JP2010270023A - Nonaqueous composition containing adipose particle holding medicament, and method for producing the same - Google Patents
Nonaqueous composition containing adipose particle holding medicament, and method for producing the same Download PDFInfo
- Publication number
- JP2010270023A JP2010270023A JP2009121613A JP2009121613A JP2010270023A JP 2010270023 A JP2010270023 A JP 2010270023A JP 2009121613 A JP2009121613 A JP 2009121613A JP 2009121613 A JP2009121613 A JP 2009121613A JP 2010270023 A JP2010270023 A JP 2010270023A
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- fat
- drug
- water
- aqueous composition
- emulsion
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Abstract
Description
本発明は、用時に注射用水や生理食塩水などの水系媒体と混合することで、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を調製することができるといった利点を備える、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法に関する。 The present invention retains a drug with the advantage that a drug-containing fat emulsion having transparency and excellent stability can be prepared by mixing with an aqueous medium such as water for injection and physiological saline at the time of use. The present invention relates to a non-aqueous composition containing fat particles and a method for producing the same.
薬物含有脂肪乳剤は、例えばステロイド（パルミチン酸デキサメサゾン）含有脂肪乳剤やプロスタグランジン（ＰＧＥ１）含有脂肪乳剤をはじめとするいくつかのものがすでに上市され、汎用されていることは当業者によく知られた事実である。しかしながら、それらはいずれも薬物の含量に比較して大量の油脂（その含量は少なく見積もっても例えば１０ｍｇ／ｍＬ以上である）が用いられた乳白状の製剤であり、変質や異物混入の有無、配合変化を目視で容易に確認できないことから使用の可否判断が困難である、製剤によっては安定性が劣るので冷所保存が必要であるといった制約を有している。そこでこのような制約が緩和された、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤の開発が試みられているが、その有効な解決手段は今だ見出されていない。 It is well known to those skilled in the art that several drug-containing fat emulsions have been put on the market and are widely used, including fat emulsions containing steroids (dexamethasone palmitate) and prostaglandin (PGE 1 ). It is a known fact. However, all of them are milky white preparations using a large amount of oil and fat compared to the content of the drug (the content is at least 10 mg / mL or less). Since it is difficult to visually check the change in the composition, it is difficult to determine whether it can be used, and depending on the preparation, the stability is inferior, and it is necessary to store in a cold place. Accordingly, attempts have been made to develop drug-containing fat emulsions that have such restrictions relaxed, have transparency and are excellent in stability, but no effective solution has yet been found.
上記の問題を解決するための手がかりとなる技術が特許文献１に記載されている。特許文献１は輸液製剤として用いられる脂肪乳剤に関するものであるが（換言すれば薬物を含有しない脂肪乳剤ということである）、ここには安定で澄明な脂肪乳剤を得るためには乳化剤の添加量を多くすればよいとあり、乳化剤の添加量を油脂に対する乳化剤の重量比率（乳化剤／油脂）として０．１５〜３とすること、これにより脂肪粒子の平均粒子径が３〜１００ｎｍである澄明な脂肪乳剤が得られることが開示されている。 Japanese Patent Application Laid-Open No. H10-228561 describes a technique that serves as a clue to solve the above problem. Patent Document 1 relates to a fat emulsion used as an infusion preparation (in other words, a fat emulsion not containing a drug). Here, the amount of an emulsifier added in order to obtain a stable and clear fat emulsion The amount of the emulsifier added should be 0.15 to 3 as the weight ratio of the emulsifier to the fat (emulsifier / oil), whereby the average particle diameter of the fat particles is 3 to 100 nm. It is disclosed that a fat emulsion is obtained.
特許文献１は、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤の開発のために大いに参考となるものであることは確かである。しかしながら、特許文献１に記載の方法に倣って単に乳化剤の添加量を多くすれば問題が解決するほど、ことは単純でない。その理由はいくつか挙げられる。まず、薬物を含有する以上、薬物が安定して乳剤中に存在しなければならない。特に薬物が水難溶性である場合、薬物が容易に析出するようなことがあってはならず、このようなことが起こらないようにするための方策を講じる必要がある。また、特許文献１では、乳化は少なくとも３１５０ｋｇｆ／ｃｍ２（約３１５０バール）の圧力で行わなければならないとされている。この圧力は高圧噴射ホモジナイザーのようなある種、特殊な乳化機を用いなければ実施しえない超高圧であり、このような超高圧での乳化を工業規模で行うためには、繰り返し使用される乳化機の材質を強靭で特殊な金属としなければならず、そのため装置の高価格化などを招くといった問題がある。また、医薬品製造においては汚染防止の観点から製造装置などの洗浄操作が法的（ＧＭＰ：Ｇｏｏｄ Ｍａｎｕｆａｃｔｕｒｉｎｇ Ｐｒａｃｔｉｃｅ）に厳しく義務付けられている。そのため乳化機についても乳剤が接触する箇所の完全な洗浄が求められるが、高圧噴射ホモジナイザーのように超高圧で乳剤の噴射を行う装置においては、とりわけ噴射口部分の開放洗浄ができないことから法的要求を満足させることが困難であるといった問題がある。さらに、３０００バール以上の圧力で乳化を行うと乳剤は非常に高温になる。従って、たとえ乳化後に乳剤を直ちに冷却しても、乳剤中の薬物が短時間でも高温に曝されてしまうことで劣化する危険性が大きい。通常、乳化回数を増やすことによって脂肪粒子の粒子径分布を狭くすることができることから、乳化は複数回循環させて行うことが望まれるが、このような超高圧での乳化を繰り返し行うと薬物の劣化が激しくなるので、よって循環乳化を行えないといった問題がある。加えて、薬物含有脂肪乳剤は輸液製剤として用いられる脂肪乳剤と異なり、注射剤や点眼剤や点鼻剤や吸入剤などとして製品化された場合の一容器あたりの容量がせいぜい１〜２０ｍＬである。このような小容量での製剤設計においては、構成成分を巧みに配合しなければ配合の不具合は即座に製剤の安定性に対する悪影響（例えば乳剤の相分離や薬物の凝集・析出）などに直結する。 Patent Document 1 is certainly a great reference for the development of a drug-containing fat emulsion having transparency and excellent stability. However, following the method described in Patent Document 1, simply increasing the amount of the emulsifier is not so simple that the problem is solved. There are several reasons for this. First, as long as it contains a drug, the drug must be stably present in the emulsion. In particular, when the drug is poorly water-soluble, the drug must not easily precipitate, and measures must be taken to prevent this from happening. In Patent Document 1, emulsification must be performed at a pressure of at least 3150 kgf / cm 2 (about 3150 bar). This pressure is an ultra-high pressure that cannot be implemented without using a special emulsifier, such as a high-pressure jet homogenizer, and is used repeatedly in order to carry out such ultra-high pressure emulsification on an industrial scale. There is a problem that the material of the emulsifier must be strong and special metal, which leads to an increase in the cost of the apparatus. In pharmaceutical manufacturing, a cleaning operation of a manufacturing apparatus or the like is strictly required by law (GMP: Good Manufacturing Practice) from the viewpoint of preventing contamination. For this reason, the emulsifier is required to thoroughly clean the area where the emulsion comes into contact. However, in an apparatus that injects emulsion at an ultra-high pressure, such as a high-pressure injection homogenizer, it is legal because the injection port part cannot be cleaned. There is a problem that it is difficult to satisfy the requirements. Furthermore, when emulsification is carried out at a pressure of 3000 bar or higher, the emulsion becomes very hot. Therefore, even if the emulsion is immediately cooled after emulsification, there is a great risk that the drug in the emulsion will be deteriorated by being exposed to a high temperature even for a short time. Usually, the particle size distribution of fat particles can be narrowed by increasing the number of emulsifications, so it is desirable to carry out the emulsification by circulating a plurality of times. There is a problem that the circulation emulsification cannot be performed because the deterioration becomes severe. In addition, drug-containing fat emulsions, unlike fat emulsions used as infusion preparations, have a capacity of at most 1 to 20 mL per container when manufactured as injections, eye drops, nasal drops, inhalants, etc. . In such a small-volume formulation design, if the components are not skillfully formulated, the formulation failure will immediately have an adverse effect on the stability of the formulation (for example, emulsion phase separation and drug aggregation / precipitation). .
また、薬物含有脂肪乳剤の保存安定性を高めるために、乳剤から水相を除去して乾燥状態に保つ方法が古くから提案されているが、その方法はいずれもマイナス数十℃での凍結乾燥による時間もコストもかかるものであり（例えば特許文献２）、乳剤をより温和な条件下で乾燥する方法が求められている。 In addition, in order to increase the storage stability of drug-containing fat emulsions, methods have been proposed for a long time to remove the aqueous phase from the emulsion and keep it dry. All of these methods are freeze-dried at minus several tens of degrees Celsius. Is time consuming and expensive (for example, Patent Document 2), and a method for drying an emulsion under milder conditions is demanded.
そこで本発明は、注射剤や点眼剤や点鼻剤や吸入剤などとして用いることができる、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができるといった利点を備える、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法を提供することを目的とする。 Therefore, the present invention prepares a drug-containing fat emulsion that can be used as an injection, an eye drop, a nasal drop, an inhalant, etc. and has transparency and excellent stability when mixed with an aqueous medium at the time of use. It is an object of the present invention to provide a non-aqueous composition containing fat particles retaining a drug, and a method for producing the same, with the advantage that it can be used.
本発明者は上記の点に鑑みて鋭意研究を行った結果、油脂の含量、油脂に対する薬物の重量比率、油脂に対する乳化剤の重量比率を好適な数値範囲とすることにより、特許文献１に記載されている圧力の半分以下の圧力による乳化で、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を製造できること、こうして製造された薬物含有脂肪乳剤は、水溶性担体を溶解した後、５０℃といった温和な温度条件での乾燥処理で水相が除去され、水系媒体と混合することで透明性を有するとともに安定性に優れる薬物含有脂肪乳剤に復元（再乳化）される、薬物を保持した脂肪粒子を含む非水系組成物に変換されることを知見した。 As a result of intensive studies in view of the above points, the present inventor described in Patent Document 1 by setting the content of oil and fat, the weight ratio of the drug to the oil and fat, and the weight ratio of the emulsifier to the oil and fat in a suitable numerical range. It is possible to produce a drug-containing fat emulsion having transparency and excellent stability by emulsification with a pressure less than half of the pressure under pressure, and the drug-containing fat emulsion thus produced can be obtained at 50 ° C. after dissolving the water-soluble carrier. The aqueous phase is removed by drying under mild temperature conditions, and when mixed with an aqueous medium, the drug-containing fat particles are reconstituted (re-emulsified) into a drug-containing fat emulsion that is transparent and excellent in stability. It was found that it was converted to a non-aqueous composition containing
以上の知見に基づいてなされた本発明の薬物を保持した脂肪粒子を含む非水系組成物は、請求項１記載の通り、水難溶性薬物、油脂、乳化剤、水を少なくとも構成成分とする薬物含有脂肪乳剤であって、油脂の含量が０．０５〜２ｍｇ／ｍＬ、油脂に対する薬物の重量比率（薬物／油脂）が０．０００５〜５０（但し薬物と油脂の合計含量は最大で１０ｍｇ／ｍＬ）、油脂に対する乳化剤の重量比率（乳化剤／油脂）が１〜３００である薬物含有脂肪乳剤に含まれる薬物を保持した脂肪粒子を、水相が実質的に除去された状態で水溶性担体に担持させてなることを特徴とする。
また、請求項２記載の非水系組成物は、請求項１記載の非水系組成物において、水溶性担体が糖類であることを特徴とする。
また、請求項３記載の非水系組成物は、請求項２記載の非水系組成物において、糖類がイノシトール、グルコース、ソルビトール、フルクトース、マンニトール、トレハロース、ラクトース、スクロース、マルトース、キシリトールから選択される少なくとも１種であることを特徴とする。
また、請求項４記載の非水系組成物は、請求項１記載の非水系組成物において、水溶性担体がアミノ酸であることを特徴とする。
また、請求項５記載の非水系組成物は、請求項４記載の非水系組成物において、アミノ酸がグリシン、アラニン、ノルバリン、セリン、スレオニン、システイン、メチオニン、プロリン、ヒドロキシプロリン、β−アラニン、γ−アミノ酪酸から選択される少なくとも１種であることを特徴とする。
また、請求項６記載の非水系組成物は、請求項１記載の非水系組成物において、水溶性担体が多価アルコールであることを特徴とする。
また、請求項７記載の非水系組成物は、請求項６記載の非水系組成物において、多価アルコールがグリセリン、プロピレングリコール、ポリエチレングリコールから選択される少なくとも１種であることを特徴とする。
また、請求項８記載の非水系組成物は、請求項１乃至７のいずれかに記載の非水系組成物において、脂肪粒子の平均粒子径が２〜３００ｎｍであることを特徴とする。
また、請求項９記載の非水系組成物は、請求項１乃至８のいずれかに記載の非水系組成物において、薬物含有脂肪乳剤の濁度が０．５以下であることを特徴とする。
また、本発明の薬物を保持した脂肪粒子を含む非水系組成物の製造方法は、請求項１０記載の通り、水難溶性薬物、油脂、乳化剤、水を少なくとも構成成分とする薬物含有脂肪乳剤であって、油脂の含量を０．０５〜２ｍｇ／ｍＬ、油脂に対する薬物の重量比率（薬物／油脂）を０．０００５〜５０（但し薬物と油脂の合計含量は最大で１０ｍｇ／ｍＬ）、油脂に対する乳化剤の重量比率（乳化剤／油脂）を１〜３００である薬物含有脂肪乳剤に水溶性担体を溶解した後、水相を除去することを特徴とする。
また、請求項１１記載の製造方法は、請求項１０記載の製造方法において、水相の除去を１０〜８０℃の温度範囲での乾燥処理で行うことを特徴とする。
また、本発明の医薬品製剤は、請求項１２記載の通り、請求項１記載の薬物を保持した脂肪粒子を含む非水系組成物それ自体からなるかまたは他の成分と配合してなることを特徴とする。
The non-aqueous composition containing the fat particles retaining the drug of the present invention based on the above knowledge is, as described in claim 1, a drug-containing fat comprising at least a water-insoluble drug, an oil and fat, an emulsifier, and water as constituent components. An emulsion having a fat content of 0.05 to 2 mg / mL, a weight ratio of the drug to the fat (drug / fat) of 0.0005 to 50 (provided that the total content of the drug and the fat is 10 mg / mL at the maximum), Fat particles holding a drug contained in a drug-containing fat emulsion in which the weight ratio of the emulsifier to the fat (emulsifier / fat) is 1 to 300 are supported on a water-soluble carrier in a state in which the aqueous phase is substantially removed. It is characterized by becoming.
The non-aqueous composition according to claim 2 is characterized in that, in the non-aqueous composition according to claim 1, the water-soluble carrier is a saccharide.
The non-aqueous composition according to claim 3 is the non-aqueous composition according to claim 2, wherein the saccharide is at least selected from inositol, glucose, sorbitol, fructose, mannitol, trehalose, lactose, sucrose, maltose, and xylitol. It is one type.
The non-aqueous composition according to claim 4 is characterized in that, in the non-aqueous composition according to claim 1, the water-soluble carrier is an amino acid.
The non-aqueous composition according to claim 5 is the non-aqueous composition according to claim 4, wherein the amino acids are glycine, alanine, norvaline, serine, threonine, cysteine, methionine, proline, hydroxyproline, β-alanine, γ. -At least one selected from aminobutyric acid.
The non-aqueous composition according to claim 6 is characterized in that, in the non-aqueous composition according to claim 1, the water-soluble carrier is a polyhydric alcohol.
The non-aqueous composition according to claim 7 is characterized in that, in the non-aqueous composition according to claim 6, the polyhydric alcohol is at least one selected from glycerin, propylene glycol, and polyethylene glycol.
The non-aqueous composition according to claim 8 is the non-aqueous composition according to any one of claims 1 to 7, wherein the average particle size of the fat particles is 2 to 300 nm.
The non-aqueous composition according to claim 9 is characterized in that, in the non-aqueous composition according to any one of claims 1 to 8, the turbidity of the drug-containing fat emulsion is 0.5 or less.
In addition, the method for producing a non-aqueous composition containing fat particles retaining the drug of the present invention is a drug-containing fat emulsion comprising at least the poorly water-soluble drug, fats and oils, emulsifier, and water as constituents according to claim 10. The fat content is 0.05 to 2 mg / mL, the weight ratio of the drug to the fat (drug / fat) is 0.0005 to 50 (however, the total content of the drug and the fat is 10 mg / mL at maximum), the emulsifier for the fat A water-soluble carrier is dissolved in a drug-containing fat emulsion having a weight ratio (emulsifier / oil / fat) of 1 to 300, and then the aqueous phase is removed.
The manufacturing method according to claim 11 is characterized in that in the manufacturing method according to claim 10, the aqueous phase is removed by a drying treatment in a temperature range of 10 to 80 ° C.
In addition, the pharmaceutical preparation of the present invention is characterized in that, as described in claim 12, the non-aqueous composition containing the fat particles holding the drug according to claim 1 is itself or is blended with other components. And
本発明によれば、使用できる乳化剤が限定されているとともに乳剤の安定性が特に求められる注射剤、薬物の溶解性と薬液の透明性が求められる点眼剤、薬物の吸収性向上のためにその担体の微粒子化が求められる点鼻剤、薬物が気管支や肺にたやすく到達して容易に吸収されるためにその担体の微粒子化が求められる吸入剤などとして用いることができる、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができるといった利点を備える、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法を提供することができる。 According to the present invention, the emulsifiers that can be used are limited, and injections that require particularly stable emulsion, eye drops that require drug solubility and drug solution transparency, Transparency that can be used as nasal drops that require carrier micronization, and inhalants that require micronization of the carrier because the drug easily reaches the bronchi and lungs and is easily absorbed A non-aqueous composition containing fat particles retaining a drug, and a method for producing the same, including the advantage that a drug-containing fat emulsion having excellent stability can be prepared by mixing with an aqueous medium at the time of use. Can do.
本発明の薬物を保持した脂肪粒子を含む非水系組成物は、水難溶性薬物、油脂、乳化剤、水を少なくとも構成成分とする薬物含有脂肪乳剤であって、油脂の含量が０．０５〜２ｍｇ／ｍＬ、油脂に対する薬物の重量比率（薬物／油脂）が０．０００５〜５０（但し薬物と油脂の合計含量は最大で１０ｍｇ／ｍＬ）、油脂に対する乳化剤の重量比率（乳化剤／油脂）が１〜３００である薬物含有脂肪乳剤に含まれる薬物を保持した脂肪粒子を、水相が実質的に除去された状態で水溶性担体に担持させてなることを特徴とするものである。 The non-aqueous composition containing fat particles retaining the drug of the present invention is a drug-containing fat emulsion containing at least water-insoluble drug, oil and fat, emulsifier, and water as constituents, and the fat content is 0.05 to 2 mg / mL, weight ratio of drug to fat (drug / fat) is 0.0005-50 (however, the total content of drug and fat is 10 mg / ml at maximum), and weight ratio of emulsifier to fat (emulsifier / fat) is 1 to 300 The fat particles containing the drug contained in the drug-containing fat emulsion are supported on a water-soluble carrier in a state in which the aqueous phase is substantially removed.
本発明において、水難溶性薬物としては、日本薬局方・通則に規定の水への溶解性が「やや溶けにくい」（溶質１ｇまたは１ｍＬを溶かすために要する溶媒量が３０ｍＬ以上１００ｍＬ未満：溶質が薬物に相当し溶媒が水に相当）とされる以上に水難溶性のものが挙げられるが、より好適には「溶けにくい」（同、溶媒量が１００ｍＬ以上１０００ｍＬ未満）とされる以上に水難溶性のものが挙げられ、さらに好適には「極めて溶けにくい」（同、溶媒量が１０００ｍＬ以上１００００ｍＬ未満）とされる以上に水難溶性のものが挙げられ、最も好適には「ほとんど溶けない」（同、溶媒量が１００００ｍＬ以上）とされる以上に水難溶性のものが挙げられる。薬物は水難溶性であるとともに油難溶性であってもよい。薬物の種類は特段限定されるものではなく、シクロスポリンなどの免疫抑制剤、エリスロマイシンやクラリスロマイシンなどの抗生物質、インドメタシンやアスピリンやイブプロフェンやケトプロフェンやジクロフェナックやアンピロキシカムやアセトアミノフェンなどの解熱鎮痛消炎剤、パルミチン酸デキサメサゾンやフルオロメトロンやベタメサゾンやプロピオン酸ベクロメサゾンなどの合成副腎皮質ホルモン剤、ノルフロキサシンやレボフロキサシンなどの抗菌剤、ニコチン酸トコフェロールなどの循環器官用剤、エダラボンなどの脳保護薬、グリチルリチン酸系化合物などの肝臓疾患用剤、プロスタグランジンＥ１、プロスタグランジンＥ２、プロスタグランジンＦ２α、プロスタグランジンＩ２の他、そのアルキルエステル（メチルエステル、エチルエステル、プロピルエステル、ブチルエステルなど）をはじめとする各種の誘導体を含むプロスタグランジン系化合物（プロスタン酸骨格を有する化合物）などを例示することができる。油脂としては、大豆油、トウモロコシ油、ヤシ油、サフラワー油、エゴマ油、オリーブ油、ヒマシ油、綿実油などの植物油の他、ラノリンなどの動物油、卵黄油、魚油、流動パラフィンなどの鉱物油、中鎖脂肪酸トリグリセリド、化学合成トリグリセリド、ゲル化炭化水素などが挙げられる。乳化剤としては、卵黄レシチン、大豆レシチン、水素添加卵黄レシチン、水素添加大豆レシチン、ポリソルベート、ＰＥＧ−水添ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油などが挙げられる。なお、水難溶性薬物がプロスタグランジン系化合物の場合、ホスファチジルエタノールアミンの含量が２重量％以下の乳化剤を用いることが望ましい（ホスファチジルエタノールアミンはプロスタグランジン系化合物の安定性に悪影響を与えるため）。例えばキューピー社製のＰＣ−９８Ｎは、ホスファチジルエタノールアミンの除去処理がなされた精製卵黄レシチン（ホスファチジルコリンの含量が９８重量％以上でホスファチジルエタノールアミンの含量が１重量％以下）として好適に用いることができる。 In the present invention, the poorly water-soluble drug has the solubility in water as defined in the Japanese Pharmacopoeia / General Rules (somewhat difficult to dissolve) (the amount of solvent required to dissolve 1 g or 1 mL of solute is 30 mL or more and less than 100 mL: solute is drug) In which the solvent is equivalent to water), and more preferably, it is less soluble in water than that in which it is difficult to dissolve (the amount of the solvent is 100 mL or more and less than 1000 mL). More preferable are those that are hardly soluble in water, more preferably “very difficult to dissolve” (the amount of solvent is 1000 mL or more and less than 10,000 mL), and most preferably “almost insoluble” (the same, Examples of the water-solubility are more than the amount of the solvent is 10,000 mL or more. The drug may be sparingly soluble in water and poorly oil soluble. There are no particular limitations on the type of drug. Immunosuppressants such as cyclosporine, antibiotics such as erythromycin and clarithromycin, indomethacin, aspirin, ibuprofen, ketoprofen, diclofenac, ampiroxicam, acetaminophen, and other antipyretic analgesics Agents, dexamethasone palmitate, fluorometholone, betamethasone, synthetic corticosteroids such as beclomesazone propionate, antibacterial agents such as norfloxacin and levofloxacin, cardiovascular agents such as tocopherol nicotinate, brain protective agents such as edaravone, glycyrrhizic acid liver disease dosage of such compounds, prostaglandin E 1, prostaglandin E 2, prostaglandin F 2.alpha, other prostaglandin I 2, an alkyl ester ( Chiruesuteru, ethyl ester, propyl ester, prostaglandin compounds including various derivatives, including or butyl ester) (compound having a prostanoic acid skeleton) and the like can be exemplified. Oils include vegetable oils such as soybean oil, corn oil, palm oil, safflower oil, egoma oil, olive oil, castor oil, and cottonseed oil, animal oils such as lanolin, mineral oils such as egg yolk oil, fish oil, and liquid paraffin. Examples include chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons. Examples of the emulsifier include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, polysorbate, PEG-hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil. When the poorly water-soluble drug is a prostaglandin compound, it is desirable to use an emulsifier with a phosphatidylethanolamine content of 2% by weight or less (since phosphatidylethanolamine adversely affects the stability of the prostaglandin compound). . For example, PC-98N manufactured by Kewpie Corporation can be suitably used as purified egg yolk lecithin from which phosphatidylethanolamine has been removed (the content of phosphatidylcholine is 98% by weight or more and the content of phosphatidylethanolamine is 1% by weight or less). .
本発明の薬物を保持した脂肪粒子を含む非水系組成物を製造するために用いる薬物含有脂肪乳剤について、油脂の含量を０．０５〜２ｍｇ／ｍＬと規定するのは、０．０５ｍｇ／ｍＬよりも少ないと油脂と薬物の相互作用（薬物の脂肪粒子表面への付着など）による油脂の薬物に対する安定化効果が減じられてしまい、薬物を単に乳化剤だけで乳化して可溶化した場合と同程度の安定性しか得られず、薬物が凝集・析出しやすくなる一方、２ｍｇ／ｍＬよりも多いと乳剤に濁りが生じ、透明性が損なわれやすくなるとともに、多量の油を含むことによる乳剤の安定性への悪影響が生じやすくなるからである。油脂の含量は０．０８〜１．５ｍｇ／ｍＬが望ましい。油脂に対する薬物の重量比率（薬物／油脂）を０．０００５〜５０（但し薬物と油脂の合計含量は最大で１０ｍｇ／ｍＬ）と規定するのは、０．０００５よりも小さいと薬物に対して油脂が過多となり、患者に対して無用な油脂を投与することになってしまう一方、５０よりも大きいと油脂に対して薬物が過多となり、薬物の安定性が損なわれ、薬物が凝集・析出しやすくなるからである。油脂に対する薬物の重量比率は０．００１〜３０が望ましい。薬物と油脂の合計含量を最大で１０ｍｇ／ｍＬと規定するのは、１０ｍｇ／ｍＬよりも多いと例えば１５００バール以下といった温和な圧力条件では透明性を有する乳剤を得るための乳化が困難になるからである。薬物と油脂の合計含量は最大で７ｍｇ／ｍＬが望ましい。油脂に対する乳化剤の重量比率（乳化剤／油脂）を１〜３００と規定するのは、１よりも小さいと乳化剤に対して油脂が過多となり、乳剤に濁りを発生させたり乳剤の安定性に悪影響を及ぼしたりしやすくなる他、例えば１５００バール以下といった温和な圧力条件での乳化が困難である一方、３００よりも大きいと乳化剤が凝集・析出しやすくなるからである。油脂に対する乳化剤の重量比率は５〜２００が望ましい。 With respect to the drug-containing fat emulsion used for producing a non-aqueous composition containing fat particles retaining the drug of the present invention, the fat content is defined as 0.05 to 2 mg / mL from 0.05 mg / mL If the amount is too small, the effect of stabilizing the oil / fat on the drug due to the interaction between the oil / fat and the drug (such as adhesion of the drug to the fat particle surface) will be reduced. In contrast, the drug tends to aggregate and precipitate, whereas if it exceeds 2 mg / mL, the emulsion becomes turbid, transparency tends to be impaired, and the emulsion is stabilized by containing a large amount of oil. This is because adverse effects on sex are likely to occur. The content of fat is preferably 0.08 to 1.5 mg / mL. The weight ratio of drug to fat (drug / fat) is defined to be 0.0005-50 (however, the total content of drug and fat is 10 mg / mL at the maximum). However, if it is larger than 50, the drug is excessive with respect to the fat and oil, the stability of the drug is impaired, and the drug is likely to aggregate and precipitate. Because it becomes. The weight ratio of drug to fat is preferably 0.001-30. The maximum content of the drug and oil / fat is defined as 10 mg / mL because if it exceeds 10 mg / mL, emulsification for obtaining a transparent emulsion becomes difficult under mild pressure conditions such as 1500 bar or less. It is. The total content of the drug and fat is desirably 7 mg / mL at maximum. The weight ratio of the emulsifier to the fat / oil (emulsifier / oil / fat) is defined as 1 to 300. When the ratio is less than 1, the fat / oil is excessive with respect to the emulsifier, causing turbidity in the emulsion or adversely affecting the stability of the emulsion. This is because emulsification under a mild pressure condition such as 1500 bar or less is difficult, while an emulsifier tends to agglomerate and precipitate when larger than 300. As for the weight ratio of the emulsifier with respect to fats and oils, 5-200 is desirable.
本発明の薬物を保持した脂肪粒子を含む非水系組成物は、以下の方法で製造することができる。まず、油脂の含量、油脂に対する薬物の重量比率、油脂に対する乳化剤の重量比率を上記の数値範囲に設定し、自体公知の手順、例えば、薬物、油脂、乳化剤をいったん均一に混合して溶解させて油相とし、これに水を加えた後、強力に撹拌して粗乳化液を調製し（例えば回転数が１００００〜１５０００ｒｐｍで５〜３０分間の攪拌による）、次いで粗乳化液をマントンゴーリンホモジナイザーなどの高圧乳化機を用いて乳化することにより薬物含有脂肪乳剤を製造する。脂肪粒子の粒子系分布を狭くするために、乳化は複数回行ってもよい（例えば３〜５０回）。特筆すべきは、油脂の含量、油脂に対する薬物の重量比率、油脂に対する乳化剤の重量比率を上記の数値範囲に設定することで、例えば１５００バール以下、望ましくは３５０〜１０００バールの乳化圧力であっても、脂肪粒子の平均粒子径が３００ｎｍ以下、好適には２〜１８０ｎｍ、より好適には１０〜１２０ｎｍであり、濁度が０．５以下、好適には０．４以下、より好適には０．３以下の透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を容易に調製できる点にある。 The non-aqueous composition containing fat particles retaining the drug of the present invention can be produced by the following method. First, the fat content, the weight ratio of the drug to the fat and oil, and the weight ratio of the emulsifier to the fat and oil are set in the above numerical ranges, and the procedure known per se, for example, the drug, fat and emulsifier, are once mixed and dissolved uniformly. After adding water to the oil phase and stirring strongly, a crude emulsion is prepared (for example, by stirring for 5 to 30 minutes at a rotation speed of 10,000 to 15000 rpm), and then the crude emulsion is converted into a Manton Gorin homogenizer, etc. A drug-containing fat emulsion is produced by emulsification using a high-pressure emulsifier. In order to narrow the particle distribution of the fat particles, emulsification may be performed a plurality of times (for example, 3 to 50 times). It should be noted that the emulsification pressure is, for example, 1500 bar or less, preferably 350 to 1000 bar by setting the oil content, the weight ratio of the drug to the fat, and the weight ratio of the emulsifier to the fat within the above numerical ranges. The average particle size of the fat particles is 300 nm or less, preferably 2 to 180 nm, more preferably 10 to 120 nm, and the turbidity is 0.5 or less, preferably 0.4 or less, more preferably 0. A drug-containing fat emulsion having transparency of 3 or less and excellent stability can be easily prepared.
次に、以上のようにして製造された薬物含有脂肪乳剤に水溶性担体を溶解した後、水相を除去する。水溶性担体としては、糖類やアミノ酸や多価アルコールを好適に用いることができる。糖類としては、イノシトール、グルコース、ソルビトール、フルクトース、マンニトールなどの単糖類、トレハロース、ラクトース、スクロース、マルトースなどの二糖類の他、キシリトールなどが挙げられる。アミノ酸としては、グリシン、アラニン、ノルバリン、セリン、スレオニン、システイン、メチオニン、プロリン、ヒドロキシプロリン、β−アラニン、γ−アミノ酪酸などの中性アミノ酸の他、リジン、アルギニン、オルニチン、シトルリンなどの塩基性アミノ酸などが挙げられる。多価アルコールとしては、グリセリン、ジグリセリン、ポリグリセリン、プロピレングリコール、ジエチレングリコール、トリエチレングリコール、ポリエチレングリコールなどが挙げられるが、とりわけ、グリセリンとプロピレングリコールとポリエチレングリコールは、水溶性であるとともに、本発明の薬物を保持した脂肪粒子を含む非水系組成物を製造するために用いる薬物含有脂肪乳剤に含まれる薬物を保持した脂肪粒子を破壊してしまう程の脂溶性を持たない点において望ましい。水溶性担体として糖類やアミノ酸を用いる場合、その溶解量は２０〜１０００ｍｇ／ｍＬが望ましく、５０〜５００ｍｇ／ｍＬがより望ましい。水溶性担体として多価アルコールを用いる場合、その溶解量は５０〜２０００ｍｇ／ｍＬが望ましく、１００〜１０００ｍｇ／ｍＬがより望ましい。但し、用いる水溶性担体の飽和溶解量が上記の上限値未満の場合には飽和溶解量を上限とする。水溶性担体の溶解量が少なすぎると、薬物を保持した脂肪粒子の量に対する水溶性担体の量が過少となり、薬物を保持した脂肪粒子を含む非水系組成物が安定に得られない（薬物を保持した脂肪粒子の破壊が起こりやすくなる）恐れがある。一方、水溶性担体の溶解量が多すぎると、患者に対して水溶性担体を無用に投与することになってしまう。薬物含有脂肪乳剤に水溶性担体を溶解した後の水相の除去は、どのような方法で行ってもよいが、１０〜８０℃の温度範囲での乾燥処理で行うことが、乳剤に含まれる薬物の劣化を引き起こすことなく、薬物を保持した脂肪粒子を含む非水系組成物を効率よく低コストで得ることができる点において望ましい。乾燥処理は減圧乾燥、噴霧乾燥、流動乾燥、通風乾燥などを好適に採用することができるが、温度条件は３０〜７０℃がより望ましく、４０〜６０℃がさらに望ましい。このようにして製造される本発明の薬物を保持した脂肪粒子を含む非水系組成物が優れた保存安定性を有するためには、その水分率は１５％以下が望ましく、１０％以下がより望ましく、７％以下がさらに望ましい。 Next, after dissolving the water-soluble carrier in the drug-containing fat emulsion produced as described above, the aqueous phase is removed. As the water-soluble carrier, saccharides, amino acids and polyhydric alcohols can be preferably used. Examples of the saccharide include monosaccharides such as inositol, glucose, sorbitol, fructose and mannitol, disaccharides such as trehalose, lactose, sucrose and maltose, and xylitol. Amino acids include basic amino acids such as lysine, arginine, ornithine and citrulline, as well as neutral amino acids such as glycine, alanine, norvaline, serine, threonine, cysteine, methionine, proline, hydroxyproline, β-alanine, and γ-aminobutyric acid. Examples include amino acids. Examples of the polyhydric alcohol include glycerin, diglycerin, polyglycerin, propylene glycol, diethylene glycol, triethylene glycol, and polyethylene glycol. Among them, glycerin, propylene glycol, and polyethylene glycol are water-soluble, and the present invention. It is desirable in that it does not have fat solubility enough to destroy the fat particles holding the drug contained in the drug-containing fat emulsion used to produce the non-aqueous composition containing the fat particles holding the drug. When saccharides or amino acids are used as the water-soluble carrier, the dissolution amount is preferably 20 to 1000 mg / mL, and more preferably 50 to 500 mg / mL. When polyhydric alcohol is used as the water-soluble carrier, the dissolution amount is preferably 50 to 2000 mg / mL, and more preferably 100 to 1000 mg / mL. However, when the saturated dissolution amount of the water-soluble carrier to be used is less than the above upper limit value, the saturated dissolution amount is made the upper limit. If the dissolution amount of the water-soluble carrier is too small, the amount of the water-soluble carrier relative to the amount of fat particles holding the drug becomes too small, and a non-aqueous composition containing fat particles holding the drug cannot be obtained stably (drug There is a risk that destruction of the retained fat particles is likely to occur. On the other hand, if the dissolved amount of the water-soluble carrier is too large, the water-soluble carrier is unnecessarily administered to the patient. The removal of the aqueous phase after dissolving the water-soluble carrier in the drug-containing fat emulsion may be performed by any method, but it is included in the emulsion to be performed by a drying treatment in a temperature range of 10 to 80 ° C. This is desirable in that a non-aqueous composition containing fat particles retaining a drug can be obtained efficiently and at low cost without causing the drug to deteriorate. As the drying treatment, vacuum drying, spray drying, fluidized drying, ventilation drying and the like can be suitably employed, but the temperature condition is more preferably 30 to 70 ° C, and further preferably 40 to 60 ° C. In order for the non-aqueous composition containing fat particles retaining the drug of the present invention thus produced to have excellent storage stability, the water content is desirably 15% or less, and more desirably 10% or less. 7% or less is more desirable.
なお、本発明の薬物を保持した脂肪粒子を含む非水系組成物を製造するために用いる薬物含有脂肪乳剤の構成成分としてプロピレングリコール、グリセリン、マクロゴール、乳酸、ポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、コンドロイチン硫酸またはその塩（ナトリウム塩など）、ヒアルロン酸またはその塩（ナトリウム塩など）、グリチルリチン酸またはその塩（ナトリウム塩やアンモニウム塩など）などをさらに用いることで、薬物の溶解性の向上、乳剤や薬物の安定性の向上、乳剤の等張化などを図ってもよい。これらの含量は０．０２〜３００ｍｇ／ｍＬが望ましく、０．２〜１００ｍｇ／ｍＬがより望ましい。０．０２ｍｇ／ｍＬよりも少ないと効果が発揮されにくくなる一方、３００ｍｇ／ｍＬよりも多いと粘度の上昇によって乳化が困難になったり、乳剤が酸性化されて不安定になったりしやすくなる。 In addition, propylene glycol, glycerin, macrogol, lactic acid, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, chondroitin are used as components of the drug-containing fat emulsion used for producing a non-aqueous composition containing fat particles retaining the drug of the present invention. By further using sulfuric acid or its salt (such as sodium salt), hyaluronic acid or its salt (such as sodium salt), glycyrrhizic acid or its salt (such as sodium salt or ammonium salt), it is possible to improve drug solubility, Improvement of drug stability, isotonicity of the emulsion, and the like may be achieved. These contents are preferably 0.02 to 300 mg / mL, and more preferably 0.2 to 100 mg / mL. When the amount is less than 0.02 mg / mL, the effect is hardly exerted. On the other hand, when the amount is more than 300 mg / mL, emulsification becomes difficult due to an increase in viscosity, and the emulsion tends to be acidified and unstable.
また、薬物含有脂肪乳剤の構成成分としてオレイン酸、ステアリン酸、リノール酸、リノレン酸、パルミチン酸、パルミトレイン酸、ミリスチン酸などの高級脂肪酸をさらに用いることで、乳剤の安定化を図ってもよい。高級脂肪酸の含量は０．００１〜１０ｍｇ／ｍＬが望ましく、０．０１〜５ｍｇ／ｍＬがより望ましい。０．００１ｍｇ／ｍＬよりも少ないと効果が発揮されにくくなる一方、１０ｍｇ／ｍＬよりも多いと薬物に対して劣化を招く危険性が生じる。なお、水難溶性薬物がプロスタグランジン系化合物の場合、これらの高級脂肪酸は用いないことが望ましい（プロスタグランジン系化合物の安定性に悪影響を与えるため）。 Further, the emulsion may be stabilized by further using higher fatty acids such as oleic acid, stearic acid, linoleic acid, linolenic acid, palmitic acid, palmitoleic acid, and myristic acid as constituents of the drug-containing fat emulsion. The content of higher fatty acids is preferably 0.001 to 10 mg / mL, and more preferably 0.01 to 5 mg / mL. When the amount is less than 0.001 mg / mL, the effect is hardly exhibited, while when the amount is more than 10 mg / mL, there is a risk of causing deterioration of the drug. When the poorly water-soluble drug is a prostaglandin compound, it is desirable not to use these higher fatty acids (in order to adversely affect the stability of the prostaglandin compound).
また、薬物含有脂肪乳剤の構成成分として糖類をさらに用いることで、乳剤中に時として発生しうる析出浮遊物の発生を効果的に抑制することができる。好適な糖類としては、上述の水溶性担体として用いることができる糖類の他、デキストリン、シクロデキストリン、デキストランなどが挙げられる。糖類の含量は１０〜６００ｍｇ／ｍＬが望ましい。 Further, by further using saccharides as a constituent of the drug-containing fat emulsion, it is possible to effectively suppress the occurrence of precipitation suspended matter that sometimes occurs in the emulsion. Suitable saccharides include dextrin, cyclodextrin, dextran and the like in addition to the saccharides that can be used as the above-mentioned water-soluble carrier. The sugar content is preferably 10 to 600 mg / mL.
また、薬物含有脂肪乳剤の構成成分として自体公知のｐＨ調整剤や浸透圧調整剤をさらに用い、ｐＨを調整したり（例えば４〜８）、浸透圧を調整したりしてもよい。なお、必要に応じて防腐剤や抗酸化剤などを構成成分としてもよいことは言うまでもない。また、薬物含有脂肪乳剤は、水溶性薬物を構成成分とすることを妨げるものではない。 Further, a pH adjusting agent or an osmotic pressure adjusting agent known per se may be further used as a constituent of the drug-containing fat emulsion to adjust the pH (for example, 4 to 8) or the osmotic pressure. Needless to say, preservatives and antioxidants may be used as constituents as necessary. The drug-containing fat emulsion does not prevent the water-soluble drug from being a constituent component.
本発明の薬物を保持した脂肪粒子を含む非水系組成物は、その製造過程における水相を除去する前の段階や製造後に高圧蒸気滅菌を行うことができる。高圧蒸気滅菌は、一般的な条件（例えば１２０〜１２２℃×１０〜１５分間）で行えばよい。また、その製造過程における水相を除去する前の段階であれば、例えば脂肪粒子の平均粒子径を１００ｎｍ以下に設定することで、ろ過滅菌を行うこともできる。このようにして製造される本発明の薬物を保持した脂肪粒子を含む非水系組成物は、保存安定性に優れるので常温保存ができる（但し薬物が非常に不安定なものである場合はこの限りでない）。本発明の薬物を保持した脂肪粒子を含む非水系組成物を注射用水や生理食塩水などの水系媒体と混合することで、非水化前の薬物含有脂肪乳剤と同様の、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を調製することができるが、こうして調製される薬物含有脂肪乳剤が透明性を有することは、変質や異物混入の有無、配合変化の目視での確認を容易にする他、投与される患者に対して安心感を与える。このように本発明の薬物を保持した脂肪粒子を含む非水系組成物は、それ自体を用時溶解型の医薬品製剤として用いることができる他、各種の医薬品添加物（製剤助剤など）と配合して経口剤や外用剤などの様々な形態の医薬品製剤とすることもできる。ここで特筆すべきは、従来から知られている大量の油脂（例えば１０ｍｇ／ｍＬ以上）を用いて調製された薬物含有脂肪乳剤は、例えば５０℃といった温和な温度条件での乾燥処理で水相を除去すると、脂肪粒子が破壊されてしまうことで、その復元がもはやできないということである（この事実は特許文献２をはじめとしてこれまでに提案されている薬物含有脂肪乳剤の乾燥方法が凍結乾燥に限定されていることを裏付けるものである）。 The non-aqueous composition containing the fat particles retaining the drug of the present invention can be subjected to high-pressure steam sterilization before or after the production of the aqueous phase in the production process. High-pressure steam sterilization may be performed under general conditions (for example, 120 to 122 ° C. for 10 to 15 minutes). Moreover, if it is a stage before the removal of the aqueous phase in the manufacturing process, filtration sterilization can also be performed by setting the average particle diameter of fat particles to 100 nm or less, for example. The non-aqueous composition containing the fat particles retaining the drug of the present invention produced in this way is excellent in storage stability and can be stored at room temperature (provided that this is not necessary if the drug is very unstable). Not) By mixing a non-aqueous composition containing fat particles retaining the drug of the present invention with an aqueous medium such as water for injection or physiological saline, it has transparency similar to that of a drug-containing fat emulsion prior to non-hydration. Drug-containing fat emulsions with excellent stability can be prepared, but the drug-containing fat emulsions prepared in this way have transparency, making it easy to visually check for alterations, foreign matter contamination, and compounding changes. In addition, it gives a sense of security to the patient being administered. As described above, the non-aqueous composition containing the fat particles holding the drug of the present invention can be used as a pharmaceutical preparation which is dissolved at the time of use, and is combined with various pharmaceutical additives (formulation aids, etc.). Thus, various forms of pharmaceutical preparations such as oral preparations and external preparations can be prepared. It should be noted here that a drug-containing fat emulsion prepared using a large amount of fats and oils known in the art (for example, 10 mg / mL or more) can be obtained by subjecting the aqueous phase to drying in a mild temperature condition such as 50 ° C. (2), the fat particles are destroyed and cannot be restored anymore. (This fact is based on the fact that the drying method of drug-containing fat emulsions proposed so far, including Patent Document 2, is freeze-dried. That it is limited to).
以下、本発明を実施例によって詳細に説明するが、本発明は以下の記載に限定して解釈されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is limited to the following description and is not interpreted.
実施例１：エダラボンを保持した脂肪粒子を含む非水系組成物（その１）
２００ｍＬビーカーにエダラボン３００ｍｇ、精製大豆油１００ｍｇ、ポリソルベート（ポリソルベート８０）１．８ｇ、オレイン酸２４０ｍｇ、プロピレングリコール２．２１ｇを採り、ウォーターバスで４５℃に加温し、窒素気流下、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサー（ＨＧ９２：ＳＭＴ社製、以下同じ）を用いて攪拌下、４５℃の精製水７０ｍＬを少量ずつ添加し、添加終了後、１２０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１００ｍＬにメスアップした後、ｐＨを０．１Ｎ水酸化ナトリウム水溶液で６．５０に調整し、高圧ホモジナイザー（ＬＡＢ２０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は７５０バールとし、乳化回数は２０回とした。こうして得られた薄黄色の微濁したエダラボン含有脂肪乳剤（表１参照）１０ｍＬを５０ｍＬビーカーに採り、水溶性担体としてマンニトール１ｇを加えて均一溶解した後、フィルターろ過（孔口径：０．４μｍ）し、窒素送入しながら２０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の全量を５０ｍＬナスフラスコに採り、５０℃で約２０分間の減圧乾燥（エバポレーション）を行うことで、目的とするエダラボンを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：６．１１％）を得た。この白色粉末１４５ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、黄色透明のエダラボン含有脂肪乳剤を復元することができた（表２参照）。
Example 1: Non-aqueous composition containing fat particles retaining edaravone (Part 1)
In a 200 mL beaker, take edaravone 300 mg, refined soybean oil 100 mg, polysorbate (polysorbate 80) 1.8 g, oleic acid 240 mg, propylene glycol 2.21 g, warm to 45 ° C. in a water bath, and mix with a stirrer under a nitrogen stream. Oil phase. To this oil phase, 70 mL of purified water at 45 ° C. was added little by little with stirring using a high flex disperser (HG92: manufactured by SMT, the same shall apply hereinafter). Purified water was further added to make up the volume to 100 mL, and then the pH was adjusted to 6.50 with a 0.1N aqueous sodium hydroxide solution, and precise emulsification was performed using a high-pressure homogenizer (LAB2000: manufactured by SMT). The emulsification pressure was 750 bar and the emulsification frequency was 20 times. 10 mL of the pale yellow, slightly turbid edaravone-containing fat emulsion thus obtained (see Table 1) was put in a 50 mL beaker, and 1 g of mannitol was added as a water-soluble carrier and uniformly dissolved, followed by filter filtration (pore size: 0.4 μm) Then, it was filled in a 20 mL vial and sealed while nitrogen was introduced, and autoclaving was performed under conditions of 121 ° C. × 12 minutes. After sterilization, the vial is opened in a sterile booth, the entire amount in the vial is taken into a 50 mL eggplant flask, and dried at 50 ° C. for about 20 minutes under reduced pressure (evaporation), thereby retaining fat particles containing the desired edaravone A non-aqueous composition (white powder, moisture content: 6.11%) was obtained. When 145 mg of this white powder was put into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a yellow transparent edaravone-containing fat emulsion could be restored (see Table 2).
実施例２：エダラボンを保持した脂肪粒子を含む非水系組成物（その２）
精製大豆油の使用量を１０ｍｇとすること以外は実施例１と同様にして薄黄色の微濁したエダラボン含有脂肪乳剤（表１参照）を得た後、実施例１と同様にして目的とするエダラボンを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：５．７４％）を得た。この白色粉末１４５ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、黄色透明のエダラボン含有脂肪乳剤を復元することができた（表２参照）。
Example 2: Non-aqueous composition containing fat particles retaining edaravone (Part 2)
A light yellow slightly turbid edaravone-containing fat emulsion (see Table 1) was obtained in the same manner as in Example 1 except that the amount of refined soybean oil was changed to 10 mg. A non-aqueous composition (white powder, moisture content: 5.74%) containing fat particles retaining edaravone was obtained. When 145 mg of this white powder was put into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a yellow transparent edaravone-containing fat emulsion could be restored (see Table 2).
実施例３：グリチルリチン酸モノアンモニウムを保持した脂肪粒子を含む非水系組成物
２００ｍＬビーカーにグリチルリチン酸モノアンモニウム５００ｍｇ、精製大豆油１００ｍｇ、ポリソルベート（ポリソルベート８０）１．８ｇ、プロピレングリコール２．２１ｇを採り、ウォーターバスで６０℃に加温し、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、６０℃の精製水７０ｍＬを少量ずつ添加し、添加終了後、１１０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１００ｍＬにメスアップした後、高圧ホモジナイザー（ＬＡＢ２０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は６００バールとし、乳化回数は２０回とした。こうして得られた無色透明のグリチルリチン酸モノアンモニウム含有脂肪乳剤（表１参照）２０ｍＬを５０ｍＬビーカーに採り、水溶性担体としてマンニトール２ｇを加えて均一溶解した後、フィルターろ過（孔口径：０．４μｍ）し、２０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、５０℃で約４０分間の減圧乾燥を行うことで、目的とするグリチルリチン酸モノアンモニウムを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：４．４５％）を得た。この白色粉末１４６ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、無色透明のグリチルリチン酸モノアンモニウム含有脂肪乳剤を復元することができた（表２参照）。
Example 3: Non-aqueous composition containing fat particles retaining monoammonium glycyrrhizinate In a 200 mL beaker, 500 mg of monoammonium glycyrrhizinate, 100 mg of refined soybean oil, 1.8 g of polysorbate (polysorbate 80), 2.21 g of propylene glycol were taken. The mixture was heated to 60 ° C. with a water bath and mixed with a stirrer to obtain an oil phase. To this oil phase, 70 mL of 60 ° C. purified water was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 11000 rpm for 10 minutes. Purified water was further added to make up the volume of the solution to 100 mL, followed by precise emulsification using a high-pressure homogenizer (LAB2000: manufactured by SMT). The emulsification pressure was 600 bar and the emulsification frequency was 20 times. 20 mL of the colorless and transparent monoammonium glycyrrhizinate-containing fat emulsion thus obtained (see Table 1) was placed in a 50 mL beaker, and 2 g of mannitol was added as a water-soluble carrier and uniformly dissolved, followed by filter filtration (pore size: 0.4 μm) Then, it was filled in a 20 mL vial and sealed, and autoclaving was performed under the conditions of 121 ° C. × 12 minutes. After sterilization, the vial is opened in a sterile booth, the entire amount in the vial is taken into a 100 mL eggplant flask, and dried under reduced pressure at 50 ° C. for about 40 minutes, so that the fat particles holding the target monoammonium glycyrrhizinate are obtained. A non-aqueous composition (white powder, moisture content: 4.45%) was obtained. When 146 mg of this white powder was taken into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a colorless and transparent monoammonium glycyrrhizinate-containing fat emulsion could be recovered (see Table 2).
実施例４：アスピリンを保持した脂肪粒子を含む非水系組成物
２００ｍＬビーカーにアスピリン４７５ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ：日清製油社製）２５ｍｇ、ポリソルベート（ポリソルベート８０）１．８ｇ、プロピレングリコール２．２１ｇを採り、ウォーターバスで６０℃に加温し、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、６０℃の精製水７０ｍＬを少量ずつ添加し、添加終了後、１２０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１００ｍＬにメスアップした後、高圧ホモジナイザー（ＬＡＢ２０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は６００バールとし、乳化回数は２０回とした。こうして得られた無色透明のアスピリン含有脂肪乳剤（表１参照）２０ｍＬを５０ｍＬビーカーに採り、水溶性担体としてマンニトール２ｇを加えて均一溶解した後、フィルターろ過（孔口径：０．４μｍ）し、１００ｍＬナスフラスコに入れ、５０℃で約４０分間の減圧乾燥を行うことで、目的とするアスピリンを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：７．７８％）を得た。この白色粉末１４６ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、無色透明のアスピリン含有脂肪乳剤を復元することができた（表２参照）。
Example 4 Nonaqueous Composition Containing Fat Particles Retaining Aspirin In a 200 mL beaker, 475 mg of aspirin, 25 mg of medium chain fatty acid triglyceride (ODO: manufactured by Nisshin Oil Co., Ltd.), 1.8 g of polysorbate (polysorbate 80), propylene glycol 21 g was taken, heated to 60 ° C. with a water bath, and mixed with a stirrer to obtain an oil phase. To this oil phase, 70 mL of 60 ° C. purified water was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 12,000 rpm for 10 minutes. Purified water was further added to make up the volume of the solution to 100 mL, followed by precise emulsification using a high-pressure homogenizer (LAB2000: manufactured by SMT). The emulsification pressure was 600 bar and the emulsification frequency was 20 times. 20 mL of the colorless and transparent aspirin-containing fat emulsion thus obtained (see Table 1) was put in a 50 mL beaker, and 2 g of mannitol as a water-soluble carrier was added and uniformly dissolved, followed by filter filtration (pore diameter: 0.4 μm), 100 mL A non-aqueous composition (white powder, moisture content: 7.78%) containing fat particles retaining the target aspirin was obtained by placing in an eggplant flask and drying under reduced pressure at 50 ° C. for about 40 minutes. When 146 mg of this white powder was taken into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a colorless and transparent aspirin-containing fat emulsion could be recovered (see Table 2).
実施例５：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その１）
３００ｍＬビーカーにプロスタグランジンＥ１１．２ｍｇ、精製大豆油２００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ：キューピー社製）３．６ｇを採り、ウォーターバスで４０℃に加温し、窒素気流下、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、４０℃の精製水１７０ｍＬを少量ずつ添加し、添加終了後、１１０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を２００ｍＬにメスアップした後、ｐＨを０．１Ｎ塩酸水溶液で５．００〜５．５０に調整し、高圧ホモジナイザー（ＬＡＢ１０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は６００バールとし、乳化回数は２０回とした。こうして得られたほぼ無色透明のプロスタグランジンＥ１含有脂肪乳剤（表１参照）５０ｍＬを１００ｍＬビーカーに採り、水溶性担体としてトレハロース５ｇを加えて均一溶解した後、フィルターろ過（孔口径：０．８μｍ）し、窒素送入しながら５０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の１０ｍＬを２００ｍＬナスフラスコに採り、５０℃で約２０分間の減圧乾燥を行うことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：５．９６％）を得た。この白色粉末１１９ｍｇを試験管に採り、精製水１ｍＬを加えて２分間、手で振とうしたところ、無色の微濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表２参照）。
Example 5: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 1)
In a 300 mL beaker, take 1.2 mg of prostaglandin E 1 , 200 mg of refined soybean oil, 3.6 g of purified egg yolk lecithin (PC-98N: manufactured by Kewpie), heat to 40 ° C. in a water bath, stirrer under nitrogen flow To obtain an oil phase. To this oil phase, 170 mL of 40 ° C. purified water was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 11000 rpm for 10 minutes. Purified water was further added to make up the volume to 200 mL, and then the pH was adjusted to 5.00 to 5.50 with a 0.1N hydrochloric acid aqueous solution, and precision emulsification was performed using a high-pressure homogenizer (LAB1000: manufactured by SMT). did. The emulsification pressure was 600 bar and the emulsification frequency was 20 times. 50 mL of the substantially colorless and transparent prostaglandin E 1- containing fat emulsion thus obtained (see Table 1) was placed in a 100 mL beaker, and 5 g of trehalose was added as a water-soluble carrier and uniformly dissolved, followed by filter filtration (pore size: 0. 0). 8 μm), filled in a 50 mL vial with nitrogen, sealed, and autoclaved under conditions of 121 ° C. × 12 minutes. After sterilization, the vial is opened in a sterile booth, 10 mL of the vial is taken into a 200 mL eggplant flask and dried under reduced pressure at 50 ° C. for about 20 minutes, thereby retaining the target prostaglandin E 1 A non-aqueous composition (white powder, moisture content: 5.96%) was obtained. When 119 mg of this white powder was put into a test tube and 1 mL of purified water was added and shaken by hand for 2 minutes, a colorless and turbid prostaglandin E 1- containing fat emulsion could be recovered (see Table 2). ).
実施例６：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その２）
実施例５と同様にしてほぼ無色透明のプロスタグランジンＥ１含有脂肪乳剤（表１参照）を得た後、水溶性担体としてトレハロースのかわりにマルトースを用いること以外は実施例５と同様にして目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：４．８８％）を得た。この白色粉末１１９ｍｇを試験管に採り、精製水１ｍＬを加えて２分間、手で振とうしたところ、無色の微濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表２参照）。
Example 6: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 2)
After obtaining the nearly colorless transparent prostaglandin E 1 containing fat emulsion (see Table 1) in the same manner as in Example 5, but using maltose instead of trehalose as water-soluble carrier in the same manner as in Example 5 nonaqueous compositions containing fat particles holding the prostaglandin E 1 for the purpose (white powder, water content: 4.88%) was obtained. When 119 mg of this white powder was put into a test tube and 1 mL of purified water was added and shaken by hand for 2 minutes, a colorless and turbid prostaglandin E 1- containing fat emulsion could be recovered (see Table 2). ).
比較例１：プロスタグランジンＥ１を含む非水系組成物（その１）
３００ｍＬビーカーにプロスタグランジンＥ１０．９ｍｇ、精製大豆油１５ｇ、精製卵黄レシチン（ＰＣ−９８Ｎ：キューピー社製）２．７ｇ、オレイン酸３６０ｍｇ、プロピレングリコール３．３１５ｇを採り、ウォーターバスで４０℃に加温し、窒素気流下、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、４０℃の精製水１２０ｍＬを少量ずつ添加し、添加終了後、１１０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１５０ｍＬにメスアップした後、ｐＨを０．１Ｎ水酸化ナトリウム水溶液で５．００〜５．５０に調整し、高圧ホモジナイザー（ＬＡＢ１０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は６００バールとし、乳化回数は２０回とした。こうして得られた乳白色のプロスタグランジンＥ１含有脂肪乳剤（表１参照）をフィルターろ過（孔口径：０．８μｍ）し、その２０ｍＬを窒素送入しながら５０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１０分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてトレハロース４ｇを加えて５０℃に加温して均一溶解した後、５０℃で約５０分間の減圧乾燥を行ったところ、ナスフラスコの内壁に水分率が５．２６％の薄乳白色のフィルム状物が形成された。このフィルム状物３４３ｍｇを試験管に採り、精製水１ｍＬを加えて２分間、手で振とうしたところ、試験管の内壁に油状成分がべっとりと付着した乳白色液となり、プロスタグランジンＥ１含有脂肪乳剤を復元することはできなかった（表２参照）。
Comparative Example 1: Non-aqueous composition containing prostaglandin E 1 (Part 1)
In a 300 mL beaker, 0.9 mg of prostaglandin E 1 , 15 g of purified soybean oil, 2.7 g of purified egg yolk lecithin (PC-98N: manufactured by Kewpie), 360 mg of oleic acid, 3.315 g of propylene glycol, and 40 ° C. in a water bath And mixed with a stirrer under a nitrogen stream to obtain an oil phase. To this oil phase, 120 mL of 40 ° C. purified water was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 11000 rpm for 10 minutes. After further adding purified water to make up the liquid volume to 150 mL, the pH was adjusted to 5.00-5.50 with a 0.1N aqueous sodium hydroxide solution, and a high-pressure homogenizer (LAB1000: manufactured by SMT) was used. Precision emulsification. The emulsification pressure was 600 bar and the emulsification frequency was 20 times. Milky prostaglandin E 1 containing fat emulsion (see Table 1) a filtration (pore diameter: 0.8 [mu] m) thus obtained was, sealed and filled with its 20mL to 50mL vial with nitrogen fed, high pressure Steam sterilization was performed at 121 ° C. for 10 minutes. After sterilization, the vial is opened in a sterile booth, the entire amount in the vial is taken into a 100 mL eggplant flask, 4 g of trehalose is added as a water-soluble carrier, heated to 50 ° C. and uniformly dissolved, and then at 50 ° C. for about 50 minutes. As a result of drying under reduced pressure, a thin milky white film-like material having a moisture content of 5.26% was formed on the inner wall of the eggplant flask. When 343 mg of this film-like material was taken into a test tube, and 1 mL of purified water was added and shaken by hand for 2 minutes, it became a milky white liquid with oily components adhering to the inner wall of the test tube, resulting in a fat containing prostaglandin E 1 The emulsion could not be restored (see Table 2).
実施例７：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その３）
３００ｍＬビーカーにプロスタグランジンＥ１１．２ｍｇ、精製大豆油２００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ：キューピー社製）３．６ｇ、プロピレングリコール４．４２ｇを採り、ウォーターバスで４０℃に加温し、窒素気流下、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、４０℃の精製水１７０ｍｌを少量ずつ添加し、添加終了後、１１０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を２００ｍＬにメスアップした後、ｐＨを０．１Ｎ水酸化ナトリウム水溶液で５．００〜５．５０に調整し、高圧ホモジナイザー（ＬＡＢ１０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は５８０バールとし、乳化回数は２０回とした。こうして得られたほぼ無色透明のプロスタグランジンＥ１含有脂肪乳剤（表１参照）５０ｍＬを１００ｍＬビーカーに採り、トレハロース１ｇを加えて均一溶解した後、フィルターろ過（孔口径：０．８μｍ）し、窒素送入しながら５０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の１０ｍＬを２００ｍＬナスフラスコに採り、水溶性担体としてグリセリン２．５ｇを加えて均一溶解した後、５０℃で約４０分間の減圧乾燥を行うことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（無色透明の粘性液体、水分率：５．０１％）を得た。この粘性液体６２２ｍｇを試験管に採り、精製水２ｍＬを加えて１分間、手で振とうしたところ、無色の微濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表２参照）。
Example 7: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 3)
In a 300 mL beaker, take 1.2 mg of prostaglandin E 1 , 200 mg of purified soybean oil, 3.6 g of purified egg yolk lecithin (PC-98N: manufactured by Kewpie), 4.42 g of propylene glycol, and heat to 40 ° C. in a water bath. The mixture was mixed with a stirrer under a nitrogen stream to obtain an oil phase. To this oil phase, 170 ml of 40 ° C. purified water was added little by little with stirring using a high-flex disperser. After the addition was completed, the emulsion was roughly emulsified at 11000 rpm for 10 minutes. After further adding purified water to make up the liquid volume to 200 mL, the pH was adjusted to 5.00-5.50 with 0.1N sodium hydroxide aqueous solution, and using a high-pressure homogenizer (LAB1000: manufactured by SMT). Precision emulsification. The emulsification pressure was 580 bar and the emulsification frequency was 20 times. 50 mL of the substantially colorless and transparent prostaglandin E 1- containing fat emulsion thus obtained (see Table 1) was placed in a 100 mL beaker, 1 g of trehalose was added and uniformly dissolved, and then filtered (pore size: 0.8 μm). A 50 mL vial was filled and sealed while nitrogen was introduced, and autoclaving was performed under conditions of 121 ° C. × 12 minutes. After sterilization, the vial is opened in a sterile booth, 10 mL of the vial is taken into a 200 mL eggplant flask, 2.5 g of glycerin as a water-soluble carrier is added and uniformly dissolved, and then dried at 50 ° C. for about 40 minutes under reduced pressure. it is, nonaqueous compositions containing fat particles holding the prostaglandin E 1 for the purpose (viscous liquid, the moisture content of the colorless and transparent: 5.01%) was obtained. When 622 mg of this viscous liquid was taken into a test tube and 2 mL of purified water was added and shaken by hand for 1 minute, a colorless and turbid prostaglandin E 1- containing fat emulsion could be recovered (see Table 2). ).
比較例２：プロスタグランジンＥ１を含む非水系組成物（その２）
比較例１で得た乳白色のプロスタグランジンＥ１含有脂肪乳剤（表１参照）２０ｍＬを封入した高圧蒸気滅菌済みの５０ｍＬバイアルを無菌ブース内で開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてグリセリン４ｇを加えて５０℃に加温して均一溶解した後、５０℃で約５０分間の減圧乾燥を行ったところ、水分率が７．０８％の無色透明の粘性液体が得られた。この粘性液体３４３ｍｇを試験管に採り、精製水１ｍＬを加えて２分間、手で振とうしたところ、油分感が強い乳白色液となり、しばらくすると油状分離が起こってしまい、プロスタグランジンＥ１含有脂肪乳剤を復元することはできなかった（表２参照）。
Comparative Example 2: Non-aqueous composition containing prostaglandin E 1 (Part 2)
A 50 mL vial sterilized by autoclaving and containing 20 mL of the milky white prostaglandin E 1- containing fat emulsion obtained in Comparative Example 1 (see Table 1) was opened in a sterile booth, and the entire amount in the vial was placed in a 100 mL eggplant flask. Then, 4 g of glycerin was added as a water-soluble carrier, heated to 50 ° C. and uniformly dissolved, and then dried under reduced pressure at 50 ° C. for about 50 minutes. As a result, a colorless transparent viscous liquid having a moisture content of 7.08% was obtained. Obtained. When 343 mg of this viscous liquid was put into a test tube and shaken by hand for 2 minutes after adding 1 mL of purified water, it became a milky white liquid with a strong oily feeling, and after a while, oily separation occurred, and the fat containing prostaglandin E 1 The emulsion could not be restored (see Table 2).
比較例３：プロスタグランジンＥ１を含む非水系組成物（その３）
比較例１で得た乳白色のプロスタグランジンＥ１含有脂肪乳剤（表１参照）２０ｍＬを封入した高圧蒸気滅菌済みの５０ｍＬバイアルを無菌ブース内で開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてグリセリン４０ｇを加えて５０℃に加温して均一溶解した後、５０℃で約９０分間の減圧乾燥を行ったところ、水分率が６．８３％の無色透明の粘性液体が得られた。この粘性液体２１４３ｍｇを試験管に採り、精製水１ｍＬを加えて２分間、手で振とうしたところ、油分感が強い乳白色液となり、しばらくすると油状分離が起こってしまい、プロスタグランジンＥ１含有脂肪乳剤を復元することはできなかった（表２参照）。
Comparative Example 3: Non-aqueous composition containing prostaglandin E 1 (Part 3)
A 50 mL vial sterilized by autoclaving and containing 20 mL of the milky white prostaglandin E 1- containing fat emulsion obtained in Comparative Example 1 (see Table 1) was opened in a sterile booth, and the entire amount in the vial was placed in a 100 mL eggplant flask. After adding 40 g of glycerin as a water-soluble carrier and heating to 50 ° C. to dissolve uniformly, drying under reduced pressure at 50 ° C. for about 90 minutes revealed that a colorless transparent viscous liquid having a moisture content of 6.83% was obtained. Obtained. When 2143 mg of this viscous liquid was put into a test tube and shaken by hand for 2 minutes after adding 1 mL of purified water, it became a milky white liquid with a strong oily feeling, and after a while, oily separation occurred, and the fat containing prostaglandin E 1 The emulsion could not be restored (see Table 2).
実施例８：アセトアミノフェンを保持した脂肪粒子を含む非水系組成物（その１）
３００ｍＬビーカーにアセトアミノフェン６００ｍｇ、精製大豆油１５０ｍｇ、ポリソルベート（ポリソルベート８０）２．７ｇ、プロピレングリコール３．３１ｇを採り、ウォーターバスで４０℃に加温し、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、４０℃の精製水１３０ｍＬを少量ずつ添加し、添加終了後、１２０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１５０ｍＬにメスアップした後、高圧ホモジナイザー（ＬＡＢ１０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は６００バールとし、乳化回数は２０回とした。こうして得られた無色透明のアセトアミノフェン含有脂肪乳剤（表１参照）をフィルターろ過（孔口径：０．８μｍ）し、その１０ｍＬを２０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてグリセリン１ｇを加えて均一溶解した後、５０℃で約２０分間の減圧乾燥を行うことで、目的とするアセトアミノフェンを保持した脂肪粒子を含む非水系組成物（無色透明の粘性液体、水分率：３．７２％）を得た。この粘性液体１４５ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、無色透明のアセトアミノフェン含有脂肪乳剤を復元することができた（表２参照）。
Example 8: Non-aqueous composition containing fat particles retaining acetaminophen (Part 1)
In a 300 mL beaker, 600 mg of acetaminophen, 150 mg of purified soybean oil, 2.7 g of polysorbate (polysorbate 80) and 3.31 g of propylene glycol were taken, heated to 40 ° C. in a water bath, and mixed with a stirrer to obtain an oil phase. To this oil phase, 130 mL of 40 ° C. purified water was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 12,000 rpm for 10 minutes. Purified water was further added to make up the volume of the solution to 150 mL, followed by precise emulsification using a high-pressure homogenizer (LAB1000: manufactured by SMT). The emulsification pressure was 600 bar and the emulsification frequency was 20 times. The colorless and transparent acetaminophen-containing fat emulsion thus obtained (see Table 1) was filtered (pore size: 0.8 μm), 10 mL of which was filled in a 20 mL vial and sealed, and autoclaved at 121 ° C. × The test was performed for 12 minutes. After sterilization, the vial is opened in a sterile booth, the whole amount in the vial is taken into a 100 mL eggplant flask, 1 g of glycerin is added as a water-soluble carrier and uniformly dissolved, and then dried at 50 ° C. under reduced pressure for about 20 minutes. A non-aqueous composition (colorless and transparent viscous liquid, moisture content: 3.72%) containing fat particles retaining the target acetaminophen was obtained. When 145 mg of this viscous liquid was taken into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a colorless and transparent acetaminophen-containing fat emulsion could be recovered (see Table 2).
実施例９：シクロスポリンを保持した脂肪粒子を含む非水系組成物
３００ｍＬビーカーにシクロスポリン１２０ｍｇ、精製大豆油３０ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ：キューピー社製）２．７ｇ、オレイン酸３６０ｍｇ、プロピレングリコール３．３１ｇを採り、ウォーターバスで６０℃に加温し、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、６０℃の精製水１２０ｍＬを少量ずつ添加し、添加終了後、１１０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１５０ｍＬにメスアップした後、高圧ホモジナイザー（ＬＡＢ１０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は８００バールとし、乳化回数は２５回とした。乳化後、ｐＨを０．１Ｎ塩酸水溶液で６．５０に調整し、その１０ｍＬを１０ｍＬアンプルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。こうして得られた薄黄色で透明のシクロスポリン含有脂肪乳剤（表１）を封入した高圧蒸気滅菌済みの１０ｍＬアンプルを無菌ブース内で開封し、アンプル内の６ｍＬを５０ｍＬナスフラスコに採り、水溶性担体としてトレハロース２ｇを加えて均一溶解した後、５０℃で約２０分間の減圧乾燥を行うことで、目的とするシクロスポリンを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：２．７１％）を得た。この白色粉末３７６ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、薄黄色の微濁したシクロスポリン含有脂肪乳剤を復元することができた（表２参照）。
Example 9: Non-aqueous composition containing fat particles retaining cyclosporine In a 300 mL beaker, 120 mg of cyclosporine, 30 mg of purified soybean oil, 2.7 g of purified egg yolk lecithin (PL-100M: manufactured by Kewpie), 360 mg of oleic acid, propylene glycol 3 .31 g was taken, heated to 60 ° C. with a water bath, and mixed with a stirrer to obtain an oil phase. To this oil phase, 120 mL of 60 ° C. purified water was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 11000 rpm for 10 minutes. Purified water was further added to make up the volume of the solution to 150 mL, followed by precise emulsification using a high-pressure homogenizer (LAB1000: manufactured by SMT). The emulsification pressure was 800 bar and the emulsification frequency was 25 times. After emulsification, the pH was adjusted to 6.50 with 0.1N hydrochloric acid aqueous solution, 10 mL of the solution was sealed in a 10 mL ampule, and autoclaving was performed under the conditions of 121 ° C. × 12 minutes. The 10 mL ampoule sterilized by autoclaving and containing the light yellow and transparent cyclosporine-containing fat emulsion (Table 1) thus obtained was opened in a sterile booth, and 6 mL of the ampoule was taken into a 50 mL eggplant flask and used as a water-soluble carrier. After adding 2 g of trehalose and homogeneously dissolving, it is dried under reduced pressure at 50 ° C. for about 20 minutes, whereby a non-aqueous composition containing fat particles retaining the desired cyclosporine (white powder, moisture content: 2.71% ) When 376 mg of this white powder was taken into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a pale yellow slightly cloudy cyclosporine-containing fat emulsion could be recovered (see Table 2).
実施例１０：パルミチン酸デキサメサゾンを保持した脂肪粒子を含む非水系組成物
２００ｍＬビーカーにパルミチン酸デキサメサゾン１００ｍｇ、精製大豆油２０ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ：キューピー社製）１．８ｇ、オレイン酸２４０ｍｇ、グリセリン２．２１ｇを採り、ウォーターバスで６０℃に加温し、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、６０℃の精製水８０ｍＬを少量ずつ添加し、添加終了後、１２０００ｒｐｍで１５分間、粗乳化した。精製水をさらに添加して液容量を１００ｍＬにメスアップした後、高圧ホモジナイザー（ＬＡＢ１０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は８００バールとし、乳化回数は２０回とした。乳化後、ｐＨを０．１Ｎ塩酸水溶液で６．７０に調整し、その１０ｍＬを１０ｍＬアンプルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。こうして得られた黄色透明のパルミチン酸デキサメサゾン含有脂肪乳剤（表１）を封入した高圧蒸気滅菌済みの１０ｍＬアンプルを無菌ブース内で開封し、アンプル内の６ｍＬを５０ｍＬナスフラスコに採り、水溶性担体としてトレハロース２ｇを加えて均一溶解した後、５０℃で約１５分間の減圧乾燥を行うことで、目的とするパルミチン酸デキサメサゾンを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：４．２０％）を得た。この白色粉末３７６ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、黄色の微濁したパルミチン酸デキサメサゾン含有脂肪乳剤を復元することができた（表２参照）。
Example 10: Non-aqueous composition containing fat particles retaining dexamethasone palmitate In a 200 mL beaker, 100 mg dexamethasone palmitate, 20 mg purified soybean oil, 1.8 g purified egg yolk lecithin (PL-100M: manufactured by Kewpie), 240 mg oleic acid Then, 2.21 g of glycerin was taken, heated to 60 ° C. with a water bath, and mixed with a stirrer to obtain an oil phase. To this oil phase, 80 mL of purified water at 60 ° C. was added little by little with stirring using a high-flex disperser. After the addition, the emulsion was roughly emulsified at 12000 rpm for 15 minutes. Purified water was further added to make up the volume of the solution to 100 mL, followed by precise emulsification using a high-pressure homogenizer (LAB1000: manufactured by SMT). The emulsification pressure was 800 bar and the emulsification frequency was 20 times. After emulsification, the pH was adjusted to 6.70 with 0.1N aqueous hydrochloric acid, 10 mL of the solution was sealed in a 10 mL ampoule, and autoclaving was performed at 121 ° C. for 12 minutes. The 10 mL ampoule that has been sterilized under high pressure steam and enclosed with the yellow transparent dexamethasone palmitate-containing fat emulsion (Table 1) thus obtained is opened in a sterile booth, and 6 mL of the ampoule is taken into a 50 mL eggplant flask and used as a water-soluble carrier. 2 g of trehalose is added and uniformly dissolved, and then dried under reduced pressure at 50 ° C. for about 15 minutes, whereby a non-aqueous composition containing fat particles holding the target dexamethasone palmitate (white powder, moisture content: 4. 20%). When 376 mg of this white powder was taken into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a yellow turbid dexamethasone palmitate-containing fat emulsion could be recovered (see Table 2).
実施例１１：アセトアミノフェンを保持した脂肪粒子を含む非水系組成物（その２）
実施例８で得た無色透明のアセトアミノフェン含有脂肪乳剤（表１参照）１０ｍＬを封入した高圧蒸気滅菌済みの２０ｍＬバイアルを無菌ブース内で開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてγ−アミノ酪酸１ｇを加えて均一溶解した後、５０℃で約４０分間の減圧乾燥を行うことで、目的とするアセトアミノフェンを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：７．８６％）を得た。この白色粉末１４５ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、無色透明のアセトアミノフェン含有脂肪乳剤を復元することができた（表２参照）。
Example 11: Non-aqueous composition containing fat particles retaining acetaminophen (Part 2)
A 20 mL vial that had been autoclaved and sealed with 10 mL of the colorless and transparent acetaminophen-containing fat emulsion (see Table 1) obtained in Example 8 was opened in a sterile booth, and the entire amount in the vial was taken into a 100 mL eggplant flask. After adding 1 g of γ-aminobutyric acid as a water-soluble carrier and homogeneously dissolving it, it is dried under reduced pressure at 50 ° C. for about 40 minutes, whereby a non-aqueous composition containing fat particles holding the target acetaminophen (white) Powder, moisture content: 7.86%). When 145 mg of this white powder was taken into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a colorless and transparent acetaminophen-containing fat emulsion could be recovered (see Table 2).
実施例１２：ニコチン酸トコフェロールを保持した脂肪粒子を含む非水系組成物（その１）
２００ｍＬビーカーにニコチン酸トコフェロール１５０ｍｇ、精製大豆油１００ｍｇ、ポリオキシエチレン硬化ヒマシ油（ＨＣＯ−６０：日光ケミカルズ社製）３．０ｇ、オレイン酸４５０ｍｇ、グリセリン３．３１ｇを採り、ウォーターバスで６０℃に加温し、スターラーで混合して油相とした。この油相に、ハイフレックスディスパーサーを用いて攪拌下、６０℃の精製水８０ｍＬを少量ずつ添加し、添加終了後、１２０００ｒｐｍで１０分間、粗乳化した。精製水をさらに添加して液容量を１００ｍＬにメスアップした後、高圧ホモジナイザー（ＬＡＢ２０００：ＳＭＴ社製）を用いて精密乳化した。乳化圧力は７００バールとし、乳化回数は１５回とした。こうして得られた無色透明のニコチン酸トコフェロール含有脂肪乳剤（表１参照）をフィルターろ過（孔口径：０．４５μｍ）し、その１０ｍＬを２０ｍＬバイアルに充填して密封し、高圧蒸気滅菌を１２１℃×１２分間の条件で行った。滅菌後、無菌ブース内でバイアルを開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてプロピレングリコール１ｇを加えて均一溶解した後、５０℃で約３０分間の減圧乾燥を行うことで、目的とするニコチン酸トコフェロールを保持した脂肪粒子を含む非水系組成物（無色透明の粘性液体、水分率：２．３３％）を得た。この粘性液体１４５ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、無色透明のニコチン酸トコフェロール含有脂肪乳剤を復元することができた（表２参照）。
Example 12: Non-aqueous composition containing fat particles retaining tocopherol nicotinate (Part 1)
In a 200 mL beaker, take 150 mg of tocopherol nicotinate, 100 mg of refined soybean oil, 3.0 g of polyoxyethylene hydrogenated castor oil (HCO-60: manufactured by Nikko Chemicals), 450 mg of oleic acid, 3.31 g of glycerin, and heat to 60 ° C. with a water bath. The mixture was heated and mixed with a stirrer to obtain an oil phase. To this oil phase, 80 mL of purified water at 60 ° C. was added little by little with stirring using a high flex disperser. After the addition was completed, the emulsion was roughly emulsified at 12,000 rpm for 10 minutes. Purified water was further added to make up the volume of the solution to 100 mL, followed by precise emulsification using a high-pressure homogenizer (LAB2000: manufactured by SMT). The emulsification pressure was 700 bar and the emulsification frequency was 15 times. The colorless and transparent tocopherol nicotinate-containing fat emulsion thus obtained (see Table 1) was filtered through a filter (pore size: 0.45 μm), 10 mL of which was filled in a 20 mL vial and sealed, and high-pressure steam sterilization was performed at 121 ° C. × The test was performed for 12 minutes. After sterilization, open the vial in an aseptic booth, take the entire amount in a 100 mL eggplant flask, add 1 g of propylene glycol as a water-soluble carrier and uniformly dissolve, and then dry under reduced pressure at 50 ° C. for about 30 minutes Thus, a non-aqueous composition (colorless and transparent viscous liquid, water content: 2.33%) containing fat particles holding the desired tocopherol nicotinate was obtained. When 145 mg of this viscous liquid was put into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a colorless and transparent tocopherol nicotinate-containing fat emulsion could be restored (see Table 2).
実施例１３：ニコチン酸トコフェロールを保持した脂肪粒子を含む非水系組成物（その２）
実施例１２で得た無色透明のニコチン酸トコフェロール含有脂肪乳剤（表１参照）１０ｍＬを封入した高圧蒸気滅菌済みの２０ｍＬバイアルを無菌ブース内で開封し、バイアル内の全量を１００ｍＬナスフラスコに採り、水溶性担体としてポリエチレングリコール（ＰＥＧ４００）１ｇを加えて均一溶解した後、５０℃で約３０分間の減圧乾燥を行うことで、目的とするニコチン酸トコフェロールを保持した脂肪粒子を含む非水系組成物（無色微濁の粘性液体、水分率：５．４３％）を得た。この粘性液体１４５ｍｇを試験管に採り、精製水１ｍＬを加えて１分間、手で振とうしたところ、無色透明のニコチン酸トコフェロール含有脂肪乳剤を復元することができた（表２参照）。
Example 13: Non-aqueous composition containing fat particles retaining tocopherol nicotinate (Part 2)
A 20 mL vial that had been autoclaved and sealed with 10 mL of the colorless and transparent tocopherol nicotinate-containing fat emulsion obtained in Example 12 (see Table 1) was opened in a sterile booth, and the entire amount in the vial was placed in a 100 mL eggplant flask. After adding 1 g of polyethylene glycol (PEG400) as a water-soluble carrier and uniformly dissolving it, it is dried under reduced pressure at 50 ° C. for about 30 minutes, whereby a non-aqueous composition containing fat particles retaining the desired tocopherol nicotinate ( A colorless and turbid viscous liquid, water content: 5.43%) was obtained. When 145 mg of this viscous liquid was put into a test tube and 1 mL of purified water was added and shaken by hand for 1 minute, a colorless and transparent tocopherol nicotinate-containing fat emulsion could be restored (see Table 2).
なお、濁度の測定は、紫外分光光度計（ＵＶ２４０：島津製作所社製）を用い、サンプルをセル幅が１ｃｍの測定セルに入れて波長λ＝６２０ｎｍで行った（ブランクは水）。サンプルが透けて見え、凝集や沈殿などの変質や異物混入の有無、配合変化を目視で容易に確認できる透明〜半透明領域はＡｂｓ（吸光度）＝０．５以下であるので、この濁度を合否の境界とした。平均粒子径の算出は、光子相関法を用いた粒子径測定装置（ゼータサイザー３０００ＨＳ：シスメックス社製）を用いて行った。 The turbidity was measured using an ultraviolet spectrophotometer (UV240: manufactured by Shimadzu Corporation), and the sample was placed in a measurement cell having a cell width of 1 cm at a wavelength λ = 620 nm (the blank is water). The sample can be seen through, and the transparent to translucent region where Abs (absorbance) = 0.5 or less can be easily confirmed by visual inspection of alteration such as agglomeration and precipitation, presence or absence of foreign matter, and change in composition. It was set as a pass / fail boundary. The average particle size was calculated using a particle size measuring device (Zeta Sizer 3000HS: manufactured by Sysmex Corporation) using a photon correlation method.
製剤例１：エダラボン含有注射剤用粉末
実施例１で得たエダラボンを保持した脂肪粒子を含む非水系組成物（白色粉末）それ自体をエダラボン含有注射剤用粉末とした。
Formulation Example 1: Edaravone-containing powder for injection The non-aqueous composition (white powder) containing fat particles retaining edaravone obtained in Example 1 itself was used as a powder for injection containing edaravone.
製剤例２：アスピリン含有含嗽剤用粉末
実施例４で得たアスピリンを保持した脂肪粒子を含む非水系組成物（白色粉末）１４．５ｇ、白糖３．５ｇ、カルメロースナトリウム２．０ｇを小型混合機で攪拌混合することによりアスピリン含有含嗽剤用粉末を得た。
Formulation Example 2: Aspirin-containing powder for gargle containing 14.5 g of non-aqueous composition (white powder) containing fat particles retaining aspirin obtained in Example 4, 3.5 g of sucrose, and 2.0 g of carmellose sodium The powder for an aspirin-containing gargle was obtained by stirring and mixing with a machine.
製剤例３：プロスタグランジンＥ１含有軟膏
実施例５で得たプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末）１１．９ｇに、６０℃で加温溶解したマクロゴール軟膏８８．１ｇを攪拌しながら徐々に加え、均一になるまで混合し、冷却固化することによりプロスタグランジンＥ１含有軟膏を得た。
Formulation Example 3: Prostaglandin E 1- Containing Ointment Macro dissolved in 11.9 g of non-aqueous composition (white powder) containing fat particles retaining prostaglandin E 1 obtained in Example 5 at 60 ° C. slowly added with stirring a goal ointment 88.1 g, and mixed until uniform, to obtain a prostaglandin E 1 salve by cooling and solidified.
製剤例４：プロスタグランジンＥ１含有ゲル
実施例７で得たプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（無色透明の粘性液体）１１．９ｇを注射用水２５ｍＬに混合した後、４．５％カルメロースナトリウム溶液７５ｍＬを加えて十分に練合することによりプロスタグランジンＥ１含有ゲルを得た。
Formulation Example 4 were mixed prostaglandin E 1 nonaqueous composition containing fat particles holding the prostaglandin E 1 obtained in containing gel Example 7 (colorless transparent viscous liquid) 11.9 g water for injection 25mL after, to obtain a prostaglandin E 1 containing gel by sufficiently kneading by adding 4.5% carmellose sodium solution 75 mL.
製剤例５：シクロスポリン含有経口シロップ剤用粉末
実施例９で得たシクロスポリンを保持した脂肪粒子を含む非水系組成物（白色粉末）３７．６８ｇ、白糖２．２７ｇ、パラオキシ安息香酸メチル３３ｍｇ、パラオキシ安息香酸プロピル１７ｍｇを小型混合機で攪拌混合することによりシクロスポリン含有経口シロップ剤用粉末を得た。
Formulation Example 5: Cyclosporine-containing powder for oral syrup 37.68 g of non-aqueous composition (white powder) containing fat particles retaining cyclosporine obtained in Example 9, 2.27 g of sucrose, 33 mg of paraoxybenzoate, paraoxybenzoate Cyclosporine-containing powder for oral syrup was obtained by stirring and mixing 17 mg of propyl acid with a small mixer.
本発明は、注射剤や点眼剤や点鼻剤や吸入剤などとして用いることができる、透明性を有するとともに安定性に優れる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができるといった利点を備える、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法を提供することができる点において産業上の利用可能性を有する。
The present invention is prepared by mixing a drug-containing fat emulsion having transparency and excellent stability, which can be used as an injection, eye drops, nasal drops, inhalants, etc., with an aqueous medium at the time of use. The present invention has industrial applicability in that it can provide a non-aqueous composition containing fat particles holding a drug and a method for producing the same, with the advantage of being capable of being produced.
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| US8940786B2 (en) | 2012-10-01 | 2015-01-27 | Teikoku Pharma Usa, Inc. | Non-aqueous taxane nanodispersion formulations and methods of using the same |
| CN107441044A (en) * | 2017-08-29 | 2017-12-08 | 辅必成（上海）医药科技有限公司 | A kind of nanometer fat emulsion |
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| US20190160008A1 (en) * | 2017-01-12 | 2019-05-30 | Techno Guard Co. Ltd. | Drug-containing fat emulsion and method for producing same |
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