Moisturizing ingredients such as lactic acid and sodium lactate; Mica, talc, kaolin, synthetic mica, calcium carbonate, macamate which may be surface-treated Powders of gnesium, silicic acid anhydride (silica), aluminum oxide, barium sulfate, etc .; surface-treated, red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine blue, dark blue, titanium oxide, Inorganic pigments of zinc oxide; Mica titanium, fish phosphorus foil, bismuth oxychloride, and other pearl agents, which may be surface-treated; Red 202, Red 228, Red 226, which may be laked , Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc .; Organic powders such as polyethylene powder, polymethylmethacrylate, nylon powder, organopolysiloxane elastomer, etc .; para-aminobenzoic acid type External line absorber; Anthranilic acid type UV absorber; Salicylic acid type UV absorber ;; Cinnamic acid type UV absorber ;; Benzophenone type UV absorber; Sugar type UV absorber; 2- (2'-hydroxy-5'-t Preferred examples include ultraviolet absorbers such as -octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; antibacterial agents such as phenoxyethanol. Furthermore, a polyhydric alcohol can be preferably exemplified as a solvent other than the polar solvent, and the polyhydric alcohol can be used alone or in combination with a plurality of polyhydric alcohols in a pharmaceutical composition. Preferable examples of the polyhydric alcohol include 1,3-butylene glycol, propylene glycol, and 1,2-pentanediol, and 1,3-butylene glycol is particularly preferable. The content of the polyhydric alcohol is 5 to 40% by mass, more preferably 8 to 35% by mass. By using these, according to a conventional method, a solubilized pharmaceutical composition is processed, and a pharmaceutical composition for external use that exhibits a foamy state at the time of use, in particular, is processed into a non-aerosol pharmaceutical external preparation by filling a pump type former. can do. In addition, the external pharmaceutical composition exhibiting a foam-like state during use of the present invention can be applied without particular limitation as long as it is a pharmaceutical external preparation exhibiting a foam-like state during use. For example, it is filled in a gas-filled type former container. The external pharmaceutical composition and the external pharmaceutical composition to be filled in the non-gas type former container can be preferably exemplified, and the external pharmaceutical composition of the type to be filled in the non-gas type former container is particularly preferable. This is because the external preparation of the type filled in the non-gas type pump former container has excellent foam quality and uniformity during use.
かくして得られた外用医薬組成物は、泡の細かさ、持続性等の泡質、感触のよさ等の使用感に優れ、使用時に泡の形状で使用できるため、スムースに刺激を感じさせることなく患部に延展でき、患部に均一に有効成分を分布させることができる。このような態様により、薬剤を含有させた場合、薬剤の薬理作用をいかんなく発揮させることができる。また、本発明の泡質、使用感の評価は、前記特性を評価できるであれば特段の限定なく適用することができ、後述する感応試験に限定されるものではない。
以下、実施例を挙げて本発明についてさらに詳細に説明を加える。
The external pharmaceutical composition thus obtained is excellent in feeling of use such as fineness of foam, foam quality such as sustainability and good feel, and can be used in the form of foam at the time of use, without causing irritation smoothly. It can be spread over the affected area and the active ingredient can be evenly distributed over the affected area. According to such an aspect, when the drug is contained, the pharmacological action of the drug can be exerted at all. Further, the evaluation of the foam quality and the feeling of use of the present invention can be applied without particular limitation as long as the above characteristics can be evaluated, and is not limited to the sensitivity test described below.
Hereinafter, the present invention will be described in more detail with reference to examples.
以下の表1に示す処方に従って、本発明の外用医薬組成物1を作成した。即ち、処方成分を80℃で加熱攪拌し、可溶化し、攪拌下室温まで冷却し、本発明の外用医薬組成物1を得た。前記外用医薬組成物1をポンプ式フォーマーに充填し、本発明の外用医薬1を得た。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。 According to the formulation shown in Table 1 below, the external pharmaceutical composition 1 of the present invention was prepared. That is, the prescription ingredients were heated and stirred at 80 ° C., solubilized, and cooled to room temperature with stirring to obtain the external pharmaceutical composition 1 of the present invention. The external pharmaceutical composition 1 was filled in a pump former to obtain the external pharmaceutical 1 of the present invention. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.
<比較例1>
表1に示す処方成分のうち、極性溶剤であるN−メチル−2−ピロリドン及びアジピン酸ジイソプロピルを除いた処方の製剤(比較例1の外用医薬組成物)を作成した。比較例1の外用医薬組成物をポンプ式フォーマーに充填し、比較例1の外用医薬を得た。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。
<Comparative Example 1>
Among the formulation ingredients shown in Table 1, a formulation (external pharmaceutical composition of Comparative Example 1) having a formulation excluding N-methyl-2-pyrrolidone and diisopropyl adipate, which are polar solvents, was prepared. The external preparation pharmaceutical composition of Comparative Example 1 was filled in a pump former to obtain the external preparation pharmaceutical composition of Comparative Example 1. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.
<比較例2>
以下に示す処方に従って、比較例2の外用医薬組成物を作成した。即ち、イの部分を80℃で加熱可溶化し、予め80℃に温度調節しておいたロの成分に攪拌下、混合し分散させた。しかる後に攪拌下室温まで冷却して比較例2の外用医薬組成物を得た。比較例2の外用医薬組成物をポンプ式フォーマーに充填し、比較例2の外用医薬を得た。比較例2の外用医薬は、本発明の外用医薬とは構成の異なる泡状を呈する外用医薬であった。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。
<Comparative example 2>
The external pharmaceutical composition of Comparative Example 2 was prepared according to the following formulation. That is, the portion (1) was heated and solubilized at 80 ° C., and the components (2) whose temperature had been adjusted to 80 ° C. were mixed and dispersed under stirring. Then, the mixture was cooled to room temperature with stirring to obtain a pharmaceutical composition for external use of Comparative Example 2. The external preparation pharmaceutical composition of Comparative Example 2 was filled in a pump former to obtain the external preparation pharmaceutical composition of Comparative Example 2. The external medicine of Comparative Example 2 was an external medicine having a foamy form different from that of the external medicine of the present invention. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.
<比較試験1>
実施例1の外用医薬1、比較例1及び比較例2の外用医薬の泡の質(起泡性、持続性)、使用感(べたつき、しっとり感)を以下の方法に従い評価した。
(1)泡の質(起泡性、持続性):10名の被験者により25℃に保たれた室内で各試料を吐出させ手にとり、泡の質(起泡性、持続性)の観察を行った。尚、評価基準は以下の通りである。
◎非常に良好(良いと回答した被験者が8名以上)
○良好(良いと回答した被験者が6名以上8名未満)
△やや悪い(良いと回答した被験者が4名以上6名未満)
×悪い(良いと回答した被験者が4名未満)
(2)使用感(べたつき感、しっとり感):10名の被験者により25℃に保たれた室内で各試料を吐出させ手にとり、使用感(べたつき、しっとり感)の評価を行った。尚、評価基準は以下の通りである。
◎非常に良好(良いと回答した被験者が8名以上)
○良好(良いと回答した被験者が6名以上8名未満)
△やや悪い(良いと回答した被験者が4名以上6名未満)
×悪い(良いと回答した被験者が4名未満)
<Comparative test 1>
The foam quality (foaming property, sustainability) and the feeling of use (stickiness, moist feeling) of the external medicine 1 of Example 1 and the external medicines of Comparative Examples 1 and 2 were evaluated according to the following methods.
(1) Foam quality (foaming property, persistence): Each of 10 subjects discharged each sample in a room kept at 25 ° C. and picked up to observe the foam quality (foaming property, persistence). went. The evaluation criteria are as follows.
◎ Very good (more than 8 subjects answered good)
○ Good (6 or more and less than 8 subjects answered good)
△ Somewhat bad (4 or more and less than 6 subjects answered good)
× Poor (less than 4 subjects answered good)
(2) Feeling of use (feeling of stickiness, feeling of moistness): Ten test subjects discharged each sample in a room kept at 25 ° C. and picked up by hand to evaluate feeling of use (feeling of stickiness, feeling of moistness). The evaluation criteria are as follows.
◎ Very good (more than 8 subjects answered good)
○ Good (6 or more and less than 8 subjects answered good)
△ Somewhat bad (4 or more and less than 6 subjects answered good)
× Poor (less than 4 subjects answered good)
実施例1の外用医薬1、比較例1及び比較例2の外用医薬について、泡質及び使用感を評価したところ、本発明の外用医薬1は、泡質及び使用感に優れる外用医薬であることが分かった。一方、本発明の外用医薬1から極性溶剤を除いた場合には、泡質及び使用感が顕著に低下することが分かった。 When the foam quality and the feeling of use of the external medicine 1 of Example 1 and the external medicines of Comparative Examples 1 and 2 were evaluated, the external medicine 1 of the present invention was a topical medicine excellent in foam quality and feeling of use. I understood. On the other hand, it was found that when the polar solvent was removed from the external medicine 1 of the present invention, the foam quality and the feeling of use were significantly reduced.
実施例1と同様に、以下の表4に示す処方に従って本発明の外用医薬組成物2〜19を作成した。このものをポンプ式フォーマーに充填し、本発明の外用医薬2〜19を得た。さらに、実施例2に示す試験方法に従い、外用医薬2〜19の泡の質(起泡性、持続性)、使用感(しっとり感)を評価した。本発明の外用医薬2〜19は、泡質及び使用感に優れる外用医薬組成物であることが分かった。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。 Similar to Example 1, the external pharmaceutical compositions 2 to 19 of the present invention were prepared according to the formulations shown in Table 4 below. This was filled in a pump former to obtain external medicines 2 to 19 of the present invention. Furthermore, according to the test method shown in Example 2, the quality of foam (foaming property, sustainability) and the feeling of use (moist feeling) of the external medicines 2 to 19 were evaluated. It was found that the external medicines 2 to 19 of the present invention are external medicine compositions excellent in foam quality and feeling in use. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.
実施例1と同様に、以下の表5に示す処方に従って本発明の外用医薬組成物20〜22を作成した。このものをポンプ式フォーマーに充填し、本発明の外用医薬20〜22を得た。さらに、実施例2に示す試験方法に従い、外用医薬20〜22の泡の質(起泡性、持続性)、使用感(しっとり感、べたつき感)を評価した。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。本発明の外用医薬20〜22は、泡質及び使用感に優れる外用医薬組成物であることが分かった。 Similar to Example 1, the external pharmaceutical compositions 20 to 22 of the present invention were prepared according to the formulations shown in Table 5 below. This was filled in a pump former to obtain external medicines 20 to 22 of the present invention. Further, according to the test method shown in Example 2, the foam quality (foaming property, sustainability) and the feeling of use (moisturizing feeling, sticky feeling) of the external medicines 20 to 22 were evaluated. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition. It was found that the external medicines 20 to 22 of the present invention are external medicine compositions excellent in foam quality and feeling in use.
以下の表6に示す処方に従って本発明の外用医薬組成物23及び24、比較例4の外用医薬組成物を作成した。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。外用医薬組成物の調整直後の状態を目視にて観察した(白濁なし:○、白濁あり:×)。さらに、外用医薬組成物23及び24、比較例4の外用医薬組成物 100(g)をビーカに入れ、3000rpmで1分間撹拌した後、2分間静置し泡と溶液の境界線が明瞭になったところで生成した泡の高さ(mm)を測定し、泡質(撹拌後に肌理の細かい泡が得られる(○)、撹拌後に粗い泡が得られる(△)、撹拌後に泡が得られない(×))を目視にて確認した。結果を表6に示した。本発明の外用医薬組成物は、優れた泡形成能を示した。一方、比較例3の外用医薬組成物は、本発明の外用医薬組成物に比較し、泡立ち、泡質が悪かった。 External pharmaceutical compositions 23 and 24 of the present invention and external pharmaceutical compositions of Comparative Example 4 were prepared according to the formulations shown in Table 6 below. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition. The state immediately after preparation of the pharmaceutical composition for external use was visually observed (no turbidity: ◯, with turbidity: x). Furthermore, the external pharmaceutical compositions 23 and 24 and the external pharmaceutical composition 100 (g) of Comparative Example 4 were put into a beaker, stirred at 3000 rpm for 1 minute, and allowed to stand for 2 minutes, whereby the boundary line between the foam and the solution became clear. The height (mm) of the generated foam was measured, and the foam quality (foam with fine texture was obtained after stirring (○), coarse foam was obtained after stirring (Δ), and no foam was obtained after stirring ( X)) was visually confirmed. The results are shown in Table 6. The external pharmaceutical composition of the present invention showed excellent foam-forming ability. On the other hand, the external use pharmaceutical composition of Comparative Example 3 had poor foaming and foam quality as compared with the external use pharmaceutical composition of the present invention.
以下の表7に示す処方に従って本発明の外用医薬組成物25及び26を作成した。尚、表中の製剤成分の含有量は、組成物全量に対する質量%にて表示した。外用医薬組成物の調整直後の状態を目視にて観察した(白濁なし:○、白濁あり:×)。さらに、外用医薬組成物25及び26 100(g)をビーカに入れ、3000rpmで1分間撹拌した後、2分間静置し泡と溶液の境界線が明瞭になったところで生成した泡の高さ(mm)を測定し、泡質(撹拌後に肌理の細かい泡が得られる(○)、撹拌後に粗い泡が得られる(△)、撹拌後に泡が得られない(×))を目視にて確認した。結果を表7に示した。本発明の外用医薬組成物は、優れた泡形成能を示した。 Topical pharmaceutical compositions 25 and 26 of the present invention were prepared according to the formulations shown in Table 7 below. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition. The state immediately after preparation of the pharmaceutical composition for external use was visually observed (no turbidity: ◯, with turbidity: x). Further, 100 (g) of the external pharmaceutical compositions 25 and 26 were placed in a beaker, stirred at 3000 rpm for 1 minute, and allowed to stand for 2 minutes, and the height of the foam generated when the boundary line between the foam and the solution became clear ( mm) was measured to visually confirm the foam quality (fine bubbles were obtained after stirring (○), coarse bubbles were obtained after stirring (Δ), and no bubbles were obtained after stirring (×)). . The results are shown in Table 7. The external pharmaceutical composition of the present invention showed excellent foam-forming ability.
以下の表に示す処方に従って本発明の外用医薬組成物27及び28、比較例4の外用医薬組成物を作成する。実施例6に記載の方法に従い、本発明の外用医薬組成物27及び28、比較例4の外用医薬組成物の泡立ち、泡質を検討する。本発明の外用医薬組成物は、比較例4の外用医薬組成物に比較し、組成物の安定性、泡立ち、持続性、泡の肌理細かさなどの泡質、使用感に優れる。 The external pharmaceutical compositions 27 and 28 of the present invention and the external pharmaceutical composition of Comparative Example 4 are prepared according to the formulations shown in the following table. According to the method described in Example 6, foaming and foam quality of the external pharmaceutical compositions 27 and 28 of the present invention and the external pharmaceutical composition of Comparative Example 4 are examined. The topical pharmaceutical composition of the present invention is superior to the topical pharmaceutical composition of Comparative Example 4 in stability, foaming, sustainability, foam quality such as texture of foam, and feeling of use.
本発明は医薬に応用できる。
The present invention can be applied to medicine.
Claims (1)
1)〜3)を含む混合物を加熱攪拌して前記混合物を可溶化する加熱攪拌工程と、
加熱攪拌工程を経た前記混合物を攪拌下室温まで冷却する冷却工程と、
冷却工程を経た前記混合物をノンガスタイプのフォーマー容器に充填する充填工程と、を備え、
前記極性溶剤が、炭素数1〜4のアルキル鎖を有するN−アルキルピロリドン、炭酸ジエステルより選択される1種又は2種以上であり、
前記非イオン性界面活性剤が、ポリオキシエチレンが付加されていても良い脂肪酸モノグリセリド、ポリグリセリンの脂肪酸エステル、ポリオキシエチレンが付加されていても良いソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンのアルキル乃至はアルケニルエーテル、ポリオキシエチレンポリオキシプロピレンアルキルエーテル、脂肪酸ジエタノールアミド及び水素添加されていても良いポリオキシエチレンヒマシ油より選択される1種又は2種以上であり、
前記多価アルコールが、1,3−ブチレングリコール、プロピレングリコール及び1,2−ペンタンジオールより選ばれる1種又は2種以上であり、
界面活性剤として、前記非イオン性界面活性剤のみを含むことを特徴とする、外用医薬の製造方法。 A method for producing an external medicine, comprising 1) a polar solvent, 2) a nonionic surfactant, and 3) a polyhydric alcohol, which is foamy when used and which is used in a mode without cleaning action. hand,
A heating and stirring step of heating and stirring a mixture containing 1) to 3) to solubilize the mixture ;
A cooling step of cooling the mixture that has undergone the heating and stirring step to room temperature with stirring;
A filling step of filling the mixture having undergone the cooling step into a non-gas type former container,
The polar solvent is one or more selected from N-alkylpyrrolidone having an alkyl chain having 1 to 4 carbon atoms and carbonic acid diester,
The nonionic surfactant is a fatty acid monoglyceride to which polyoxyethylene may be added, a fatty acid ester of polyglycerin, a sorbitan fatty acid ester to which polyoxyethylene may be added, a polyoxyethylene fatty acid ester, polyoxy One or more selected from the alkyl or alkenyl ethers of ethylene, polyoxyethylene polyoxypropylene alkyl ether, fatty acid diethanolamide, and optionally hydrogenated polyoxyethylene castor oil,
The polyhydric alcohol is one or more selected from 1,3-butylene glycol, propylene glycol and 1,2-pentanediol,
A method for producing a pharmaceutical for external use, which comprises, as a surfactant, only the nonionic surfactant.
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