JP2017186317A - Amorphizing agent, amorphous composition comprising amorphizing agent, and utilization thereof - Google Patents
Amorphizing agent, amorphous composition comprising amorphizing agent, and utilization thereof Download PDFInfo
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Abstract
Description
本発明は、以下の一般式(1)で表される化合物及び/又はその塩の非晶質化剤、該非晶質化剤を含んでなる非晶質の組成物並びにその使用に関する。 The present invention relates to an amorphizing agent for a compound represented by the following general formula (1) and / or a salt thereof, an amorphous composition comprising the amorphizing agent, and use thereof.
ルリコナゾール或いはラノコナゾールといった一般式(1)で表される化合物は、結晶性が高く、すぐれた抗真菌活性を有していることが知られているが、その反面、結晶析出性も高く、製造工程において扱いにくい特性を有している。また、安定性の面でも光安定性に難があるため、製造或いは製剤化の工程において、時間がかかりすぎると、類縁体の産生量が多くなる可能性も存していた(例えば、特許文献1〜2を参照)。また、製剤においても即時的結晶化が生体内への移行を阻害することもこれらの特許文献では明らかにされ、結晶化の抑制手段の開発も一般式(1)で表される化合物の製剤上の課題でもあった。また、これらの特許文献には、乳酸などのα−ヒドロキシ酸が一般式(1)で表される化合物の即時結晶性を抑制することも開示されていたが、かかる即時結晶性の抑制がどの様なメカニズムによるかは全く開示されていない。 The compound represented by the general formula (1) such as luliconazole or lanconazole is known to have high crystallinity and excellent antifungal activity, but on the other hand, the crystal precipitation is also high, and the production process It is difficult to handle. In addition, there is also a possibility that the production amount of analogs increases if it takes too much time in the process of production or formulation because the light stability is also difficult in terms of stability (for example, patent document) 1-2). In addition, these patent documents also show that immediate crystallization inhibits the transfer into the living body in the preparation, and the development of a means for suppressing crystallization is also possible on the preparation of the compound represented by the general formula (1). It was also an issue. In addition, these patent documents also disclose that α-hydroxy acids such as lactic acid suppress the immediate crystallinity of the compound represented by the general formula (1). It is not disclosed at all whether such a mechanism is used.
この様な結晶化の抑制技術としては、例えば、ポリオキシエチレンポリオキシプロピレン等の可塑剤を大過剰に用い液状の粘ちょう性被膜を作成する技術が知られていた(例えば、特許文献3を参照)が、かかる技術では被膜に含有できる一般式(1)で表される化合物の質量が限られている欠点が存した。 As a technique for suppressing such crystallization, for example, a technique of creating a liquid viscous film using a plasticizer such as polyoxyethylene polyoxypropylene in a large excess has been known (for example, Patent Document 3). However, this technique has a drawback in that the mass of the compound represented by the general formula (1) that can be contained in the film is limited.
一般的に、非晶質化することにより、溶解性、特に溶解速度が改善されることは知られている。その為、注射剤などでは非晶質化が重要な技術となっている(例えば、特許文献4を参照)。 In general, it is known that the amorphization improves the solubility, particularly the dissolution rate. Therefore, amorphization is an important technique for injections and the like (see, for example, Patent Document 4).
一方、一般式(1)で表される化合物について、単斜晶の結晶系は知られているが、非晶質の固体については全く知られていない。 On the other hand, for the compound represented by the general formula (1), a monoclinic crystal system is known, but an amorphous solid is not known at all.
即ち、一般式(1)で表される化合物及び/又はその塩の使用性を高めるべく、一般式(1)で表される化合物及び/又はその塩の非晶質化技術の開発が望まれていた。 That is, in order to improve the usability of the compound represented by the general formula (1) and / or a salt thereof, development of an amorphization technique for the compound represented by the general formula (1) and / or a salt thereof is desired. It was.
本発明は、このような状況下為されたものであり、一般式(1)で表される化合物及び/又はその塩の使用性を高めるべく、一般式(1)で表される化合物及び/又はその塩の非晶質化技術を提供することを課題とする。 The present invention has been made under such circumstances, and in order to enhance the usability of the compound represented by the general formula (1) and / or a salt thereof, the compound represented by the general formula (1) and / or Alternatively, it is an object of the present invention to provide an amorphization technique for a salt thereof.
このような状況に鑑みて、本発明者らは、一般式(1)で表される化合物及び/又はその塩の使用性を高めるべく、一般式(1)で表される化合物及び/又はその塩の非晶質化技術を求めて、鋭意研究努力を重ねた。その結果、水溶性高分子及び酸から選ばれる1種乃至は2種以上を非晶質化剤として用いることにより、このような非晶質化をなし得ることを見出し、発明を完成させるに至った。即ち、本発明は、以下に示すとおりである。 In view of such a situation, the present inventors have improved the compound represented by the general formula (1) and / or a salt thereof in order to enhance the usability of the compound represented by the general formula (1) and / or a salt thereof. In search of salt amorphization technology, we made extensive research efforts. As a result, it has been found that such amorphization can be achieved by using one or more selected from water-soluble polymers and acids as an amorphizing agent, and the present invention has been completed. It was. That is, the present invention is as follows.
[1] 水溶性高分子及び酸から選ばれる1種又は2種以上からなる、以下の一般式(1)で表される化合物及び/又はその塩の非晶質化剤。 [1] An amorphizing agent for a compound represented by the following general formula (1) and / or a salt thereof comprising one or more selected from water-soluble polymers and acids.
(但し、式中R1、R2はそれぞれ独立に、水素原子又はハロゲン原子を表す。) (However, in the formula, R 1 and R 2 each independently represents a hydrogen atom or a halogen atom.)
[2] 前記水溶性高分子は、ビニル系水溶性高分子又はセルロース系水溶性高分子である、[1]に記載の非晶質化剤。
[3] 前記ビニル系水溶性高分子は、ポリビニルピロリドン又はカルボキシビニルポリマーである、[2]に記載の非晶質化剤。
[4] 前記セルロース系水溶性高分子は、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルメチルセルロース、メチルセルロース又はエチルセルロースである、[2]に記載の非晶質化剤。
[5] 前記酸は、有機酸である、[1]〜[4]の何れかに記載の非晶質化剤。
[6] 水溶性高分子及び酸からなる、[1]〜[5]の何れかに記載の非晶質化剤。
[7] 前記一般式(1)で表される化合物は、ルリコナゾール又はラノコナゾールである、[1]〜[6]の何れかに記載の非晶質化剤。
[2] The amorphizing agent according to [1], wherein the water-soluble polymer is a vinyl-based water-soluble polymer or a cellulose-based water-soluble polymer.
[3] The amorphizing agent according to [2], wherein the vinyl-based water-soluble polymer is polyvinylpyrrolidone or carboxyvinyl polymer.
[4] The amorphizing agent according to [2], wherein the cellulose-based water-soluble polymer is hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, or ethylcellulose.
[5] The amorphizing agent according to any one of [1] to [4], wherein the acid is an organic acid.
[6] The amorphizing agent according to any one of [1] to [5], comprising a water-soluble polymer and an acid.
[7] The amorphizing agent according to any one of [1] to [6], wherein the compound represented by the general formula (1) is luliconazole or lanoconazole.
[8] 一般式(1)で表される化合物及び/又はその塩と、該化合物及び/又はその塩の質量の0.05〜10倍の質量の[1]〜[7]の何れかに記載の非晶質化剤を均一に混合し、固化させる工程を含む、一般式(1)で表される化合物及び/又はその塩の非晶質化方法。
[9] 一般式(1)で表される化合物及び/又はその塩と、該化合物及び/又はその塩の質量の0.05〜10倍の質量の[1]〜[7]の何れかに記載の非晶質化剤とを含んでなる非晶質の組成物。
[10] [9]に記載の非晶質の組成物を中間仕掛品として、該中間仕掛品を溶解する工程を含む、一般式(1)で表される化合物及び/又はその塩を含有する医薬組成物の製造方法。
[11] 一般式(1)で表される化合物及び/又はその塩と、該化合物及び/又はその塩の質量の0.05〜10倍の質量の[1]〜[7]の何れかに記載の非晶質化剤を含んでなる、組成物。
[12] 更に、揮散すべき溶媒を含む、[11]に記載の組成物。
[13] 医薬である、[11]又は[12]に記載の組成物。
[8] The compound represented by the general formula (1) and / or a salt thereof and any one of [1] to [7] having a mass 0.05 to 10 times the mass of the compound and / or the salt thereof. A method for amorphizing a compound represented by the general formula (1) and / or a salt thereof, comprising a step of uniformly mixing and solidifying the described amorphizing agent.
[9] The compound represented by the general formula (1) and / or a salt thereof and any one of [1] to [7] having a mass of 0.05 to 10 times the mass of the compound and / or the salt thereof. An amorphous composition comprising the described amorphizing agent.
[10] A compound represented by the general formula (1) and / or a salt thereof, comprising the step of dissolving the intermediate work-in-process using the amorphous composition described in [9] as an intermediate work-in-process. A method for producing a pharmaceutical composition.
[11] The compound represented by the general formula (1) and / or a salt thereof and any one of [1] to [7] having a mass of 0.05 to 10 times the mass of the compound and / or the salt thereof. A composition comprising the described amorphizing agent.
[12] The composition according to [11], further comprising a solvent to be stripped.
[13] The composition according to [11] or [12], which is a medicine.
本発明によれば、一般式(1)で表される化合物及び/又はその塩の非晶質化技術を提供できる。 ADVANTAGE OF THE INVENTION According to this invention, the amorphization technique of the compound represented by General formula (1) and / or its salt can be provided.
(1)本発明の非晶質化剤
本発明の非晶質化剤は、一般式(1)で表される化合物及び/またはその塩の非晶質化
剤であって、水溶性高分子及び酸から選ばれる1種又は2種以上からなることを特徴とする。
前記水溶性高分子としては、例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマーなどのビニル系水溶性高分子、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルローステレフタレート、ヒドロキシエチルメチルセルロース、エチルセルロースなどのセルロース系水溶性高分子、アラビアゴム、トラガカントゴム、キサンタンゴムなどの多糖類水溶性高分子などが好適に例示できる。これらのうちビニル系水溶性高分子又はセルロース系水溶性高分子が好ましく例示できる。ビニル系高分子としては、ポリビニルピロリドン又はカルボキシビニルポリマーが好ましく例示でき、セルロース系水溶性高分子としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルメチルセルロース、メチルセルロース又はエチルセルロースが好ましく例示できる。水溶性高分子として、1種又は2種以上を用いることができる。
(1) Amorphizing agent of the present invention The amorphizing agent of the present invention is an amorphizing agent of a compound represented by the general formula (1) and / or a salt thereof, and is a water-soluble polymer. And one or more selected from acids.
Examples of the water-soluble polymer include vinyl-based water-soluble polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, and carboxyvinyl polymer, and cellulose-based polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose terephthalate, hydroxyethylmethylcellulose, and ethylcellulose. Preferable examples include water-soluble polymers, polysaccharide water-soluble polymers such as gum arabic, tragacanth gum, and xanthan gum. Of these, vinyl water-soluble polymers and cellulose water-soluble polymers are preferred. Preferred examples of the vinyl polymer include polyvinyl pyrrolidone and carboxyvinyl polymer, and preferred examples of the cellulose water-soluble polymer include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, methyl cellulose, and ethyl cellulose. 1 type (s) or 2 or more types can be used as a water-soluble polymer.
又、酸としては、有機酸や無機酸が好ましく例示でき、前記有機酸としては、クエン酸、乳酸、グルコン酸などのヒドロキシ酸、蓚酸、酒石酸、アジピン酸などの二塩基酸、ギ酸、酢酸などのカルボン酸などが好ましく例示でき、ヒドロキシ酸又は二塩基酸が特に好ましい。中でも、ヒドロキシ酸としては乳酸が好ましく、二塩基酸としては酒石酸が特に好ましい。前記無機酸としては、鉱酸などが好ましく例示できる。酸として、1種又は2種以上を用いることができる。 Examples of the acid include organic acids and inorganic acids. Examples of the organic acid include hydroxy acids such as citric acid, lactic acid and gluconic acid, dibasic acids such as succinic acid, tartaric acid and adipic acid, formic acid and acetic acid. Of these, preferred are carboxylic acids, and hydroxy acid or dibasic acid is particularly preferred. Of these, lactic acid is preferred as the hydroxy acid, and tartaric acid is particularly preferred as the dibasic acid. Preferred examples of the inorganic acid include mineral acids. As an acid, 1 type (s) or 2 or more types can be used.
水溶性高分子及び酸は、ただ1種を用いることもできるし、2種以上を組み合わせて使用することもできる。好ましい態様は、水溶性高分子と酸とを併用する態様である。 As the water-soluble polymer and the acid, only one kind can be used, or two or more kinds can be used in combination. A preferred embodiment is an embodiment in which a water-soluble polymer and an acid are used in combination.
本発明の非晶質化剤は、一般式(1)で表される化合物及び/又はその塩の総質量に対して、0.05〜10倍の質量で用いることが好ましく、より好ましくは0.5〜5倍の質量、更に好ましくは0.7〜3倍の質量が例示できる。これは量が少ないと充分に非晶質化できない場合が存し、多すぎると剤形的な制限が生じるためである。水溶性高分子と酸とを併用した場合、その質量比は酸に対して水溶性高分子が1〜15質量%になるように設定することが好ましく、4〜10質量%になる様に設定することがより好ましい。 The amorphizing agent of the present invention is preferably used in a mass of 0.05 to 10 times, more preferably 0, based on the total mass of the compound represented by the general formula (1) and / or a salt thereof. The mass is 5 to 5 times, more preferably 0.7 to 3 times. This is because if the amount is too small, there may be cases where the material cannot be sufficiently amorphized. When the water-soluble polymer and the acid are used in combination, the mass ratio is preferably set so that the water-soluble polymer is 1 to 15% by mass with respect to the acid, and is set to be 4 to 10% by mass. More preferably.
本発明の非晶質化剤としては、一般式(1)で表される化合物としてルリコナゾールを用いた場合には、非晶質化剤としては、乳酸とポリビニルピロリドンの組み合わせが好ましく、ラノコナゾールを用いた場合には、ヒドロキシプロピルセルロース、酒石酸及び乳酸の組み合わせが好ましい。 As the amorphizing agent of the present invention, when luliconazole is used as the compound represented by the general formula (1), a combination of lactic acid and polyvinylpyrrolidone is preferable as the amorphizing agent, and lanconazole is used. If so, a combination of hydroxypropylcellulose, tartaric acid and lactic acid is preferred.
(2)一般式(1)で表される化合物及び/またはその塩
本発明の非晶質化剤が対象とする化合物は、一般式(1)で表されることを特徴とする。
一般式(1)において、R1、R2で表される基は、水素原子又はハロゲン原子であり、当該ハロゲン原子としては、塩素原子、臭素原子、フッ素原子、ヨウ素原子などが好適に例示でき、水素原子又は塩素原子が特に好ましい。
(2) Compound represented by general formula (1) and / or salt thereof The compound targeted by the amorphizing agent of the present invention is represented by general formula (1).
In general formula (1), the groups represented by R 1 and R 2 are hydrogen atoms or halogen atoms, and preferred examples of the halogen atoms include chlorine atoms, bromine atoms, fluorine atoms, and iodine atoms. A hydrogen atom or a chlorine atom is particularly preferred.
一般式(1)で表される化合物及び/またはその塩のうち、特に好ましいものは、ルリコナゾール(R1=R2=Cl;(R)−(−)−(E)−〔4−(2,4−ジクロロフェニル)−1,3−ジチオラン−2−イリデン〕−1−イミダゾリルアセトニトリル)とラノコナゾール(R1=Cl、R2=H;4−(2−クロロフェニル)−1,3−ジチオラン−2−イリデン−1−イミダゾリルアセトニトリル)であり、ルリコナゾールが特に好ましい。
かかる化合物は、例えば、特開昭60−218387号に記載されている方法に従って
合成することができる。具体的には、下記式に記載の方法により合成することができる。即ち、以下のように、1−シアノメチルイミダゾールと二硫化炭素とを反応させ、(III)の化合物を得、これと脱離基を有する一般式(II)の化合物と反応させることにより、一般式(I)で表される化合物を得ることができる。脱離基としては、例えば、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、p−トルエンスルホニルオキシ基又はハロゲン原子等が好適に例示できる。下記式中、R及びXは、水素原子又はハロゲン原子を表す。
Among the compounds represented by the general formula (1) and / or salts thereof, particularly preferred are luliconazole (R 1 = R 2 = Cl; (R)-(−)-(E)-[4- (2 , 4-dichlorophenyl) -1,3-dithiolane-2-ylidene] -1-imidazolylacetonitrile) and ranoconazole (R 1 = Cl, R 2 = H; 4- (2-chlorophenyl) -1,3-dithiolane-2 -Iridene-1-imidazolylacetonitrile), with luliconazole being particularly preferred.
Such a compound can be synthesized, for example, according to the method described in JP-A-60-218387. Specifically, it can be synthesized by the method described in the following formula. That is, as shown below, 1-cyanomethylimidazole and carbon disulfide are reacted to obtain a compound of (III), which is reacted with a compound of the general formula (II) having a leaving group. A compound represented by the formula (I) can be obtained. Preferable examples of the leaving group include a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, and a halogen atom. In the following formulae, R and X represent a hydrogen atom or a halogen atom.
本発明の非晶質化剤が対象とする一般式(1)で表される化合物は、硫酸、塩酸、硝酸、リン酸等ともに生理学的に許容できる塩と為して用いることもできる。この時、塩は前記非晶質化剤の存在下、安定に存在できる塩とする。 The compound represented by the general formula (1) targeted by the amorphizing agent of the present invention can be used as a physiologically acceptable salt for sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid and the like. At this time, the salt is a salt that can exist stably in the presence of the amorphizing agent.
(3)本発明の非晶質の組成物
本発明の非晶質の組成物は、前記本発明の非晶質化剤と、前記一般式(1)で表される化合物及び/又はその塩とを必須の構成とする。本発明の非晶質の組成物は、一般式(1)で表される化合物及び/又は塩と、該化合物/又はその塩の質量の0.05〜10倍の質量の非晶質化剤を均一に混合し、溶媒揮散させ固化させて得ることができる。また、一般式(1)で表される化合物及び/又は塩と、該化合物及び/又はその塩の質量の0.05〜10倍の質量の非晶質化剤を均一に混合させて得られる組成物は、本発明の組成物である。本発明の組成物は、一般式(1)で表される化合物及び/又は塩と、非晶質化剤に加え、さらに、溶媒を含んでもよい。本発明の組成物は、一般式(1)で表される化合物及び/又はその塩が、抗真菌効果を有することから、医薬組成物であってよく、好ましくは抗真菌医薬組成物、より好ましくは爪用の抗真菌医薬組成物である。また、本発明の組成物は、医薬品調製用の組成物、即ち、医薬品製造のための中間仕掛品であってよい。
本発明の非晶質の組成物もまた、一般式(1)で表される化合物及び/又はその塩が、抗真菌効果を有することから、医薬組成物であってよく、好ましくは抗真菌医薬組成物、より好ましくは爪用の抗真菌医薬組成物である。
該医薬組成物の剤形としては、被膜剤形が好ましい。その使用態様は、患者の体重、年令、性別、症状等を考慮して適宜選択できるが、通常成人の場合、一般式(1)で表される化合物及び/又はその塩を1日当たり0.01〜1g投与するのが好ましい。また、真菌による疾病に通常使用されている一般式(1)で表される化合物及び/又はその塩の使
用量を参考にすることができる。
例えば、一日に一回又は数回、疾病の箇所に適量を塗布することが例示でき、かかる処置は連日行われることが好ましい。
(3) Amorphous composition of the present invention The amorphous composition of the present invention comprises an amorphizing agent of the present invention, a compound represented by the general formula (1) and / or a salt thereof. Is an essential configuration. The amorphous composition of the present invention comprises a compound and / or salt represented by the general formula (1) and an amorphizing agent having a mass 0.05 to 10 times the mass of the compound / or salt thereof. Can be obtained by uniformly mixing, evaporating the solvent and solidifying. Moreover, it is obtained by uniformly mixing the compound and / or salt represented by the general formula (1) and the amorphizing agent having a mass of 0.05 to 10 times the mass of the compound and / or the salt thereof. The composition is a composition of the present invention. The composition of the present invention may further contain a solvent in addition to the compound and / or salt represented by the general formula (1) and the amorphizing agent. The composition of the present invention may be a pharmaceutical composition, preferably an antifungal pharmaceutical composition, more preferably, since the compound represented by the general formula (1) and / or a salt thereof has an antifungal effect. Is an antifungal pharmaceutical composition for nails. The composition of the present invention may be a composition for preparing a pharmaceutical product, that is, an intermediate work-in-process for manufacturing a pharmaceutical product.
The amorphous composition of the present invention may also be a pharmaceutical composition since the compound represented by the general formula (1) and / or a salt thereof has an antifungal effect, and preferably an antifungal medicament. A composition, more preferably an antifungal pharmaceutical composition for nails.
The dosage form of the pharmaceutical composition is preferably a film dosage form. The mode of use can be appropriately selected in consideration of the patient's weight, age, sex, symptoms, etc. In general, in the case of an adult, the compound represented by the general formula (1) and / or a salt thereof is reduced to 0. It is preferable to administer 01 to 1 g. Moreover, the usage-amount of the compound represented by General formula (1) normally used for the disease by fungi and / or its salt can be referred.
For example, an appropriate amount can be applied to the site of the disease once or several times a day, and such treatment is preferably performed every day.
かかる組成物は必須成分以外に、医薬組成物等で用いられる任意の成分を含有することができる。この様な任意成分としては、例えば、賦形剤、分散剤、矯味矯臭剤、着色剤、界面活性剤等が好適に例示できる。本発明の組成物における任意成分の割合は、非晶質を保つ限りにおいて制限はないが、大凡、その上限は非晶質の組成物全体に対して、50質量%が好ましい。すなわち、かかる組成物は、非晶質化剤と、前記一般式(1)で表される化合物及び/又はその塩とを、非晶質の組成物全体に対して、50質量%超〜100質量%含有することができる。非晶質化剤と、前記一般式(1)で表される化合物及び/又はその塩との配合割合は、「(1)本発明の非晶質化剤」に前記された配合割合と同様である。 Such a composition can contain, in addition to the essential components, any component used in a pharmaceutical composition or the like. As such optional components, for example, excipients, dispersants, flavoring agents, colorants, surfactants and the like can be suitably exemplified. The ratio of the optional component in the composition of the present invention is not limited as long as it is amorphous, but the upper limit is preferably 50% by mass with respect to the entire amorphous composition. That is, in such a composition, the amorphizing agent and the compound represented by the general formula (1) and / or a salt thereof are more than 50% by mass to 100% with respect to the whole amorphous composition. It can be contained by mass%. The blending ratio of the amorphizing agent and the compound represented by the general formula (1) and / or a salt thereof is the same as the blending ratio described in “(1) Amorphizing agent of the present invention”. It is.
また、本発明は、本発明の非晶質化剤による、一般式(1)で表される化合物及び/またはその塩の非晶質化方法に関する。本発明の非晶質化方法は、一般式(1)で表される化合物及び/又は塩と、該化合物/又はその塩の質量の0.05〜10倍の質量の非晶質化剤を均一に混合し、固化させることを含む。一般式(1)で表される化合物及び/またはその塩と、非晶質化剤を均一に混合する方法としては、例えば、一般式(1)で表される化合物及び/またはその塩を溶媒で溶解し、非晶質化剤を加えて混合する方法が挙げられる。固化させる方法としては、例えば、混合後室温下保存し、溶媒除去することにより為しうる。 The present invention also relates to a method for amorphizing the compound represented by the general formula (1) and / or a salt thereof by the amorphizing agent of the present invention. The amorphization method of the present invention comprises a compound and / or salt represented by the general formula (1) and an amorphizing agent having a mass of 0.05 to 10 times the mass of the compound / or salt thereof. Including uniformly mixing and solidifying. As a method of uniformly mixing the compound represented by the general formula (1) and / or a salt thereof and the amorphizing agent, for example, the compound represented by the general formula (1) and / or the salt thereof is used as a solvent. And a method in which an amorphizing agent is added and mixed. As a method of solidifying, for example, it can be performed by storing at room temperature after mixing and removing the solvent.
また、本発明は、本発明の非晶質の組成物を中間仕掛品として、該中間仕掛品を溶解する工程を含む、一般式(1)で表される化合物及び/又は塩を含有する医薬組成物の製造方法に関する。
中間仕掛品としての本発明の非晶質の組成物は、溶解しやすい安定な中間仕掛品を提供する。この様な中間仕掛品を用いることにより、類縁体生成の少ない一般式(1)で表される化合物及び/又は塩を含有する医薬組成物の製造方法が提供できる。
Moreover, this invention uses the amorphous composition of this invention as an intermediate work-in-process, The pharmaceutical containing the compound and / or salt represented by General formula (1) including the process of melt | dissolving this intermediate work-in-process. The present invention relates to a method for producing a composition.
The amorphous composition of the present invention as an intermediate work-in-process provides a stable intermediate work-in-process that is easy to dissolve. By using such an intermediate work-in-process, it is possible to provide a method for producing a pharmaceutical composition containing a compound and / or a salt represented by the general formula (1) with little analog production.
また、本発明の非晶質の組成物は、医薬品において、製品としての最終塗膜、製品製造のための中間仕掛品として用いることもできる。 The amorphous composition of the present invention can also be used in pharmaceuticals as a final coating film as a product and an intermediate work product for product production.
本発明の非晶質の組成物は、一般式(1)で表される化合物及び/またはその塩を安定に含有する医薬組成物を得るための中間仕掛品(「製造中間体」、「中間品」とも言う)とすることができる。この様な中間仕掛品を用いることにより、医薬組成物製造過程での類縁体の生成を少なく抑えることができる。 The amorphous composition of the present invention comprises an intermediate work product (“production intermediate”, “intermediate product” for obtaining a pharmaceutical composition stably containing the compound represented by the general formula (1) and / or a salt thereof. Product "). By using such an intermediate work-in-process, it is possible to suppress the generation of analogs in the pharmaceutical composition manufacturing process.
また、本発明の非晶質の組成物は、製品としての塗膜製剤、あるいは、最終的に医薬組成物を対象部位に投与した際に生じる被膜であってよく、この様な非晶質化により、一般式(1)で表される化合物及び/またはその塩の皮膚への透過性を高め、且つ、組織内濃度を長時間高く保つこともできる。これは非晶質がリザーバーとして機能するためである。この様な最終製剤としての膜の非晶質化も、膜が非晶質膜という特質を有している限りにおいて、本発明の権利の関与するところである。 Further, the amorphous composition of the present invention may be a coating preparation as a product, or a film produced when a pharmaceutical composition is finally administered to a target site. Thus, the permeability of the compound represented by the general formula (1) and / or a salt thereof to the skin can be increased, and the tissue concentration can be kept high for a long time. This is because amorphous functions as a reservoir. The amorphization of the film as such a final preparation also involves the right of the present invention as long as the film has the characteristic of an amorphous film.
前記最終製品としての塗膜は、例えば、顆粒等の担体上に有効成分の被膜として形成せしめ用いることもできるし、例えば、皮膚や爪上に形成する医薬組成物の塗膜として用いることもできる。この様な非晶質の組成物の塗膜は、有効成分である一般式(1)で表される化合物及び/又は塩の生体利用率を高めることができる。これは前記のリザーバー効果による。 The coating film as the final product can be used as a coating film of an active ingredient on a carrier such as a granule, for example, or can be used as a coating film of a pharmaceutical composition formed on the skin or nails, for example. . A coating film of such an amorphous composition can increase the bioavailability of the compound and / or salt represented by the general formula (1), which is an active ingredient. This is due to the reservoir effect described above.
以下に実施例を挙げて、本発明について更に詳細に説明を加えるが、本発明はその要旨を超えない限り、これらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples as long as the gist thereof is not exceeded.
<実施例1>
ルリコナゾール1質量%含有エタノール溶液と、ルリコナゾール1質量%及びポリビニルピロリドン0.1質量%含有エタノール溶液を調製し、スライドグラス上に滴下し、その性状を、滴下直後、滴下後室温保存4時間、滴下後室温保存1日、滴下後室温保存4日に顕微鏡下観察した。顕微鏡観察は、通常の光学顕微鏡及び偏光顕微鏡で行った。結果を図1に示す。これより、本発明の非晶質化剤により、結晶化に差異が見られ、ポリビニルピロリドンが非晶質化剤として作用していることがわかる。このように、結晶と非晶質が混在する場合においても、本来結晶のみであるべき状態であるものが、本発明の非晶質化剤を含有することにより、非晶質が並存する(非晶質構造が現れる)場合には、本発明の非晶質化剤の効果と判断する。
<Example 1>
An ethanol solution containing 1% by mass of luliconazole and an ethanol solution containing 1% by mass of luliconazole and 0.1% by mass of polyvinylpyrrolidone were prepared and dropped on a slide glass. The properties were added immediately after the dropwise addition and stored at room temperature for 4 hours after the dropwise addition. Thereafter, it was observed under a microscope for 1 day after storage at room temperature and 4 days after storage at room temperature. Microscopic observation was performed with a normal optical microscope and a polarizing microscope. The results are shown in FIG. From this, it can be seen that there is a difference in crystallization by the amorphizing agent of the present invention, and that polyvinylpyrrolidone acts as an amorphizing agent. Thus, even in the case where crystals and amorphous are mixed, what is originally in a state of being only crystals is amorphous by the inclusion of the amorphizing agent of the present invention (non-native). In the case where a crystalline structure appears), it is judged as an effect of the amorphizing agent of the present invention.
<実施例2>
以下に示す処方の医薬組成物1について、次に示す手順で被膜製剤を製造した。
<Example 2>
About pharmaceutical composition 1 of the prescription shown below, the film formulation was manufactured in the procedure shown next.
ルリコナゾールと、エタノールとを合わせ、70℃で加熱攪拌し可溶化させ、次いで、乳酸とポリビニルピロリドンとを加え、70℃で加熱攪拌し、可溶化を確認した後、残りの溶剤成分を加え希釈し、攪拌可溶化し、可溶化を確認した後、室温まで攪拌冷却して医薬組成物1を得た。 Luliconazole and ethanol are combined and heat-stirred at 70 ° C. to solubilize. Then, lactic acid and polyvinylpyrrolidone are added, and heat-stirred at 70 ° C. After confirming solubilization, the remaining solvent components are added and diluted. After solubilization with stirring, solubilization was confirmed, the mixture was stirred and cooled to room temperature to obtain pharmaceutical composition 1.
<製造された医薬組成物1の被膜形成過程>
医薬組成物1 1mLをチューブに取り、これに10mgのニュートラルレッドを200μLのメタノールで溶解させた液を100μL加え、良く攪拌した後、スライドグラスに滴下し、室温下、溶剤揮散、被膜形成過程を顕微鏡(400倍)で観察した。観察の経過を図2〜4に示す。一様な相に、ミセル様の構造が現れはじめ(図2)、このミセル構造が増加し(図3)、連続相様の構造にミセル様の構造が一様に分散した非晶質の膜(図4)が観察された。これより、本発明の非晶質化剤である、ポリビニルピロリドンと乳酸の非晶質化効果が確かめられた。
<Film formation process of manufactured pharmaceutical composition 1>
Take 1 mL of pharmaceutical composition 1 in a tube, add 100 μL of 10 mg neutral red dissolved in 200 μL of methanol, stir well, drop it onto a slide glass, and evaporate the solvent at room temperature. It observed with the microscope (400 time). The course of observation is shown in FIGS. A micelle-like structure begins to appear in a uniform phase (FIG. 2), the micelle structure increases (FIG. 3), and an amorphous film in which the micelle-like structure is uniformly dispersed in a continuous phase-like structure (FIG. 4) was observed. This confirmed the amorphizing effect of polyvinylpyrrolidone and lactic acid, which are the amorphizing agents of the present invention.
<実施例3>
実施例2に示す手順に従い、以下の表2に示す処方の医薬組成物2及び3(被膜製剤)
を製造した。さらに、実施例2に記載する方法に従い被膜形成過程を顕微鏡(400倍)で観察した。医薬組成物1と同様に、医薬組成物2及び3には、連続相様の構造にミセル様の構造が一様に分散した非晶質の膜が観察され非晶質化効果が認められた。
<Example 3>
According to the procedure shown in Example 2, pharmaceutical compositions 2 and 3 (film preparations) having the formulations shown in Table 2 below
Manufactured. Furthermore, the film formation process was observed with a microscope (400 times) according to the method described in Example 2. Similar to the pharmaceutical composition 1, in the pharmaceutical compositions 2 and 3, an amorphous film in which the micelle-like structure was uniformly dispersed in the continuous phase-like structure was observed, and an amorphization effect was observed. .
本発明は、医薬品及び医薬品製造に応用できる。 The present invention can be applied to pharmaceuticals and pharmaceutical manufacturing.
Claims (13)
し、固化させる工程を含む、一般式(1)で表される化合物及び/又はその塩の非晶質化方法。 The compound represented by the general formula (1) and / or a salt thereof, and the mass of 0.05 to 10 times the mass of the compound and / or the salt thereof, according to any one of claims 1 to 7. A method for amorphizing a compound represented by the general formula (1) and / or a salt thereof, comprising a step of uniformly mixing and solidifying a crystallization agent.
一般式(1)で表される化合物及び/又はその塩を含有する医薬組成物の製造方法。 Including the step of dissolving the intermediate work-in-process as the intermediate work-in-process using the amorphous composition according to claim 9 as an intermediate work-in-process.
A method for producing a pharmaceutical composition comprising a compound represented by the general formula (1) and / or a salt thereof.
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001048731A (en) * | 1999-08-04 | 2001-02-20 | Pola Chem Ind Inc | Surface treated powder and skin lotion containing the same |
WO2007102243A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
JP2008074911A (en) * | 2006-09-20 | 2008-04-03 | Pola Chem Ind Inc | Fine particle powder and method for producing the same |
WO2009031643A1 (en) * | 2007-09-05 | 2009-03-12 | Pola Pharma Inc. | Antifungal composition |
JP2015114210A (en) * | 2013-12-12 | 2015-06-22 | 株式会社ポーラファルマ | Evaluation method and index substance for formulation containing luliconazole |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003105841A1 (en) | 2002-06-18 | 2003-12-24 | ポーラ化成工業株式会社 | Antifungal medicinal compositions |
JP2006312598A (en) | 2005-05-09 | 2006-11-16 | Pola Chem Ind Inc | Medicinal composition |
WO2010117089A2 (en) * | 2009-04-09 | 2010-10-14 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
US20140206717A1 (en) * | 2011-08-16 | 2014-07-24 | John Higgins | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
JP5662495B2 (en) * | 2013-02-08 | 2015-01-28 | 株式会社ポーラファルマ | Pharmaceutical composition in solubilizer form |
JP6503626B2 (en) * | 2013-03-28 | 2019-04-24 | 大正製薬株式会社 | Pharmaceutical composition |
-
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001048731A (en) * | 1999-08-04 | 2001-02-20 | Pola Chem Ind Inc | Surface treated powder and skin lotion containing the same |
WO2007102243A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
JP2008074911A (en) * | 2006-09-20 | 2008-04-03 | Pola Chem Ind Inc | Fine particle powder and method for producing the same |
WO2009031643A1 (en) * | 2007-09-05 | 2009-03-12 | Pola Pharma Inc. | Antifungal composition |
JP2015114210A (en) * | 2013-12-12 | 2015-06-22 | 株式会社ポーラファルマ | Evaluation method and index substance for formulation containing luliconazole |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017181387A (en) * | 2016-03-31 | 2017-10-05 | 株式会社ポーラファルマ | Evaluation method of film formed by pharmaceutical composition |
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PH12018502095A1 (en) | 2019-07-15 |
CN108883190B (en) | 2022-07-01 |
WO2017170509A1 (en) | 2017-10-05 |
AU2017244688B2 (en) | 2022-11-10 |
MY197992A (en) | 2023-07-25 |
KR102359641B1 (en) | 2022-02-08 |
AU2017244688A1 (en) | 2018-11-22 |
JP7021827B2 (en) | 2022-02-17 |
CN108883190A (en) | 2018-11-23 |
KR20180126058A (en) | 2018-11-26 |
SG11201808660UA (en) | 2018-11-29 |
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