JP5531230B2 - Oily external preparation and method for producing the same - Google Patents
Oily external preparation and method for producing the same Download PDFInfo
- Publication number
- JP5531230B2 JP5531230B2 JP2009168306A JP2009168306A JP5531230B2 JP 5531230 B2 JP5531230 B2 JP 5531230B2 JP 2009168306 A JP2009168306 A JP 2009168306A JP 2009168306 A JP2009168306 A JP 2009168306A JP 5531230 B2 JP5531230 B2 JP 5531230B2
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- JP
- Japan
- Prior art keywords
- oil
- acid ester
- external preparation
- surfactant
- oily
- 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
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Medicines Containing Plant Substances (AREA)
Description
本発明は、新規な油性外用製剤及びその製造方法に関する。 The present invention relates to a novel oily external preparation and a method for producing the same.
一般に、外来物質の体内侵入を阻止するバリアとして働く皮膚角質層を透過できる物質は、分子量５００Ｄａ以下の分子とされている。これにはさらに物質の溶解性が影響し、皮膚層を形成する脂質に対して親和性の低い水溶性物質は、より皮膚透過が困難とされている。これらの皮膚非親和性物質を皮膚及び皮下へ浸透させるために、例えば１）物理的処理による角質層の除去、エレクトロポレーション等の電気的な皮膚層の一時的な破壊、２）マイクロニードル等による痛みをできるだけ抑えた皮下注入等が開発されているが、いずれも技術的な課題を残しており、実用化に至っていない。注射投与に対して、これらの方法は非侵襲的とされ、ＱＯＬ向上のためにさらなる技術開発が期待されているが、それぞれの治療個別のデバイス開発が必要となる。これに対し、従来の塗布型外用薬により、皮膚親和性の低い薬物を効果的に皮膚に作用させる基材の開発も進められている。 In general, a substance that can permeate the skin stratum corneum serving as a barrier that prevents foreign substances from entering the body is a molecule having a molecular weight of 500 Da or less. This further affects the solubility of the substance, and it is considered that a water-soluble substance having a low affinity for the lipid forming the skin layer is more difficult to permeate the skin. In order to permeate these skin non-affinity substances into the skin and subcutaneous, for example, 1) removal of the stratum corneum by physical treatment, temporary destruction of the electrical skin layer such as electroporation, 2) microneedle, etc. Subcutaneous injection has been developed to minimize the pain caused by the above, but none of them have been put into practical use because they still have technical problems. Although these methods are non-invasive for injection administration and further technological development is expected to improve QOL, it is necessary to develop individual devices for each treatment. On the other hand, development of a base material that allows a drug having low skin affinity to effectively act on the skin by a conventional application-type external medicine has been promoted.
外用薬（外用製剤）においては、その経皮吸収性等の見地より、より大きな分子量をもつ活性成分であっても小さな粒子（特にナノ粒子）として調製することが望ましいと言えるが、この場合にその粒度分布及び経時安定性が問題となる。すなわち、粒径を小さくしようとする場合には、その粒度分布をシャープにする必要があると同時に、経時的に粒径が大きくならないような技術が必要である。 In the case of an external medicine (external preparation), it can be said that it is desirable to prepare an active ingredient having a larger molecular weight as a small particle (especially a nanoparticle) from the viewpoint of its transdermal absorbability. Its particle size distribution and stability over time are problematic. That is, in order to reduce the particle size, it is necessary to sharpen the particle size distribution, and at the same time, a technique that does not increase the particle size over time is required.
例えば、特許文献１には「薬剤含有複合体が油相に溶解または分散しているものを含み、且つ当該複合体は、親水性薬剤が界面活性剤により被覆されている固体状のものであることを特徴とする経皮吸収性に優れたＳ／Ｏ型外用剤」が開示されている。しかし、上記外用剤では、親水性薬剤の分子量としては１００００以下を指定しており、より好ましい分子量として５０００以下、さらに好ましい分子量として１０００以下としているものの、完成した固体分散粒子の粒子径はもとより、その粒度分布、経時安定性等についても一切触れられていない。 For example, Patent Document 1 includes a “solid containing a drug-containing complex dissolved or dispersed in an oil phase, and the complex is a solid in which a hydrophilic drug is coated with a surfactant. An S / O-type external preparation excellent in transdermal absorbability characterized by the above is disclosed. However, in the above-mentioned external preparation, the molecular weight of the hydrophilic drug is specified to be 10000 or less, more preferably 5000 or less, and even more preferably 1000 or less, but not only the particle diameter of the completed solid dispersion particles, No mention is made of its particle size distribution, stability over time, etc.
また例えば、特許文献２には、Ｗ／Ｏエマルションを脱水することにより、平均粒子径が２０ｎｍ〜１０μｍの粒子として水溶性固体物質が油相中に分散したＳ／Ｏサスペンションを製造する方法が開示されている。Ｓ／Ｏに封入する水溶性固体物質として抗癌剤、タンパク質製剤、酵素薬剤、ＤＮＡ等いずれの水溶性薬剤であっても良く、用途に応じた水溶性の固体物質とを適宜選択することができるものの、分子量の大きな活性成分をナノ粒子としてより効果的に分散させるための具体的な方法については言及されていない。また、特許文献２には、上記サスペンションを外用製剤として用いることには触れられていない。 For example, Patent Document 2 discloses a method for producing an S / O suspension in which a water-soluble solid substance is dispersed in an oil phase as particles having an average particle diameter of 20 nm to 10 μm by dehydrating a W / O emulsion. Has been. The water-soluble solid substance to be encapsulated in S / O may be any water-soluble drug such as an anticancer drug, a protein preparation, an enzyme drug, or DNA, and a water-soluble solid substance can be appropriately selected depending on the application. There is no mention of a specific method for more effectively dispersing active ingredients having a large molecular weight as nanoparticles. Patent Document 2 does not mention the use of the suspension as an external preparation.
一方、特許文献３には外用医薬品や化粧品の基材として利用されてきたリオトロピック液晶を有効成分とする経皮吸収促進剤について開示されている。この発明によれば、リオトロピック液晶は、界面活性剤と水の他に油を含んでも良く、油分を含むことで液晶構造は角質層の細胞間脂質が形成するラメラ構造に近似したものとなり、皮膚表面に塗布した際に相転移を起こしやすくする。すなわち、皮膚角質層のバリア機能を一時的に開放状態にし、高分子物質や水溶性物質の経皮吸収性を向上できることが開示されている。しかし、バリア機能が開放状態になることで、真皮層からの水分放出あるいは外環境からの異物混入の危険性をはらんでいる。 On the other hand, Patent Document 3 discloses a transdermal absorption enhancer containing lyotropic liquid crystal as an active ingredient, which has been used as a base material for external medicines and cosmetics. According to the present invention, the lyotropic liquid crystal may contain oil in addition to the surfactant and water, and by containing the oil, the liquid crystal structure is similar to the lamellar structure formed by intercellular lipids in the stratum corneum. Facilitates phase transition when applied to the surface. That is, it is disclosed that the barrier function of the skin stratum corneum can be temporarily opened to improve the transdermal absorbability of a polymer substance or a water-soluble substance. However, when the barrier function is in an open state, there is a risk of moisture release from the dermis layer or contamination by foreign substances from the outside environment.
外用薬（外用製剤）においては、その経皮吸収性等の見地より、より大きな分子量をもつ活性成分であっても小さな粒子（特にナノ粒子）として調製することが望ましいと言えるが、この場合にその粒度分布及び経時安定性が問題となる。すなわち、粒径を小さくしようとする場合、その実効性を発揮させるためには粒度分布をシャープ（単分散性）にする必要がある。また、そのように粒径を小さく制御しても合一化等により経時的に粒径が大きくなれば用時に支障を来すおそれがあるため、その経時安定性を付与することも必要となる。 In the case of an external medicine (external preparation), it can be said that it is desirable to prepare an active ingredient having a larger molecular weight as a small particle (especially a nanoparticle) from the viewpoint of its transdermal absorbability. Its particle size distribution and stability over time are problematic. That is, when trying to reduce the particle size, it is necessary to make the particle size distribution sharp (monodispersity) in order to exhibit its effectiveness. In addition, even if the particle size is controlled to be small in this way, if the particle size increases over time due to unification or the like, there is a risk of hindering use, and it is also necessary to provide stability over time. .
しかしながら、前記の通り、従来技術では、未だ単分散性と安定性とを兼ね備えた油性製剤の開発には至っていないことから、そのような技術の開発が切望されているのが実情である。 However, as described above, in the prior art, since the development of an oil-based preparation having both monodispersity and stability has not yet been achieved, the development of such a technique is eagerly desired.
また、非特許文献１には、低分子物質は経皮膚・経付属器官（汗腺、毛包等）経路の両方を透過可能であるが５００Ｄａ以上の物質では角質実質経路を通りにくくなることが記載されている。よって５００Ｄａ以上の有効成分を角質実質を透過させる技術の開発が望まれている。 Non-Patent Document 1 describes that low-molecular substances can penetrate both the transcutaneous and trans-adjunct organ (sweat glands, hair follicles, etc.) pathways, but substances of 500 Da or more are difficult to pass through the stratum corneum pathway. Has been. Therefore, development of a technique for allowing an active ingredient of 500 Da or more to pass through the stratum corneum is desired.
従って、本発明の主な目的は、特に、単分散性及び安定性に加え、皮膚（表皮、真皮又は皮下組織）に対する浸透性に優れた油性外用製剤を提供することにある。さらなる本発明の目的は、生薬成分を活性成分とする油性外用製剤を提供することにもある。 Therefore, the main object of the present invention is to provide an oily external preparation excellent in permeability to the skin (epidermis, dermis or subcutaneous tissue), in addition to monodispersibility and stability. A further object of the present invention is to provide an oily external preparation containing a crude drug component as an active ingredient.
本発明者は、従来技術の問題点に鑑みて鋭意研究を重ねた結果、特定の方法により油性の外用製剤を調製することによって上記目的を達成できることを見出し、本発明を完成するに至った。 As a result of intensive studies in view of the problems of the prior art, the present inventors have found that the above object can be achieved by preparing an oily external preparation by a specific method, and have completed the present invention.
すなわち、本発明は、下記の油性外用製剤及びその製造方法に係る。
１． 活性成分、界面活性剤及び油剤を含み、当該活性成分を含む活性粒子が界面活性剤及び油剤を含む油相中に単分散されている油性外用製剤であって、
（１）活性成分が生薬の水抽出成分及び／又は分子量１０００以上の親水性高分子であり、
（２）活性粒子の平均粒子径が２００ｎｍ以下であり、
（３）水分含有量が０．５重量％以下である、
（４）界面活性剤が、テトラグリセリン縮合リシノレイン酸エステル、ヘキサグリセリン縮合リシノレイン酸エステル、デカグリセリン縮合リシノレイン酸エステル及びポリグリセリン縮合リシノレイン酸エステルの少なくとも１種であり、
（５）当該界面活性剤の含有量が油剤及び界面活性剤の合計量に対して１２重量％以上であり、
（６）当該製剤の調製直後の活性粒子の平均粒子径に対する９ヶ月静置後の当該平均粒子径の変化率が２０％以下である、
ことを特徴とする油性外用製剤。
２． 活性粒子の単分散性が積算体積分布において、１）当該分布の１０体積％に対応する粒径（１０％Ｄ）と当該分布の５０体積％に対応する粒径（５０％Ｄ）との比Ｒ１＝（１０％Ｄ）／（５０％Ｄ）が５０％以上であり、かつ、２）当該分布の９０体積％に対応する粒径（９０％Ｄ）と上記５０％Ｄとの比Ｒ２＝（９０％Ｄ）／（５０％Ｄ）が２００％以下である、前記項１に記載の油性外用製剤。
３． 油剤の含有量が４０重量％以上である、前記項１に記載の油性外用製剤。
４． 生薬が、ウイキョウ、ダイオウ、ゲンノショウコ、コウブシ、カンゾウ、人参、オウバク、チンピ、ガジュツ、オウゴン、ニガキ、コウボク、カミツレ花、ボレイ、キキョウコン、クレンピ及びセンキュウの少なくとも１種を含む、前記項１に記載の油性外用製剤。
５． 薬学的に許容される金属塩の少なくとも１種をさらに含む、前記項１に記載の油性外用製剤。
６． 油剤が１）炭素数６以上の脂肪酸、２）炭素数６以上の脂肪酸エステル及び３）油脂の少なくとも１種である、前記項１に記載の油性外用製剤。
７． 脂肪酸エステルが、カプロン酸エステル、カプリル酸エステル、カプリン酸エステル、ラウリン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、ステアリン酸エステル、アラキジン酸エステル、オレイン酸エステル、スルシン酸エステル、リノール酸エステル及びリノレン酸エステルの少なくとも１種である、前記項６に記載の油性外用製剤。
８． 油脂が、大豆油、ごま油、オリーブ油、サフラワー油、サンフラワー油、ナタネ油、綿実油、パーム油、グレープシード油、シソ油、コーン油、落花生油、ウイキョウ油、カカオ油、ケイヒ油、ハッカ油、ベルガモット油、ヤシ油、アマニ油、つばき油、玄米胚芽油、米油、小麦胚芽油、エゴマ油、カポック油、月見草油、シア脂及びけし油の少なくとも１種である、前記項６に記載の油性外用製剤。
９． 皮膚外用剤として用いる、前記項１〜８のいずれかに記載の油性外用製剤。
１０． 抗菌外用剤として用いる、前記項１〜８のいずれかに記載の油性外用製剤。
１１． 抗白癬菌皮膚外用剤として用いる、前記項１〜８のいずれかに記載の油性外用製剤。
１２． 活性成分、油剤、界面活性剤及び水を混合してなる乳化液を脱水することにより得られる、前記項１に記載の油性外用製剤。
１３． 前記項１〜１２のいずれかに記載の油性外用製剤を製造する方法であって、１）ａ）生薬水抽出液又はその希釈液あるいはｂ）生薬の水溶液及び／又は２）分子量１０００以上の親水性高分子、油剤、界面活性剤及び水を混合してなる乳化液を脱水することにより油性外用製剤を製造する方法において、界面活性剤が、テトラグリセリン縮合リシノレイン酸エステル、ヘキサグリセリン縮合リシノレイン酸エステル、デカグリセリン縮合リシノレイン酸エステル及びポリグリセリン縮合リシノレイン酸エステルの少なくとも１種であり、界面活性剤の含有量が油剤及び界面活性剤の合計量に対して１２重量％以上であることを特徴とする油性外用製剤の製造方法。
１４． 乳化液が、１）活性成分の水溶液と２）油剤及び界面活性剤の混合液とを体積比２：１〜１：４で混合して得られるものである、前記項１３に記載の製造方法。
１５． 脱水を加熱脱水又は真空脱水により行う、前記項１３に記載の製造方法。
１６． 乳化液が、Ｗ／Ｏエマルションである、前記項１３に記載の製造方法。
That is, this invention relates to the following oil-based external preparation and its manufacturing method.
1. An oily external preparation comprising an active ingredient, a surfactant and an oil, wherein the active particles containing the active ingredient are monodispersed in an oil phase containing the surfactant and the oil ,
(1) The active ingredient is a herbal extract component and / or a hydrophilic polymer having a molecular weight of 1000 or more,
(2) The average particle diameter of the active particles is 200 nm or less,
(3) The water content is 0.5% by weight or less,
(4) The surfactant is at least one of tetraglycerin condensed ricinoleic acid ester, hexaglycerin condensed ricinoleic acid ester, decaglycerin condensed ricinoleic acid ester and polyglycerin condensed ricinoleic acid ester,
(5) The content of the surfactant is 12% by weight or more based on the total amount of the oil agent and the surfactant,
(6) The rate of change of the average particle size after standing for 9 months relative to the average particle size of the active particles immediately after preparation of the formulation is 20% or less,
An oily external preparation characterized by that.
2. In the cumulative volume distribution where the monodispersity of the active particles is 1) the ratio of the particle size (10% D) corresponding to 10% by volume of the distribution to the particle size (50% D) corresponding to 50% by volume of the distribution R1 = (10% D) / (50% D) is 50% or more, and 2) the ratio of the particle size (90% D) corresponding to 90% by volume of the distribution to the above 50% D R2 = The oily external preparation according to Item 1, wherein (90% D) / (50% D) is 200% or less.
3. Item 2. The oily external preparation according to Item 1, wherein the content of the oil is 40% by weight or more.
4). Item 1. The herbal medicine comprises at least one of fennel, diopium, gentian, kobushi, licorice, carrot, duck, chimpi, gadget, oxon, oyster, koboku, chamomile flower, boray, kyokon, krempi and senkyu Oily topical formulation.
5. Item 2. The oily external preparation according to Item 1, further comprising at least one pharmaceutically acceptable metal salt.
6). Item 2. The oily external preparation according to Item 1, wherein the oil agent is at least one of 1) fatty acids having 6 or more carbon atoms, 2) fatty acid esters having 6 or more carbon atoms, and 3) fats and oils.
7). Fatty acid ester is caproic acid ester, caprylic acid ester, capric acid ester, lauric acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, arachidic acid ester, oleic acid ester, sulnic acid ester, linoleic acid ester and linolenic acid Item 7. The oily external preparation according to Item 6 , which is at least one ester.
8). Fats and oils are soybean oil, sesame oil, olive oil, safflower oil, sunflower oil, rapeseed oil, cottonseed oil, palm oil, grape seed oil, perilla oil, corn oil, peanut oil, fennel oil, cacao oil, cinnamon oil, mint oil , bergamot oil, coconut oil, linseed oil, camellia oil, brown rice germ oil, rice oil, wheat germ oil, perilla oil, kapok oil, evening primrose oil, at least one shea butter and poppy oil, according to the claim 6 Oily topical formulation.
9. The oily external preparation according to any one of Items 1 to 8 , which is used as a skin external preparation.
10. The oily external preparation according to any one of Items 1 to 8 , which is used as an antibacterial external preparation.
11. Item 9. The oily external preparation according to any one of Items 1 to 8 , which is used as an anti-tinea fungus skin external preparation.
12 Item 2. The oily external preparation according to Item 1, obtained by dehydrating an emulsion obtained by mixing an active ingredient, an oil agent, a surfactant and water.
13. 13. A method for producing an oily external preparation according to any one of Items 1 to 12, wherein 1) a) a crude drug water extract or a diluted solution thereof or b) a crude drug solution and / or 2) a hydrophilicity having a molecular weight of 1000 or more. In the method for producing an oily external preparation by dehydrating an emulsion obtained by mixing a water- soluble polymer , an oil agent, a surfactant and water , the surfactant is tetraglycerin condensed ricinoleic acid ester, hexaglycerin condensed ricinoleic acid ester , At least one of decaglycerin condensed ricinoleic acid ester and polyglycerin condensed ricinoleic acid ester, wherein the content of the surfactant is 12% by weight or more based on the total amount of the oil agent and the surfactant. A method for producing an oily external preparation.
14 Item 14. The method according to Item 13 , wherein the emulsion is obtained by mixing 1) an aqueous solution of an active ingredient and 2) a mixture of an oil and a surfactant in a volume ratio of 2: 1 to 1: 4. .
15. Item 14. The method according to Item 13 , wherein the dehydration is performed by heat dehydration or vacuum dehydration.
16. Item 14. The method according to Item 13 , wherein the emulsion is a W / O emulsion.
本発明によれば、単分散性及び経時安定性に優れた油性外用製剤を提供することができる。特に、油相中に分散した活性粒子がナノオーダーの微粒子であることから、皮膚浸透性等に優れた製剤を提供することも可能である。例えば、後記の試験例にも示すように、薬剤そのままでは皮膚浸透性が低いために外用剤として利用することが困難であったり、外用剤としては効果が十分に発揮できないような場合においても、優れた皮膚浸透性、さらには患部での高い貯留性・滞留性、徐放性等を付与することができる。 ADVANTAGE OF THE INVENTION According to this invention, the oil-based external preparation excellent in monodispersibility and temporal stability can be provided. In particular, since the active particles dispersed in the oil phase are nano-order fine particles, it is possible to provide a preparation excellent in skin permeability and the like. For example, as shown in the test examples described later, even if the drug itself is difficult to use as an external preparation because the skin permeability is low, or even if the effect cannot be sufficiently exhibited as an external preparation, It can provide excellent skin permeability, high retention and retention in the affected area, sustained release, and the like.
１．油性外用製剤
本発明の油性外用製剤（本発明製剤）は、活性成分、界面活性剤及び油剤を含み、当該活性成分を含む活性粒子が界面活性剤及び油剤を含む油相中に単分散されており、
（１）活性成分が生薬抽出成分及び／又は分子量１０００以上の親水性高分子であり、
（２）活性粒子の平均粒子径が２００ｎｍ以下であり、
（３）水分含有量が０．５重量％以下である、
ことを特徴とする。
1. Oily external preparation The oily external preparation of the present invention (formulation of the present invention) contains an active ingredient, a surfactant and an oil, and the active particles containing the active ingredient are monodispersed in an oil phase containing the surfactant and the oil. And
(1) The active ingredient is a herbal extract component and / or a hydrophilic polymer having a molecular weight of 1000 or more,
(2) The average particle diameter of the active particles is 200 nm or less,
(3) The water content is 0.5% by weight or less,
It is characterized by that.
活性成分（有効成分）としては、生薬抽出成分及び／又は分子量１０００以上、好ましくは２０００以上の親水性高分子であれば限定的でなく、公知又は市販の活性成分も用いることができる。 The active ingredient (active ingredient) is not limited as long as it is a herbal extract component and / or a hydrophilic polymer having a molecular weight of 1000 or more, preferably 2000 or more, and known or commercially available active ingredients can also be used.
生薬としては、特に、生薬の水抽出成分を本発明製剤の活性成分として好適に使用することができる。生薬の種類は特に限定されず、効能等に応じて公知又は市販のものを使用することもできる。例えばウイキョウ、ダイオウ、ゲンノショウコ、コウブシ、カンゾウ、人参、オウバク、チンピ、ガジュツ、オウゴン、ニガキ、コウボク、カミツレ花、ボレイ、キキョウコン、クレンピ及びセンキュウの少なくとも１種を好適に用いることができる。 Especially as a crude drug, the water extraction component of a crude drug can be used conveniently as an active ingredient of this invention formulation. The type of crude drug is not particularly limited, and known or commercially available drugs can be used depending on the efficacy and the like. For example, at least one kind of fennel, daisou, genou shouko, kobushi, licorice, carrot, duck, chimpi, gadget, oxon, nigaki, kokuboku, chamomile flower, borei, kyoukon, krempi and senkyu can be preferably used.
また、前記親水性高分子としては限定的でなく、例えばタンパク、ペプチド、核酸、ポリフェノール、多糖類、ビタミン類、ヒアルロン酸、海草由来物質、植物由来物質、酵母等の細菌由来物質、抗生物質等を挙げることができる。 Further, the hydrophilic polymer is not limited, and examples thereof include proteins, peptides, nucleic acids, polyphenols, polysaccharides, vitamins, hyaluronic acid, seaweed-derived substances, plant-derived substances, bacteria-derived substances such as yeast, antibiotics, etc. Can be mentioned.
なお、前記親水性成分の分子量の上限は通常は２００万程度とすれば良いが、これに限定されない。例えば、核酸のように分子量１００万以上のものにも適用することができる。 In addition, although the upper limit of the molecular weight of the said hydrophilic component should just be about 2 million normally, it is not limited to this. For example, the present invention can be applied to a nucleic acid having a molecular weight of 1 million or more.
活性成分の用途（効能）については、外用製剤として使用されている用途であれば限定的でない。例えば、抗菌剤（抗白癬菌、抗大腸菌等）、抗アレルギー剤、美白剤、保湿剤、皮膚角質保護剤、創傷治癒剤、火傷治療剤、脱毛剤、育毛剤、鎮痛消炎剤、血行促進剤、虚血性心疾患治療剤、ホルモン剤等を挙げることができる。また、医薬品、医薬部外品、化粧品等のいずれにも用いることができる。さらに、投与方法（投薬形態）の点からみれば、例えば経皮吸収剤、経粘膜吸収剤等のいずれにも適用することができる。従って、本発明製剤は、例えば皮膚外用剤等として好適に用いることができる。 About the use (efficacy) of an active ingredient, if it is a use currently used as an external preparation, it will not be limited. For example, antibacterial agents (anti-tinea, anti-E. Coli, etc.), antiallergic agents, whitening agents, moisturizers, skin keratin protective agents, wound healing agents, burn treatment agents, hair removal agents, hair restorers, analgesic / antiinflammatory agents, blood circulation promoters , Therapeutic agents for ischemic heart disease, hormonal agents and the like. Moreover, it can be used for any of pharmaceuticals, quasi drugs, cosmetics and the like. Furthermore, from the viewpoint of administration method (dosage form), it can be applied to any of transdermal absorbents, transmucosal absorbents, and the like. Therefore, the preparation of the present invention can be suitably used, for example, as a skin external preparation.
また、適用対象としても、ヒトのほか、家畜（ウシ、ブタ、トリ（鶏））、伴侶動物（イヌ、ネコ）等にも適用することができる。本発明製剤（特に生薬を活性成分とする本発明製剤）は、例えばウシ又はブタに対する抗白癬菌用外用剤として好適に用いることができる。 In addition to humans, the present invention can also be applied to livestock (cattle, pigs, birds (chicken)), companion animals (dogs, cats) and the like. The preparation of the present invention (particularly the preparation of the present invention containing a crude drug as an active ingredient) can be suitably used as an external preparation for anti-tinea, for example, for cattle or pigs.
前記親水性成分は、親水性であることが前提であるが、特に、使用する油剤に対する溶解度が１μＭ／Ｌ以下であり、かつ、油水分配係数が１０００以上であることが好ましい。通常は油に溶解しないこのような親水性の高い成分を経時安定性等に優れたナノ粒子とすることができる。 The hydrophilic component is premised on being hydrophilic, but it is particularly preferable that the solubility in the oil used is 1 μM / L or less and the oil-water distribution coefficient is 1000 or more. Such highly hydrophilic components that do not normally dissolve in oil can be made into nanoparticles having excellent temporal stability and the like.
活性成分の本発明製剤中における含有量は、用いる活性成分の種類等に応じて適宜設定することができるが、通常は０．００００１〜１０重量％、好ましくは０．１〜５重量％の範囲内で適宜調整すれば良い。 The content of the active ingredient in the preparation of the present invention can be appropriately set according to the type of the active ingredient to be used, but is usually in the range of 0.00001 to 10% by weight, preferably 0.1 to 5% by weight. May be adjusted as appropriate.
界面活性剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、非イオン性界面活性剤、両性界面活性剤等のいずれも使用することができるが、本発明では特に非イオン性界面活性剤を用いることが好ましい。非イオン性界面活性剤としては、例えばポリグリセリン縮合リシノレイン酸エステル（ＰＧＣＲ）、モノグリセリン縮合リシノレイン酸エステル、ジグリセリン縮合リシノレイン酸エステル、トリグリセリン縮合リシノレイン酸エステル、テトラグリセリン縮合リシノレイン酸エステル、ペンタグリセリン縮合リシノレイン酸エステル、ヘキサグリセリン縮合リシノレイン酸エステル、ヘプタグリセリン縮合リシノレイン酸エステル、オクタグリセリン縮合リシノレイン酸エステル、ノナグリセリン縮合リシノレイン酸エステル、デカグリセリン縮合リシノレイン酸エステル、デカグリセリンエステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビット脂肪酸エステル、ポリオキシエチレンヒマシ油・硬化ヒマシ油、ショ糖脂肪酸エステル（ショ糖ステアリン酸エステル、ショ糖パルミチン酸エステル、ショ糖ミリスチン酸エステル、ショ糖オレイン酸エステル、ショ糖ラウリン酸エステル、ショ糖エルカ酸エステル、ショ糖混合脂肪酸エステル）等の少なくとも１種を用いることができる。この中でも、例えばテトラグリセリン縮合リシノレイン酸エステル、ヘキサグリセリン縮合リシノレイン酸エステル、デカグリセリン縮合リシノレイン酸エステル及びポリグリセリン縮合リシノレイン酸エステルの少なくとも１種を好適に用いることができる。 As the surfactant, any of a cationic surfactant, an anionic surfactant, a nonionic surfactant, an amphoteric surfactant, and the like can be used. It is preferred to use an activator. Examples of the nonionic surfactant include polyglycerin condensed ricinoleic acid ester (PGCR), monoglycerin condensed ricinoleic acid ester, diglycerin condensed ricinoleic acid ester, triglycerin condensed ricinoleic acid ester, tetraglycerin condensed ricinoleic acid ester, and pentaglycerin. Condensed ricinoleic acid ester, hexaglycerin condensed ricinoleic acid ester, heptaglycerol condensed ricinoleic acid ester, octaglycerin condensed ricinoleic acid ester, nonaglycerin condensed ricinoleic acid ester, decaglycerin condensed ricinoleic acid ester, decaglycerin ester, glycerin fatty acid ester, polyglycerin Fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester Polyoxyethylene sorbite fatty acid ester, polyoxyethylene castor oil / hardened castor oil, sucrose fatty acid ester (sucrose stearate ester, sucrose palmitate ester, sucrose myristic acid ester, sucrose oleate ester, sucrose lauric acid Ester, sucrose erucic acid ester, sucrose mixed fatty acid ester) or the like can be used. Among these, for example, at least one of tetraglycerin condensed ricinoleic acid ester, hexaglycerin condensed ricinoleic acid ester, decaglycerin condensed ricinoleic acid ester and polyglycerin condensed ricinoleic acid ester can be preferably used.
界面活性剤の含有量は、油剤及び界面活性剤の合計量に対して１２重量％以上であり、好ましくは１５〜５０重量％であり、より好ましくは１５〜４５重量％であり、最も好ましくは２０〜４０重量％とする。上記範囲に設定することによって、より単分散性で安定した製剤を調製することができる。上記含有量が１５重量％未満の場合は、本発明製剤においては単分散性又は経時安定性のいずれかが劣ることになる。 The content of the surfactant is 12% by weight or more, preferably 15 to 50% by weight, more preferably 15 to 45% by weight, most preferably based on the total amount of the oil agent and the surfactant. 20 to 40% by weight. By setting to the above range, a more monodispersed and stable preparation can be prepared. When the content is less than 15% by weight, either monodispersity or stability over time is inferior in the preparation of the present invention.
油剤は、公知又は市販の油剤を使用することができる。また、天然由来品又は合成品のいずれも使用することができる。本発明製剤では、脂肪酸、脂肪酸エステル及び油脂の少なくとも１種を好適に用いることができる。 As the oil agent, a known or commercially available oil agent can be used. Moreover, either a naturally derived product or a synthetic product can be used. In the preparation of the present invention, at least one of fatty acids, fatty acid esters and fats and oils can be suitably used.
脂肪酸としては、炭素数６以上の脂肪酸を好適に用いることができる。例えば、カプロン酸、カプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、アラキジン酸、オレイン酸、スルシン酸、リノール酸、リノレン酸、エルカ酸、エイコサペンタエン酸、ドコサヘキサエン酸等を使用することができる。 As the fatty acid, a fatty acid having 6 or more carbon atoms can be suitably used. For example, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, succinic acid, linoleic acid, linolenic acid, erucic acid, eicosapentaenoic acid, docosahexaenoic acid, etc. can do.
脂肪酸エステルとしては、炭素数が６以上の脂肪酸エステルを好適に用いることができる。例えば、カプロン酸エステル、カプリル酸エステル、カプリン酸エステル、ラウリン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、ステアリン酸エステル、アラキジン酸エステル、オレイン酸エステル、スルシン酸エステル、リノール酸エステル、リノレン酸エステル等を挙げることができる。より具体的には、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、トリ２−エチルヘキサン酸グリセリル、スクワラン、イソノナン酸イソトリデシル、ジカプリン酸ネオペンチルグリコール、トリイソステアリン酸ジグリセリル、モノイソステアリン酸モノミリスチン酸グリセリル、乳酸オクチルドデシル、トリ（カプリル・カプリン酸）グリセリル、ジカプリン酸プロピレングリコール、アジピン酸ジイソプロピル、ミツロウ脂肪酸オクチルドデシル等を例示することができる。 As the fatty acid ester, a fatty acid ester having 6 or more carbon atoms can be suitably used. For example, caproic acid ester, caprylic acid ester, capric acid ester, lauric acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, arachidic acid ester, oleic acid ester, sulnic acid ester, linoleic acid ester, linolenic acid ester, etc. Can be mentioned. More specifically, isopropyl myristate, isopropyl palmitate, glyceryl tri-2-ethylhexanoate, squalane, isotridecyl isononanoate, neopentyl glycol dicaprate, diglyceryl triisostearate, glyceryl monoisostearate, octyl lactate Examples include dodecyl, tri (capryl / capric acid) glyceryl, propylene glycol dicaprate, diisopropyl adipate, beeswax fatty acid octyldodecyl and the like.
油脂としては、植物油脂又は動物油脂のいずれであっても良い。動物油としては、例えば豚脂、牛脂、鯨油、羊脂、イワシ油、スクワラン、魚油等の少なくとも１種を好適に用いることができる。植物油としては、例えば大豆油、ごま油、オリーブ油、サフラワー油、サンフラワー油、ナタネ油、綿実油、パーム油、グレープシード油、シソ油、コーン油、落花生油、ウイキョウ油、カカオ油、ケイヒ油、ハッカ油、ベルガモット油、ヤシ油、アマニ油、つばき油、玄米胚芽油、米油、小麦胚芽油、エゴマ油、カポック油、月見草油、シア脂、けし油等の少なくとも１種を好適に用いることができる。 As fats and oils, either vegetable oils or animal fats may be used. As the animal oil, for example, at least one of pork fat, beef tallow, whale oil, sheep fat, sardine oil, squalane, fish oil and the like can be suitably used. Examples of vegetable oils include soybean oil, sesame oil, olive oil, safflower oil, sunflower oil, rapeseed oil, cottonseed oil, palm oil, grape seed oil, perilla oil, corn oil, peanut oil, fennel oil, cacao oil, cinnamon oil, Preferably at least one of mint oil, bergamot oil, coconut oil, flaxseed oil, camellia oil, brown rice germ oil, rice oil, wheat germ oil, sesame oil, kapok oil, evening primrose oil, shea butter, poppy oil, etc. Can do.
本発明製剤では、活性成分を含む活性粒子が界面活性剤及び油剤を含む油相中に分散されている。活性粒子は、活性成分を主成分とするものであるが、必要に応じて他の成分が含まれていても良い。例えば、ｐＨ調整等のために、薬学的に許容される金属塩を用いることができる。このような金属塩としては、無機酸又は有機酸の金属塩を例示することができる。例えば重炭酸ナトリウム、炭酸カルシウム、塩化ナトリウム、リン酸ナトリウム、酢酸ナトリウム、アスコルビン酸ナトリウム等を用いることができる。その他にも、医薬品添加物等も適宜配合することができる。他の成分の含有量は、本発明製剤中１０重量％以下、特に０〜５重量％とすることが好ましい。 In the preparation of the present invention, active particles containing an active ingredient are dispersed in an oil phase containing a surfactant and an oil agent. Active particles are composed mainly of active ingredients, but may contain other ingredients as required. For example, a pharmaceutically acceptable metal salt can be used for pH adjustment and the like. As such a metal salt, a metal salt of an inorganic acid or an organic acid can be exemplified. For example, sodium bicarbonate, calcium carbonate, sodium chloride, sodium phosphate, sodium acetate, sodium ascorbate and the like can be used. In addition, pharmaceutical additives and the like can be appropriately blended. The content of other components is preferably 10% by weight or less, particularly 0 to 5% by weight in the preparation of the present invention.
本発明製剤における活性粒子の平均粒子径は、２００ｎｍ以下であり、好ましくは１００ｎｍ以下である。このようなナノオーダーの粒径に制御することによって、より優れた浸透性等を得ることができる。なお、活性粒子の平均粒子径の下限値は限定されないが、通常は３０ｎｍ程度である。粒子径測定法は厳密なものから大雑把なものまであり、特にサブミクロンからナノ領域については測定精度が不十分なものまで様々な方法があるが、本発明における平均粒子径は動的光散乱法を用いて油用製剤の２５℃での粘度をパラメーターとして測定し、キュムラント解析された数値である。 The average particle diameter of the active particles in the preparation of the present invention is 200 nm or less, preferably 100 nm or less. By controlling to such a nano-order particle size, better permeability and the like can be obtained. The lower limit of the average particle size of the active particles is not limited, but is usually about 30 nm. There are various particle size measurement methods from strict to rough, and in particular, there are various methods from the submicron to the nano region where measurement accuracy is insufficient, but the average particle size in the present invention is the dynamic light scattering method. Is a numerical value obtained by measuring the viscosity at 25 ° C. of an oil formulation as a parameter and analyzing the cumulant.
特に、本発明製剤においては、平均粒子径の経時的な変化が小さいことが好ましい。すなわち、経時的安定性に優れていることが望ましい。より具体的には、当該製剤の調製直後の活性粒子の平均粒子径（Ｄｓ）に対する９ヶ月静置後の当該平均粒子径の変化率が２０％以下、好ましくは１５％以下、より好ましくは１０％以下、最も好ましくは５％以下である。変化率は、本発明製剤が調製された直後から密閉状態で２０℃の温度に９ヶ月静置した後の平均粒子径の変化率（Ｒ）をいう。調製直後の平均粒子径をＤｓ１、９ヶ月経過後の平均粒子径をＤｓ２とした場合、Ｒは［１００×（Ｄｓ２−Ｄｓ１）］／Ｄｓ１の絶対値で示される。なお、上記の平均粒子径（Ｄｓ）は、動的光散乱法でキュムラント解析された平均粒子径をいう。 In particular, in the preparation of the present invention, it is preferable that the change with time of the average particle diameter is small. That is, it is desirable that the stability over time is excellent. More specifically, the rate of change of the average particle size after standing for 9 months relative to the average particle size (Ds) of the active particles immediately after preparation of the preparation is 20% or less, preferably 15% or less, more preferably 10 % Or less, most preferably 5% or less. The rate of change refers to the rate of change (R) of the average particle diameter after standing for 9 months at a temperature of 20 ° C. in a sealed state immediately after the preparation of the present invention is prepared. When the average particle diameter immediately after preparation is Ds1, and the average particle diameter after 9 months is Ds2, R is represented by an absolute value of [100 × (Ds2−Ds1)] / Ds1. In addition, said average particle diameter (Ds) says the average particle diameter analyzed by the cumulant by the dynamic light scattering method.
また、本発明製剤の活性粒子の粒度分布は単分散である。具体的には、活性粒子の積算体積分布において、１）当該分布の１０体積％に対応する粒径（以下「１０％Ｄ」という。）と当該分布の５０体積％に対応する粒径（以下「５０％Ｄ」という。）との比Ｒ１＝（１０％Ｄ）／（５０％Ｄ）が５０％以上であり、かつ、２）当該分布の９０体積％に対応する粒径（以下「９０％Ｄ」という。）と上記５０％Ｄとの比Ｒ２＝（９０％Ｄ）／（５０％Ｄ）が２００％以下であることが好ましい。 Moreover, the particle size distribution of the active particles of the preparation of the present invention is monodisperse. Specifically, in the cumulative volume distribution of active particles, 1) a particle size corresponding to 10% by volume of the distribution (hereinafter referred to as “10% D”) and a particle size corresponding to 50% by volume of the distribution (hereinafter referred to as “%”). R1 = (10% D) / (50% D) with respect to “50% D”) is 50% or more, and 2) a particle size corresponding to 90% by volume of the distribution (hereinafter referred to as “90”). % D ”) and the above 50% D, the ratio R2 = (90% D) / (50% D) is preferably 200% or less.
本発明製剤中に含まれる水分含有量は、通常０．５重量％以下であり、好ましくは０．２重量％以下、より好ましくは０．１重量％以下である。すなわち、本発明製剤は、実質的に水分を含まないＳ／Ｏサスペンションとなり得る。 The water content contained in the preparation of the present invention is usually 0.5% by weight or less, preferably 0.2% by weight or less, more preferably 0.1% by weight or less. That is, the preparation of the present invention can be an S / O suspension substantially free of moisture.
本発明製剤は、必要に応じて所望の剤形としても良い。例えば、軟膏剤、エアゾール剤、硬膏剤等の公知の剤形とすることができるが、これらに限定されない。 The preparation of the present invention may have a desired dosage form as necessary. For example, known dosage forms such as ointments, aerosols, and plasters can be used, but the present invention is not limited thereto.
本発明製剤の投与量は、配合する活性成分の種類、含有量等のほか、例えば対象、症状等に応じて適宜調整すれば良い。 What is necessary is just to adjust the dosage amount of this invention formulation suitably according to a subject, a symptom, etc. other than the kind of active ingredient to mix | blend, content, etc., for example.
本発明製剤の投与方法は、前記の剤形等に応じて適宜選択することができる。本発明製剤は外用剤として用いられるが、特に皮膚に適用するための外用剤として最適である。従って、例えば塗布、スプレー、貼付等の公知の方法によって皮膚に投与することもできる。 The administration method of the preparation of the present invention can be appropriately selected depending on the dosage form and the like. The preparation of the present invention is used as an external preparation, and is particularly suitable as an external preparation for application to the skin. Therefore, it can also be administered to the skin by a known method such as application, spraying or sticking.
２．油性外用製剤の製造方法
本発明製剤は、種々の方法により製造することができるが、特に本発明の製造方法により好適に製造することができる。すなわち、活性成分、油剤、界面活性剤及び水を混合してなる乳化液を脱水することにより油性外用製剤を製造する方法であって、界面活性剤の含有量が油剤及び界面活性剤の合計量に対して１２重量％以上であることを特徴とする油性外用製剤の製造方法により調製することができる。
2. Manufacturing method of oily external preparation The preparation of the present invention can be manufactured by various methods, and can be particularly preferably manufactured by the manufacturing method of the present invention. That is, a method for producing an oily external preparation by dehydrating an emulsion obtained by mixing an active ingredient, an oil agent, a surfactant and water, wherein the surfactant content is the total amount of the oil agent and the surfactant. It can be prepared by a method for producing an oily external preparation characterized by being 12% by weight or more based on the weight.
活性成分、油剤及び界面活性剤は、前記１．で述べたものと同様のものを使用することができる。これらの成分のほか、本発明の製造方法では、必要に応じて親油性有効成分、浸透補助剤、溶解補助剤等を添加することもできる。 The active ingredient, oil agent and surfactant are the same as those described in 1. above. The same as described in the above can be used. In addition to these components, in the production method of the present invention, a lipophilic active ingredient, a penetration aid, a solubilizing aid, and the like can be added as necessary.
なお、活性成分として、生薬を用いる場合は、１）生薬水抽出液又はその希釈液あるいは２）生薬の水溶液を水相として用いることができる。生薬抽出液は、公知の方法によっても得ることができ、例えば水抽出、熱水抽出、搾取等の方法により抽出液を得ることができ、必要に応じて精製（濾過、遠心分離等）等を実施しても良い。好ましくは、粗濾過後の水相を遠心分離により上清液を回収し、上清液をさらに濾過より不溶物を除去する。 In addition, when using a crude drug as an active ingredient, 1) a crude drug water extract or a diluted solution thereof, or 2) an aqueous solution of a crude drug can be used as an aqueous phase. The crude drug extract can also be obtained by a known method, for example, an extract can be obtained by a method such as water extraction, hot water extraction, extraction, etc., and purification (filtration, centrifugation, etc.) can be performed as necessary. You may carry out. Preferably, the supernatant is recovered by centrifugation of the aqueous phase after coarse filtration, and the supernatant is further filtered to remove insolubles.
本発明の製造方法では、界面活性剤の含有量が油剤及び界面活性剤の合計量に対して１２重量％以上、好ましくは１５〜５０重量％であり、より好ましくは１５〜４５重量％であり、最も好ましくは２０〜４０重量％となるようにする。上記範囲内の含有量にて界面活性剤を用いることにより、より単分散性で安定した製剤を調製することができる。上記含有量が１２重量％未満の場合は、本発明製剤においては単分散性又は経時安定性のいずれかが劣ることになる。 In the production method of the present invention, the content of the surfactant is 12% by weight or more, preferably 15 to 50% by weight, more preferably 15 to 45% by weight, based on the total amount of the oil agent and the surfactant. The most preferable content is 20 to 40% by weight. By using a surfactant with a content within the above range, a more monodispersed and stable preparation can be prepared. When the content is less than 12% by weight, either monodispersity or stability over time is inferior in the preparation of the present invention.
乳化液の調製方法は特に限定されず、公知の方法も採用することができる。例えば、少なくとも活性成分が水に溶解した水溶液を調製する。一方、界面活性剤及び油剤を含む混合液を調製する。次いで、前記水溶液を水相とし、前記混合液を油相として、両者を混合することによって乳化液を得ることができる。すなわち、少なくとも活性成分が水に溶解した水溶液からなる水相と、界面活性剤及び油剤を含む油相とを混合することにより乳化液を調製することができる。 The preparation method of an emulsion is not specifically limited, A well-known method is also employable. For example, an aqueous solution in which at least the active ingredient is dissolved in water is prepared. On the other hand, a mixed solution containing a surfactant and an oil agent is prepared. Next, an emulsion can be obtained by mixing both the aqueous solution as an aqueous phase and the mixed liquid as an oil phase. That is, an emulsion can be prepared by mixing an aqueous phase composed of an aqueous solution in which at least an active ingredient is dissolved in water and an oil phase containing a surfactant and an oil agent.
本発明の製造方法では、乳化液は、特にＷ／Ｏエマルションの形態で得ることが好ましい。すなわち、少なくとも活性成分が水に溶解した水溶液の液滴が界面活性剤及び油剤を含む混合液からなる油相中に分散してなるＷ／Ｏエマルションを好適に用いることができる。この場合の液滴の平均粒子径は特に限定されないが、内水滴が凝集せずに均一分散していること及び通常３０００ｎｍ以下であることが好ましい。 In the production method of the present invention, the emulsion is preferably obtained in the form of a W / O emulsion. That is, a W / O emulsion in which droplets of an aqueous solution in which at least an active ingredient is dissolved in water is dispersed in an oil phase composed of a mixed solution containing a surfactant and an oil agent can be suitably used. The average particle size of the droplets in this case is not particularly limited, but it is preferable that the inner water droplets are uniformly dispersed without agglomeration and usually 3000 nm or less.
この場合、水相中における活性成分の溶解量は、用いる活性成分の種類等に応じて適宜選択すれば良いが、通常０．１〜３００ｇ／Ｌ程度である。 In this case, the amount of the active ingredient dissolved in the aqueous phase may be appropriately selected according to the type of the active ingredient used, but is usually about 0.1 to 300 g / L.
また、油相中における油剤及び界面活性剤の合計量は限定的ではないが、通常は９０〜１００重量％、特に９５〜１００重量％とすることが好ましい。 Further, the total amount of the oil agent and the surfactant in the oil phase is not limited, but is usually 90 to 100% by weight, and particularly preferably 95 to 100% by weight.
水相と油相との混合（乳化）に際しては、１）少なくとも活性成分が水に溶解した水溶液と２）油剤及び界面活性剤を含む混合液とを体積比２：１〜０．２５：１（特に１．２：１〜０．８：１）で混合することが好ましい。 In mixing (emulsification) of the aqueous phase and the oil phase, 1) an aqueous solution in which at least an active ingredient is dissolved in water and 2) a mixed solution containing an oil agent and a surfactant are in a volume ratio of 2: 1 to 0.25: 1. It is preferable to mix (especially 1.2: 1 to 0.8: 1).
乳化手段は、安定な乳化液（特にＷ／Ｏエマルション）が調製できるものであれば特に限定されるものではない。例えば、攪拌（スターラー撹拌、撹拌翼等による方法）のほか、ホモジナイザー、ホモミキサー、多孔質ガラス膜等を用いる方法のような一般的な乳化操作によって、Ｗ／Ｏエマルションを調製することができる。例えば、ホモミキサーを用いる場合の条件は、特に限定されるものではないが、通常６００〜５０，０００ｒｐｍ程度（好ましくは７，０００〜２４，０００ｒｐｍ程度）にて０．５〜６０分間程度（好ましくは１〜１０分間程度）とすれば良い。 The emulsifying means is not particularly limited as long as a stable emulsion (especially a W / O emulsion) can be prepared. For example, the W / O emulsion can be prepared by a general emulsification operation such as a method using a homogenizer, a homomixer, a porous glass membrane, or the like in addition to stirring (a method using a stirrer, a stirring blade, or the like). For example, conditions for using a homomixer are not particularly limited, but are usually about 600 to 50,000 rpm (preferably about 7,000 to 24,000 rpm) for about 0.5 to 60 minutes (preferably Is about 1 to 10 minutes).
次いで、乳化液（Ｗ／Ｏエマルション）の脱水を行う。乳化液の脱水操作は、水相粒子が合一、分離あるいは分裂しなければ特に限定されるものではなく、加熱脱水、真空脱水等の通常の方法を採用することができる。例えば、加熱脱水する場合は、油剤の沸点や分解温度、乳化剤の曇点（乳化力がなくなる上限温度）、水溶性固体物質の分解温度を考慮し、それらを超えない温度に加熱して脱水することができる。真空脱水する場合は、温度と真空度を調節しながら脱水できるエバポレーター（ロータリーエバポレーター）のような市販の装置を使用することもできる。脱水操作は、脱水された水の量が当該乳化液（Ｗ／Ｏエマルション）を調製する際に用いた水相に含まれる水の量と同程度になった時点で終了すれば良い。このようにして乳化液（Ｗ／Ｏエマルション）の水相に溶解させた含有量の活性成分を含む活性粒子がナノオーダーの微細粒子として分散する製剤を得ることができる。 Next, the emulsion (W / O emulsion) is dehydrated. The dehydration operation of the emulsion is not particularly limited as long as the water phase particles do not coalesce, separate or break up, and usual methods such as heat dehydration and vacuum dehydration can be employed. For example, in the case of heat dehydration, dehydration is performed by heating to a temperature not exceeding these in consideration of the boiling point and decomposition temperature of the oil, the cloud point of the emulsifier (the upper limit temperature at which the emulsifying power disappears), and the decomposition temperature of the water-soluble solid substance. be able to. In the case of vacuum dehydration, a commercially available apparatus such as an evaporator (rotary evaporator) capable of dehydrating while adjusting the temperature and the degree of vacuum can be used. The dehydration operation may be terminated when the amount of dehydrated water becomes approximately the same as the amount of water contained in the aqueous phase used in preparing the emulsion (W / O emulsion). In this way, it is possible to obtain a preparation in which active particles containing a content of an active ingredient dissolved in an aqueous phase of an emulsion (W / O emulsion) are dispersed as nano-order fine particles.
以下に実施例及び比較例を示し、本発明の特徴をより具体的に説明する。ただし、本発明の範囲は、実施例に限定されない。 The features of the present invention will be described more specifically with reference to the following examples and comparative examples. However, the scope of the present invention is not limited to the examples.
比較例１
大豆油（和光純薬）２０ｍＬに１０ｍｇ／ｍＬの平均分子量７０，０００のＦＩＴＣ−デキストラン（Ｓｉｇｍａ社製、以下「ＦＤ７０」）水溶液１０ｍＬを滴下混合し、３時間均一になるまで撹拌した。この混合液は、油相（大豆油）と水相が分離したままであり、均一な状態に至らなかった。その結果を表１に示す。なお、表１中における油剤及び界面活性剤の含有量（重量％）は、上記体積を２５℃の比重で換算した値で示す（以下同じ。）。
Comparative Example 1
10 mL of a 10 mg / mL FITC-dextran (Sigma, hereinafter, “FD70”) aqueous solution having an average molecular weight of 70,000 was added dropwise to 20 mL of soybean oil (Wako Pure Chemical Industries, Ltd.) and stirred until it was uniform for 3 hours. In this mixed solution, the oil phase (soybean oil) and the aqueous phase remained separated and did not reach a uniform state. The results are shown in Table 1. In addition, content (weight%) of the oil agent and surfactant in Table 1 is shown by the value which converted the said volume with the specific gravity of 25 degreeC (hereinafter the same).
比較例２
大豆油１９．８ｍｌとＴＧＣＲ（阪本薬品工業製「ＣＲ−３１０」）０．２ｍＬを混合し、音叉型粘度計（エイアンドデイ）で粘度を測定した。この油相に、１０ｍｇ／ｍＬのＦＤ７０水溶液１０ｍＬを滴下混合して３時間撹拌し、平均内水滴径３．１７７μｍ（島津製作所製 レーザー回折散乱式粒度分布計「ＳＡＬＤ−２０００」で測定）の乳化物を得た。ロータリーエバポレーターを用いて、この乳化物を４０℃に加温しながら一時間減圧脱水し、水分含量０．２％（京都電子製 ＫＦ水分計にて測定）、ＦＤ７０の分散平均粒子径（Ｄｓ）２３０ｎｍ（大塚電子製 動的光散乱式粒度分布測定装置「ＥＬＳ−８００」にて測定）の均一な油性外用製剤を得た。この製剤は不透明な外観であった。その結果を表１に示す。
Comparative Example 2
19.8 ml of soybean oil and 0.2 mL of TGCR (“CR-310” manufactured by Sakamoto Pharmaceutical Co., Ltd.) were mixed, and the viscosity was measured with a tuning fork viscometer (A & D). To this oil phase, 10 mL of a 10 mg / mL aqueous FD70 solution was added dropwise, stirred for 3 hours, and emulsified with an average internal water droplet size of 3.177 μm (measured with a laser diffraction scattering particle size distribution analyzer “SALD-2000” manufactured by Shimadzu Corporation). I got a thing. Using a rotary evaporator, this emulsion was dehydrated under reduced pressure for one hour while being heated to 40 ° C., water content 0.2% (measured with a KF moisture meter manufactured by Kyoto Electronics Co., Ltd.), dispersion average particle size (Ds) of FD70. A uniform oily external preparation of 230 nm (measured with a dynamic light scattering particle size distribution measuring device “ELS-800” manufactured by Otsuka Electronics Co., Ltd.) was obtained. This formulation had an opaque appearance. The results are shown in Table 1.
比較例３
大豆油１９ｍｌとＴＧＣＲ１ｍＬを混合した油相を用いたほかは、比較例２と同様の処理を行った。撹拌後の平均内水滴径は１．８４７μｍ、脱水後の水分含量は０．０９％、ＦＤ７０の分散平均粒子径（Ｄｓ）は１５４．４ｎｍであり、やや不透明な外観であった。その結果を表１に示す。
Comparative Example 3
The same treatment as in Comparative Example 2 was performed, except that an oil phase obtained by mixing 19 ml of soybean oil and 1 mL of TGCR was used. The average water droplet diameter after stirring was 1.847 μm, the water content after dehydration was 0.09%, and the dispersion average particle diameter (Ds) of FD70 was 154.4 nm. The results are shown in Table 1.
実施例１
大豆油１６ｍＬとＴＧＣＲ４ｍＬを混合した油相を用いたほかは、比較例２と同様の処理を行った。撹拌後の平均内水滴径は７１７ｎｍ、脱水後の水分含量は０．０６％、ＦＤ７０の分散平均粒子径（Ｄｓ）は５８．１ｎｍであり、透明な外観であった。その結果を表１に示す。
Example 1
The same treatment as in Comparative Example 2 was performed, except that an oil phase obtained by mixing 16 mL of soybean oil and 4 mL of TGCR was used. The average water droplet diameter after stirring was 717 nm, the water content after dehydration was 0.06%, and the dispersion average particle diameter (Ds) of FD70 was 58.1 nm, which was a transparent appearance. The results are shown in Table 1.
実施例２
大豆油１４ｍＬとＴＧＣＲ６ｍＬを混合した油相を用いたほかは、比較例２と同様の処理を行った。撹拌後の平均内水滴径は４７７ｎｍ、脱水後の水分含量は０．１％、ＦＤ７０の分散平均粒子径（Ｄｓ）は４５．８ｎｍであり、透明な外観であった。その結果を表１に示す。
Example 2
The same treatment as in Comparative Example 2 was performed except that an oil phase in which 14 mL of soybean oil and 6 mL of TGCR were mixed was used. The average water droplet diameter after stirring was 477 nm, the water content after dehydration was 0.1%, and the dispersion average particle diameter (Ds) of FD70 was 45.8 nm. The results are shown in Table 1.
実施例３
大豆油８．９ｍＬとＴＧＣＲ１．１ｍＬを混合した油相と、５ｍｇ／ｍＬのＢＳＡ水溶液１０ｍＬを内水相として用いたほかは、比較例２と同様の処理を行った。撹拌後の平均内水滴径は１，２１２ｎｍ、脱水後の水分含量は０．０６％、ＢＳＡの分散平均粒子径（Ｄｓ）は８８．１ｎｍであり、ほぼ透明な外観であった。その結果を表１に示す。
Example 3
The same treatment as in Comparative Example 2 was performed except that an oil phase in which 8.9 mL of soybean oil was mixed with 1.1 mL of TGCR and 10 mL of 5 mg / mL BSA aqueous solution were used as the inner aqueous phase. The average internal water droplet diameter after stirring was 1,212 nm, the water content after dehydration was 0.06%, and the BSA dispersion average particle diameter (Ds) was 88.1 nm, which was almost transparent. The results are shown in Table 1.
実施例４
大豆油８ｍＬとＨＧＣＲ（阪本薬品工業製「ＣＲ−５００」）２ｍＬを混合した油相を用いたほかは、実施例３と同様の処理を行った。撹拌後の平均内水滴径は７９５．３ｎｍ、脱水後の水分含量は０．０７％、ＢＳＡの分散平均粒子径（Ｄｓ）は５３．５ｎｍであり、透明な外観であった。その結果を表１に示す。
Example 4
The same treatment as in Example 3 was performed except that an oil phase in which 8 mL of soybean oil and 2 mL of HGCR (“CR-500” manufactured by Sakamoto Pharmaceutical Co., Ltd.) were mixed was used. The average water droplet diameter after stirring was 795.3 nm, the water content after dehydration was 0.07%, and the BSA dispersion average particle diameter (Ds) was 53.5 nm, which was a transparent appearance. The results are shown in Table 1.
表１の結果からも明らかなように、界面活性剤添加濃度が本発明の範囲内にある実施例１〜４では、良好なＦＤ７０又はＢＳＡ含有油性外用製剤を調製することができた。これに対し、比較例１〜３では、所望の油性外用製剤を得ることが困難ないしは不可能であった。 As is clear from the results in Table 1, in Examples 1 to 4 in which the surfactant addition concentration is within the range of the present invention, a good FD70 or BSA-containing oily external preparation could be prepared. On the other hand, in Comparative Examples 1 to 3, it was difficult or impossible to obtain a desired oily external preparation.
実施例５
大豆油１６ｍＬとＰＧＣＲ４ｍＬを混合した油相に、５ｍｇ／ｍＬのＢＳＡ水溶液２０ｍＬを滴下混合して６７時間撹拌し、平均内水滴径１．５２６μｍの乳化物を得た。ロータリーエバポレーターを用いて、この乳化物を４０℃に加温しながら一時間減圧脱水し、ＢＳＡの分散平均粒子径５７．３ｎｍの均一な油性外用製剤を得た。
Example 5
To an oil phase in which 16 mL of soybean oil and 4 mL of PGCR were mixed, 20 mL of 5 mg / mL BSA aqueous solution was added dropwise and stirred for 67 hours to obtain an emulsion having an average inner water droplet diameter of 1.526 μm. Using a rotary evaporator, this emulsion was dehydrated under reduced pressure for 1 hour while warming to 40 ° C. to obtain a uniform oily external preparation having a BSA dispersion average particle diameter of 57.3 nm.
実施例６
５ｍｇ／ｍＬのチトクロームＣ水溶液を用いたほかは、実施例６と同様の処理を行った。撹拌後の平均内水滴径は８４９ｎｍ、チトクロームＣの分散平均粒子径は４３．１ｎｍであり、透明な外観であった。
Example 6
The same treatment as in Example 6 was performed, except that a 5 mg / mL cytochrome C aqueous solution was used. The average internal water droplet diameter after stirring was 849 nm, and the dispersion average particle diameter of cytochrome C was 43.1 nm, which was a transparent appearance.
実施例７
５ｍｇ／ｍＬのミオグロビン水溶液を用いたほかは、実施例６と同様の処理を行った。撹拌後の平均内水滴径は９１８ｎｍ、ミオグロビンの分散平均粒子径は９７．５ｎｍであり、透明な外観であった。
Example 7
The same treatment as in Example 6 was performed except that a 5 mg / mL myoglobin aqueous solution was used. The average internal water droplet diameter after stirring was 918 nm, and the dispersion average particle diameter of myoglobin was 97.5 nm, which was a transparent appearance.
実施例８
５ｍｇ／ｍＬのヘモグロビン水溶液を用いたほかは、実施例６と同様の処理を行った。撹拌後の平均内水滴径は１，０７４ｎｍ、ヘモグロビンの分散平均粒子径は５１．５ｎｍであり、透明な外観であった。
Example 8
The same treatment as in Example 6 was performed except that a 5 mg / mL hemoglobin aqueous solution was used. The average internal water droplet diameter after stirring was 1,074 nm, and the dispersion average particle diameter of hemoglobin was 51.5 nm, which was a transparent appearance.
実施例９
５ｍｇ／ｍＬのゼラチン水溶液を用いたほかは、実施例６と同様の処理を行った。撹拌後の平均内水滴径は１，４２３ｎｍ、ゼラチンの分散平均粒子径は５１．５ｎｍであり、透明な外観であった。
Example 9
The same treatment as in Example 6 was performed except that a 5 mg / mL gelatin aqueous solution was used. The average internal water droplet size after stirring was 1,423 nm, and the dispersed average particle size of gelatin was 51.5 nm, which was a transparent appearance.
実施例１０
２０ｍｇ／ｍＬのＦＤ７０水溶液を用いたほかは、実施例６と同様の処理を行った。撹拌後の平均内水滴径は６２３ｎｍ、ＦＤ７０の分散平均粒子径は５０．０ｎｍであり、透明な外観であった。
Example 10
The same treatment as in Example 6 was performed except that a 20 mg / mL aqueous FD70 solution was used. The average internal water droplet diameter after stirring was 623 nm, and the dispersion average particle diameter of FD70 was 50.0 nm, which was a transparent appearance.
試験例１
実施例５〜１０で得られた油性外用製剤を室温にて保存し、９ヵ月後にそれぞれ分散粒子径Ｄｓを測定した。その結果、外観はほとんど変化がなく、平均粒子径（５０％Ｄｓ）の変化率Ｒ（Ｒ＝［｜調製直後と９ヶ月保存後の粒子径差｜／調製直後のＤｓ］／１００［％］）は２０％以下であった。これら実施例５〜１０の結果を表２及び図１に示す。
Test example 1
The oily external preparations obtained in Examples 5 to 10 were stored at room temperature, and the dispersed particle diameter Ds was measured after 9 months. As a result, the appearance hardly changed, and the change rate R of the average particle size (50% Ds) R (R = [| Difference in particle size immediately after preparation and after storage for 9 months | / Ds immediately after preparation] / 100 [%] ) Was 20% or less. The results of Examples 5 to 10 are shown in Table 2 and FIG.
実施例１１
大豆油１６ｍＬとＰＧＣＲ４ｍＬを混合した油相と、１０ｍｇ／ｍＬのオリゴコラーゲン（分子量約１，０００）水溶液２０ｍＬを、ホモジナイザイーを用いて１６，０００ｒｐｍで５分間撹拌混合し、乳化物を得た。ロータリーエバポレーターを用いて、この乳化物を４０℃に加温しながら一時間減圧脱水し、オリゴコラーゲン分散平均粒子径９９．０ｎｍ、水分含量０．０８％の均一な油性外用製剤を得た。この製剤について分散粒子径Ｄｓを測定し、その累積１０％Ｄと累積５０％Ｄの比（Ｒ１＝１０％Ｄ／５０％Ｄ［％］）及び累積９０％Ｄと累積５０％Ｄの比（Ｒ２＝９０％Ｄ／５０％Ｄ［％］）を求めた結果、Ｒ１が７２％、Ｒ２が１３８％であり、単分散分布であった。活性粒子の粒度分布を図２に示す。また、前記の分散粒子径等を表３に示す。
Example 11
An oil phase obtained by mixing 16 mL of soybean oil and 4 mL of PGCR and 20 mL of a 10 mg / mL aqueous solution of oligocollagen (molecular weight of about 1,000) were stirred and mixed at 16,000 rpm for 5 minutes using a homogenizer to obtain an emulsion. Using a rotary evaporator, this emulsion was dehydrated under reduced pressure for 1 hour while heating to 40 ° C. to obtain a uniform oily external preparation having an oligocollagen dispersed average particle size of 99.0 nm and a water content of 0.08%. The dispersion particle diameter Ds of this preparation was measured, and the ratio of cumulative 10% D to cumulative 50% D (R1 = 10% D / 50% D [%]) and the ratio of cumulative 90% D to cumulative 50% D ( R2 = 90% D / 50% D [%]) As a result, R1 was 72% and R2 was 138%, which was a monodisperse distribution. The particle size distribution of the active particles is shown in FIG. In addition, Table 3 shows the dispersed particle diameter and the like.
実施例１２
１０ｍｇ／ｍＬのバンコマイシン塩酸塩（分子量１，４８５．７１）水溶液を用いたほかは、実施例１１と同様の処理を行った。バンコマイシン分散平均粒子径８１．８ｎｍ、水分含量０．１７％の均一な油性外用製剤を得た。また、実施例１１と同様にしてＲ１及びＲ２を求めた。その結果、Ｒ１は７２％、Ｒ２は１４０％であり、単分散分布であった。活性粒子の粒度分布を図２に示す。また、前記の分散粒子径等を表３に示す。
Example 12
The same treatment as in Example 11 was performed, except that an aqueous solution of 10 mg / mL vancomycin hydrochloride (molecular weight 1,485.71) was used. A uniform oily external preparation having a vancomycin dispersion average particle diameter of 81.8 nm and a water content of 0.17% was obtained. Further, R1 and R2 were determined in the same manner as in Example 11. As a result, R1 was 72% and R2 was 140%, which was a monodisperse distribution. The particle size distribution of the active particles is shown in FIG. In addition, Table 3 shows the dispersed particle diameter and the like.
実施例１３
１０ｍｇ／ｍＬのポリビニルアルコール（分子量２，８００）水溶液を用いたほかは、実施例１１と同様の処理を行った。ポリビニルアルコール分散平均粒子径５５．８ｎｍ、水分含量０．０９％の均一な油性外用製剤を得た。また、実施例１１と同様にしてＲ１及びＲ２を求めた。その結果、Ｒ１は６９％、Ｒ２は１４７％であり、単分散分布であった。活性粒子の粒度分布を図２に示す。また、前記の分散粒子径等を表３に示す。
Example 13
The same treatment as in Example 11 was performed except that a 10 mg / mL aqueous solution of polyvinyl alcohol (molecular weight 2,800) was used. A uniform oily external preparation having a polyvinyl alcohol dispersion average particle size of 55.8 nm and a water content of 0.09% was obtained. Further, R1 and R2 were determined in the same manner as in Example 11. As a result, R1 was 69% and R2 was 147%, which was a monodisperse distribution. The particle size distribution of the active particles is shown in FIG. In addition, Table 3 shows the dispersed particle diameter and the like.
比較例４
１０ｍｇ／ｍＬのトリパンブルー（分子量９６０．８１）水溶液を用いたほかは、実施例１１と同様の処理を行った。トリパンブルーは色素であり、着色のため動的光散乱法では測定できなかった。水分含量は６．９１％であった。
Comparative Example 4
The same treatment as in Example 11 was performed, except that a 10 mg / mL aqueous solution of trypan blue (molecular weight 960.81) was used. Trypan blue is a pigment and could not be measured by dynamic light scattering due to coloration. The water content was 6.91%.
実施例１４
活性成分として生薬を用いた油性外用製剤を調製した。
１）生薬抽出液の調製
重炭酸ナトリウム、炭酸カルシウム、ウイキョウ、ダイオウ、ゲンノショウコ、コウブシ、カンゾウ、ニンジン、オウバク、チンピ、ガジュツ、オウゴン、ニガキ、コウボク、カミツレ、ボレイ、キキョウコン、クレンピ及びセンキュウの破砕混合物１００ｇをさらし袋に入れ、水２Ｌ中で加熱し、水分が約半量になるまで煮出した。次いで、得られた煮出し液を二重ガーゼで漉し、３０００ｒｐｍで３０分間遠心し、回収した遠心上清を細孔径０．０２μｍのAnodisc（Whatman製）に５ＭＰａのガス圧で透過させ、沈殿物のない生薬抽出液を得た。
Example 14
An oily external preparation using a crude drug as an active ingredient was prepared.
1) Preparation of herbal extract Sodium bicarbonate, Calcium Carbonate, Fennel, Daio, Gennosho, Koubushi, Licorice, Carrot, Pepper, Chimpi, Gadju, Ogon, Nigaki, Koboku, Chamomile, Boray, Kyokokon, Krempi and Senku 100 g of the mixture was placed in an exposed bag, heated in 2 L of water, and boiled until the water content was about half. Next, the resulting boiled liquid was crushed with double gauze, centrifuged at 3000 rpm for 30 minutes, and the collected centrifugal supernatant was permeated through an Anodisc (manufactured by Whatman) with a pore size of 0.02 μm at a gas pressure of 5 MPa. No crude drug extract was obtained.
２）油性外用製剤の調製
大豆油８０ｍＬとＰＧＣＲ２０ｍＬの混合油相に、前記１）の抽出液１００ｍＬを滴下混合し、ホモミキサーを用いて１６，０００ｒｐｍで５分間撹拌した。これを５６℃に加温しながらロータリーエバポレーターを用いて減圧脱水し、生薬成分含有油性外用製剤を得た。生薬成分の分散平均粒子径は１０２．５ｎｍであり、褐色でやや透明感のある外観であった。
2) Preparation of oily external preparation 100 mL of the extract of 1) above was mixed in a mixed oil phase of soybean oil 80 mL and PGCR 20 mL and stirred at 16,000 rpm for 5 minutes using a homomixer. This was dehydrated under reduced pressure using a rotary evaporator while heating to 56 ° C. to obtain a crude drug component-containing oily external preparation. The dispersion average particle diameter of the crude drug component was 102.5 nm, and the appearance was brown and slightly transparent.
試験例２
ユカタンマイクロ豚（５ヶ月齢メス、チャールズ・リバー社）背部皮膚を、皮下脂肪を取り除き、直径約３ｃｍに切り出して縦型拡散セル（バイオコム・システムズ）に設置した。拡散セルのレセプター側に１０ｍＬのリン酸緩衝生理食塩水（ＰＢＳ）をいれ、セルジャケットに恒温槽より温水を循環させ、セル内環境を３７℃に保たせる状態とした。ドナー側に、リン酸緩衝生理食塩水（ＰＢＳ）２００μＬを添加し、ガラス玉で蓋をした。レセプター相をスターラーで緩やかに撹拌し、１８時間後に皮膚を回収した。回収した皮膚をエタノールで２回リンスして表面に付着している成分を除去し、直径８ｍｍのバイオプシーパンチを用いて同一面積の皮膚を切り出し、テープストリップにて角質層を採取し、ピンセットで表皮層を真皮層から剥離した。表皮層と真皮層はメスで細かく裁断した。メタノールにて４８時間浸漬後、ホモジナイザーで氷中にて５分撹拌抽出し、１２０００ｒｐｍにて５分間遠心を行い、上清を抽出サンプルとして、各層から抽出された成分について、実施例１４の前記１）の生薬抽出液の凍結乾燥品を検量線に用い、分光光度計にて２６８ｎｍの吸収を測定して単位面積当たりの生薬成分貯留量を算出した。この試験例をコントロールとした。
Test example 2
Yucatan micropig (5-month-old female, Charles River) dorsal skin was removed of subcutaneous fat, cut into a diameter of about 3 cm, and placed in a vertical diffusion cell (Biocom Systems). 10 mL of phosphate buffered saline (PBS) was added to the receptor side of the diffusion cell, and warm water was circulated from the thermostatic chamber to the cell jacket so that the internal environment of the cell was maintained at 37 ° C. To the donor side, 200 μL of phosphate buffered saline (PBS) was added, and the lid was covered with a glass ball. The receptor phase was gently stirred with a stirrer and the skin was collected after 18 hours. The collected skin is rinsed twice with ethanol to remove the components adhering to the surface, the skin of the same area is cut out using a biopsy punch with a diameter of 8 mm, the stratum corneum is collected with a tape strip, and the epidermis is collected with tweezers. The layer was peeled from the dermis layer. The epidermis layer and dermis layer were finely cut with a scalpel. After soaking in methanol for 48 hours, the mixture was stirred and extracted in ice with a homogenizer for 5 minutes, centrifuged at 12000 rpm for 5 minutes, and the components extracted from each layer using the supernatant as an extraction sample, the above 1 of Example 14 ) Was used as a calibration curve, and absorption at 268 nm was measured with a spectrophotometer to calculate the amount of stored crude drug components per unit area. This test example was used as a control.
試験例３
試験例２と同じ条件で、ＰＢＳに代えてドナー槽に実施例１４の前記１）の生薬抽出液（水溶成分抽出液）２００μＬを添加して試験例２と同様に皮膚を処理し、皮膚各層の生薬成分貯留量を算出した。その結果を図３に示す。
Test example 3
Under the same conditions as in Test Example 2, the skin was treated in the same manner as in Test Example 2 by adding 200 μL of the herbal extract (aqueous component extract) of Example 1 above in Example 14 to the donor tank instead of PBS. The crude drug component storage amount was calculated. The result is shown in FIG.
試験例４
試験例２と同じ条件で、ＰＢＳに代えてドナー槽に実施例１５の前記２）の油性外用製剤２００μＬを添加して試験例２と同様に皮膚を処理し、皮膚各層の生薬貯留量を算出した。その結果を図３に示す。
図３からも明らかなように、試験例４の油性外用製剤は、試験例３の抽出液に対して２倍以上の生薬成分が角質層へ達しており、表皮層においては試験例４の油性外用製剤が生薬成分の貯留、すなわち表皮層への浸透性に優れていることがわかる。
Test example 4
Under the same conditions as in Test Example 2, instead of PBS, 200 μL of the oily external preparation of Example 15 2) above was added to the donor tank, the skin was treated in the same manner as in Test Example 2, and the amount of herbal medicine stored in each skin layer was calculated. did. The result is shown in FIG.
As apparent from FIG. 3, the oily external preparation of Test Example 4 has more than twice the amount of herbal medicine components reaching the stratum corneum with respect to the extract of Test Example 3, and the oily property of Test Example 4 in the epidermal layer. It can be seen that the preparation for external use is excellent in the storage of crude drug components, that is, the permeability to the epidermis layer.
試験例５
牛白癬（Ｔｒｉｃｏｐｈｙｔｏｎ ｖｅｒｒｕｃｏｓｕｍ）に罹患している子牛の体表に実施例１４の前記１）の煮出した生薬抽出液を４日間連続噴霧し、経過観察を行った。その結果、９週間後には患部がほぼ治癒したことから、生薬抽出液の治療効果を確認した。
Test Example 5
The herbal extract boiled in 1) of Example 14 was sprayed continuously for 4 days on the body surface of a calf suffering from trichophyton verrucosum, followed by follow-up. As a result, the affected area was almost healed after 9 weeks, and the therapeutic effect of the herbal extract was confirmed.
試験例６
生薬抽出液に代わりに実施例１４の前記１）の不溶物をろ過により除去した生薬抽出液を用いたほかは、試験例５と同様にして罹患子牛（別個体）の体表に４日間連続して前記製剤を噴霧し、経過観察を行った。その結果、９週間後には患部がほぼ治癒した。このことから、生薬抽出液の濾過により治療効果が変化しないことを確認した。
Test Example 6
4 days on the body surface of the affected calf (separate body) in the same manner as in Test Example 5 except that the crude drug extract obtained by removing the insoluble matter of Example 1) by filtration was used instead of the crude drug extract. The formulation was continuously sprayed and followed up. As a result, the affected area was almost cured after 9 weeks. From this, it was confirmed that the therapeutic effect was not changed by filtration of the herbal extract.
試験例７
牛白癬に罹患している子牛の右顔面に、実施例１４の前記１）の生薬抽出液（１０重量％抽出液）１００ｍＬを霧吹きで患部を含む領域全体に噴霧し、これを週一回、５週間後まで継続し、観察した。治療前、２週間、４週間後に患部より落剥を採取して培養し、菌コロニー数をカウントした。その結果を図４に示す。
Test Example 7
On the right face of a calf suffering from cattle ringworm, 100 mL of the herbal medicine extract (10 wt% extract) of Example 1 above was sprayed on the entire area including the affected area by spraying, and this was performed once a week. Observation continued for 5 weeks. Before treatment, 2 weeks and 4 weeks later, the exfoliation was collected from the affected area and cultured, and the number of bacterial colonies was counted. The result is shown in FIG.
試験例８
試験例７と同個体の子牛の左顔面の患部に、実施例１４の前記２）の油性外用製剤（１０重量％抽出液相当の成分含有製剤）２０ｍＬを患部全体に塗布し、これを週一回、５週間後まで継続し、観察した。試験例５〜７では、薬液が液状であることから患部のみに塗布するのが困難なため、霧吹きで患部を含めた領域全体に噴霧したが、油性製剤は粘性があり患部になじめが良いため、患部のみに塗布することが可能になり、少量で患部全体に行き渡らせることができた。治療前、２週間、４週間後に患部より落剥を採取して培養し、菌コロニー数をカウントした。その結果を図４に示す。
Test Example 8
20 mL of the oily topical preparation of Example 14 (component-containing preparation equivalent to 10% by weight extract) was applied to the affected area on the left face of the calf of the same individual as in Test Example 7, and this was applied to the entire affected area. The observation was continued once until 5 weeks later. In Test Examples 5 to 7, it was difficult to apply only to the affected area because the chemical solution was liquid, and thus the spray was sprayed over the entire area including the affected area with a mist sprayer, but the oil-based preparation is viscous and is well adapted to the affected area. It was possible to apply only to the affected area, and it was possible to spread the entire affected area with a small amount. Before treatment, 2 weeks and 4 weeks later, the exfoliation was collected from the affected area and cultured, and the number of bacterial colonies was counted. The result is shown in FIG.
図４の結果からも明らかなように、５週間では、実施例１４の前記１）生薬抽出液では患部かさぶた（白い部分）に変化がなく、治癒に至らなかった（白い部分（患部）がなお存在している）のに対し、実施例１４の前記２）の油性外用製剤では投与量が少ないにもかかわらず、一週間後からかさぶたの減少と発毛が認められ、２週間後からは患部落剥より菌が検出されなくなり、５週間後に完治した。 As is clear from the results of FIG. 4, in 5 weeks, the above-mentioned 1) herbal medicine extract of Example 14 showed no change in the affected scab (white part) and did not lead to healing (the white part (affected part) was still On the other hand, in the oily external preparation of Example 14 above, the scab reduction and hair growth were observed after one week despite the small dose, and the disease was observed after two weeks. Bacteria were no longer detected from the exfoliation, and the disease was completely cured after 5 weeks.
本発明製剤は、特に皮膚より作用させる多様な薬剤・生理活性物質の送達システム（ＤＤＳシステム）に有効利用することができる。例えば、皮膚創傷治療、真菌症治療、育毛、皮膚保湿等の皮膚に関わる多様な目的に対し、所望の効果をもたらすことが可能である。具体的には、ヒト用医薬品及び動物用医薬品として、また医薬部外品又は化粧品として、多様な成分の皮膚浸透性等に優れた製品に提供することができる。また、本発明製剤は、経皮ワクチン等への応用も期待される。 The preparation of the present invention can be effectively used for a delivery system (DDS system) of various drugs and physiologically active substances that act from the skin. For example, it is possible to bring a desired effect to various skin-related purposes such as skin wound treatment, mycosis treatment, hair growth, skin moisturizing and the like. Specifically, it can be provided as a human drug and veterinary drug, as a quasi-drug or as a cosmetic, in a product excellent in skin permeability of various components. The preparation of the present invention is also expected to be applied to transdermal vaccines and the like.
Claims (16)
（１）活性成分が生薬の水抽出成分及び／又は分子量１０００以上の親水性高分子であり、
（２）活性粒子の平均粒子径が２００ｎｍ以下であり、
（３）水分含有量が０．５重量％以下である、
（４）界面活性剤が、テトラグリセリン縮合リシノレイン酸エステル、ヘキサグリセリン縮合リシノレイン酸エステル、デカグリセリン縮合リシノレイン酸エステル及びポリグリセリン縮合リシノレイン酸エステルの少なくとも１種であり、
（５）当該界面活性剤の含有量が油剤及び界面活性剤の合計量に対して１２重量％以上であり、
（６）当該製剤の調製直後の活性粒子の平均粒子径に対する９ヶ月静置後の当該平均粒子径の変化率が２０％以下である、
ことを特徴とする油性外用製剤。 An oily external preparation comprising an active ingredient, a surfactant and an oil, wherein the active particles containing the active ingredient are monodispersed in an oil phase containing the surfactant and the oil ,
(1) The active ingredient is a herbal extract component and / or a hydrophilic polymer having a molecular weight of 1000 or more,
(2) The average particle diameter of the active particles is 200 nm or less,
(3) The water content is 0.5% by weight or less,
(4) The surfactant is at least one of tetraglycerin condensed ricinoleic acid ester, hexaglycerin condensed ricinoleic acid ester, decaglycerin condensed ricinoleic acid ester and polyglycerin condensed ricinoleic acid ester,
(5) The content of the surfactant is 12% by weight or more based on the total amount of the oil agent and the surfactant,
(6) The rate of change of the average particle size after standing for 9 months relative to the average particle size of the active particles immediately after preparation of the formulation is 20% or less,
An oily external preparation characterized by that.
The production method according to claim 13 , wherein the emulsion is a W / O emulsion.
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| KR101744137B1 (en) | 2017-03-16 | 2017-06-07 | 강원대학교산학협력단 | Microemulsion composition of natural product extract with enhanced oral absorption and process for the preparation thereof |
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