JP2002212075A - Fat emulsion and pharmaceutical preparation - Google Patents
Fat emulsion and pharmaceutical preparationInfo
- Publication number
- JP2002212075A JP2002212075A JP2001008459A JP2001008459A JP2002212075A JP 2002212075 A JP2002212075 A JP 2002212075A JP 2001008459 A JP2001008459 A JP 2001008459A JP 2001008459 A JP2001008459 A JP 2001008459A JP 2002212075 A JP2002212075 A JP 2002212075A
- Authority
- JP
- Japan
- Prior art keywords
- fat emulsion
- fat
- oil
- water
- aqueous phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、医薬として有用
な、溶媒への溶解性が極めて低い特定のピラゾロ〔１，
５−ａ〕ピリミジン誘導体を含有する脂肪乳剤並びに乾
燥製剤に関する。TECHNICAL FIELD The present invention relates to a specific pyrazolo [1, 1, which is useful as a medicament and has extremely low solubility in a solvent.
5-a] A fat emulsion containing a pyrimidine derivative and a dry preparation.
【０００２】[0002]
【従来の技術】一般式（１）2. Description of the Related Art General formula (1)
【化２】 （式中、Ｒ１は低級アルキル基を、Ｒ２は置換基として
低級アルコキシ基の１〜３個を有するフェニル基を示
す。）で表されるピラゾロ〔１，５−ａ〕ピリミジン誘
導体は、鎮痛剤として有用な化合物である（特開平８−
３１１０６８号）。しかし、該化合物は溶媒への溶解度
が極めて低く（例えば、水への溶解度：４０ｎｇ／ｍ
ｌ；大豆油への溶解度：３ｍｇ／ｍｌ）、注射剤や液剤
等への製剤化にさらなる改善が望まれていた。Embedded image (Wherein R 1 represents a lower alkyl group, and R 2 represents a phenyl group having 1 to 3 lower alkoxy groups as a substituent.) A pyrazolo [1,5-a] pyrimidine derivative represented by the formula: It is a compound useful as an analgesic.
No. 31068). However, the compound has extremely low solubility in a solvent (for example, solubility in water: 40 ng / m2).
l; Solubility in soybean oil: 3 mg / ml), and further improvement in formulation into injections, liquid preparations and the like has been desired.
【０００３】[0003]
【発明が解決しようとする課題】前記ピラゾロ〔１，５
−ａ〕ピリミジン誘導体（１）は、通常その結晶の大き
さ（長径）が平均３μｍ程度であり、これを用いた製剤
は、吸収動態において必ずしも満足すべきものではなか
った。そこで、本発明者らは、吸収動態を良くするため
に、まず上記化合物を微粒子化（粒子径１μｍ以下）す
ることを考えた。ところが、上記化合物は溶媒に難溶で
あるため、一般に混合粉砕、ジェットミル、ボールミル
等の物理的な方法しか用いることができず、かかる粉砕
方法は、時間がかかる上汚染防止にかなりの配慮を必要
とする等の問題点がある。したがって本発明は、鎮痛剤
として有用な、難溶性ピラゾロ〔１，５−ａ〕ピリミジ
ン誘導体を含有し、改善された吸収動態を有する脂肪乳
剤並びに乾燥製剤を提供することを目的とする。The pyrazolo [1,5]
-A] The pyrimidine derivative (1) usually has an average crystal size (major axis) of about 3 μm, and a preparation using the same was not always satisfactory in absorption kinetics. Therefore, the present inventors have conceived to first make the compound into fine particles (particle diameter of 1 μm or less) in order to improve the absorption kinetics. However, since the above compounds are hardly soluble in a solvent, generally only physical methods such as mixing and pulverization, a jet mill and a ball mill can be used, and such pulverization methods are time-consuming and require considerable consideration for prevention of contamination. There are problems such as necessity. Accordingly, an object of the present invention is to provide a fat emulsion and a dry preparation containing a sparingly soluble pyrazolo [1,5-a] pyrimidine derivative and having improved absorption kinetics, which are useful as an analgesic.
【０００４】[0004]
【課題を解決するための手段】本発明は（１） 油脂を
乳化剤の存在下乳化した水中油型脂肪乳剤であって、乳
化粒子の平均粒子径が１μｍ以下であり、かつ乳化粒子
中に一般式（１）The present invention relates to (1) an oil-in-water fat emulsion obtained by emulsifying a fat or oil in the presence of an emulsifier, wherein the average particle size of the emulsified particles is 1 μm or less, and Equation (1)
【化３】 （式中、Ｒ１は低級アルキル基を、Ｒ２は置換基として
低級アルコキシ基の１〜３個を有するフェニル基を示
す。）で表される化合物を含有させたことを特徴とする
脂肪乳剤、（２） 一般式（１）で表される化合物が、
油脂１ｍｌ中に５〜１０００ｍｇ含有されている前記
（１）記載の脂肪乳剤、（３） 一般式（１）で表され
る化合物の、Ｒ１がｎ−ブチル基で、Ｒ２が３，４，５
−トリメトキシフェニル基である前記（１）又は（２）
記載の脂肪乳剤、（４） 油脂含量が０．５〜３０ｗ／
ｖ％、乳化剤含有量が油脂１ｇに対して０．０１〜１ｇ
である前記（１）〜（３）のいずれかに記載の脂肪乳
剤、（５） さらに水溶性高分子化合物が水相に溶解さ
れている前記（１）〜（４）のいずれかに記載の脂肪乳
剤、（６） 水溶性高分子化合物がセルロース系ポリマ
ーであり、その配合量が脂肪乳剤中０．１〜２０ｗ／ｖ
％である前記（５）記載の脂肪乳剤、（７） 水相にさ
らに糖類及びアミノ酸から選ばれる添加剤が、脂肪乳剤
中の濃度として２〜３０ｗ／ｖ％添加されている前記
（１）〜（６）に記載の脂肪乳剤、（８） 前記（７）
に記載の脂肪乳剤を乾燥処理することにより水相を実質
的に除去してなる乾燥製剤、及び（９） さらに多孔性
無機吸着体が油脂１ｇに対して１〜１０００ｍｇ添加さ
れている前記（８）記載の乾燥製剤、に関する。Embedded image (Wherein, R 1 represents a lower alkyl group, and R 2 represents a phenyl group having 1 to 3 lower alkoxy groups as substituents). , (2) a compound represented by the general formula (1):
The fat emulsion according to the above (1), which is contained in an amount of 5 to 1000 mg in 1 ml of fat or oil, (3) R 1 of the compound represented by the general formula (1) is an n-butyl group, and R 2 is 3,4. , 5
The above (1) or (2), which is a trimethoxyphenyl group;
The fat emulsion as described in (4), wherein the fat content is 0.5 to 30 w /
v%, emulsifier content is 0.01 to 1 g per 1 g of fats and oils
(5) The fat emulsion according to any one of (1) to (3), wherein the water-soluble polymer compound is further dissolved in an aqueous phase. Fat emulsion, (6) the water-soluble polymer compound is a cellulosic polymer, and its blending amount is 0.1 to 20 w / v in the fat emulsion.
% Of the fat emulsion according to the above (5), and (7) the aqueous phase is further added with an additive selected from saccharides and amino acids at a concentration of 2 to 30 w / v% in the fat emulsion. The fat emulsion according to (6), (8) the above (7).
And (9) a dry preparation obtained by substantially removing the aqueous phase by subjecting the fat emulsion described in (1) to a drying treatment, and (9) wherein the porous inorganic adsorbent is added in an amount of 1 to 1000 mg per 1 g of fat or oil. )).
【０００５】本発明によれば、油脂を乳化剤の存在下乳
化した水中油型脂肪乳剤であって、乳化粒子の平均粒子
径が１μｍ以下であり、かつ乳化粒子中に一般式（１）According to the present invention, there is provided an oil-in-water type fat emulsion obtained by emulsifying an oil or fat in the presence of an emulsifier, wherein the average particle size of the emulsified particles is 1 μm or less, and the emulsified particles have the general formula (1)
【化４】 （式中、Ｒ１は低級アルキル基を、Ｒ２は置換基として
低級アルコキシ基の１〜３個を有するフェニル基を示
す。）で表される化合物を含有させたことを特徴とする
脂肪乳剤、並びに該脂肪乳剤を乾燥処理することにより
水相を実質的に除去してなる乾燥製剤を提供することが
できる。Embedded image (Wherein, R 1 represents a lower alkyl group, and R 2 represents a phenyl group having 1 to 3 lower alkoxy groups as substituents). In addition, a dried preparation obtained by substantially removing an aqueous phase by subjecting the fat emulsion to a drying treatment can be provided.
【０００６】本発明の脂肪乳剤及び乾燥製剤は、好まし
くは次のようにして製造することができる。水中油型脂
肪乳剤の調製は、一般の脂肪乳剤とほぼ同様にして製造
することができる。具体的には、先ず油脂中に化合物
（１）を懸濁させ、これを乳化剤の存在下、水（例え
ば、水道水、精製水、蒸留水、注射用水等）中に分散し
て粗乳化後高圧乳化機等を用いて精乳化することにより
製造することができる。上記粗乳化は、例えば、特殊機
化工業（株）製Ｔ．Ｋ．ホモミクサー等のホモミキサー
を用い、通常５０００ｒｐｍ以上で５分間以上処理する
ことにより実施することができる。精乳化は、例えば、
マントンゴウリンホモジナイザー（ゴウリン社製）等の
高圧ホモジナイザー又は超音波ホモジナイザーを用いて
実施でき、高圧ホモジナイザーを用いる場合、一般には
約２００ｋｇ／ｃｍ２以上の圧力条件下に、２〜５０回
程度、好ましくは５〜５０回程度の通過で実施すること
ができる。これらの混合乳化操作常温下に実施してもよ
いが、若干の加温操作を採用してもよい。本発明の脂肪
乳剤の粒子径は、約１μｍ以下、好ましくは約１００〜
７００ｎｍ、より好ましくは約１５０〜４００ｎｍとす
るのがよい。また、本発明の脂肪乳剤のｐＨは、通常の
脂肪乳剤と同様６〜８程度とするのが好ましい。[0006] The fat emulsion and the dry preparation of the present invention can be preferably produced as follows. The oil-in-water type fat emulsion can be prepared almost in the same manner as a general fat emulsion. Specifically, first, compound (1) is suspended in fats and oils, and this is dispersed in water (for example, tap water, purified water, distilled water, water for injection, etc.) in the presence of an emulsifier, and then coarsely emulsified. It can be produced by fine emulsification using a high-pressure emulsifier or the like. The coarse emulsification can be performed, for example, using T.K. K. It can be carried out by using a homomixer such as a homomixer or the like, and usually treating at 5000 rpm or more for 5 minutes or more. Fine emulsification, for example,
Manton Gaulin homogenizer (manufactured by Gourin Co.) can be carried out using a high-pressure homogenizer or an ultrasonic homogenizer or the like, when using a high pressure homogenizer, typically from about 200 kg / cm 2 or more pressure conditions, about 2 to 50 times, preferably Can be carried out in about 5 to 50 passes. These mixing and emulsification operations may be carried out at normal temperature, but a slight heating operation may be employed. The particle size of the fat emulsion of the present invention is about 1 μm or less, preferably about 100 to
The thickness is preferably 700 nm, more preferably about 150 to 400 nm. Further, the pH of the fat emulsion of the present invention is preferably about 6 to 8 as in a normal fat emulsion.
【０００７】上記のようにして得られる本発明脂肪乳剤
は、化合物が乳化粒子中に懸濁した状態で閉じ込められ
ており、化合物の水相中への結晶析出は抑えられてい
る。しかしながら、上記結晶析出防止を含め、本発明脂
肪乳剤の安定性をより高めるために、水溶性高分子化合
物、コレステロール、コレステロールエステル、アルブ
ミン等を添加することができるが、中でも水溶性高分子
化合物を水相に添加するのが好ましい。該高分子化合物
としては、セルロース系の高分子化合物を好適に例示で
き、例えば、ヒドロキシプロピルメチルセルロース、ヒ
ドロキシプロピルセルロース、メチルセルロース等を挙
げることができる。該高分子化合物の配合量は、脂肪乳
剤中での濃度として約０．１〜２０ｗ／ｖ％、好ましく
は約０．３〜１０ｗ／ｖ％程度とするのが良く、これに
より優れた乳化安定性を有する微細な脂肪粒子を水中に
均一に分散させた所望の乳剤を調整することができる。The fat emulsion of the present invention obtained as described above is confined in a state where the compound is suspended in emulsified particles, and the precipitation of the compound in the aqueous phase is suppressed. However, in order to further enhance the stability of the fat emulsion of the present invention, including the above-mentioned crystal precipitation prevention, a water-soluble polymer compound, cholesterol, cholesterol ester, albumin, etc. can be added. It is preferably added to the aqueous phase. Suitable examples of the polymer compound include cellulose-based polymer compounds, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose. The compounding amount of the polymer compound is preferably about 0.1 to 20 w / v%, preferably about 0.3 to 10 w / v% as a concentration in the fat emulsion, and thereby excellent emulsion stability was obtained. It is possible to prepare a desired emulsion in which fine fat particles having properties are uniformly dispersed in water.
【０００８】更に、本発明脂肪乳剤には、主薬や油脂の
参加防止を目的に抗酸化剤を、金属イオンによる酸化や
乳化破壊の防止を目的にキレート剤を、更に等張化剤を
添加することもできる。抗酸化剤としてはアスコルビン
酸、リボフラビン、ヒスチジン、トコフェロール、没食
子酸プロピル等を例示することができ、キレート剤とし
てはクレン酸、酒石酸及びそれらの塩類を例示すること
ができ、等張化剤としてはグリセリン、ブドウ糖等を例
示することができる。Further, an antioxidant is added to the fat emulsion of the present invention for the purpose of preventing the participation of the main drug or fats and oils, a chelating agent is added for the purpose of preventing oxidation or emulsification destruction by metal ions, and a tonicity agent is further added. You can also. Examples of the antioxidant include ascorbic acid, riboflavin, histidine, tocopherol, propyl gallate, and the like.Examples of the chelating agent include crenic acid, tartaric acid, and salts thereof. Glycerin, glucose and the like can be exemplified.
【０００９】本発明において、一般式（１）で表される
ピラゾロ〔１，５−ａ〕ピリミジン誘導体は、特開平８
−３１１０６８号に記載の方法により製造することがで
きる。一般式（１）において、Ｒ１で表される低級アル
キル基としては、メチル基、エチル基、プロピル基、イ
ソプロピル基、ｎ−ブチル基、イソブチル基、tert-ブ
チル基等のＣ１−５の直鎖又は分枝状のアルキル基を例
示することができ、又、Ｒ２で表される置換基（低級ア
ルコキシ基の１〜３個を有するフェニル基）における低
級アルコキシ基としては、メトキシ基、エトキシ基、プ
ロポキシ基、イソプロポキシ基、ｎ−ブトキシ基等のＣ
１−５の直鎖又は分枝状の低級アルコキシル基を例示す
ることができるが、中でもＲ１がｎ−ブチル基で、Ｒ２
が３，４，５−トリメトキシフェニル基である化合物が
鎮痛作用が強く、好ましい化合物である。該化合物の油
脂中への配合量は、薬物の使用目的や対象患者、あるい
は用いる油脂の量にもよるが、通常約５〜１０００ｍ
ｇ、好ましくは約１０〜５００ｍｇ、より好適には約３
０〜３００ｍｇ程度とするのがよい。いずれにしてもそ
の配合量は、油脂への溶解度を超えた量であってよく、
その方が好ましい。In the present invention, the pyrazolo [1,5-a] pyrimidine derivative represented by the general formula (1) is disclosed in
It can be produced by the method described in US Pat. In the general formula (1), examples of the lower alkyl group represented by R 1 include C 1-5 such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group and tert-butyl group. Examples of the lower alkoxy group in the substituent represented by R 2 (a phenyl group having 1 to 3 lower alkoxy groups) include a methoxy group and a straight-chain or branched alkyl group. C such as ethoxy, propoxy, isopropoxy and n-butoxy groups
Examples thereof include a linear or branched lower alkoxyl group of 1-5 , wherein R 1 is an n-butyl group and R 2 is
Is a 3,4,5-trimethoxyphenyl group, which has a strong analgesic effect and is a preferred compound. The compounding amount of the compound in fats and oils depends on the purpose of use of the drug and the target patient, or the amount of fats and oils to be used.
g, preferably about 10-500 mg, more preferably about 3
The amount is preferably about 0 to 300 mg. In any case, the compounding amount may be an amount exceeding the solubility in fats and oils,
That is preferred.
【００１０】また、本発明において用いることのできる
油脂は、通常の脂肪乳剤に用いられている油脂と同じも
のであれば特に制限なく採用することができる。例え
ば、大豆油、綿実油、サフラワー油、トウモロコシ油、
ヤシ油、エゴマ油、アマニ油等の植物油やイワシ油、タ
ラ肝油等の魚油等の必須脂肪酸源としての長鎖脂肪酸ト
リグリセリド（ＬＴＣ）（好ましくは長鎖脂肪酸の炭素
数は１１〜２４）、及び易吸収性、易燃焼性、難蓄積性
を特徴とするトリグリセリド、例えば、商品名パナセー
ト（日本油脂（株）製）、商品名ＯＤＯ（日清製油
（株）製）等の通常炭素数８〜１０の脂肪酸からなる中
鎖脂肪酸トリグリセリド（ＭＣＴ）をその代表例として
例示することができる。更に上記油脂としては、例えば
２−リノレオイル−１，３−ジオクタノイルグリセロー
ル等の化学合成トリグリセリドも使用することができ
る。The fats and oils that can be used in the present invention can be used without any particular limitation as long as they are the same as those used in ordinary fat emulsions. For example, soybean oil, cottonseed oil, safflower oil, corn oil,
Long-chain fatty acid triglyceride (LTC) (preferably long-chain fatty acid has 11 to 24 carbon atoms) as an essential fatty acid source such as coconut oil, perilla oil, vegetable oil such as linseed oil, fish oil such as sardine oil and cod liver oil, and Triglycerides characterized by easy absorbability, easy combustibility, and low accumulation properties, for example, usually having 8 to 8 carbon atoms, such as Panaset (trade name, manufactured by NOF Corporation) and ODO (trade name, manufactured by Nisshin Oil Co., Ltd.) Medium chain fatty acid triglyceride (MCT) consisting of 10 fatty acids can be exemplified as a typical example. Further, as the above fats and oils, for example, chemically synthesized triglycerides such as 2-linoleoyl-1,3-dioctanoylglycerol can be used.
【００１１】上記油脂は、通常調製される水中油型乳剤
中に油脂濃度として０．５〜３０ｗ／ｖ％程度、好まし
くは０．５〜２０ｗ／ｖ％、より好ましくは０．５〜１
０ｗ／ｖ％となる範囲で配合されるのが好適である。上
記油脂を乳化分散させるための乳化剤としては、例え
ば、卵黄レシチン、水素添加卵黄レシチン、大豆レシチ
ン、水素添加大豆レシチン等のリン脂質や合成界面活性
剤（例えば、ツイーン８０、ＨＣＯ−６０（ポリオキシ
エチレン硬化ヒマシ油）、プルロニックＦ６８等の市販
品）等の一般によく用いられている乳化剤が使用でき
る。これらはその１種を単独で用いてもよく、また、２
種以上を併用することもできる。該乳化剤の使用量は、
油脂１ｇに対して約０．０１〜１ｇ程度、好ましくは
０．０３〜０．５g、より好ましくは０．０５〜０．３g
程度から選ばれるのがよい。The above fats and oils are contained in a generally prepared oil-in-water emulsion in a concentration of about 0.5 to 30 w / v%, preferably 0.5 to 20 w / v%, more preferably 0.5 to 1 w / v%.
It is preferable to be blended within a range of 0 w / v%. Examples of the emulsifier for emulsifying and dispersing the above fats and oils include phospholipids such as egg yolk lecithin, hydrogenated egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, and synthetic surfactants (for example, Tween 80, HCO-60 (polyoxygen Commonly used emulsifiers such as ethylene-hardened castor oil) and commercially available products such as Pluronic F68) can be used. One of these may be used alone, or 2
More than one species may be used in combination. The amount of the emulsifier used is
About 0.01 to 1 g, preferably 0.03 to 0.5 g, more preferably 0.05 to 0.3 g per 1 g of fat and oil.
It is better to choose from degrees.
【００１２】上記のようにして得られる脂肪乳剤は、乾
燥処理して水相を実質的に除去すれば通常は粉末状の乾
燥製剤とすることができ、本発明はかかる乾燥製剤も包
含するものである。乾燥処理を行う際には、乾燥粒子を
安定に保つため、水相に予め糖類及びアミノ酸から選ば
れる添加剤を、脂肪乳剤中の濃度として約２〜３０ｗ／
ｖ％の濃度となるよう添加しておくのが好ましい。該添
加剤としての糖類としては、好ましくはブドウ糖、ガラ
クトース、マンノース等の単糖類、ショ糖、マルトー
ス、トレハロース等の２等類、ソルビトール、キシリト
ール等の糖アルコール類が挙げられ、また、アミノ酸と
しては、通常のアミノ酸輸液の成分として用いられる必
須アミノ酸及び非必須アミノ酸を便宜に用いることがで
きる。The fat emulsion obtained as described above can be usually made into a powdery dry preparation by drying and substantially removing the aqueous phase, and the present invention also includes such a dry preparation. It is. In performing the drying treatment, an additive selected from saccharides and amino acids is previously added to the aqueous phase in a concentration of about 2 to 30 w / w in the fat emulsion in order to keep the dried particles stable.
It is preferable to add so that the concentration becomes v%. Examples of the saccharide as the additive preferably include glucose, galactose, monosaccharides such as mannose, sucrose, maltose, trehalose and the like, sorbitol, xylitol and the like, and alcohols such as amino acids. Essential amino acids and non-essential amino acids used as components of ordinary amino acid infusions can be used for convenience.
【００１３】脂肪乳剤の乾燥処理は、一般的に行われて
いる凍結乾燥法や噴霧乾燥法等を採用することができ
る。凍結乾燥の条件としては、特に限定されず一般に行
われている条件より適宜選択でき、例えば約−５０〜−
１５０℃程度の温度範囲にて、１〜５時間凍結後約１０
〜５０時間乾燥させればよく、また、噴霧乾燥は、例え
ば一般に市販されている噴霧乾燥機（ディスク型及びノ
ズル型のいずれをも用い得る。）により、入り口温度２
００℃前後、出口温度１３０℃前後にて行い得る。尚、
乾燥時の結晶析出を防止するために、更には乾燥製剤を
用時分散型製剤として用いる場合の結晶析出防止のた
め、多孔性無機吸着体を油脂１ｇに換算して約１〜１０
００ｍｇ程度を脂肪乳剤に添加するのが好ましい。多孔
性無機吸着体としては、例えば、二酸化ケイ素（無水ケ
イ酸、シリカ）、ケイ酸カルシウム、ケイ酸アルミン酸
マグネシウム、メタケイ酸アルミン酸マグネシウム等を
例示でき、中でもコロイド状シリカ（例えば、富士シリ
シア社製の商品名サイシリア３５０等）及び軽質無水ケ
イ酸（例えば、日本アエロジル社製の商品名アエロジル
２００等）が好適である。The fat emulsion can be dried by a commonly used freeze drying method, spray drying method or the like. The lyophilization conditions are not particularly limited and can be appropriately selected from commonly used conditions, for example, about -50 to-
In a temperature range of about 150 ° C, about 10 hours after freezing for 1-5 hours.
The drying may be carried out for up to 50 hours, and the spray drying may be carried out, for example, by a commercially available spray dryer (both of a disk type and a nozzle type may be used).
It can be carried out at around 00 ° C. and at an exit temperature around 130 ° C. still,
In order to prevent the precipitation of crystals during drying, and to prevent the precipitation of crystals when the dried preparation is used as a ready-to-use dispersible preparation, the porous inorganic adsorbent is converted to about 1 to 10
It is preferable to add about 00 mg to the fat emulsion. Examples of the porous inorganic adsorbent include, for example, silicon dioxide (silicic anhydride, silica), calcium silicate, magnesium silicate, magnesium metasilicate, and the like. Among them, colloidal silica (eg, Fuji Silysia Co., Ltd.) And light anhydrous silicic acid (eg, Aerosil 200 manufactured by Nippon Aerosil Co., Ltd.) are suitable.
【００１４】乾燥製剤は、用時分散型の粉末製剤として
用いることもできるが、常法により錠剤やカプセル剤と
することもできるし、これを用い常法に従って打錠して
錠剤としてもよい。尚、打錠の際には、必要に応じ通常
の医薬固形単体（例えば賦形剤、結合剤、崩壊剤、滑沢
剤等）を適宜使用することができる。[0014] The dry preparation can be used as a powder preparation of a dispersing type at the time of use, but it can also be made into tablets or capsules by a conventional method, and can be made into tablets by using this in a conventional manner. In addition, at the time of tableting, an ordinary solid pharmaceutical substance (eg, excipient, binder, disintegrant, lubricant, etc.) can be used as needed.
【００１５】[0015]
【発明の実施の形態】また、用時分散型製剤は上記のよ
うにして得られる乾燥製剤を、例えば精製水、注射用
水、蒸留水等の希釈剤で希釈し攪拌することにより容易
に得られる。DESCRIPTION OF THE PREFERRED EMBODIMENTS A time-dispersed preparation can be easily obtained by diluting a dry preparation obtained as described above with a diluent such as purified water, water for injection, distilled water and the like and stirring. .
【００１６】[0016]
【実施例】〔実施例１〕大豆油１ｍｌに卵黄レシチン７
５ｍｇ及び５−ｎ−ブチル−７−（３，４，５−トリメ
トキシベンゾイルアミノ）ピラゾロ〔１，５−ａ〕ピリ
ミジン（平均長径３μｍの結晶、以下、「化合物Ａ」と
いう）７５ｍｇを加え、プローブ型超音波ホモジナイザ
ー（ＵＬＴＲＡＳＯＮＩＣ ＤＩＳＲＵＰＴＯＲ ＵＲ−
２００Ｐ、トミー精工）を用いて３０分間超音波処理を
施し脂肪乳剤を得た。得られた脂肪乳剤の重量ベースの
平均粒子径は、動的光散乱粒子径測定装置（ＬＰＡ−３
００、大塚電子）により測定した結果、２４６．１ｎｍ
であった。また、この脂肪乳剤の顕微鏡観察の結果、水
相に化合物Ａの結晶を認めなかった。即ち、全ての化合
物Ａが平均粒子径２４６．１ｎｍの油滴内に含まれるこ
とが明かとなった。[Example 1] Egg yolk lecithin 7 in 1 ml of soybean oil
5 mg and 75 mg of 5-n-butyl-7- (3,4,5-trimethoxybenzoylamino) pyrazolo [1,5-a] pyrimidine (crystal having an average major axis of 3 μm, hereinafter referred to as “compound A”) were added, Probe type ultrasonic homogenizer (ULTRASONIC DISRUPTOR UR-
(200P, Tommy Seiko) for 30 minutes to obtain a fat emulsion. The weight-based average particle size of the obtained fat emulsion was measured using a dynamic light scattering particle size analyzer (LPA-3).
00, Otsuka Electronics Co., Ltd.) 246.1 nm
Met. As a result of microscopic observation of this fat emulsion, no compound A crystal was observed in the aqueous phase. That is, it became clear that all the compounds A were contained in oil droplets having an average particle size of 246.1 nm.
【００１７】〔実施例２〕中鎖脂肪酸トリグリセリド
（Ｔｒｉｅｓｔｅｒ Ｆ−８１０）１ｍｌに７５ｍｇの
ポリソルベート８０及び化合物Ａ７５ｍｇを加え、これ
に水１０ｍｌを加えて、プローブ型超音波ホモジナイザ
ーを用いて３０分間超音波処理を施し、本発明の脂肪乳
剤を得た。得られた脂肪乳剤の平均粒子径は、動的光散
乱粒子径測定装置（ＬＰＡ−３００、大塚電子）により
測定した結果、２５２．６ｎｍであった。Example 2 75 mg of polysorbate 80 and 75 mg of compound A were added to 1 ml of medium-chain fatty acid triglyceride (Triester F-810), and 10 ml of water was added thereto. After the treatment, a fat emulsion of the present invention was obtained. The average particle size of the obtained fat emulsion was 252.6 nm as a result of measurement by a dynamic light scattering particle size measuring device (LPA-300, Otsuka Electronics).
【００１８】〔実施例３〕大豆油１ｍｌに７５ｍｇのポ
リソルベート８０及び７５ｍｇの化合物Ａを加え、これ
に水１０ｍｌを加えて、プローブ型超音波ホモジナイザ
ーを用いて３０分間超音波処理を施し、本発明の脂肪乳
剤を得た。得られた脂肪乳剤の平均粒子径は、動的光散
乱粒子径測定装置（ＬＰＡ−３００、大塚電子）により
測定した結果、３５８．２ｎｍであった。Example 3 75 mg of polysorbate 80 and 75 mg of compound A were added to 1 ml of soybean oil, 10 ml of water was added thereto, and the mixture was subjected to ultrasonic treatment using a probe-type ultrasonic homogenizer for 30 minutes. To obtain a fat emulsion. The average particle size of the obtained fat emulsion was 358.2 nm as a result of measurement using a dynamic light scattering particle size analyzer (LPA-300, Otsuka Electronics).
【００１９】〔実施例４〕大豆油２ｍｌにポリオキシエ
チレン硬化ヒマシ油（Ｃｒｅｍｏｐｈｏｒ ＥＬＰ）１
５０ｍｇ及び化合物Ａ７５ｍｇを加え、これに１０％ヒ
ドロキシプロピルメチルセルロース水溶液１０ｍｌを加
えて、プローブ型超音波ホモジナイザーを用いて３０分
間超音波処理を施し、本発明の脂肪乳剤を得た。得られ
た脂肪乳剤の平均粒子径は、動的光散乱粒子径測定装置
（ＬＰＡ−３００、大塚電子）により測定した結果、４
２０ｎｍであった。Example 4 Polyoxyethylene hydrogenated castor oil (Cremophor ELP) in 2 ml of soybean oil
50 mg and 75 mg of compound A were added, and 10 ml of a 10% aqueous solution of hydroxypropylmethylcellulose was added thereto, followed by sonication for 30 minutes using a probe-type ultrasonic homogenizer to obtain a fat emulsion of the present invention. The average particle size of the obtained fat emulsion was measured using a dynamic light scattering particle size analyzer (LPA-300, Otsuka Electronics).
20 nm.
【００２０】〔実施例５〕中鎖脂肪酸トリグリセリド
（Ｔｒｉｅｓｔｅｒ Ｆ−８１０）２ｍｌにポリオキシ
エチレン硬化ヒマシ油（Ｃｒｅｍｏｐｈｏｒ ＥＬＰ）
１５０ｍｇ及び化合物Ａ７５ｍｇを加え、これに１０％
トレハロース水溶液１０ｍｌを加えて、プローブ型超音
波ホモジナイザーを用いて３０分間超音波処理を施し、
本発明の脂肪乳剤を得た。得られた脂肪乳剤を、常法に
準じ先ず−１００℃で２時間凍結し、次いで−１００℃
で２４時間凍結乾燥して粉末状の本発明乾燥製剤を得
た。得られた製剤の平均粒子径は、５００ｎｍ未満であ
った。Example 5 Polyoxyethylene hydrogenated castor oil (Cremophor ELP) was added to 2 ml of medium-chain fatty acid triglyceride (Triester F-810).
150 mg and 75 mg of compound A were added, and 10%
10 ml of a trehalose aqueous solution was added, and sonication was performed for 30 minutes using a probe-type ultrasonic homogenizer,
A fat emulsion of the present invention was obtained. The resulting fat emulsion was first frozen at -100 ° C for 2 hours according to a conventional method, and then frozen at -100 ° C.
For 24 hours to obtain a powdered dry preparation of the present invention. The average particle size of the obtained preparation was less than 500 nm.
【００２１】〔実施例６〕中鎖脂肪酸トリグリセリド
（Ｔｒｉｅｓｔｅｒ Ｆ−８１０）１．２ｍｌに９０ｍ
ｇの水素添加卵黄レシチン及び４５ｍｇの化合物Ａを加
え、これに水６ｍｌを加えて、プローブ型超音波ホモジ
ナイザーを用いて３０分間超音波処理を施し、本発明の
脂肪乳剤を得た。得られた脂肪乳剤を、トレハロース３
００ｍｇ及びコロイダルシリカ（サイリシア３５０；富
士シリシア社製）２０ｍｇを含んだ水１０ｍｌで希釈
し、これを実施例５と同一条件により凍結乾燥し、本発
明乾燥製剤を得た。得られた製剤５３０．５ｍｇを３７
℃の水２．０ｍｌに再分散させた結果、その乳剤の平均
粒子径は、光散乱粒子径測定装置により測定した結果、
２１４ｎｍであった。Example 6 Medium chain fatty acid triglyceride (Triester F-810) is 90 m in 1.2 ml.
g of hydrogenated egg yolk lecithin and 45 mg of compound A, 6 ml of water was added thereto, and the mixture was subjected to ultrasonic treatment using a probe-type ultrasonic homogenizer for 30 minutes to obtain a fat emulsion of the present invention. The obtained fat emulsion was treated with trehalose 3
It was diluted with 10 ml of water containing 00 mg and 20 mg of colloidal silica (Sylysia 350; manufactured by Fuji Silysia), and lyophilized under the same conditions as in Example 5 to obtain a dry preparation of the present invention. 530.5 mg of the obtained preparation was added to 37
As a result of redispersion in 2.0 ml of water at ℃, the average particle size of the emulsion was measured by a light scattering particle size measuring device,
It was 214 nm.
【００２２】〔比較例１〕卵黄レシチン１５０ｍｇ及び
化合物Ａ７５ｍｇを水１０ｍｌに加え、プローブ型超音
波ホモジナイザーを用いて３０分間超音波処理を施し
た。得られた懸濁液の粒子の平均粒子径は、光散乱粒子
径測定装置により測定した結果、化合物Ａの元の結晶の
粒子径である３μｍのままであった。Comparative Example 1 150 mg of egg yolk lecithin and 75 mg of compound A were added to 10 ml of water, and sonicated for 30 minutes using a probe-type ultrasonic homogenizer. The average particle diameter of the particles of the obtained suspension was measured by a light scattering particle diameter measuring apparatus, and as a result, the particle diameter of the original crystal of Compound A was still 3 μm.
【００２３】[0023]
【発明の効果】本発明の脂肪乳剤及び乾燥製剤は微粒子
化されており、乾燥製剤は易分散であるので、吸収が極
めて良好である。The fat emulsion and the dry preparation of the present invention are finely divided, and the dry preparation is easily dispersed, so that the absorption is extremely good.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 47/30 Ａ６１Ｋ 47/30 47/38 47/38 47/44 47/44 Ａ６１Ｐ 25/04 Ａ６１Ｐ 25/04 // Ｃ０７Ｄ 487/04 １４２ Ｃ０７Ｄ 487/04 １４２ Ｆターム(参考） 4C050 AA01 BB05 CC08 EE03 FF02 GG04 HH01 4C076 AA17 AA29 CC01 DD01F DD51 DD66 EE01 EE31 EE51 FF01 FF16 GG05 GG46 4C086 AA01 CB05 MA03 MA05 MA22 MA43 NA02 ZA08 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61K 47/30 A61K 47/30 47/38 47/38 47/44 47/44 A61P 25/04 A61P 25 / 04 // C07D 487/04 142 C07D 487/04 142 F term (reference) 4C050 AA01 BB05 CC08 EE03 FF02 GG04 HH01 4C076 AA17 AA29 CC01 DD01F DD51 DD66 EE01 EE31 EE51 FF01 FF16 GG05 GG46 MA05 MA03 MA01 MA03
Claims (9)
脂肪乳剤であって、乳化粒子の平均粒子径が１μｍ以下
であり、かつ乳化粒子中に一般式（１） 【化１】 （式中、Ｒ１は低級アルキル基を、Ｒ２は置換基として
低級アルコキシ基の１〜３個を有するフェニル基を示
す。）で表される化合物を含有させたことを特徴とする
脂肪乳剤。1. An oil-in-water type fat emulsion obtained by emulsifying fats and oils in the presence of an emulsifier, wherein the average particle size of the emulsified particles is 1 μm or less, and the emulsified particles have the general formula (1) (Wherein, R 1 represents a lower alkyl group, and R 2 represents a phenyl group having 1 to 3 lower alkoxy groups as substituents). .
１ｍｌ中に５〜１０００ｍｇ含有されている請求項１記
載の脂肪乳剤。2. The fat emulsion according to claim 1, wherein the compound represented by the general formula (1) is contained in an amount of 5 to 1000 mg per 1 ml of fat or oil.
がｎ−ブチル基で、Ｒ２が３，４，５−トリメトキシフ
ェニル基である請求項１又は２記載の脂肪乳剤。Of 3. A compound represented by the general formula (1), R 1
There in n- butyl group, according to claim 1 or 2 wherein fat emulsion R 2 is 3,4,5-trimethoxyphenyl group.
剤含有量が油脂１ｇに対して０．０１〜１ｇである請求
項１〜３のいずれかに記載の脂肪乳剤。4. The fat emulsion according to claim 1, wherein the fat content is 0.5 to 30 w / v%, and the emulsifier content is 0.01 to 1 g per 1 g of fat.
されている請求項１〜４のいずれかに記載の脂肪乳剤。5. The fat emulsion according to claim 1, wherein the water-soluble polymer compound is further dissolved in an aqueous phase.
マーであり、その配合量が脂肪乳剤中０．１〜２０ｗ／
ｖ％である請求項５記載の脂肪乳剤。6. The water-soluble polymer compound is a cellulosic polymer, and the compounding amount thereof is 0.1 to 20 w /
The fat emulsion according to claim 5, which is v%.
れる添加剤が、脂肪乳剤中の濃度として２〜３０ｗ／ｖ
％添加されている請求項１〜６に記載の脂肪乳剤。7. An aqueous phase further containing an additive selected from saccharides and amino acids in a concentration of 2 to 30 w / v in the fat emulsion.
%.
ることにより水相を実質的に除去してなる乾燥製剤。8. A dry preparation, wherein the aqueous phase is substantially removed by subjecting the fat emulsion according to claim 7 to a drying treatment.
して１〜１０００ｍｇ添加されている請求項８記載の乾
燥製剤。9. The dry preparation according to claim 8, further comprising 1 to 1000 mg of a porous inorganic adsorbent per 1 g of fat or oil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001008459A JP2002212075A (en) | 2001-01-17 | 2001-01-17 | Fat emulsion and pharmaceutical preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001008459A JP2002212075A (en) | 2001-01-17 | 2001-01-17 | Fat emulsion and pharmaceutical preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2002212075A true JP2002212075A (en) | 2002-07-31 |
Family
ID=18876073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001008459A Pending JP2002212075A (en) | 2001-01-17 | 2001-01-17 | Fat emulsion and pharmaceutical preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2002212075A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007508249A (en) * | 2003-10-10 | 2007-04-05 | ライフサイクル ファーマ アクティーゼルスカブ | Solid dosage form containing fibrates and statins |
| WO2013087815A1 (en) | 2011-12-15 | 2013-06-20 | Merz Pharma Gmbh & Co. Kgaa | Liquid pharmaceutical composition containing a pyrazolopyrimidine derivative and pharmaceutical uses thereof |
-
2001
- 2001-01-17 JP JP2001008459A patent/JP2002212075A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007508249A (en) * | 2003-10-10 | 2007-04-05 | ライフサイクル ファーマ アクティーゼルスカブ | Solid dosage form containing fibrates and statins |
| WO2013087815A1 (en) | 2011-12-15 | 2013-06-20 | Merz Pharma Gmbh & Co. Kgaa | Liquid pharmaceutical composition containing a pyrazolopyrimidine derivative and pharmaceutical uses thereof |
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