JP4438147B2 - Powder aerosol formulation containing antifungal agent - Google Patents
Powder aerosol formulation containing antifungal agent Download PDFInfo
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- JP4438147B2 JP4438147B2 JP34791499A JP34791499A JP4438147B2 JP 4438147 B2 JP4438147 B2 JP 4438147B2 JP 34791499 A JP34791499 A JP 34791499A JP 34791499 A JP34791499 A JP 34791499A JP 4438147 B2 JP4438147 B2 JP 4438147B2
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Description
【0001】
【発明の属する技術分野】
本発明は抗真菌剤を含むエアゾール製剤に関し、更に詳しくは患部を乾燥させ治癒を促進させる目的から粉末成分を配合した抗真菌剤含有エアゾールにおいて、抗真菌剤の十分な効果が期待できる粉末エアゾール製剤に関するものである。
【0002】
【従来の技術】
皮膚における真菌感染症には、白癬、カンジタ症、澱風等があり、皮膚症状としては、紅斑と落屑からなる乾燥型と、紅斑、小水疱、浸軟、びらんを呈する湿潤型とがある。これらの治療には抗真菌剤が用いられ、製剤としても、軟膏、クリーム剤、液剤、エアゾール剤など多くの剤形が開発されている。そんな中で湿潤型のジュクジュクした患部を乾かし、治療を早めたり2次感染を防止する目的で、抗真菌剤と粉末成分を配合した粉末エアゾール製剤が開発されている。特開平5−246843号には乾式スプレー型の抗真菌剤含有組成物の開示がある。特開平8−12964号には、皮膚からの脱落がしにくい抗真菌剤を含んだ粉末エアゾール剤についての開示がある。
【0003】
近年、白癬菌ばかりでなく、カンジタ菌に対しても抗菌スペクトルを有する硝酸ミコナゾール、硝酸エコナゾール、硝酸オキシコナゾールなどのアゾール系薬物が真菌感染症に対して賞用されている。しかしながら、これらの薬物は外用剤に一般的に使用される基剤成分の水やアルコールなどの溶媒に対する溶解度が極めて低い。このため、特開平4−173734号では、ジフェンヒドラミン、リドカイン、ジエタノールアミンなどのアミン類を用いて抗真菌剤を外用基剤に溶解して配合した抗真菌性外用剤が開示されている。しかしながら、この技術は、多量の外用基剤に抗真菌剤を溶解する技術であって、粉末エアゾール製剤のような速乾性を要求されることから少量の溶解成分しか配合できない製剤や多量の噴射剤が貧溶媒として作用してしまうエアゾール製剤では抗真菌剤を溶解することができない。結晶状態でエアゾール製剤中に存在している抗真菌剤は、結晶状態で噴射塗布されるため、角質への吸収性、浸透性が低く、実際の治療効果は十分ではない。また、抗真菌剤が結晶状態でエアゾール缶の底に沈降しているため、使用前の振とうが不十分な場合は、エアゾール缶中の抗真菌剤が均一に分散されず、目的とした薬剤濃度の塗布ができず、十分な治療効果が期待できない。
【0004】
【発明が解決しようとする課題】
本発明は、速乾性を要求されることから少量の溶解成分しか配合できない粉末エアゾール製剤中において、抗真菌剤を溶解状態で存在させた抗真菌剤含有粉末エアゾール製剤を提供するものである。
【0005】
【課題を解決するための手段】
本発明者らは前記課題を解決すべく鋭意研究を行った結果、抗真菌剤に低級アルコールとイソプロパノールアミン類及びアミルアミン類の少なくとも一方を組み合わせて配合することにより、またそれらを所定量とすることにより、噴射剤を充填しても抗真菌剤がエアゾール製剤中で均一に溶解状態で存在させることができることを見出し、本発明を完成した。
すなわち、本発明は、抗真菌剤、低級アルコール、イソプロパノールアミン類及びアミルアミン類の少なくとも一方並びに噴射剤を含有することを特徴とする抗真菌剤含有粉末エアゾール製剤である。
【0006】
【発明の実施の形態】
本発明において、抗真菌剤とは、難溶性で知られるアゾール系の抗真菌剤が好適に用いられる。アゾール系抗真菌剤中、特にエタノールに溶けにくい、硝酸ミコナゾール、硝酸エコナゾール、硝酸オキシコナゾール、硝酸スルコナゾール、ケトコナゾール、ラトコナゾール、イトラコナゾールなどが好ましい。抗真菌剤の配合量は、製剤全量中0.03%〜5質量%である。これらは、薬物の有効性と安全性を考慮して決められる。
【0007】
低級アルコールは、噴射時の粉末の皮膚への付着性を向上させたり、有効成分を溶解する目的で用いられる液状の基剤の一成分として有効である。本発明で低級アルコールとは炭素数1〜3の一価アルコールであり、例えばメタノール、エタノール、イソプロパノール、変性エタノールなどを挙げることができる。特にエタノール及びイソプロパノールが好ましい。これらの成分は、抗真菌剤の溶解を助ける基剤となるとともに、沸点が比較的低く、粉末エアゾール剤の特徴である、速乾性を付与する液状基剤として有効である。配合量としては、製剤全量中1〜20質量%、好ましくは3〜15質量%である。配合量が1%未満では抗真菌剤の溶解を助けることができず、20%以上では抗真菌剤含有粉末エアゾール剤としての速乾性が実現できなくなってしまう。
【0008】
本発明では、抗真菌剤の溶解性を助ける成分として、更にイソプロパノールアミン類及びアミルアミン類の少なくとも一方を配合する必要がある。他のアミン類では本発明の目的を達成することができない。イソプロパノールアミン類としては、モノイソプロパノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミンなどが挙げられる。アミルアミン類としては、ノルマルアミルアミン、イソアミルアミン、ネオアミルアミン等などが挙げられる。これらは低級アルコールと共に配合することにより、抗真菌剤の溶解性を向上させ、貧溶媒として作用する噴射剤を充填しても、抗真菌剤の析出が認められなくなる。これらの物質の配合量としては、製剤全量中0.001〜5質量%。好ましくは0.01〜3質量%である。0.001質量%以下では上記目的を達成することが難しく、また5質量%以上では、皮膚に対する安全性が懸念される。
【0009】
粉末エアゾール剤とするために添加される粉末成分は、有効成分の皮膚への付着性を高めたり、湿潤部の乾燥性を向上させたり、滑り、潤沢性などを向上させて使用感を向上させたり、又は、粉末エアゾール剤の製造適性を考慮する等の目的で配合されるものである。それらは特に限定はされないが、例えば、無機粉末としては無水ケイ酸、ケイ酸マグネシウム、タルク、カオリン、アエロジル、マイカ、酸化亜鉛、酸化チタン、酸化マグネシウム、炭酸マグネシウム、カラミン、メタケイ酸アルミン酸マグネシウムなどが挙げられ、有機粉末としてコンスターチ、馬鈴薯デンプン、ナイロンパウダー、ポリエチレンパウダー、ポリスチレンパウダー、セルロースパウダーなどが挙げられる。これらの粉末成分は、単独で又は2種以上を混合して用いられる。粉末成分の配合量は製剤全量中0.5〜15質量%、好ましくは2〜10質量%である。配合量が0.5質量%未満では、上記目的を満足させることが難しく、また15%以上では、粉末による噴射詰まりが発生して好ましくない。
【0010】
本発明において、噴射剤としては液化ガスが用いられる。それらのうち液化石油ガスが好ましく、その他ジメチルエーテルを添加してもよい。噴射剤の配合量は製剤全量中65〜98質量%、好ましくは75〜95質量%である。なお、ここでの液化石油ガスは、通常のプロパン、イソブタン、ノルマルブタンの他、ノルマルペンタン、イソペンタン、ネオペンタンなどの成分の組み合わせも含む。
【0011】
本発明では、抗真菌剤の作用を補助する目的で、特に限定はしないが、局所麻酔薬(リドカイン、アミノ安息香酸エチルなど)、消炎剤(アラントイン、酸化亜鉛など)、殺菌剤(塩化デカリニウム、塩化ベンザルコニウムなど)、抗ヒスタミン剤(ジフェンヒドラミン、マレイン酸クロルフェニラミンなど)、清涼化剤(l−メントール、dl−カンフルなど)などを配合することができる。
その他、有効成分の吸収、浸透性の向上、皮膚安全性の向上、エアゾール製剤中での粉末の分散安定性の向上、噴射時の粉末及び有効成分の展着性向上、使用感の向上等の目的で、特に限定はしないが、以下のものを配合することができる。例えば、シリコーンオイル(メチルポリシロキサンなど)、炭化水素(流動パラフィン、スクワランなど)、高級脂肪酸エステル(ミリスチン酸イソプロピル、ミリスチン酸オクチルドデシル、ステアリン酸ブチルなど)、植物油(オリーブ油、ヒマシ油など)、動物油(ミツロウ、スクワレンなど)、非イオン性界面活性剤(セスキオレイン酸ソルビタン、ポリグリセリン脂肪酸エステルなど)などがあり、これらは単独で又は2種以上を混合して用いられ、適量配合される。
【0012】
【発明の効果】
本発明の抗真菌剤含有粉末エアゾール製剤は、エアゾール剤中において抗真菌剤を溶解状態で存在させることが可能であり、そのため、薬物の角質への浸透性が高く、常に均一な薬物濃度の噴射塗布が可能であり、更に速乾性で使用感がよく、粉末により患部を乾燥させる効果に優れる。このため、白癬、カンジタ症、澱風などの真菌性皮膚疾患に優れた治療効果と使用感を示す粉末エアゾール剤を提供することができる。
【0013】
【実施例】
次に、実施例により本発明を詳細に説明する。なお、本発明はこれにより限定されるものではない。配合量は質量%で示した。
【0014】
実施例1〜5、比較例1〜8
表1及び2に示した処方にて、常法によりエアゾール剤を製造した。
【0015】
試験例1[抗真菌剤のエアゾール剤中での溶解状態]
表1及び2に示した実施例又は比較例中の液相及び噴射剤をガラス耐圧瓶に充填し(粉末成分は充填しない)、抗真菌剤のエアゾール剤中での溶解状態を評価した。
溶解 :ガラス耐圧瓶中の液状内容物は一液で、抗真菌剤は溶解している。
非溶解:ガラス耐圧瓶の液状内容物の底に抗真菌剤が結晶又は油状物として沈降している。
【0016】
【表1】
【0017】
【表2】
【0018】
実施例6及び比較例9
表3に示した処方にて、常法によりエアゾール剤を製造した。
【0019】
試験例2[基剤からの薬物の放出性評価]
表3に示した実施例又は比較例のエアゾール剤をシリコンゴム膜(2.5cm×2.5cm)に噴射塗布し、35℃湿度75%の環境下に保存し、6時間後と12時間後のシリコンゴム膜中の硝酸ミコナゾール濃度を測定し、製剤の基剤からの硝酸ミコナゾールの放出性を評価した。試験は3回繰り返し、その平均値を求めた。結果を表3に示した。
放出率%=(シリコンゴム膜内硝酸ミコナゾール量/シリコンゴム膜塗布硝酸ミコナゾール量)×100
【0020】
試験例3[角質貯留性評価]
表3に示した実施例又は比較例のエアゾール剤をヘアレスラット腹部に噴射塗布し、6時間後に皮膚上の塗布残留物をアルコール溶液を染み込ませたレーヨン布で拭き取り後、透明粘着テープにて塗布部の角質層を剥がし、そこに含まれる硝酸ミコナゾール量を測定し、角質内に貯留している薬物量を求めた。試験は3回繰り返し、その平均値を求めた。結果を表3に示した。
【0021】
【表3】
【0022】
実施例6は基剤からの硝酸ミコナゾールの放出性が高く、ラットを用いた実験において、皮膚真菌症の真菌の存在場所である角質内への硝酸ミコナゾールの貯留量も高く、高い治療効果が期待できる。使用感においても、噴射塗布後直ちに乾燥し、さらさらの使用感があった。比較例9は結晶状態で噴射されるため基剤からの放出性が低く、角質への貯留量も少なく、十分な治療効果が期待できない。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an aerosol preparation containing an antifungal agent, and more specifically, in an antifungal agent-containing aerosol containing a powder component for the purpose of drying the affected area and promoting healing, a powder aerosol preparation that can be expected to have a sufficient effect of the antifungal agent It is about.
[0002]
[Prior art]
Fungal infections in the skin include ringworm, candidiasis, starch and the like. Skin symptoms include a dry type consisting of erythema and desquamation, and a wet type showing erythema, small blisters, maceration and erosion. Antifungal agents are used for these treatments, and many dosage forms such as ointments, creams, liquids, and aerosols have been developed as preparations. Under such circumstances, a powder aerosol formulation containing an antifungal agent and a powder component has been developed for the purpose of drying the affected part of the wet type and accelerating treatment or preventing secondary infection. JP-A-5-246843 discloses a dry spray type antifungal agent-containing composition. Japanese Patent Application Laid-Open No. 8-12964 discloses a powder aerosol containing an antifungal agent that does not easily fall off the skin.
[0003]
In recent years, azole drugs such as miconazole nitrate, econazole nitrate, and oxyconazole nitrate, which have an antibacterial spectrum not only against ringworm but also against Candida, have been used for fungal infections. However, these drugs have extremely low solubility in a solvent such as water or alcohol of base components generally used for external preparations. For this reason, JP-A-4-173734 discloses an antifungal external preparation prepared by dissolving an antifungal agent in an external base using amines such as diphenhydramine, lidocaine and diethanolamine. However, this technique is a technique for dissolving an antifungal agent in a large amount of a base for external use, and requires quick drying such as a powder aerosol formulation. In an aerosol formulation that acts as a poor solvent, the antifungal agent cannot be dissolved. Since the antifungal agent present in the aerosol formulation in the crystalline state is spray-applied in the crystalline state, it has low absorbability and penetrability into the keratin, and the actual therapeutic effect is not sufficient. In addition, since the antifungal agent has settled in the bottom of the aerosol can in a crystalline state, the antifungal agent in the aerosol can is not uniformly dispersed when shaking before use is insufficient, and the intended drug The concentration cannot be applied, and a sufficient therapeutic effect cannot be expected.
[0004]
[Problems to be solved by the invention]
The present invention provides an antifungal agent-containing powder aerosol formulation in which an antifungal agent is present in a dissolved state in a powder aerosol formulation in which only a small amount of dissolved components can be blended because quick drying is required.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors have formulated a combination of at least one of a lower alcohol, isopropanolamines and amylamines with an antifungal agent, and set them to a predetermined amount. Thus, the present inventors have found that even when filled with a propellant, the antifungal agent can be present in a uniform dissolved state in the aerosol preparation, and the present invention has been completed.
That is, the present invention is an antifungal agent-containing powder aerosol formulation characterized by containing at least one of an antifungal agent, a lower alcohol, isopropanolamines and amylamines, and a propellant.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, as the antifungal agent, an azole antifungal agent known to be hardly soluble is preferably used. Of the azole antifungal agents, miconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, ketoconazole, latoconazole, itraconazole and the like are particularly preferable. The compounding amount of the antifungal agent is 0.03% to 5% by mass in the total amount of the preparation. These are determined taking into account the effectiveness and safety of the drug.
[0007]
The lower alcohol is effective as one component of a liquid base used for the purpose of improving the adhesion of the powder upon injection to the skin or dissolving the active ingredient. In the present invention, the lower alcohol is a monohydric alcohol having 1 to 3 carbon atoms, and examples thereof include methanol, ethanol, isopropanol, and modified ethanol. Ethanol and isopropanol are particularly preferable. These components are effective as a liquid base imparting quick drying, which is a base that assists dissolution of the antifungal agent, has a relatively low boiling point, and is characteristic of a powder aerosol. As a compounding quantity, it is 1-20 mass% in a formulation whole quantity, Preferably it is 3-15 mass%. If the blending amount is less than 1%, dissolution of the antifungal agent cannot be assisted, and if it is 20% or more, quick drying as an antifungal agent-containing powder aerosol cannot be realized.
[0008]
In this invention, it is necessary to mix | blend at least one of isopropanolamines and amylamines as a component which assists the solubility of an antifungal agent. Other amines cannot achieve the object of the present invention. Examples of isopropanolamines include monoisopropanolamine, diisopropanolamine, and triisopropanolamine. Examples of amylamines include normal amylamine, isoamylamine, neoamylamine and the like. When these are mixed with a lower alcohol, the solubility of the antifungal agent is improved, and even when a propellant that acts as a poor solvent is filled, precipitation of the antifungal agent is not recognized. The compounding amount of these substances is 0.001 to 5% by mass in the total amount of the preparation. Preferably it is 0.01-3 mass%. If it is 0.001% by mass or less, it is difficult to achieve the above object, and if it is 5% by mass or more, there is a concern about safety against the skin.
[0009]
The powder component added to make a powder aerosol agent improves the feeling of use by improving the adhesion of the active ingredient to the skin, improving the dryness of the wet part, and improving the sliding and abundantness. Or blended for the purpose of considering the suitability for production of powder aerosols. Although they are not particularly limited, for example, inorganic powders such as silicic anhydride, magnesium silicate, talc, kaolin, aerosil, mica, zinc oxide, titanium oxide, magnesium oxide, magnesium carbonate, calamine, magnesium aluminate metasilicate, etc. Examples of the organic powder include starch, potato starch, nylon powder, polyethylene powder, polystyrene powder, and cellulose powder. These powder components are used alone or in admixture of two or more. The compounding quantity of a powder component is 0.5-15 mass% in a formulation whole quantity, Preferably it is 2-10 mass%. If the blending amount is less than 0.5% by mass, it is difficult to satisfy the above-mentioned purpose, and if it is 15% or more, injection clogging with the powder occurs, which is not preferable.
[0010]
In the present invention, liquefied gas is used as the propellant. Among them, liquefied petroleum gas is preferable, and other dimethyl ether may be added. The amount of the propellant is 65 to 98% by mass, preferably 75 to 95% by mass, based on the total amount of the preparation. Here, the liquefied petroleum gas includes a combination of components such as normal pentane, isopentane and neopentane in addition to normal propane, isobutane and normal butane.
[0011]
In the present invention, for the purpose of assisting the action of the antifungal agent, although not particularly limited, local anesthetics (such as lidocaine and ethyl aminobenzoate), anti-inflammatory agents (such as allantoin and zinc oxide), bactericides (such as decalinium chloride, Benzalkonium chloride, etc.), antihistamines (diphenhydramine, chlorpheniramine maleate, etc.), cooling agents (l-menthol, dl-camphor, etc.) and the like can be blended.
In addition, absorption of active ingredients, improved permeability, improved skin safety, improved dispersion stability of powders in aerosol formulations, improved spreadability of powders and active ingredients during spraying, improved usability, etc. Although it does not specifically limit with the objective, The following can be mix | blended. For example, silicone oil (such as methylpolysiloxane), hydrocarbon (such as liquid paraffin, squalane), higher fatty acid ester (such as isopropyl myristate, octyldodecyl myristate, butyl stearate), vegetable oil (such as olive oil, castor oil), animal oil (Such as beeswax and squalene), nonionic surfactants (such as sorbitan sesquioleate and polyglycerin fatty acid ester), and the like. These may be used alone or in admixture of two or more, and may be blended in appropriate amounts.
[0012]
【The invention's effect】
The antifungal agent-containing powder aerosol formulation of the present invention allows the antifungal agent to be present in a dissolved state in the aerosol agent. Therefore, the drug has a high permeability to the keratin and is always sprayed with a uniform drug concentration. It can be applied, is quick-drying and has a good feeling of use, and is excellent in the effect of drying the affected area with powder. For this reason, the powder aerosol agent which shows the therapeutic effect excellent in fungal skin diseases, such as ringworm, candidiasis, and starch, and a feeling of use can be provided.
[0013]
【Example】
Next, the present invention will be described in detail by way of examples. In addition, this invention is not limited by this. The blending amount is indicated by mass%.
[0014]
Examples 1-5, Comparative Examples 1-8
Aerosols were produced by conventional methods with the formulations shown in Tables 1 and 2.
[0015]
Test Example 1 [Dissolved state of antifungal agent in aerosol agent]
The liquid phase and propellant in Examples and Comparative Examples shown in Tables 1 and 2 were filled into glass pressure-resistant bottles (no powder component was filled), and the dissolution state of the antifungal agent in the aerosol was evaluated.
Dissolution: The liquid content in the glass pressure-resistant bottle is one solution, and the antifungal agent is dissolved.
Non-dissolving: The antifungal agent is precipitated as crystals or oil at the bottom of the liquid contents of the glass pressure bottle.
[0016]
[Table 1]
[0017]
[Table 2]
[0018]
Example 6 and Comparative Example 9
With the formulation shown in Table 3, an aerosol was produced by a conventional method.
[0019]
Test Example 2 [Evaluation of drug release from base]
The aerosol agents of Examples or Comparative Examples shown in Table 3 were spray-coated on a silicone rubber film (2.5 cm × 2.5 cm) and stored in an environment of 35 ° C. and 75% humidity, after 6 hours and 12 hours. The concentration of miconazole nitrate in the silicone rubber film was measured to evaluate the release of miconazole nitrate from the formulation base. The test was repeated three times and the average value was determined. The results are shown in Table 3.
Release rate% = (Amount of miconazole nitrate in silicon rubber film / Amount of miconazole nitrate coated with silicon rubber film) × 100
[0020]
Test Example 3 [Evaluation of keratin retention]
The aerosols of Examples or Comparative Examples shown in Table 3 were spray-applied to the abdomen of hairless rats, and after 6 hours, the application residue on the skin was wiped off with a rayon cloth soaked with an alcohol solution and then applied with a transparent adhesive tape. The stratum corneum was peeled off, the amount of miconazole nitrate contained therein was measured, and the amount of drug stored in the stratum corneum was determined. The test was repeated three times and the average value was determined. The results are shown in Table 3.
[0021]
[Table 3]
[0022]
Example 6 has a high releasability of miconazole nitrate from the base. In an experiment using rats, the amount of miconazole nitrate stored in the stratum corneum where the fungus of dermatomycosis is present is high, and a high therapeutic effect is expected. it can. In terms of the feeling of use, it was dried immediately after spray coating and had a smooth feeling of use. Since Comparative Example 9 is injected in a crystalline state, the release from the base is low, the amount stored in the stratum corneum is small, and a sufficient therapeutic effect cannot be expected.
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JP3783104B2 (en) * | 2004-03-31 | 2006-06-07 | 小林製薬株式会社 | Antifungal composition for external use |
KR20060009093A (en) * | 2004-07-20 | 2006-01-31 | 송재신 | Powder spray composition containing terbinafine hcl |
JP3800232B2 (en) * | 2004-09-30 | 2006-07-26 | 小林製薬株式会社 | Antifungal composition for external use |
JP2006232856A (en) * | 2006-06-05 | 2006-09-07 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
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JP2006232854A (en) * | 2006-06-05 | 2006-09-07 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
CN100448443C (en) * | 2006-09-21 | 2009-01-07 | 西北农林科技大学 | Nanometer antifungal econazole nitrate emulsion medicine and its prepn process |
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