JP2600726C

JP2600726C -

Info

Publication number: JP2600726C
Authority: JP
Original assignee: Taisho Pharmaceutical Co Ltd
Current assignee: Taisho Pharmaceutical Co Ltd
Publication date: 1999-07-19

Description

【発明の詳細な説明】【産業上の利用分野】本発明は脂肪乳剤に関し、更に詳しくは粒子が微細で含有する脂溶性の薬理活
性物質の血中濃度が低下しにくい脂肪乳剤に関する。【従来の技術】種々の薬理活性物質を脂肪乳剤に調製してその薬理作用を高める試みがこれま
でなされてきた。たとえば、ステロイド類，プロスタグランジン類，制癌薬など
についての脂肪乳剤が知られ、その薬理作用の増大も一応認められているが、ま
だ十分とは言い難い。【発明が解決しようとする問題点】本発明の目的は、脂溶性の薬理活性物質を含有する脂肪乳剤の薬理作用を高め
ることにある。【問題点を解決するための手段】本発明者らは、鋭意研究の結果、脂溶性の薬理活性物質を含有する脂肪乳剤を
静注投与すると、その血中濃度の急激な低下現象を起こすにもかかわらず、脂肪
乳剤の粒子径を70nm以下にすると、このような現象を起こすことなく、薬理活性
物質の作用が著しく高まることを見いだして本発明を完成した。本発明は、脂溶性の薬理活性物質（但し、制癌剤を除く。）を含有し、５〜30
w/v％の油相成分、及びリン脂質類を必須成分とする0.1〜20w/v％の乳化剤から
なり、平均粒子径が40〜70nmである薬物の血中濃度の急激な低下現象を起こさない
微粒子脂肪乳剤である。また、他の本発明は、粗乳化後に７００ｋｇ／ｃｍ²以
上の能力を有する高圧乳化機を使用して精乳化することを特徴とする上記薬物の
血中濃度の急激な低下現象を起こさない微粒子脂肪乳剤の製造方法である。本発明において、脂溶性の薬理活性物質とは、薬理活性を有する物質で油脂に
溶解するものであればよく、たとえば、麻酔薬，鎮静薬，トランキライザー，鎮
痛薬，下熱薬，中枢興奮薬，筋弛緩薬，交感神経興奮薬，交感神経抑制薬，副交
感神経興奮薬，副交感神経抑制薬，自律神経遮断薬，鎮痙薬，抗ヒスタミン薬，
強心薬，不整脈治療薬，血管拡張薬，鎮咳薬，抗凝血薬，止血薬，ビタミン，ホ
ルモン，化学療法薬，抗生物質などである。本発明の脂肪乳剤は５〜30w/v％の油相成分と0.1〜20w/v％の乳化剤および適
量の水から主としてなる。油相成分として、大豆油，綿実油などの植物油，およびパナセート800、同810
［商品名，日本油脂（株）製］などの合成トリグリセライドを使用することがで
きる。乳化剤として、リン脂質，水素添加リン脂質，レシチン，水素添加レシチンな
どリン脂質類，またはポリオキシエチレン硬化ヒマシ油誘導体［ニッコールHCO
−50、同60など，日光ケミカルズ（株）製］、ポリオキシエチレンソルビタン脂
肪酸エステル［ニッコールTO−10M、同106など，日光ケミカルズ（株）製］、ポ
リオキシエチレンポリオキシプロピレングリコール［プルロニックF68など，旭
電化工業（株）製］などの非イオン界面活性剤を使用することができる。その他必要に応じて乳化補助剤，安定化剤，等張化剤、pH調整剤なども使用す
ることができる。本発明の脂肪乳剤は、たとえば下記の方法により製造することができる。すなわち、70〜80℃に加温した前記油相成分に前記脂溶性の薬理活性物質を溶
解する。これに前記乳化剤を分散した後、必要に応じて乳化補助剤，安定化剤そ
の他必要な補助成分を添加した後、適量の水を加え、常法により粗乳化する。この粗乳化液を、７００ｋｇ／ｃｍ²以上の能力を有する高圧乳化機を用いて
適当時間精乳化を行ない、その平均粒子径が４０〜７０ｎｍの脂肪乳剤をアンプ
ルに充填し、高圧蒸気滅菌して製剤とする。この製剤は注射剤として使用することができる。粗乳化に使用できる乳化機としては、たとえば日音医理化器械（株）製の超高
速ホモジナイザーヒスコトロンNS−60、みずほ工業（株）製の卓上型クイック
ホモミキサーLR−１などがある。また精乳化に使用できる高圧乳化機としては、たとえばマントンゴーリン社製
のマントンゴーリン型噴射乳化機１５Ｍ（圧力７００ｋｇ／ｃｍ²以上）、アミ
ンコ社製高圧細胞破砕機フレンチプレッシャーＡＦＰＳ−２０ＫＭ（圧力２２０
０ｋｇ／ｃｍ²以上）などがある。【実施例】以下、実施例と試験例を挙げて本発明を具体的に説明する。実施例１予め、80℃に加温した大豆油25gにビタミンA250万I.U.、リン脂質4.5g、ニッ
コールHCO−60 25gを加え、撹拌，分散した。これにグリセリン5.5gと水酸化ナ
トリウム1.5mgを添加し、注射用滅菌蒸留水を加えて全量を250mlとした。この液
を超高速ホモジナイザーヒスコトロンNS−60を用いて、10000回転／分で10分
間乳化し、粗乳化液とした。この粗乳化液をマントンゴーリン型噴射乳化機15Mを用い、圧力７００ｋｇ／
ｃｍ²で１５分間精乳化を行なって平均粒子径が60nmの脂肪乳剤を得た。この脂
肪乳剤を1mlのアンブルに分注し、常法により高圧蒸気滅菌を行ない、ビタミン
Ａ注射剤を得た。実施例２実施例１において、ビタミンA250万I.U.の代わりにビタミンD25万I.U.を用い
、精乳化を10分間行なって、平均粒子径が70nmのビタミンＤ注射剤を得た。実施例３実施例１において、ビタミンA250万I.U.の代わりにビタミンE12.5gを用い、大
豆油を12.5gに減じ、精乳化を15分間行なって、平均粒子径が63nmのビタミンＥ
の注射剤を得た。実施例４実施例１において、ビタミンA250万I.U.の代わりにビタミンK2.5gを用い、精
乳化を15分間行なって、平均粒子径が50nmのビタミンＫの注射剤を得た。実施例５実施例１において、ビタミンA250万I.U.の代わりにコエンザイムＱ₁₀２．５ｇ
を用い、精乳化を１５分間行なって、平均粒子径が４８ｎｍのコエンザイムＱ₁₀
の注射剤を得た。実施例６実施例１において、ビタミンA250万I.U.の代わりにプロスタグランジンＥ₁２
．５ｍｇを用い、精乳化を１５分間行なって、平均粒子径が５５ｎｍのプロスタ
グランジンＥ₁の注射剤を得た。実施例７実施例１において、ビタミンA250万I.U.の代わりにプロスタグランジンＥ₁エ
チル１．２５ｍｇを用い、精乳化を１２分間行なって、平均粒子径が６０ｎｍの
プロスタグランジンＥ₁エチル注射剤を得た。試験例１（試料の調製）予め70℃に加温した大豆油4gにトレーサーとして¹⁴Ｃ−グリセロールトリオ
レート４０μＣｉ、リン脂質0.72gを加え、撹拌して均一に分散した。これにニッコールHCO−60 4g、水酸化ナトリウム0.32mgを加えて分散した後、
注射用滅菌蒸留水を加えて全量を40mlとした。この液を超高速ホモジナイザーヒ
スコトロンNS−60を用いて10000回転／分で10分間乳化し、粗乳化液とした。この粗乳化液を高圧細胞破砕機フレンチブレッシャーＡＦＰＳ−２０ＫＭを用
いて、圧力２２００ｋｇ／ｃｍ²で９回精乳化を行ない、平均粒子径が７０ｎｍ
の脂肪乳剤を調製した。これを試料１とした。乳化剤の種類および量並びに精乳化の回数を第１表に示すように変え、前記試
料の調製法に準じて試料２〜７を調製した。各試料の平均粒子径を第１表に示す。試験例２脂肪粒子血中濃度の経時変化（試料の調製）試験例１で調製した標識試料１〜７をそのまま用いた。（供試動物）体重250〜270gの雄性ウィスター系ラット３匹を１群とし、前記各試料に１群
ずつの動物を用意した。（試験）前記標識試料を、それぞれに割当てられた群の動物の左大腿静脈より1ml/kg静注投与した。各群の動物の動脈から経時的に血液を採取し、その放射活性を測定
して脂肪粒子血中濃度の経時変化を調べた。その結果を第１図に示す。第１図より平均粒子径が70nm以下のグループと90nm以上のグループとは、その
脂肪粒子血中濃度の経時変化に歴然とした差異があることが認められた。試験例３コエンザイムＱ₁₀血中濃度の経時変化（試料の調製）試験例１の試料の調製において、トレーサーとして¹⁴Ｃ−グリセロールト
リオレート４０μＣｉの代わりに¹⁴Ｃ−コエンザイムＱ₁₀４０μＣｉを用い、試
料１、３、６に相当する試料を調製してそれぞれ試料８、９、１０とした。（供試動物）試験例２に準じて供試動物を用意した。（試験）前記標識試料について試験例２の同様の試験を行ない、コエンザイムＱ₁₀血中
濃度の経時変化を調べた。その結果を第２図に示す。第２図より、コエンザイムＱ₁₀血中濃度の経時変化は脂肪粒子のそれと同一の
傾向を示すことが認められた。この傾向は他の脂溶性薬理活性物質についても同じように現れるものと考えら
れる。【発明の効果】本発明の脂肪乳剤は、その平均粒子径を４０〜７０ｎｍにすることにより、粒
子径が大きい通常の脂肪乳剤において見られる薬物の血中濃度の急激な低下現象
を起こさず、前記薬理活性物質の薬理作用を著しく高めることができる。Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fat emulsion, and more particularly to a fat emulsion in which the blood concentration of a fat-soluble pharmacologically active substance containing fine particles is hardly reduced. 2. Description of the Related Art Attempts have been made to increase the pharmacological action of various pharmacologically active substances by preparing them in fat emulsions. For example, fat emulsions for steroids, prostaglandins, anticancer drugs and the like are known, and their pharmacological actions have been increased for some time, but they are still not enough. SUMMARY OF THE INVENTION An object of the present invention is to enhance the pharmacological action of a fat emulsion containing a fat-soluble pharmacologically active substance. [Means for Solving the Problems] As a result of intensive studies, the present inventors have found that when a fat emulsion containing a fat-soluble pharmacologically active substance is administered intravenously, the blood concentration thereof suddenly decreases. Nevertheless, the inventors have found that when the particle size of the fat emulsion is reduced to 70 nm or less, the effect of the pharmacologically active substance is remarkably enhanced without such a phenomenon, thereby completing the present invention. The present invention contains a fat-soluble pharmacologically active substance (however, excluding an anticancer drug), and contains 5 to 30 pharmacologically active substances .
It is composed of w / v% oil phase component and 0.1 ~ 20w / v% emulsifier containing phospholipids as essential components, and causes a sharp decrease in blood concentration of drug with an average particle size of 40 ~ 70nm. There is no fine particle fat emulsion. Another aspect of the present invention is a fine particle which does not cause a rapid decrease in blood concentration of the drug, wherein the fine emulsification is performed using a high-pressure emulsifier having a capacity of 700 kg / cm ² or more after the coarse emulsification. This is a method for producing a fat emulsion. In the present invention, the fat-soluble pharmacologically active substance may be any substance having a pharmacological activity and soluble in fats and oils, such as an anesthetic, sedative, tranquilizer, analgesic, hypothermic, central stimulant, Muscle relaxants, sympathomimetics, sympathomimetics, parasympathomimetics, parasympathomimetics, autonomic blockers, antispasmodics, antihistamines,
Inotropic agent, antiarrhythmics, vasodilators, antitussive agents, anticoagulants, hemostatics, vitamins, hormones, chemotherapeutic agents, it etc. antibiotics. The fat emulsion of the present invention mainly comprises 5 to 30% w / v oil phase component, 0.1 to 20% w / v emulsifier and an appropriate amount of water. Oil phase components include vegetable oils such as soybean oil and cottonseed oil, and Panassate 800, 810
Synthetic triglycerides such as [trade name, manufactured by NOF Corporation] can be used. Emulsifiers include phospholipids such as phospholipids, hydrogenated phospholipids, lecithin, hydrogenated lecithin, or polyoxyethylene hydrogenated castor oil derivatives [Nikkor HCO
-50, 60, etc., manufactured by Nikko Chemicals Co., Ltd.], polyoxyethylene sorbitan fatty acid ester [Nikkor TO-10M, 106, etc., manufactured by Nikko Chemicals Co., Ltd.], polyoxyethylene polyoxypropylene glycol [Pluronic F68, etc.] , Manufactured by Asahi Denka Kogyo Co., Ltd.]. In addition, emulsifying aids, stabilizers, isotonic agents, pH adjusters and the like can be used as necessary. The fat emulsion of the present invention can be produced, for example, by the following method. That is, the fat-soluble pharmacologically active substance is dissolved in the oil phase component heated to 70 to 80 ° C. After the emulsifier is dispersed therein, if necessary, an emulsifying aid, a stabilizer and other necessary auxiliary components are added, and then an appropriate amount of water is added, followed by coarse emulsification by a conventional method. This coarse emulsion is subjected to fine emulsification for a suitable time using a high-pressure emulsifier having a capacity of 700 kg / cm ² or more, and a fat emulsion having an average particle size of 40 to 70 nm is filled in an ampoule, and subjected to high-pressure steam sterilization. Formulation. This preparation can be used as an injection. Examples of the emulsifier that can be used for the coarse emulsification include an ultra-high-speed homogenizer Hiscotron NS-60 manufactured by Nichion Medical Chemical Instruments Co., Ltd. and a desktop quick homomixer LR-1 manufactured by Mizuho Industry Co., Ltd. Examples of the high-pressure emulsifier that can be used for fine emulsification include, for example, a Menton-Gaulin type injection emulsifier 15M (pressure 700 kg / cm ² or more) manufactured by Manton Gorin, and a high-pressure cell crusher French Pressure AFPS-20KM (pressure 220) manufactured by Aminco.
0 kg / cm ² or more). EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples and Test Examples. Example 1 2.5 million IU of vitamin A, 4.5 g of phospholipid, and 25 g of Nikkor HCO-60 were added to 25 g of soybean oil heated to 80 ° C. in advance, and the mixture was stirred and dispersed. To this, 5.5 g of glycerin and 1.5 mg of sodium hydroxide were added, and sterile distilled water for injection was added to make a total volume of 250 ml. This liquid was emulsified for 10 minutes at 10,000 rpm using an ultra-high speed homogenizer Hiscotron NS-60 to obtain a coarse emulsion. This crude emulsion was subjected to a Manton-Gaulin type injection emulsifier 15M at a pressure of 700 kg /
Fine emulsification was performed at 15 cm ² for 15 minutes to obtain a fat emulsion having an average particle size of 60 nm. This fat emulsion was dispensed into 1 ml ambles and subjected to high-pressure steam sterilization by a conventional method to obtain a vitamin A injection. Example 2 A vitamin D injection having an average particle size of 70 nm was obtained by emulsifying for 10 minutes using 250,000 IU of vitamin D instead of 2.5 million IU of vitamin A in Example 1. Example 3 In Example 1, vitamin E having 12.5 g of vitamin E was used instead of 2.5 million IU of vitamin A, soybean oil was reduced to 12.5 g, emulsification was performed for 15 minutes, and vitamin E having an average particle diameter of 63 nm was obtained.
Was obtained. Example 4 In Example 1, 2.5 g of vitamin K was used in place of 2.5 million IU of vitamin A, and emulsification was carried out for 15 minutes to obtain an injection of vitamin K having an average particle diameter of 50 nm. Example 5 In Example 1, 2.5 g of coenzyme Q ₁₀ was used in place of 2.5 million IU of vitamin A.
And then subjected to fine emulsification for 15 minutes to obtain a coenzyme Q ₁₀ having an average particle diameter of 48 nm.
Was obtained. Example 6 In Example 1, prostaglandin E ₁₂ was used in place of 2.5 million IU of vitamin A.
. With 5 mg, the precise emulsification is performed for 15 minutes, the average particle diameter was obtained injections 55nm of prostaglandin E _1. Example 7 In Example 1, 1.25 mg of prostaglandin E ₁ ethyl was used in place of 2.5 million IU of vitamin A, and emulsification was performed for 12 minutes to give a prostaglandin E ₁ ethyl injection having an average particle diameter of 60 nm. Obtained. Test Example 1 (Preparation of sample) ¹⁴ g of ¹⁴ C-glycerol triolate as a tracer and 0.72 g of phospholipid were added as tracers to 4 g of soybean oil preheated to 70 ° C., and the mixture was stirred and uniformly dispersed. After adding and dispersing 4 g of Nikkor HCO-60 and 0.32 mg of sodium hydroxide to this,
The total volume was made up to 40 ml by adding sterile distilled water for injection. This liquid was emulsified for 10 minutes at 10,000 rpm using an ultra-high speed homogenizer Hiscotron NS-60 to obtain a coarse emulsion. This coarse emulsion was finely emulsified 9 times at a pressure of 2200 kg / cm ² using a high-pressure cell crusher French Brescher AFPS-20KM, and the average particle diameter was 70 nm.
Was prepared. This was designated as Sample 1. The types and amounts of emulsifiers and the number of times of fine emulsification were changed as shown in Table 1, and Samples 2 to 7 were prepared in accordance with the above-mentioned sample preparation method. Table 1 shows the average particle size of each sample. Test Example 2 Time-dependent change in blood concentration of fat particles (preparation of sample) Labeled samples 1 to 7 prepared in Test Example 1 were used as they were. (Test Animals) Three male Wistar rats weighing 250 to 270 g were set as one group, and one animal was prepared for each of the samples. (Test) The labeled samples were intravenously administered at 1 ml / kg from the left femoral vein of the animals of each group. Blood was collected over time from the arteries of the animals in each group, and the radioactivity was measured to examine the change over time in the fat particle blood concentration. The result is shown in FIG. From FIG. 1, it was recognized that there was a clear difference in the change over time in blood concentration of fat particles between the group having an average particle diameter of 70 nm or less and the group having an average particle diameter of 90 nm or more. In the preparation of Test Example 3 Coenzyme Q ₁₀ time course of blood concentration (Preparation of Sample) Test Example 1 sample with ¹⁴ C-Coenzyme Q ₁₀ 40MyuCi instead of ¹⁴ C-glycerol trioleate 40MyuCi as a tracer, sample 1 Samples corresponding to Samples 3, 9, and 6 were prepared, and Samples 8, 9, and 10 were obtained. (Test Animals) Test animals were prepared according to Test Example 2. (Test) subjected to similar tests described above for the labeled sample Test Example 2 were examined the time course of coenzyme Q ₁₀ blood concentration. The result is shown in FIG. From Figure 2, time course of coenzyme Q ₁₀ blood concentration was found to exhibit identical tendency of fat particles. It is thought that this tendency appears in the same manner for other fat-soluble pharmacologically active substances. The fat emulsion of the present invention has an average particle size of 40 to 70 nm, thereby preventing a sudden drop in blood concentration of a drug which is observed in a normal fat emulsion having a large particle size, The pharmacological action of the pharmacologically active substance can be significantly increased.

【図面の簡単な説明】【図１】第１図は、脂肪乳剤の粒子径の相違による脂肪粒子の血中濃度の経時変化を示
すグラフである。【図２】第２図は、脂肪乳剤の粒子径の相違によるコエンザイムＱ₁₀血中濃度の経時変
化を示すグラフである。BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the change over time in the blood concentration of fat particles depending on the particle size of the fat emulsion. [Figure 2] Figure 2 is a graph showing the time course of coenzyme Q ₁₀ blood concentration due to the difference of the particle diameter of the fat emulsion.

Claims

Claims: 1. A fat-soluble pharmacologically active substance (excluding an anticancer drug) , comprising:
0.1 to 20 w / v containing an oil phase component of 〜30 w / v% and phospholipids as essential components.
A fine particle fat emulsion comprising v% emulsifier and having an average particle size of 40 to 70 nm, which does not cause a rapid decrease in blood concentration of the drug. 2. The method according to claim 1, wherein the emulsion is finely emulsified using a high-pressure emulsifier having a capacity of 700 kg / cm ² or more after the coarse emulsification. A method for producing a fine particle fat emulsion.