WO1991007962A1 - Fat emulsion - Google Patents

Fat emulsion Download PDF

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Publication number
WO1991007962A1
WO1991007962A1 PCT/JP1990/001552 JP9001552W WO9107962A1 WO 1991007962 A1 WO1991007962 A1 WO 1991007962A1 JP 9001552 W JP9001552 W JP 9001552W WO 9107962 A1 WO9107962 A1 WO 9107962A1
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WO
WIPO (PCT)
Prior art keywords
present
emulsion
fat emulsion
drug
miconazole
Prior art date
Application number
PCT/JP1990/001552
Other languages
French (fr)
Japanese (ja)
Inventor
Junzo Seki
Kouichi Ushimaru
Makoto Sugiyama
Original Assignee
Nippon Shinyaku Co., Ltd.
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Nippon Shinyaku Co., Ltd. filed Critical Nippon Shinyaku Co., Ltd.
Priority to JP03500277A priority Critical patent/JP3074731B2/en
Publication of WO1991007962A1 publication Critical patent/WO1991007962A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a preparation of an imidazole compound which has antifungal activity and is hardly soluble forever. More specifically, the present invention relates to a pharmaceutical composition for treating infectious diseases comprising an imidazole antifungal agent, a simple lipid, a phospholipid and ice.
  • miconazole a representative of imidazole antifungal agents, is an important antifungal agent that can be administered systemically and is expected to have certain effects.
  • the injectable preparation had to be solubilized with a surfactant such as polyoxyethylene hydrogenated castor oil (HCO-60) because miconazole was poorly soluble in water.
  • a surfactant such as polyoxyethylene hydrogenated castor oil (HCO-60) because miconazole was poorly soluble in water.
  • the present inventors have developed water without containing a harmful surfactant such as polyoxyethylene hydrogenated castor oil (HCO-60). Formulates an imidazole antifungal agent that is hardly soluble in water, and in addition, transfers the drug to the infected site without affecting the pharmacological action mechanism (antifungal action) of the molecular reper of the imidazole antifungal agent As a result of continued study for the purpose of providing a dosage form having excellent properties, the present invention has finally been successfully completed.
  • a harmful surfactant such as polyoxyethylene hydrogenated castor oil (HCO-60).
  • the administered drug moves and distributes in the living body due to the inherent properties of the drug molecule. Then, it reaches the site of action and develops its efficacy. At this time, it is preferable that the drug concentrates only at the site necessary for the onset of the drug effect, but in general, the drug is distributed throughout the body, and the drug moves to the unnecessary site. Sometimes this causes side effects. This raises the importance and need for improving the pharmacokinetics of drugs.
  • the present inventors have determined that (1) the pharmacological action of a drug can be effectively transferred to a focus tissue without giving a hairpin to the drug itself; ⁇ A new formulation of a safe and effective imidazole antifungal agent that can maintain the blood concentration of, reduce the required drug dosage, and use no harmful additives. As a result of continuing to study the present invention, the present invention was finally successfully completed.
  • the gist of the present invention is that, when producing a fat emulsion containing an imidazole antifungal agent as a main component, the composition ratio of each of the simple lipid, the phospholipid, and the permanent lipid is limited. O O
  • the imidazole antifungal is contained in an amount of 0.001 to 10% (w / v) based on the whole fat emulsion.
  • the simple lipid is contained in an amount of 0.05 to 30% (w / v) based on the whole fat emulsion.
  • the phospholipid is contained in an amount of 0.05 to 2 times the weight of the simple lipid by weight.
  • Ice which is a component of the present invention, has an appropriate amount.
  • the present invention has revealed for the first time that a stable micronized emulsion can be obtained from these components and that this is a pharmaceutical composition having extremely excellent characteristics and can be used as a novel imidazole antifungal agent.
  • a stable micronized emulsion can be obtained from these components and that this is a pharmaceutical composition having extremely excellent characteristics and can be used as a novel imidazole antifungal agent.
  • the fat emulsion of the present invention has an average particle size of 0.5i or less.
  • the fat emulsion of the present invention does not contain 1 ⁇ or more emulsion grains.
  • the fat emulsion of the present invention is extremely fine and stable.
  • the emulsion particles of the fat emulsion of the present invention are: 1) migrate to phagocytic cells such as macrophages which locally aggregate due to inflammation due to infectious disease and biological defense reactions, and 2) inflammatory blood vessels have increased vascular permeability. At the site of infection from the blood vessel to the lesion tissue Because of selective and easy leakage, efficient drug transfer to the lesion site can be achieved for the following reasons.
  • the emulsion particles below about 100 nm can avoid the non-specific uptake by the reticuloendothelial system such as the liver, and have the effect of maintaining the blood concentration of the drug even higher. This leads to more of the emulsion particles of the present invention entering the lesion tissue. As the emulsion particles move into the lesion, the drug contained in the emulsion particles also moves into the lesion. As a result, the drug can be easily and selectively transferred to the lesion, so that the drug concentration at the lesion can be increased and the effect can be increased.
  • the imidazole antifungal agent is present in oil droplets of lipids, and is present in a state of being shielded from the surrounding environment, so that enzymatic or non-enzymatic degradation can be suppressed. Even after administration, the stability of the drug can be improved.
  • the simple lipid used in the fat emulsion of the present invention includes, for example, refined soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, triolein, trilinolein, Neutral lipids such as lino, 'lumitin, tristin-lin, trimyristin, triarachidonin and the like can be mentioned.
  • cholesterol derivatives such as cholesteryl cholesterol, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, and cholesteryl lactide can also be mentioned.
  • Neutral lipid by various lipases existing in vascular endothelium Is relatively easily degraded, whereas cholesterol derivatives are less susceptible to degradation by these enzymes, further increasing their stability in the body.
  • Examples of the y-lipid include phospholipids derived from egg yolk, soybean, cow, Takuya, etc., and purely or semi-synthetically obtained phospholipids. That is, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and the like can be mentioned.
  • egg yolk phosphatidylcholine soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, dimiristoylphosphatidylcholine, distair mouth irirephosphatidylcholine, dioleylphosphatidylcholine, dinolmitoglycidylphosphatidylcholine.
  • Those elastomer additives can also be used.
  • a preferable representative example is purified egg yolk lecithin.
  • lipids having an anion such as stearylamine, dicetylphosphate, phosphatidic acid, and phosphatidylglycerol can be used to impart surface charge to the emulsion particles.
  • the fat emulsion of the present invention various conventional emulsion production methods can be applied as they are.
  • all components, including drugs can be made sufficiently fine by a pressurized injection homogenizer such as a manton-one-gaulin type, a microfluidizer, an ultrasonic homogenizer, etc. Is generally used.
  • physiologically acceptable sterols, fatty acids, or derivatives thereof, and the like can be added as commonly known emulsification aids or stabilizers.
  • Representative examples of these include cholesterol, oleic acid and the like.
  • the shape and the particle diameter of the fat emulsion of the present invention can be easily confirmed by an electron microscope, a particle scattering analysis method using a light scattering method, transmission through a membrane filter, and the like.
  • the fat emulsion of the present invention in addition to the main component of the present invention, for example, additives and auxiliary substances generally used for injections can be provided.
  • Suitable examples thereof include, for example, antioxidants, preservatives, stabilizers, tonicity agents, mildeners and the like.
  • antioxidants for example, antioxidants, preservatives, stabilizers, tonicity agents, mildeners and the like.
  • the required and optimal amounts of these additives, auxiliary substances, etc. can be varied according to the purpose.
  • the fat emulsion of the present invention obtained as described above can be sterilized as necessary (eg, sterilized by filtration, reduced pressure steam, etc.) and enclosed in a sample together with nitrogen gas. In addition, it can be freeze-dried if necessary.
  • the lyophilized fat and oil emulsion of the present invention can be reconstituted by adding an appropriate solution.
  • the preparation comprising the fat emulsion of the present invention may be used for the treatment or prevention of fungal infections, viral infections, etc. It is common to administer intravenously to animals.
  • the preparation comprising the fat emulsion of the present invention can be administered as an injection into the artery, intramuscularly, intrathecally, subcutaneously, etc. as in the case of the conventional product, if necessary.
  • the fat emulsion of the present invention can be formulated and used as eye drops, drops, pills, inhalants, bladder injections, suppositories, ointments and the like.
  • pharmaceutically acceptable bases, additives such as excipients, and the like can be contained in the fat emulsion of the present invention in addition to the main component of the present invention.
  • the dose of the preparation comprising the fat emulsion of the present invention varies depending on the route of administration, dosage form, disease, and purpose, but generally 1 to 1000 milliliters of emulsion is preferred. Generally, the dosage of imidazole antifungal is 5 to 500 mg / dose for adults.o
  • the imidazole antifungal agent applicable to the present invention a compound hardly soluble in water is desired, and miconazole is the most preferable.
  • ADVANTAGE OF THE INVENTION According to this invention, the clinical use value plant of an imidazole antifungal agent can be raised remarkably.
  • the effects of the present invention overcome the problems of the prior art; 1) without affecting the pharmacological action of the drug itself; 2) enabling the efficient and selective transfer of the drug into the lesion tissue; During ⁇ Achieved a new formulation of imidazole-based antifungals that can maintain the concentration, 4 reduce the required drug dosage, ⁇ ⁇ use no harmful additives, and be safe and effective. Can be aggregated. These effects are achieved for the first time by the present invention.
  • the constituents of the fat emulsion of the present invention are mainly lipids that are medically acceptable and have been used for medical purposes in the medical field, they can be used safely by contacting them. This is also one of the important effects of the present invention.
  • Production Example 2 2 g of miconazole, 50 g of refined soybean oil and 5 g of refined egg yolk lecithin are heated and mixed for about 60 t, and 500 ml of 0.24 glycerin aqueous solution is added thereto, and the mixture is stirred with a homomixer to form a coarse emulsion. You. The crude emulsified liquid was emulsified under reduced pressure by a manton-gaurine homogenizer to obtain a fat emulsion having extremely fine miconazole.
  • mice 1 mg, cholesteryl cholesterol 0.5 g, and After mixing and dissolving 0.5 g of the purified egg yolk lecithin in a mixture of mouth form / methanol (1/1, v / v), the solvent is completely removed under reduced pressure using a rotary evaporator. to this,
  • mice 5 Miconazole 5 ing, refined soybean oil 0.5 g, and cryogen-added egg yolk lecithin 0.4 g, cholesterol 0.lg mixed with Cloguchi Form Z methanol (1/1, v / v) 100 JH £ After mixing and dissolving with a rotary evaporator, the solvent is completely removed under reduced pressure with a rotary evaporator. Leave. To this, a 9% aqueous solution of ratatose 8 is added, and the mixture is stirred with a homogenizer to obtain a rough drip solution.
  • a 9% lactose aqueous solution was added to adjust the volume to ⁇ , and then emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes to obtain a very fine fat emulsion containing miconazole.
  • Specimen sample the fat emulsion of the present invention obtained in Production Example 3.
  • Control sample Commercially available miconazole preparation for injection (trade name: Fliplead F Note, registered trademark; Mochida Pharmaceutical). This is a solubilized preparation with the surfactant HCO-60.
  • Test example 1 Change of blood-chuo degree
  • An SD male rat (body weight: about 250 g) was used as an experimental animal, and a test sample and a control sample were intravenously administered via a tail vein.
  • the dose was lOmgZkg as miconazole.
  • a small amount of blood was collected from the jugular vein to obtain plasma.
  • the concentration of miconazole in plasma was measured by high-speed liquid chromatography.
  • Figure 1 shows the results.
  • the plasma miconazole concentration when the test sample was administered was higher than the control sample. It has been shown that the fat emulsion of the present invention achieves a "blood" concentration as compared with conventionally known preparations.
  • Test Example 2 Drug transferability to inflammatory site
  • the concentration of miconazole in the leachate was measured by a high-speed liquid mouth chromatography. The results are shown in FIG. The change in the concentration of miconazole in the leachate when the test sample was administered was larger than that in the control sample.
  • the lipid emulsion of the present invention has a remarkable accumulation property at the site of inflammation (infected site) as compared with conventionally known preparations, and it has been shown that more effective and safe drug therapy can be achieved.
  • Test Example 3 Measurement of particle size.
  • the particle size of the emulsion particles of Production Example 2 and Production Example 3 was evaluated using a dynamic light scattering particle size measurement device g using a laser beam. As a result, the particle size of Production Example 2 was about 150 to about 250 mn. The fat emulsion of Production Example 2 was 1 The upper particles were not included.
  • the average particle size of Production Example 3 was about 20 to about 100 nm.
  • the fat emulsion of Production Example 3 did not contain one or more particles. It is clear that the fat emulsions of the invention consist of very fine and uniform emulsion grains. Also, when administered intravenously, it does not contain particles of more than 1 ju, which are toxic problems, and it is clear that effective and safe drug therapy is achieved.
  • FIG. 1 shows the results of Test Example 1.
  • the vertical axis shows the concentration of the drug in plasma (g / mi), and the horizontal axis shows the elapsed time (minute) after administration.
  • Art indicates a control sample, and ⁇ indicates a sample sample.
  • FIG. 2 shows the results of Test Example 2.
  • the vertical axis indicates the drug concentration (ig / mi) of the pleural effusion of the drug, and the horizontal axis indicates the elapsed time (minute) after administration.
  • Hajime indicates a control sample, and ⁇ indicates a specimen sample.
  • an imidazole compound having an antifungal action can be safely administered as an injection in an effective amount, which is useful in the pharmaceutical industry.

Abstract

A fat emulsion comprising 0.001 to 10 % (w/v) of an imidazole fungicide, 0.5 to 30 % (w/v) of a simple lipid, 0.05 to 2 times by weight as much a phospholipid as the simple lipid, and a suitable amount of water as the principal ingredients. This emulsion makes it possible to introduce the imidazole fungicide in the form of injection into the tissue efficiently, to keep the blood level constant, and to administer an effective dose safely.

Description

明 細 寄  Akira
脂 肪 乳 剤 技 術 分 野  Fatty milk technology
本発明は、 抗真菌活性を有し永に難溶なィ ミダゾール系 化合物の製剤に関する。 さらに詳しく は、 ィ ミダゾール系 抗真菌剤、 単純脂質、 リ ン脂質および氷を舍有してなる感 染症治癍用医薬組成物に関する。  The present invention relates to a preparation of an imidazole compound which has antifungal activity and is hardly soluble forever. More specifically, the present invention relates to a pharmaceutical composition for treating infectious diseases comprising an imidazole antifungal agent, a simple lipid, a phospholipid and ice.
背 景 技 術  Background technology
各種ィ ミダゾール系抗真菌剤は優れた抗真菌作用を有し, 既に臨床で種々の感染症の治療に用いられている。  Various imidazole antifungals have excellent antifungal activity and have already been used clinically for the treatment of various infectious diseases.
例えば、 ィ ミダゾール系抗真菌剤の代表的存在である ミ コナゾールは、 全身投与でき、 確実な効果が期待される重 要な抗真菌剤である。  For example, miconazole, a representative of imidazole antifungal agents, is an important antifungal agent that can be administered systemically and is expected to have certain effects.
しかし、 その注射用製剤は、 ミ コナゾールが水に難溶な ため、 ポ リオキシエチレン硬化ヒマシ油 （H C 0— 6 0 ) 等の界面活性剤により可溶化する必要があった。  However, the injectable preparation had to be solubilized with a surfactant such as polyoxyethylene hydrogenated castor oil (HCO-60) because miconazole was poorly soluble in water.
この界面活性剤 H C O— 6 0 は最近、 了ナフイ ラキシー 型ショ クを引き起こすことが判り、 医薬品の添加物と し て問題視されている。 それ故、 この製剤の臨床使用は、 著 しく制限され、 十分な薬物療法を行うことができない難点 を有しており、 改善が望まれていた。  This surfactant, HCO-60, has recently been shown to cause naphtha-rhyxic shock and has been viewed as a problem as an additive for pharmaceuticals. Therefore, the clinical use of this preparation has been severely restricted, and there is a drawback that sufficient drug therapy cannot be performed.
本発明者らは、 有害なポ リオキシエチレン硬化ヒマシ油 ( H C O - 6 0 ) 等の界面活性剤を含有することなく、 水 に難溶なィ ミダゾール系抗真菌剤を製剤化し、 加えてィ ミ ダゾール系抗真菌剤のもつ分子レペルの薬理作用機構 （抗 真菌作用〉 そのものに影響を与えることなく、 感染部位へ の薬物移行性にも優れた投与剤形を提供することを目的に 検討し続けた結果、 ようやく本発明を完成させることに成 功したものである。 The present inventors have developed water without containing a harmful surfactant such as polyoxyethylene hydrogenated castor oil (HCO-60). Formulates an imidazole antifungal agent that is hardly soluble in water, and in addition, transfers the drug to the infected site without affecting the pharmacological action mechanism (antifungal action) of the molecular reper of the imidazole antifungal agent As a result of continued study for the purpose of providing a dosage form having excellent properties, the present invention has finally been successfully completed.
通常、 投与された薬物は、 その薬物分子の持つ固有の性 質により生体内を移動分布する。 そして作用部位に到達し 薬効を発現する。 このとき薬効発現に必要な部位にのみ薬 物が集中することが好ましいが、 一般には身体全体に薬物 は分布し、 不要な部位にも薬物が移動する。 時にこれが副 作用の原因となる。 そこで、 薬物の体内動態を改善するこ との重要性及び必要性が生じる。  Usually, the administered drug moves and distributes in the living body due to the inherent properties of the drug molecule. Then, it reaches the site of action and develops its efficacy. At this time, it is preferable that the drug concentrates only at the site necessary for the onset of the drug effect, but in general, the drug is distributed throughout the body, and the drug moves to the unnecessary site. Sometimes this causes side effects. This raises the importance and need for improving the pharmacokinetics of drugs.
本発明者らは、 上記の事情に鑑み、 ①薬物の薬理作用そ のものに影簪を与えることなく、 ②薬物の効率的な病巣組 織内への選択的移行を可能たらしめ、 ③薬物の血中濃度を 持続させ、 ④必要とされる薬物投与量を減じることができ、 ⑤有害な添加物を用いない、 安全で一靥有効なィ ミダゾ一 ル系抗真菌剤の新規な製剤化を検討し続けた結果、 ようや く本発明を完成させることに成功したものである。  In view of the above circumstances, the present inventors have determined that (1) the pharmacological action of a drug can be effectively transferred to a focus tissue without giving a hairpin to the drug itself;血 A new formulation of a safe and effective imidazole antifungal agent that can maintain the blood concentration of, reduce the required drug dosage, and use no harmful additives. As a result of continuing to study the present invention, the present invention was finally successfully completed.
発 明 の 開 示  Disclosure of the invention
本発明の要旨は、 ィ ミダゾール系抗真菌剤を主成分とす る脂肪乳剤を製造するにあたって、 単純脂質、 リ ン脂質お よび永のそれぞれの構成成分の組成比を限定したところに め O o The gist of the present invention is that, when producing a fat emulsion containing an imidazole antifungal agent as a main component, the composition ratio of each of the simple lipid, the phospholipid, and the permanent lipid is limited. O O
本発明においては、 ィ ミダゾール系抗真菌剤は全体の脂 肪乳剤に対して 0. 001〜10% (w/v) 含有するようにする。 本発明においては、 単純脂質は全体の脂肪乳剤に対して 0. 05 〜30% (w/v) 含有するようにする。  In the present invention, the imidazole antifungal is contained in an amount of 0.001 to 10% (w / v) based on the whole fat emulsion. In the present invention, the simple lipid is contained in an amount of 0.05 to 30% (w / v) based on the whole fat emulsion.
本発明においては、 リ ン脂質は上記の単純脂質に対して 重量比にして 0. 05 〜 2倍量含有するようにする。  In the present invention, the phospholipid is contained in an amount of 0.05 to 2 times the weight of the simple lipid by weight.
これより少ない量では、 粗大粒子の混入が避けられず、 薬物を含有した安定な脂肪乳剤とすることができない。 こ れより多い量のり ン脂質を用いた場合は、 リ ポソー厶粒子 の混入が避けられず、 均一な脂肪乳剤が得られない。  If the amount is smaller than this, coarse particles are unavoidably mixed, and a stable lipid emulsion containing a drug cannot be obtained. When a larger amount of phospholipid is used, liposome particles are inevitably mixed, and a uniform fat emulsion cannot be obtained.
本発明の構成成分である氷は、 適当量舍有するようにす る 0  Ice, which is a component of the present invention, has an appropriate amount.
これらの成分構成により、 安定な微粒子化乳剤が得られ、 このものがきわめて優れた特徴を有する医薬組成物であり、 新規のィ ミダゾール系抗真菌剤製剤として利用できること が本発明により初めて明らかになった。  The present invention has revealed for the first time that a stable micronized emulsion can be obtained from these components and that this is a pharmaceutical composition having extremely excellent characteristics and can be used as a novel imidazole antifungal agent. Was.
本発明の脂肪乳剤は、 平均粒子径が 0. 5 i以下である。 本発明の脂肪乳剤は、 1 <以上の乳剤粒子を含まない。 本 発明の脂肪乳剤は、 きわめて微細で安定である。  The fat emulsion of the present invention has an average particle size of 0.5i or less. The fat emulsion of the present invention does not contain 1 <or more emulsion grains. The fat emulsion of the present invention is extremely fine and stable.
本発明の脂肪乳剤の乳剤粒子は、 ①感染症に起因する炎 症及び生体防御反応により局所に集合するマクロファージ 等の貪食性細胞に移行するため、 ②炎症性血管は血管透過 性が亢進しているので感染部位で血管内から病巣組織内に 選択的に容易に漏出するため、 等の理由により効率的な病 巣部位への薬物移行を達成することができる。 The emulsion particles of the fat emulsion of the present invention are: 1) migrate to phagocytic cells such as macrophages which locally aggregate due to inflammation due to infectious disease and biological defense reactions, and 2) inflammatory blood vessels have increased vascular permeability. At the site of infection from the blood vessel to the lesion tissue Because of selective and easy leakage, efficient drug transfer to the lesion site can be achieved for the following reasons.
また、 約 lOOnm l下の乳剤粒子は、 肝臓等の細網内皮系 による非特異的な取り込みが回避され、 薬物の血中濃度が いっそう髙く保たれる効果を得ることができる。 これは、 より多くの本発明乳剤粒子の病変組撙内移行につながる。 乳剤粒子の病巣内移行にともない乳剤粒子に包含されて いる薬物も病巣内に移行する。 このことにより、 薬物が容 易にそして選択的に病巣部に移行するから、 病巣部位での 薬物濃度が髙まりその効果を増大させることができる。  In addition, the emulsion particles below about 100 nm can avoid the non-specific uptake by the reticuloendothelial system such as the liver, and have the effect of maintaining the blood concentration of the drug even higher. This leads to more of the emulsion particles of the present invention entering the lesion tissue. As the emulsion particles move into the lesion, the drug contained in the emulsion particles also moves into the lesion. As a result, the drug can be easily and selectively transferred to the lesion, so that the drug concentration at the lesion can be increased and the effect can be increased.
明によれば、 ィ ミダゾール系抗真菌剤は脂質の油滴 中にあるため、 周囲の環境から遮断された妆態で存在する ので、 酵素的又は非酵素的な分解を抑制することができ、 投与後においても薬物の安定性を改善することができる。  According to Ming, the imidazole antifungal agent is present in oil droplets of lipids, and is present in a state of being shielded from the surrounding environment, so that enzymatic or non-enzymatic degradation can be suppressed. Even after administration, the stability of the drug can be improved.
本発明の脂肪乳剤に使用される単純脂質としては、 例え ば、 精製大豆油、 綿実油、 菜種油、 胡麻油、 コーン油、 落 花生油、 サフラワー油、 ト リ オレイ ン、 ト リ リ ノ レイ ン、 ト リ ノ、'ルミチン、 ト リステ了 リ ン、 ト リ ミ リスチン、 ト リ ァラキドニン等の中性脂質を挙げることができる。 また、 コ レステ リ ルォレー ト、 コ レステ リルリ ノ レー ト、 コ レス テ リ ルミ リ ステー ト、 コ レステ リ ルパルミテー ト、 コ レス テ リル了ラキデー ト等のコレステロール誘導体をも挙げる ことができる。  The simple lipid used in the fat emulsion of the present invention includes, for example, refined soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, triolein, trilinolein, Neutral lipids such as lino, 'lumitin, tristin-lin, trimyristin, triarachidonin and the like can be mentioned. In addition, cholesterol derivatives such as cholesteryl cholesterol, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, and cholesteryl lactide can also be mentioned.
血管内皮等に存在する種々のリパーゼ類により中性脂質 は比較的容易に分解されるのに対し、 コ レステロール誘導 体はこれらの酵素による分解を受けにく いため、 体内での 安定性が更に増すからである。 Neutral lipid by various lipases existing in vascular endothelium Is relatively easily degraded, whereas cholesterol derivatives are less susceptible to degradation by these enzymes, further increasing their stability in the body.
y ン脂質としては、 例えば、 卵黄、 大豆、 牛、 啄等由来 のリ ン脂質または、 純合成的又は半合成的に得られる リ ン 脂質が挙げられる。 即ち、 ホスファチジルコ リ ン、 ホスフ ァチジルエタノ ールァミ ン、 ホスファチジルセ リ ン、 ホス フ ァチジルイ ノ シ トール、 ホスファチジルグリ セロール等 を挙げることができる。 例えば、 卵黄ホスファチジルコ リ ン、 大豆ホスファチジルコ リ ン、 ジパルミ トイ ルホスフ ァ チジルコ リ ン、 ジミ リス トイルホスフ ァチジルコ リ ン、 ジ ステア口イリレホスファチジルコ リ ン、 ジォレオイ ルホスフ ァチジルコ リ ン、 ジノ ルミ トイルホスファチジルグリ セ 一ル等を挙げることができる。 それらの永素添加物も用い ることができる。 なかでも好ましい代表例として、 精製卵 黄レシチンを挙げることができる。 また、 乳剤粒子に表面 荷電を賦与するためにステ了 リルアミ ン、 ジセチルホスフ エー ト、 ホスファチジン酸、 ホスファチジルグリセロール 等の荷菴を有する脂質をも用いることができる。  Examples of the y-lipid include phospholipids derived from egg yolk, soybean, cow, Takuya, etc., and purely or semi-synthetically obtained phospholipids. That is, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol and the like can be mentioned. For example, egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, dimiristoylphosphatidylcholine, distair mouth irirephosphatidylcholine, dioleylphosphatidylcholine, dinolmitoglycidylphosphatidylcholine. And the like. Those elastomer additives can also be used. Among them, a preferable representative example is purified egg yolk lecithin. In addition, lipids having an anion such as stearylamine, dicetylphosphate, phosphatidic acid, and phosphatidylglycerol can be used to impart surface charge to the emulsion particles.
本発明の脂肪乳剤の製造にあたっては、 従来から行われ てきた種々の乳剤製造法をそのまま応用することができる。 例えば、 薬物を含めた全構成成分をマン ト ン一ガウ リ ン型 等の加圧噴射式ホモジナイザー、 ミ クロフルイダイザ一、 超音波ホモジナイザー等により充分に微細化して形成せし める方法が一般的である。 In the production of the fat emulsion of the present invention, various conventional emulsion production methods can be applied as they are. For example, all components, including drugs, can be made sufficiently fine by a pressurized injection homogenizer such as a manton-one-gaulin type, a microfluidizer, an ultrasonic homogenizer, etc. Is generally used.
このとき、 一般に知られる乳化補.助剤または安定化剤と して生理的に受け入れられるステロール類、 脂肪酸あるい はそれらの誘導体等を加えることもできる。 これらの代表 例としては、 コレステロール、 ォレイ ン酸等を挙げること ができる。  At this time, physiologically acceptable sterols, fatty acids, or derivatives thereof, and the like can be added as commonly known emulsification aids or stabilizers. Representative examples of these include cholesterol, oleic acid and the like.
本発明の脂肪乳剤の形状や粒子径は、 電子顕微鏡、 光散 乱方式の粒子怪分析装匿、 メ ンブレンフィルターによる攄 過等により容易に確認することができる。  The shape and the particle diameter of the fat emulsion of the present invention can be easily confirmed by an electron microscope, a particle scattering analysis method using a light scattering method, transmission through a membrane filter, and the like.
本発明の脂肪乳剤においては、 本発明の主成分のほかに、 例えば、 一般に注射剤に用いられる添加剤及び補助物質な どを舍有させることができる。  In the fat emulsion of the present invention, in addition to the main component of the present invention, for example, additives and auxiliary substances generally used for injections can be provided.
これらの適当な例として、 例えば、 酸化防止剤、 防腐剤、 安定化剤、 等張化剤、 緩街剤等を挙げることができる。 こ れらの添加剤、 補助物質等の要求量及び最適量は、 その目 的に応じて変化させることができる。 Suitable examples thereof include, for example, antioxidants, preservatives, stabilizers, tonicity agents, mildeners and the like. The required and optimal amounts of these additives, auxiliary substances, etc. can be varied according to the purpose.
上記のようにして得られる本発明の脂肪乳剤は、 必要に 応じて滅菌 （例えば濾過滅菌ゃ髙圧蒸気滅菌等） し、 窒素 ガスとともに了ンプル中に封入することができる。 又、 必 要に応じて凍結乾燠することができる。 凍結乾燥させた本 発明の脂防乳剤は、 適当な溶液の添加によって復元するこ とができる。  The fat emulsion of the present invention obtained as described above can be sterilized as necessary (eg, sterilized by filtration, reduced pressure steam, etc.) and enclosed in a sample together with nitrogen gas. In addition, it can be freeze-dried if necessary. The lyophilized fat and oil emulsion of the present invention can be reconstituted by adding an appropriate solution.
本発明の脂肪乳剤よりなる製剤は、 真菌感染症やウィ ル ス感染症等の治療又は予防を目的として、 ヒ ト又は種々の 動物の静脈内に投与するのが一般的である。 The preparation comprising the fat emulsion of the present invention may be used for the treatment or prevention of fungal infections, viral infections, etc. It is common to administer intravenously to animals.
この場合、 乳剤粒子の粒子径等の管理を十分に行う必要 がある。 なぜならば、 一般に 1 i以上の粒子が混在すると、 種々の毒性が発現することが知られているからである。  In this case, it is necessary to sufficiently control the grain size of the emulsion grains. This is because it is generally known that when 1i or more particles are mixed, various toxicities occur.
また本発明の脂肪乳剤よりなる製剤は、 必要に応じて従 来品同様、 動脈内、 筋肉内、 髄腔内及び皮下等に注射剤と して投与することもできる。 また、 本発明の脂肪乳剤は、 点眼剤、 点 ¾剤、 柽ロ投与剤、 吸入剤、 膀胱注入剤又は坐 剤や軟膏等としても製剤化し使用することができる。 この 場合においても、 医薬上許容される基剤、 賦形剤等の添加 剤等を、 本発明に係る主成分のほかに本発明の脂肪乳剤に 含有させることができる。  Also, the preparation comprising the fat emulsion of the present invention can be administered as an injection into the artery, intramuscularly, intrathecally, subcutaneously, etc. as in the case of the conventional product, if necessary. In addition, the fat emulsion of the present invention can be formulated and used as eye drops, drops, pills, inhalants, bladder injections, suppositories, ointments and the like. Also in this case, pharmaceutically acceptable bases, additives such as excipients, and the like can be contained in the fat emulsion of the present invention in addition to the main component of the present invention.
本発明の脂肪乳剤よりなる製剤の投与量は、 投与ルー ト、 剤形、 症欤、 目的によって変化するが、 乳剤として一般に、 1 〜 1000m£ Z回が良好である。 ィ ミダゾール系抗真菌剤と しての投与量は、 成人に対して一般に 5〜 500mg /回がよ い o  The dose of the preparation comprising the fat emulsion of the present invention varies depending on the route of administration, dosage form, disease, and purpose, but generally 1 to 1000 milliliters of emulsion is preferred. Generally, the dosage of imidazole antifungal is 5 to 500 mg / dose for adults.o
本発明に適応できるィ ミダゾール系抗真菌剤として、 水 に難溶な化合物が望ましぐ、 ミ コナゾールが最も好ま しい。 本発明によれば、 ィ ミダゾール系抗真菌剤の臨床上の利 用価植を著しく高めることができる。  As the imidazole antifungal agent applicable to the present invention, a compound hardly soluble in water is desired, and miconazole is the most preferable. ADVANTAGE OF THE INVENTION According to this invention, the clinical use value plant of an imidazole antifungal agent can be raised remarkably.
本発明の効果は、 従来の問題点を克服し、 ①薬物の薬理 作用そのものに影響を与えることなく、 ②薬物の効率的な 病巣組織内への選択的移行を可能たらしめ、 ③薬物の血中 濃度を持続させ、 ④必要とされる薬物投与量を減じること ができ、 ⑤有害な添加物を用いない、 安全で一雇有効なィ ミダゾール系抗真菌剤の新規な製剤化を達成したこと等に 集約することができる。 これらの効果は、 本発明により初 めて成されたものである。 The effects of the present invention overcome the problems of the prior art; 1) without affecting the pharmacological action of the drug itself; 2) enabling the efficient and selective transfer of the drug into the lesion tissue; During ~ Achieved a new formulation of imidazole-based antifungals that can maintain the concentration, ④ reduce the required drug dosage, 用 い use no harmful additives, and be safe and effective. Can be aggregated. These effects are achieved for the first time by the present invention.
本発明脂肪乳剤の構成成分は、 従来から医療現場におい て医療用として用いられてきた医療上許容される脂質を主 とするため、 接めて安全に使用することができる。 このこ とも本発明の重要な効果の一つである。  Since the constituents of the fat emulsion of the present invention are mainly lipids that are medically acceptable and have been used for medical purposes in the medical field, they can be used safely by contacting them. This is also one of the important effects of the present invention.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
以下に本発明の脂肪乳剤の製造に Kする実施例をあげて 本発明をさらに詳しく銳明するが、 本発明がこれらのみに 限定されるものではないことは明白である。  Hereinafter, the present invention will be described in more detail with reference to Examples for producing the fat emulsion of the present invention, but it is apparent that the present invention is not limited only to these.
製造例 1 Production Example 1
ミ コナゾール 3 ing、 精製大豆油 0. 5g 、 及び精製卵黄レ シチン 0. 5g をク口 ホルム/メタノ ール （ 1 Ζ 1、 ν/ν ) 混液 lOOmg中で混合溶解した後、 D—タ り一エバポレー ターで滅圧下溶媒を完全に除去する。 これに、 0. 24 M グ リセ リ ン氷溶液を 8 m 加えホモジナイザーで撹拌し粗乳化 液とした。 0. 24 ίί グリセり ン水溶液を加えて 10m£に定容 した後、 氷冷下、 超音波ホモジナイザー （ブラ ンソ ン モ デル 1 8 5 ) で 60分間乳化し極めて敏細なミ コナゾールを 含有する脂肪乳剤を得た。  After mixing and dissolving 3 ing of miconazole, 0.5 g of refined soybean oil, and 0.5 g of refined egg yolk lecithin in lOOmg of a mixture of ethanol and methanol (1Ζ1, ν / ν). The solvent is completely removed under reduced pressure with one evaporator. To this, 8 m of 0.24 M glycerin ice solution was added, and the mixture was stirred with a homogenizer to obtain a coarse emulsion. 0.24 ίί After adding glycerin aqueous solution to make the volume to 10 ml, emulsify with an ultrasonic homogenizer (Branson Model 185) for 60 minutes under ice-cooling and contain extremely sensitive miconazole. A fat emulsion was obtained.
製造例 2 ミ コナゾール 2 g 精製大豆油 50g および精製卵黄レシ チン 5 g を約 60 tで加温混合し、 これに 0. 24 グリ セ リ ン水溶液を 500m£加えホモミキサーで携拌し粗乳化液とす る。 粗乳化液をマン ト ン一ガウ リ ン型ホモジナイザーによ り髙圧乳化し、 きわめて微細なミ コナゾールを舍有する脂 肪乳剤を得た。 Production Example 2 2 g of miconazole, 50 g of refined soybean oil and 5 g of refined egg yolk lecithin are heated and mixed for about 60 t, and 500 ml of 0.24 glycerin aqueous solution is added thereto, and the mixture is stirred with a homomixer to form a coarse emulsion. You. The crude emulsified liquid was emulsified under reduced pressure by a manton-gaurine homogenizer to obtain a fat emulsion having extremely fine miconazole.
製造例 3  Production Example 3
ミ コナゾール 29ng、 精製大豆油 0. 25 g 、 及び精製卵黄 レシチン 0. 25 g をクロ口ホルム /メタノ ール （ 1 Z 1、 v/v ) 混液 100m£中,で混合溶解した後、 ロータ リ一エバポ レーターで滅圧下溶媒を完全に除去する。 これに、 等張リ ン酸锾街液 8 を加えホモジナイザーで攪拌し粗乳化液と する。 等張リ ン酸緩街液を加えて 10m£に定容した後、 氷冷 下、 超音波ホモジナイザー （ブラ ンソン モデル 1 8 5 ) で 60分間乳化し極めて微細なミ コナゾ一ルを舍有する脂肪 乳剤を得た。  After mixing and dissolving 29 ng of miconazole, 0.25 g of refined soybean oil, and 0.25 g of refined egg yolk lecithin in a mixture of 100 ml of a mixture of black mouth form / methanol (1Z1, v / v), rotary Completely remove the solvent under reduced pressure with one evaporator. To this, add isotonic phosphoric acid solution 8 and stir with a homogenizer to obtain a coarse emulsion. After adding isotonic phosphoric acid buffer solution and adjusting the volume to 10m £, the fat is emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes under ice-cooling, and contains extremely fine miconazole. An emulsion was obtained.
製造例 4 Production Example 4
ミ コナゾール 2 g 、 精製大豆油 20g 、 及び精製卵黄レシ チン 30g. を約 60 tで加温混合し、 これに 0. 24 M グリセ り ン水溶液を 100m£加えホモミキサーで撹拌し粗乳化液とす る。 粗乳化波をマイ クロフルイダイザ一により高圧乳化し、 きわめて微細なミ コナゾ一ルを舍有する脂肪乳剤を得た。 製造例 5  2 g of miconazole, 20 g of refined soybean oil, and 30 g of refined egg yolk lecithin were heated and mixed at about 60 t, and 100 ml of 0.24 M glycerin aqueous solution was added thereto, followed by stirring with a homomixer and mixing with the coarse emulsion. You. The coarse emulsified wave was emulsified under high pressure by a microfluidizer to obtain a fat emulsion having extremely fine miconazole. Production Example 5
ミ コナゾール 1 mg、 コ レステ リルォレー ト 0. 5g 、 及び 精製卵黄レシチン 0. 5g をク 口ホルム/メタノ ール （ 1 / 1、 v/v ) 混液 100«£中で混合溶解した後、 ロータ リ ー エバポレーターで減圧下溶媒を完全に除去する。 これに、Miconazole 1 mg, cholesteryl cholesterol 0.5 g, and After mixing and dissolving 0.5 g of the purified egg yolk lecithin in a mixture of mouth form / methanol (1/1, v / v), the solvent is completely removed under reduced pressure using a rotary evaporator. to this,
0. 24 M グリセり ン永溶液 8 m£を加えホモジナイザーで撹 拌し粗乳化液とする。 0. 24 M グリセ リ ン氷溶液を加えて 10m に定容した後、 超音波ホモジナイザー （ブランソ ン モデル 1 8 5 ) で 60分間乳化し極めて微細なミ コナゾール を舍有する脂肪乳剤を得た。 Add 8 mL of 0.24 M glycerin permanent solution and stir with a homogenizer to obtain a coarse emulsion. After adding a 0.24 M glycerin ice solution and adjusting the volume to 10 m, the mixture was emulsified with an ultrasonic homogenizer (Branson Model 185) for 60 minutes to obtain a fat emulsion containing very fine miconazole.
製造例 6 Production Example 6
ミ コナゾ—ル 3 mg、 精製大豆油 0. 5g 、 及び精製卵黄レ シチン 0. 4g 、 ジミ りス トィ ルホスファチジルグリセロー ル 0. ig をクロ口ホルム Zメタノ ール （ 1 Z 1、 v/v ) 混 液 100«£中で混合溶解した後、 D—タ リ ーエバポレーター で滅圧下溶媒を完全に除去する。 これに、 9 %ラク トース 水溶液 8 miを加えホモジナイザーで撹拌し粗乳化液とする。  3 mg of miconazole, 0.5 g of refined soybean oil, 0.4 g of refined egg yolk lecithin, and 0.ig of dimyristylphosphatidylglycerol were added to Cloz-form Z methanol (1Z1, v / v). v) After mixing and dissolving the mixture in 100 <£, remove the solvent completely under reduced pressure with a D-tary evaporator. To this, 8 mi of 9% lactose aqueous solution is added and stirred with a homogenizer to obtain a coarse emulsion.
9 %ラク トース水溶液を加えて 10m£に定容した後、 超音波 ホモジナイザー （ブラ ンソ ン モデル 1 8 5 ) で 6 0分間 乳化し極めて微細なミ コナゾールを含有する脂肪乳剤を得 After adding a 9% lactose aqueous solution and adjusting the volume to 10 ml, the mixture was emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes to obtain a very fine fat emulsion containing miconazole.
3 0 3 0
製造例 7 Production Example 7
ミ コナゾール 5 ing、 精製大豆油 0. 5g 、 及び氷素添加卵 黄レシチン 0. 4g 、 コレステロール 0. lg をクロ口ホル厶 Zメ タノ ール （ 1 / 1、 v/v ) 混液 100JH£中で混合溶解し た後、 ロータ リーエバポレーターで滅圧下溶媒を完全に除 去する。 これに、 9 %ラタ トース水溶液 8 を加えホモジ ナイザーで撹拌し粗 i匕液とする。 9 %ラク トース水溶液 を加えて ΙΟπώに定容した後、 超音波ホモジナイザー （ブラ ンソ ン モデル 1 8 5 ) で 60分間乳化し極めて微細なミ コ ナゾールを含有する脂肪乳剤を得た。 Miconazole 5 ing, refined soybean oil 0.5 g, and cryogen-added egg yolk lecithin 0.4 g, cholesterol 0.lg mixed with Cloguchi Form Z methanol (1/1, v / v) 100 JH £ After mixing and dissolving with a rotary evaporator, the solvent is completely removed under reduced pressure with a rotary evaporator. Leave. To this, a 9% aqueous solution of ratatose 8 is added, and the mixture is stirred with a homogenizer to obtain a rough drip solution. A 9% lactose aqueous solution was added to adjust the volume to {π}, and then emulsified with an ultrasonic homogenizer (Branson model 185) for 60 minutes to obtain a very fine fat emulsion containing miconazole.
製造例 8  Production Example 8
製造例 1、 5及び 6で得られたミ コナゾール舍有医薬組 成物に、 アルブミ ン 0. 5g を加え、 その後凍結乾燥処理を 行い、 乾燠製剤を得た。  0.5 g of albumin was added to the miconazole pharmaceutical composition obtained in Production Examples 1, 5 and 6, followed by freeze-drying to obtain a dried silk preparation.
[特性評価試験]  [Characteristic evaluation test]
本発明の脂肪乳剤の特性評価試験結果を J¾下に記す。 各試験においては、 市販のミ コナゾール製剤を比較のた めに用いた。 各試料の詳細を以下に記す。  The results of the property evaluation test of the fat emulsion of the present invention are described below. In each study, a commercial miconazole formulation was used for comparison. Details of each sample are described below.
検体試料 ：製造例 3で得られた本発明の脂肪乳剤。 Specimen sample: the fat emulsion of the present invention obtained in Production Example 3.
対照試料 ：市販の注射用ミ コナゾ一ル製剤 （商品名 ： フ口 リ ー ド F注、 登録商標。 持田製薬） 。 このものは、 界面活 性剤 H C O— 6 0による可溶化製剤である。 Control sample: Commercially available miconazole preparation for injection (trade name: Fliplead F Note, registered trademark; Mochida Pharmaceutical). This is a solubilized preparation with the surfactant HCO-60.
試験例 1 ： 血中澳度推移 Test example 1: Change of blood-chuo degree
実験動物として S D系雄性ラ ッ ト （体重約 250g ) を用 い、 検体試料及び対照試料を尾静脈より静脈内投与した。 投与量はミ コナゾールとして lOmgZkgとした。 投与後、 各 時間において頸静脈より少量採血し血漿を得た。 血漿中の ミ コナゾール濃度は髙速液体クロマ トグラフィ 一にて測定 した。 その結果を図 1 に示した。 検¾試料を投与した場合の血漿中ミ コナゾール濃度は、 対照試料より高かった。 本発明の脂肪乳剤は従来知られる 製剤に比べ、 髙ぃ血中'濃度が達成されることが示された。 試験例 2 ：炎症部位への薬物移行性 An SD male rat (body weight: about 250 g) was used as an experimental animal, and a test sample and a control sample were intravenously administered via a tail vein. The dose was lOmgZkg as miconazole. At each time after administration, a small amount of blood was collected from the jugular vein to obtain plasma. The concentration of miconazole in plasma was measured by high-speed liquid chromatography. Figure 1 shows the results. The plasma miconazole concentration when the test sample was administered was higher than the control sample. It has been shown that the fat emulsion of the present invention achieves a "blood" concentration as compared with conventionally known preparations. Test Example 2: Drug transferability to inflammatory site
真菌等に感染した部位は炎症反応を起こすことが知られ ているので、 そのモデル系として、 実験的炎症部位への薬 物移行性について評価した。 実験動物として S D系雄 性ラ ッ ト （体重約 250 g ) .を用い、 胸腔内に 2 %スーカラ ゲニン 0. 1m を投与し、 実験的胸膜炎を作製した。 2. 5時 間後、 検体試料及び対照試料を尾静脈より静脈内投与した。 投与量は、 ミ コナゾールとして lOmgZkgとした。 投与後、 各時間において腹部大動脈より放血致死せしめ、 胸腔内に 漏出している浸出液を得た。  It is known that sites infected with fungi and the like cause an inflammatory response, and therefore, as a model system, drug transferability to experimental sites of inflammation was evaluated. As an experimental animal, an SD male rat (weighing about 250 g) was used, and 0.1% of 2% sucalagenin was administered into the pleural cavity to produce experimental pleurisy. 2.5 hours later, test samples and control samples were intravenously administered via the tail vein. The dose was lOmgZkg as miconazole. At each time after administration, blood was exsanguinated from the abdominal aorta and exudate leaked into the thoracic cavity was obtained.
浸出液中のミコナゾール濃度は髙速液体ク口マ トグラ フ ィ 一にて測定した。 その結果を図 2に示した。 検钵試料を 投与した場合の浸出液中ミ コナゾール濃度推移は、 対照試 料よりも髙かった。 本発明の脂肪乳剤は従来知られる製剤 に比べ、 顕著な炎症部位 （感染部位） への集積性を有し、 より有効で安全な薬物療法が達成されることが示された。 試験例 3 ：粒子径の測定 .  The concentration of miconazole in the leachate was measured by a high-speed liquid mouth chromatography. The results are shown in FIG. The change in the concentration of miconazole in the leachate when the test sample was administered was larger than that in the control sample. The lipid emulsion of the present invention has a remarkable accumulation property at the site of inflammation (infected site) as compared with conventionally known preparations, and it has been shown that more effective and safe drug therapy can be achieved. Test Example 3: Measurement of particle size.
製造例 2及び製造例 3の乳剤粒子の粒子怪について、 レ 一ザ一光による動的光散乱粒子怪測定装 gを用いその粒子 径について評価した。 その結果、 製造例 2の粒子径は、 約 150〜約 250 mnであった。 また製造例 2の脂肪乳剤は、 1 上の粒子を含まなかった。 The particle size of the emulsion particles of Production Example 2 and Production Example 3 was evaluated using a dynamic light scattering particle size measurement device g using a laser beam. As a result, the particle size of Production Example 2 was about 150 to about 250 mn. The fat emulsion of Production Example 2 was 1 The upper particles were not included.
製造例 3の平均粒子径は、 約 20〜約 lOOnmであった。 ま た製造例 3の脂肪乳剤は、 1 以上の粒子を含まなかった。 本発明の脂肪乳剤は極めて微細で、 均一な乳剤粒子より なることが明らかである。 また、 静脈内に投与する際、 毒 性上問題となる 1 ju以上の粒子をも含まないので、 有効で 安全な薬物療法が達成されることが明白である。  The average particle size of Production Example 3 was about 20 to about 100 nm. The fat emulsion of Production Example 3 did not contain one or more particles. It is clear that the fat emulsions of the invention consist of very fine and uniform emulsion grains. Also, when administered intravenously, it does not contain particles of more than 1 ju, which are toxic problems, and it is clear that effective and safe drug therapy is achieved.
図面の簡単な鋭明  Simple sharps of the drawing
図 1は、 試験例 1の結果を示す。 縦軸は、 薬物の血漿中 の濃度 ( g / mi ) を示し、 横軸は投与後の経過時間 （分 ) を示す。 藝は対照試料を、 〇は検体試料を、 それぞれ表 す。  FIG. 1 shows the results of Test Example 1. The vertical axis shows the concentration of the drug in plasma (g / mi), and the horizontal axis shows the elapsed time (minute) after administration. Art indicates a control sample, and 〇 indicates a sample sample.
図 2は、 試験例 2の結果を示す。 縦軸は、 薬物の胸腔内 浸出液の薬物濃度 （ i g / mi ) を示し、 横軸は投与後の柽 過時間 （分） を示す。 肇は対照試料を、 〇は検体試料を、 それぞれ表す。  FIG. 2 shows the results of Test Example 2. The vertical axis indicates the drug concentration (ig / mi) of the pleural effusion of the drug, and the horizontal axis indicates the elapsed time (minute) after administration. Hajime indicates a control sample, and 〇 indicates a specimen sample.
産業上の利用可能性  Industrial applicability
£1上のように、 本発明によれば、 抗真菌作用を有するィ ミダゾール系化合物を注射剤として安全に有効量投与でき ることから、 医薬品産 ¾において有用である。  As described above, according to the present invention, an imidazole compound having an antifungal action can be safely administered as an injection in an effective amount, which is useful in the pharmaceutical industry.

Claims

赣 求 の 範 囲 Scope of request
1. )全体の 0.001〜： I0% (w/v) のィ ミダゾ一ル系抗真 菌剤、 （ )全体の G.5〜30% (w/v) の単純脂質、 （c)単純脂質 に対して 0.05 〜 2倍 （重量比） のリ ン脂質、 及び、 （d)適 当量の'永  1.) 0.001 ~ of the whole: I0% (w / v) of imidazole antifungal agent, () G. 5-30% (w / v) of the simple lipid, (c) the simple lipid 0.05 to 2 times (weight ratio) phospholipids and (d) an appropriate amount of
の上記 (a)、 ( )s (c)、 及び (d)を含有することを特徴とする脂 防乳剤、 又はその凍結乾燥製剤。 A fat-resistant emulsion comprising the above (a), () s (c) and (d), or a freeze-dried preparation thereof.
PCT/JP1990/001552 1989-12-01 1990-11-29 Fat emulsion WO1991007962A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5814324A (en) * 1994-02-25 1998-09-29 Takeda Chemical Industries, Ltd. Injectable composition and a method of producing the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60115517A (en) * 1983-10-28 1985-06-22 バイエル・アクチエンゲゼルシヤフト Drug blend
JPS60224617A (en) * 1984-03-30 1985-11-09 ソシエテ、アノニム、デイツト：ラボラトアール、エル、ラフオン Medicine for oral administration and preparation of same by freeze drying oil-in-water emulsion
JPS6348214A (en) * 1986-08-18 1988-02-29 Morishita Seiyaku Kk O/w-type fat emulsion containing 1-(2-(2,4-dichlorophenyl)-3-methyl-1-pentenyl)-1h-imidazole
JPH02167217A (en) * 1988-09-29 1990-06-27 Shiseido Co Ltd Emulsified composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60115517A (en) * 1983-10-28 1985-06-22 バイエル・アクチエンゲゼルシヤフト Drug blend
JPS60224617A (en) * 1984-03-30 1985-11-09 ソシエテ、アノニム、デイツト：ラボラトアール、エル、ラフオン Medicine for oral administration and preparation of same by freeze drying oil-in-water emulsion
JPS6348214A (en) * 1986-08-18 1988-02-29 Morishita Seiyaku Kk O/w-type fat emulsion containing 1-(2-(2,4-dichlorophenyl)-3-methyl-1-pentenyl)-1h-imidazole
JPH02167217A (en) * 1988-09-29 1990-06-27 Shiseido Co Ltd Emulsified composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5814324A (en) * 1994-02-25 1998-09-29 Takeda Chemical Industries, Ltd. Injectable composition and a method of producing the same

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