JP7518466B2 - External pharmaceutical composition - Google Patents
External pharmaceutical composition Download PDFInfo
- Publication number
- JP7518466B2 JP7518466B2 JP2020045940A JP2020045940A JP7518466B2 JP 7518466 B2 JP7518466 B2 JP 7518466B2 JP 2020045940 A JP2020045940 A JP 2020045940A JP 2020045940 A JP2020045940 A JP 2020045940A JP 7518466 B2 JP7518466 B2 JP 7518466B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- minoxidil
- retinol
- present
- units
- 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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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 77
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical group CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 claims description 54
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 claims description 47
- 229960003632 minoxidil Drugs 0.000 claims description 47
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Natural products OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 40
- -1 polyoxyethylene Polymers 0.000 claims description 28
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- 239000004359 castor oil Substances 0.000 claims description 27
- 235000019438 castor oil Nutrition 0.000 claims description 27
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 27
- 239000011769 retinyl palmitate Chemical group 0.000 claims description 27
- 235000019172 retinyl palmitate Nutrition 0.000 claims description 27
- 229940108325 retinyl palmitate Drugs 0.000 claims description 27
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 20
- 229960003471 retinol Drugs 0.000 claims description 20
- 235000020944 retinol Nutrition 0.000 claims description 20
- 239000011607 retinol Substances 0.000 claims description 20
- 229960000342 retinol acetate Drugs 0.000 claims description 4
- 239000011770 retinyl acetate Chemical group 0.000 claims description 4
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- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical group CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 3
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- 125000002523 retinol group Chemical group 0.000 claims description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 42
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- 238000002360 preparation method Methods 0.000 description 15
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- 230000000694 effects Effects 0.000 description 6
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
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- FUWUEFKEXZQKKA-UHFFFAOYSA-N beta-thujaplicin Chemical compound CC(C)C=1C=CC=C(O)C(=O)C=1 FUWUEFKEXZQKKA-UHFFFAOYSA-N 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
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- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、ミノキシジル及びレチノール又はその誘導体を配合した外用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for external use that contains minoxidil and retinol or a derivative thereof.
ミノキシジルは化学名を6-(1-ピペリジニル)-2、4-ピリミジンジアミン-3-オキサイドと称し、育毛剤としての適応が知られており(特許文献1)、優れた育毛・発毛効果を発揮する薬剤として多数の報告がある。 Minoxidil has the chemical name 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide and is known for its use as a hair growth agent (Patent Document 1), with numerous reports of it being a drug with excellent hair growth and hair regrowth effects.
ミノキシジルを配合した育毛剤に求められる基本的な性能は、頭皮からのミノキシジルの吸収性に優れることである(特許文献2)。頭皮からのミノキシジルの吸収性を確保するためには、製剤中のミノキシジルが溶解状態で存在することが好ましく、製剤中で結晶析出等が生じないことが求められる。ミノキシジルは水やほとんどの油に対して溶解性が悪く、特に高濃度のミノキシジルの溶解性を確保するため、エタノールの配合や、リン酸やクエン酸などの酸を配合して製剤のpHを調整することが広く行われている(特許文献3、4)。 The basic performance required for a hair growth agent containing minoxidil is excellent absorption of minoxidil from the scalp (Patent Document 2). To ensure absorption of minoxidil from the scalp, it is preferable that minoxidil in the formulation is present in a dissolved state, and it is required that crystal precipitation does not occur in the formulation. Minoxidil has poor solubility in water and most oils, and in order to ensure solubility of minoxidil, especially at high concentrations, it is common to add ethanol or an acid such as phosphoric acid or citric acid to adjust the pH of the formulation (Patent Documents 3 and 4).
一方、レチノール又はその誘導体は、皮膚や粘膜の機能を正常化することが知られる成分である(特許文献5)。レチノール又はその誘導体は脂溶性が高く油に溶解する成分である。 On the other hand, retinol or its derivatives are components known to normalize the functions of the skin and mucous membranes (Patent Document 5). Retinol and its derivatives are highly lipid-soluble components that dissolve in oil.
ミノキシジルは油に対して溶解性が悪いが、レチノール又はその誘導体は脂溶性が高く油に溶解する成分である。本発明者らは、これらを配合した製剤を調製すると、直後に製剤が白濁し、レチノール由来の油滴が残存することが分かった。すなわち、ミノキシジルとレチノール又はその誘導体はそれぞれ配合する手段が異なり、両成分を配合しても直後に分離や濁りがなく、油滴のない安定な製剤を検討する必要があることが分かった。 While minoxidil has poor solubility in oil, retinol or its derivatives are highly lipid-soluble and dissolve in oil. The inventors found that when they prepared a formulation containing these ingredients, the formulation immediately became cloudy and oil droplets derived from retinol remained. In other words, the means of blending minoxidil and retinol or its derivatives are different, and it was found that it was necessary to consider a stable formulation that does not separate or become cloudy immediately after blending the two ingredients and is free of oil droplets.
本発明は、上記事情に鑑みなされたもので、ミノキシジルとレチノール又はその誘導体を配合し、透明な外用医薬組成物を提供することを課題とする。 The present invention has been made in consideration of the above circumstances, and aims to provide a transparent topical pharmaceutical composition that combines minoxidil and retinol or a derivative thereof.
本発明者らは、上記課題を解決すべく鋭意検討を重ねた結果、意外なことに、ミノキシジル、レチノール又はその誘導体、特定の非イオン界面活性剤、及び低級アルコールを配合すると、調製直後に製剤が白濁せず、レチノールパルミチン酸エステル由来の油滴が残存しない、透明な製剤が得られることを見出し、本発明を完成するに至った。 As a result of extensive research aimed at solving the above problems, the inventors unexpectedly discovered that by combining minoxidil, retinol or a derivative thereof, a specific nonionic surfactant, and a lower alcohol, a transparent formulation can be obtained that does not become cloudy immediately after preparation and does not leave oil droplets derived from retinol palmitate, leading to the completion of the present invention.
すなわち本発明は、
(1)(a)ミノキシジル、(b)レチノール又はその誘導体、(c)ポリオキシエチレン硬化ヒマシ油、(d)低級アルコールを含有することを特徴とする外用医薬組成物、
(2)ミノキシジルの濃度が5w/v%以上である、(1)に記載の外用医薬組成物、
(3)レチノール又はその誘導体の濃度が0.1万~100万単位/100mLである、(1)に記載の外用医薬組成物、
(4)剤形が、液剤、ローション剤、エアゾール剤、トニック剤、又はゲル剤である、(1)~(3)のいずれかに記載の外用医薬組成物、
である。
That is, the present invention provides:
(1) A pharmaceutical composition for external application, comprising (a) minoxidil, (b) retinol or a derivative thereof, (c) polyoxyethylene hydrogenated castor oil, and (d) a lower alcohol;
(2) The pharmaceutical composition for external application according to (1), wherein the concentration of minoxidil is 5 w/v% or more.
(3) The pharmaceutical composition for external application according to (1), wherein the concentration of retinol or a derivative thereof is 1,000 to 1,000,000 units/100 mL.
(4) The pharmaceutical composition for external application according to any one of (1) to (3), which is in the form of a liquid, a lotion, an aerosol, a tonic, or a gel.
It is.
本発明により、ミノキシジル及びレチノール又はその誘導体を含有し、透明な外用医薬組成物を提供することが可能になった。 The present invention makes it possible to provide a transparent topical pharmaceutical composition that contains minoxidil and retinol or a derivative thereof.
本発明の外用医薬組成物において用いるミノキシジルは、通常医薬品に用いられる品質のものを適宜使用することができる。また、本発明における外用医薬組成物において、ミノキシジルの含有量が多くなるにつれミノキシジルの溶解性の課題が大きくなるため、外用医薬組成物中におけるミノキシジルの濃度が高いほど、本発明を実施する意義が大きい。具体的には、本発明の外用医薬組成物中3w/v%以上が好ましく、より好ましくは5w/v%以上であり、上限は15w/v%である。 The minoxidil used in the topical pharmaceutical composition of the present invention may be of the quality normally used in pharmaceuticals. In addition, in the topical pharmaceutical composition of the present invention, as the minoxidil content increases, the problem of minoxidil solubility becomes greater, so the higher the concentration of minoxidil in the topical pharmaceutical composition, the greater the significance of implementing the present invention. Specifically, the concentration of minoxidil in the topical pharmaceutical composition of the present invention is preferably 3 w/v% or more, more preferably 5 w/v% or more, with the upper limit being 15 w/v%.
本発明の外用医薬組成物中におけるレチノール又はその誘導体としては、レチノール、レチノールパルミチン酸エステル、レチノール酢酸エステル、ビタミンA油などが挙げられる。本発明のレチノール又はその誘導体の含有量は、本発明の効果の点から本発明の外用医薬組成物中好ましくは0.1万~100万単位/100mLであり、より好ましくは1万~20万単位/100mLである。また、低温保存時の製剤安定性の観点から、さらに好ましくは1万~12万単位/100mLであり、さらに好ましくは1万~5万単位/100mLである。 Examples of retinol or a derivative thereof in the topical pharmaceutical composition of the present invention include retinol, retinol palmitate, retinol acetate, vitamin A oil, etc. The content of retinol or a derivative thereof in the topical pharmaceutical composition of the present invention is preferably 1,000 to 1,000,000 units/100 mL, more preferably 10,000 to 200,000 units/100 mL, from the viewpoint of the effects of the present invention. Furthermore, from the viewpoint of formulation stability during low-temperature storage, it is even more preferably 10,000 to 120,000 units/100 mL, even more preferably 10,000 to 50,000 units/100 mL.
本発明の外用医薬組成物中における特定の界面活性剤とは、ポリオキシエチレン硬化ヒマシ油である。本発明のポリオキシエチレン硬化ヒマシ油としては、ポリオキシエチレン硬化ヒマシ油40、ポリオキシエチレン硬化ヒマシ油50、ポリオキシエチレン硬化ヒマシ油60などが挙げられる。本発明のポリオキシエチレン硬化ヒマシ油の含有量は、本発明の低温安定性の効果の点から本発明の外用医薬組成物中0.001w/v%以上が好ましく、より好ましくは0.005w/v%以上である。また、上限は皮膚刺激性などの安全性やミノキシジルの皮膚吸収も考慮すると3w/v%以下が好ましく、より好ましくは2w/v%以下である。本発明のポリオキシエチレン硬化ヒマシ油の含有量は、本発明の効果の点からレチノール又はその誘導体の1重量部に対して1重量部~50重量部がより好ましい。 The specific surfactant in the topical pharmaceutical composition of the present invention is polyoxyethylene hydrogenated castor oil. Examples of the polyoxyethylene hydrogenated castor oil of the present invention include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60. The content of the polyoxyethylene hydrogenated castor oil of the present invention is preferably 0.001 w/v% or more in the topical pharmaceutical composition of the present invention in terms of the effect of low temperature stability of the present invention, and more preferably 0.005 w/v% or more. In addition, the upper limit is preferably 3 w/v% or less, and more preferably 2 w/v% or less, taking into consideration safety such as skin irritation and dermal absorption of minoxidil. The content of the polyoxyethylene hydrogenated castor oil of the present invention is more preferably 1 to 50 parts by weight per 1 part by weight of retinol or its derivative in terms of the effect of the present invention.
また、本発明の低級アルコールとしては、炭素数1~5のものが好ましく、例えばエタノールやイソプロパノールなどが好ましく、これらを組み合わせて使用しても良い。本発明の低級アルコールの含有量は、本発明の外用医薬組成物中20w/v%以上が好ましく、より好ましくは30w/v%以上であり、更に好ましくは35w/v%以上であり、更に好ましくは50w/v%以上である。上限は80w/v%が好ましい。 The lower alcohol of the present invention is preferably one having 1 to 5 carbon atoms, such as ethanol or isopropanol, and these may be used in combination. The content of the lower alcohol of the present invention in the topical pharmaceutical composition of the present invention is preferably 20 w/v% or more, more preferably 30 w/v% or more, even more preferably 35 w/v% or more, and even more preferably 50 w/v% or more. The upper limit is preferably 80 w/v%.
本発明の外用医薬組成物のpH調整は、通常使用されるpH調整剤を使用することができ、具体的には、例えば、クエン酸、リンゴ酸、乳酸、酒石酸などの有機酸やリン酸、塩酸、硫酸などの無機酸を挙げることができる。低温保存時の製剤安定性の観点から、酒石酸以外の有機酸や無機酸が好ましい。本発明の医薬外用組成物のpHは、5~8.1に調整することが好ましい。 The pH of the topical pharmaceutical composition of the present invention can be adjusted using a commonly used pH adjuster, and specific examples include organic acids such as citric acid, malic acid, lactic acid, and tartaric acid, and inorganic acids such as phosphoric acid, hydrochloric acid, and sulfuric acid. From the viewpoint of formulation stability during low-temperature storage, organic acids other than tartaric acid and inorganic acids are preferred. The pH of the topical pharmaceutical composition of the present invention is preferably adjusted to 5 to 8.1.
本発明の外用医薬組成物には、多価アルコールを配合することができ、具体的には、例えば1,3-ブチレングリコール、プロピレングリコール、グリセリン、ポリエチレングリコールなどが挙げられる。多価アルコールの含有量は、本発明の外用医薬組成物中0.1w/v%以上、好ましくは5w/v%以上、より好ましくは10w/v%以上であり、上限はべたつきが少なくなるなどの使用感も考慮すると30w/v%以下が好ましい。 The topical pharmaceutical composition of the present invention may contain a polyhydric alcohol, specific examples of which include 1,3-butylene glycol, propylene glycol, glycerin, and polyethylene glycol. The content of the polyhydric alcohol in the topical pharmaceutical composition of the present invention is 0.1 w/v% or more, preferably 5 w/v% or more, and more preferably 10 w/v% or more, with the upper limit being preferably 30 w/v% or less, taking into consideration the feeling of use, such as reduced stickiness.
本発明の外用医薬組成物は、更に必要により水を配合することができる。水の含有量は、本発明の外用医薬組成物中2~75w/v%が好ましく、より好ましくは5~50w/v%であり、更に好ましくは5~30w/v%である。 The topical pharmaceutical composition of the present invention may further contain water as necessary. The content of water in the topical pharmaceutical composition of the present invention is preferably 2 to 75 w/v%, more preferably 5 to 50 w/v%, and even more preferably 5 to 30 w/v%.
本発明の外用医薬組成物は、上記した各成分の他に、本発明の効果を損なわない範囲で、必要な活性成分や補助成分を加えることができる。本発明の外用医薬組成物に添加、配合することが好ましい薬効成分としては、メントール、ビタミンEアセテート、ヒノキチオール、塩酸ピリドキシン、グリチルレチン酸、塩酸ジフェンヒドラミン、パントテニールエチルエーテルから成る群より選ばれた成分が挙げられる。 In addition to the above-mentioned components, the topical pharmaceutical composition of the present invention may contain necessary active ingredients and auxiliary ingredients within the scope of not impairing the effects of the present invention. Examples of medicinal ingredients that are preferably added or blended into the topical pharmaceutical composition of the present invention include ingredients selected from the group consisting of menthol, vitamin E acetate, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, diphenhydramine hydrochloride, and pantothenyl ethyl ether.
これら選択成分の添加量は、特に制約はなく、使用感やミノキシジルの安定性又は溶剤系組成等を考慮しながら実験的に定めることができる。 There are no particular restrictions on the amounts of these optional ingredients that can be added, and they can be determined experimentally while taking into consideration the feel when used, the stability of minoxidil, the composition of the solvent system, etc.
本発明の外用医薬組成物においては、上記した成分の他、本発明の効果を損なわない範囲で、一般の外用剤に用いられる種々の活性成分や補助成分を配合することができる。例えば、賦形剤、育毛成分(6-ベンジルアミノプリン、アデノシン、ペンタデカン酸グリセリド、何首鳥等)、血管拡張剤(塩化カルプロニウム、ニコチン酸ベンジル、センブリ抽出液、オタネニンジンエキス、チクセツニンジンチンキ、トウガラシチンキ等)、抗ヒスタミン剤(塩酸イソチペンジル等)、抗炎症剤(グアイアズレン等)、角質溶解剤(尿素、サリチル酸等)、殺菌剤(グルコン酸クロルヘキシジン、イソプロピルメチルフェノール、第4級アンモニウム塩、ピロクトンオラミン等)、保湿剤(ヒアルロン酸又はその塩、コンドロイチン硫酸等)、各種動植物(イチイ、ボタンピ、カンゾウ、オトギリソウ、附子、ビワ、カワラヨモギ、コンフリー、アシタバ、サフラン、サンシシ、ローズマリー、セージ、モッコウ、セイモッコウ、ホップ、プラセンタ、ノコギリヤシ、パンプキンシード等)の抽出物、ビタミン類(アスコルビン酸、硝酸チアミン、シアノコバラミン、ビオチン等)、抗酸化剤(ジブチルヒドロキシトルエン、ピロ亜硫酸ナトリウム、トコフェロール、エデト酸ナトリウム、アスコルビン酸、イソプロピルガレート等)、溶解補助剤(アジピン酸ジイソプロピル、ミリスチン酸イソプロピル、各種植物油、各種動物油、アルキルグリセリルエーテル、炭化水素類等)、代謝賦活剤、ゲル化剤(水溶性高分子等)、粘着剤、香料、清涼化剤(ハッカ油、カンフル等)、染料等の通常使用される成分を配合することができる。 In addition to the above-mentioned ingredients, the topical pharmaceutical composition of the present invention may contain various active ingredients and auxiliary ingredients used in general topical preparations, provided that the effects of the present invention are not impaired. For example, excipients, hair growth ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, Polygonum polycuta, etc.), vasodilators (carpronium chloride, benzyl nicotinate, Swertia japonica extract, Panax ginseng extract, Panax ginseng tincture, Capsicum anguicum tincture, etc.), antihistamines (isothipendyl hydrochloride, etc.), anti-inflammatory agents (guaiazulene, etc.), keratolytic agents (urea, salicylic acid, etc.), bactericides (chlorhexidine gluconate, isopropylmethylphenol, quaternary ammonium salts, piroctone olamine, etc.), moisturizers (hyaluronic acid or its salts, chondroitin sulfate, etc.), various plants and animals (yew, moutan pi, licorice, Hypericum perforatum, aconite, loquat, artemisia capillaris, comfrey, angelica tree, It can contain commonly used ingredients such as extracts of saffron, Sanshishi, rosemary, sage, Saussurea japonica, Seimokko, hops, placenta, saw palmetto, pumpkin seed, etc., vitamins (ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizers (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), metabolic activators, gelling agents (water-soluble polymers, etc.), adhesives, fragrances, refreshing agents (peppermint oil, camphor, etc.), and dyes.
また、本発明の外用医薬組成物は、液状の剤形であることが好ましく、例えば液剤、ローション剤、エアゾール剤、トニック剤、ゲル剤などの適当な外用医薬組成物とすることができる。 The topical pharmaceutical composition of the present invention is preferably in a liquid dosage form, and can be in the form of a suitable topical pharmaceutical composition, such as a liquid, lotion, aerosol, tonic, or gel.
本発明の外用医薬組成物の調製は、常法に従い、上記各成分を含有することにより調製される。 The topical pharmaceutical composition of the present invention is prepared by incorporating the above-mentioned components according to a conventional method.
かくして得られる本発明の外用医薬組成物は、頭髪用剤、睫毛用剤、眉毛用剤等の皮膚適用製剤等として使用することができる。 The thus obtained topical pharmaceutical composition of the present invention can be used as a skin application preparation, such as for hair, eyelashes, or eyebrows.
以下に、実施例、比較例及び試験例を記載し、本発明をさらに具体的に説明するが、本発明はこれら実施例等により何ら制約されるものではない。 The present invention will be explained in more detail below with reference to examples, comparative examples, and test examples, but the present invention is not limited in any way by these examples.
(実施例1)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.14の外用医薬組成物を得た。
Example 1
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.14.
(実施例2)
ミノキシジル5g、レチノールパルミチン酸エステル20万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.15の外用医薬組成物を得た。
Example 2
5 g of minoxidil, 200,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.15.
(実施例3)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を0.0268g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.16の外用医薬組成物を得た。
Example 3
5 g of minoxidil, 50,000 units of retinol palmitate, 0.0268 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.
(実施例4)
ミノキシジル5g、レチノールパルミチン酸エステル1万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.12の外用医薬組成物を得た。
Example 4
5 g of minoxidil, 10,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.12.
(実施例5)
ミノキシジル5g、レチノールパルミチン酸エステル12万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.16の外用医薬組成物を得た。
Example 5
5 g of minoxidil, 120,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.
(実施例6)
ミノキシジル5g、レチノールパルミチン酸エステル1万単位、ポリオキシエチレン硬化ヒマシ油40を0.00536g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.12の外用医薬組成物を得た。
Example 6
5 g of minoxidil, 10,000 units of retinol palmitate, 0.00536 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.12.
(実施例7)
ミノキシジル5g、レチノール酢酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.17の外用医薬組成物を得た。
(Example 7)
5 g of minoxidil, 50,000 units of retinol acetate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.17.
(実施例8)
ミノキシジル5g、レチノール5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.16の外用医薬組成物を得た。
(Example 8)
5 g of minoxidil, 50,000 units of retinol, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.
(実施例9)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、濃グリセリン10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH5.98の外用医薬組成物を得た。
Example 9
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of concentrated glycerin, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 5.98.
(実施例10)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、プロピレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.09の外用医薬組成物を得た。
Example 10
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of propylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.09.
(実施例11)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、濃グリセリン10g、プロピレングリコール10g、エタノール50g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH5.84の外用医薬組成物を得た。
(Example 11)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of concentrated glycerin, 10 g of propylene glycol, 50 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 5.84.
(実施例12)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油50を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.11の外用医薬組成物を得た。
Example 12
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 50, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.11.
(実施例13)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油60を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.16の外用医薬組成物を得た。
(Example 13)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 60, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.
(実施例14)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、クエン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.34の外用医薬組成物を得た。
(Example 14)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of citric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.34.
(実施例15)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、エタノール60g、乳酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.24の外用医薬組成物を得た。
(Example 15)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of lactic acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.24.
(実施例16)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、ポリエチレングリコール0.2g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.16の外用医薬組成物を得た。
(Example 16)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 0.2 g of polyethylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.
(実施例17)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール14g、プロピレングリコール11g、エタノール40g、酒石酸適量、精製水で全量を100mLとし、撹拌溶解してpH6.38の外用医薬組成物を得た。
(Example 17)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 14 g of 1,3-butylene glycol, 11 g of propylene glycol, 40 g of ethanol, an appropriate amount of tartaric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.38.
(実施例18)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリオキシエチレン硬化ヒマシ油40を1g、1,3-ブチレングリコール10g、濃グリセリン10g、エタノール50g、リン酸適量、精製水で全量を100mLとし、撹拌溶解してpH8.03の外用医薬組成物を得た。
(Example 18)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 10 g of concentrated glycerin, 50 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 8.03.
(比較例1)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ポリソルベート60を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌した。撹拌後も製剤が白濁し、透明な製剤は調製できなかった。
(Comparative Example 1)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polysorbate 60, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred. Even after stirring, the preparation remained cloudy, and a transparent preparation could not be prepared.
(比較例2)
ミノキシジル5g、レチノールパルミチン酸エステル20万単位、ポリソルベート60を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌した。撹拌後も製剤が白濁し、透明な製剤は調製できなかった。
(Comparative Example 2)
5 g of minoxidil, 200,000 units of retinol palmitate, 1 g of polysorbate 60, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred. Even after stirring, the preparation remained cloudy, and a transparent preparation could not be prepared.
(比較例3)
ミノキシジル5g、レチノールパルミチン酸エステル5万単位、ステアリン酸ポリオキシル40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌した。撹拌後も製剤が白濁し、レチノールパルミチン酸エステルの油滴も残存し、透明な製剤は調製できなかった。
(Comparative Example 3)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyl 40 stearate, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred. Even after stirring, the preparation was cloudy and oil droplets of retinol palmitate remained, and a transparent preparation could not be prepared.
(比較例4)
ミノキシジル5g、レチノールパルミチン酸エステル20万単位、ステアリン酸ポリオキシル40を1g、1,3-ブチレングリコール10g、エタノール60g、リン酸適量、精製水で全量を100mLとし、撹拌した。撹拌後も製剤が白濁し、レチノールパルミチン酸エステルの油滴も残存し、透明な製剤は調製できなかった。
(Comparative Example 4)
5 g of minoxidil, 200,000 units of retinol palmitate, 1 g of polyoxyl 40 stearate, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred. Even after stirring, the preparation was cloudy and oil droplets of retinol palmitate remained, and a transparent preparation could not be prepared.
実施例1~18、比較例1~4の処方及び調製後のpHを表1~表2に示す。 The formulations and post-preparation pH for Examples 1 to 18 and Comparative Examples 1 to 4 are shown in Tables 1 and 2.
(製剤の外観)
実施例1~18、比較例1~4の調製直後の外観を評価した。製剤の外観が透明であるものを○、透明でないものを×とした。結果を表3~4に示す。
(Appearance of the formulation)
The appearance of the preparations immediately after preparation was evaluated for Examples 1 to 18 and Comparative Examples 1 to 4. Preparations with a transparent appearance were rated as ◯, and those with a non-transparent appearance were rated as ×. The results are shown in Tables 3 and 4.
比較例1~2の製剤は、白濁し、透明な製剤は調製できなかった。また、比較例3~4の製剤は、白濁し、レチノールパルミチン酸エステル由来の油滴も認められた。一方、実施例1~18の製剤はミノキシジル及びレチノールパルミチン酸エステル、レチノール酢酸エステル、レチノールを可溶化し、透明な製剤が得られた。 The formulations of Comparative Examples 1 and 2 were cloudy, and a transparent formulation could not be prepared. The formulations of Comparative Examples 3 and 4 were cloudy, and oil droplets derived from retinol palmitate were also observed. On the other hand, the formulations of Examples 1 to 18 solubilized minoxidil, retinol palmitate, retinol acetate, and retinol, and a transparent formulation was obtained.
(低温安定性)
実施例1~18の製剤をそれぞれ30mLの透明ペットボトル容器に25mLずつ充填し、5℃1週間保存した結果、実施例2の製剤は容器底面に白色粒状の析出物が認められたが、その他実施例の製剤では析出物は認めらなかった。
(Low temperature stability)
25 mL of each of the formulations of Examples 1 to 18 was filled into a 30 mL transparent PET bottle and stored at 5°C for 1 week. As a result, white granular precipitates were observed on the bottom of the container for the formulation of Example 2, but no precipitates were observed for the formulations of the other Examples.
この結果から、製剤中のレチノール又は誘導体の濃度は12万単位/100mLまでが低温保存時の製剤安定性も良好という最も好ましい結果となった。 These results show that a concentration of retinol or a derivative in the formulation of up to 120,000 units/100 mL is the most favorable for providing good formulation stability when stored at low temperatures.
本発明により、ミノキシジル、及びレチノール又はその誘導体を含有した外用組成物において、製剤安定性に優れた外用医薬組成物を提供することが可能になった。 The present invention makes it possible to provide a topical pharmaceutical composition containing minoxidil and retinol or its derivatives, which has excellent formulation stability.
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JP2001199843A (en) | 2000-01-13 | 2001-07-24 | Hifu Rinsho Yakuri Kenkyusho Kk | Hair growing agent |
JP2002060322A (en) | 2000-07-11 | 2002-02-26 | L'oreal Sa | Composition for reducing fallen hair and/or for promoting growth of hair, comprising vitamins and inorganic salts as base |
JP2003012468A (en) | 2001-06-28 | 2003-01-15 | Kaminomoto Co Ltd | Promoter for restoration and growth of hair |
JP2009519936A (en) | 2005-12-16 | 2009-05-21 | マレック,シェーン | Carrier composition for topical administration and therapeutic formulation containing the same |
JP2011051980A (en) | 2009-08-05 | 2011-03-17 | Taisho Pharmaceutical Co Ltd | Hair-growing agent |
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JP2001199843A (en) | 2000-01-13 | 2001-07-24 | Hifu Rinsho Yakuri Kenkyusho Kk | Hair growing agent |
JP2002060322A (en) | 2000-07-11 | 2002-02-26 | L'oreal Sa | Composition for reducing fallen hair and/or for promoting growth of hair, comprising vitamins and inorganic salts as base |
JP2003012468A (en) | 2001-06-28 | 2003-01-15 | Kaminomoto Co Ltd | Promoter for restoration and growth of hair |
JP2009519936A (en) | 2005-12-16 | 2009-05-21 | マレック,シェーン | Carrier composition for topical administration and therapeutic formulation containing the same |
JP2011051980A (en) | 2009-08-05 | 2011-03-17 | Taisho Pharmaceutical Co Ltd | Hair-growing agent |
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