WO1995006471A1 - Agent d'abaissement du niveau de triglycerides dans le sang - Google Patents

Agent d'abaissement du niveau de triglycerides dans le sang Download PDF

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Publication number
WO1995006471A1
WO1995006471A1 PCT/JP1994/001427 JP9401427W WO9506471A1 WO 1995006471 A1 WO1995006471 A1 WO 1995006471A1 JP 9401427 W JP9401427 W JP 9401427W WO 9506471 A1 WO9506471 A1 WO 9506471A1
Authority
WO
WIPO (PCT)
Prior art keywords
pge
blood triglyceride
fat emulsion
lowering agent
triglyceride lowering
Prior art date
Application number
PCT/JP1994/001427
Other languages
English (en)
Japanese (ja)
Inventor
Takeshi Uchida
Original Assignee
The Green Cross Corporation
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.)
Filing date
Publication date
Application filed by The Green Cross Corporation filed Critical The Green Cross Corporation
Publication of WO1995006471A1 publication Critical patent/WO1995006471A1/fr

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Classifications

    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a blood triglyceride lowering agent.
  • hyperlipidemia refers to a state in which serum lipids such as cholesterol, triglycerides, and phospholipids in the blood are abnormally increased. Therefore, treatments are roughly divided into hypercholesterolemia and hypertriglyceridemia, each of which is based on diet and moderate exercise. If these measures do not improve the condition, drug therapy has been given.
  • hypercholesterolemia with drugs, anion-exchange resins, cholesterol synthesis inhibitors (HMG-CoA reductase inhibitors), or propcol are useful for hypercholesterolemia.
  • hypertriglyceridemia clofibrate preparations, nicotinic acid preparations, etc. are useful, and each is used as a therapeutic agent for hyperlipidemia.
  • Hypercholesterolemia ultimately causes arteriosclerosis and cerebral thrombosis, and hypertriglyceridemia ultimately causes fatty liver and coronary diseases.
  • the above drugs also play a role as agents for preventing diseases such as arteriosclerosis and fatty liver.
  • these drugs are also known to have a variety of side effects, such as the antitriglyceridemia agent clofibrate, which has diarrhea, dizziness, etc.
  • hepatic tumor formation is suspected, and nicotinic acids have been suggested to have the adverse effect of suppressing the level of cyclicAMP, the mechanism of action.
  • PG prostaglandin
  • This PG and its various analogs are involved in the physiology and pathology of biological functions in a complex manner, and their pharmacological actions are quite diverse.Therefore, the development of new drugs using this as an active ingredient is expected. Have been.
  • PGE Blostar Granine £
  • An object of the present invention is to provide a novel anti-triglyceridemia agent.
  • the present invention relates to PGE, The purpose is to provide a new pharmaceutical use of the emulsion.
  • the present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found a new blood triglyceride lowering effect in PGE and other fat emulsions containing the same, and the effect is further improved.
  • the present invention was found to be stable and sustained-release (sustained), and completed the present invention.
  • the present invention provides a prostaglandin E! Or, it is a blood triglyceride lowering agent comprising a fat emulsion containing the derivative thereof.
  • the derivative of PGE, used in the present invention is a concept encompassing compounds that can retain PGE! Activity.
  • PGE! Alkyl esters JP-A-59-216820
  • alkoxycarbonylalkylesters or acyloxyalkyl esters JP-A-59-206344, JP-A-59-21664.
  • 60-137 779 Japanese Patent Application Laid-Open No. 58-39660, Japanese Patent Application Laid-Open No. Hei 3-204853 and Japanese Patent Application Laid-Open No. Hei 5-2103862) No. bulletin
  • 7-Cho body JP-A-58-110562
  • PGE! And its derivatives are also collectively referred to as PGE1s.
  • a fat emulsion containing PGE! And oil components dispersed in a dispersion medium as droplets oil-in-water emulsions, o Zw type emulsion.
  • PGE a kind-containing fat emulsion.
  • the constituent components of the PGE, and the like fat emulsion of the present invention are PGE, and the like, an oil component (such as a vegetable oil), an emulsifier (such as a phospholipid), and water.
  • an oil component such as a vegetable oil
  • an emulsifier such as a phospholipid
  • the fat emulsion containing PGE or the like of the present invention is mainly composed of 5 to 50% (w / V) of vegetable oil, 1 to 50 parts by weight per 100 parts by weight of vegetable oil, preferably 5 to 50 parts by weight. It consists of 30 parts by weight of phosphorus fat and an appropriate amount of water.
  • vegetable oils examples include soybean oil, sesame oil, castor oil, cottonseed oil, and olive oil.
  • it is refined soybean oil of high purity, and more preferably, refined soybean oil obtained by further purifying refined soybean oil, for example, by a steam distillation method (purity: g) 99.9% or more as glycerides, diglycerides and monoglycerides). It may also contain medium-chain fatty acid triglycerides (so-called MCT), fish oil and the like.
  • MCT medium-chain fatty acid triglycerides
  • phospholipids examples include egg yolk phospholipids and soybean phospholipids, and these purified phospholipids are particularly preferably used.
  • the purified phospholipid can be prepared by a conventional method by a fractionation method using an organic solvent. It is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and the other phospholipids are phosphatidyl inositol and phosphatidylinositol. Tidylserine, sphingomye Also contains phosphorus.
  • purified phospholipids from which phosphatidylethanolamine has been further removed may be used. This can be achieved by using a phospholipid such as egg yolk soybean and extracting the organic solvent in a conventional manner. It is obtained by purifying with an inorganic adsorbent such as silica gel or alumina after performing the painting.
  • the phospholipid thus obtained is mainly composed of phosphatidylcholine (Japanese Patent Application Laid-Open No. 60-149524).
  • phosphatidylinositol itself, phosphatidylinoleitol, phosphatidylinolenormin, and phosphatidylserine can also be used.
  • the PGE or other fat emulsion containing PGE used in the present invention may further contain, if necessary, an emulsifying aid, a preservative, a stabilizer, a polymer, a tonicity agent, etc., in addition to the above-mentioned components. .
  • emulsifying aid examples include fatty acids having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or pharmaceutically acceptable salts thereof, and aliphatic amines having 2 to 22 carbon atoms. And the like.
  • the fatty acid is not particularly limited as long as it can be added to pharmaceuticals, and may be either linear or branched, but concretely, linear stearic acid or carboxylic acid It is preferable to use oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid and the like.
  • pharmacologically acceptable salts include, for example, alkali metal salts (sodium salt, potassium salt, etc.), Lucari earth metal salts (calcium salt, magnesium salt, etc.) and the like.
  • the aliphatic amine is not particularly limited as long as it can be added to pharmaceuticals. Examples thereof include linear or branched primary amines having 2 to 22 carbon atoms, Examples are secondary amines, such as ethanolamine, propylamine, octinoreamin, stearylamine, oreoleamine, etc. .
  • the mixing ratio is PGE! If the fatty acid-containing fat emulsion is 100%, the amount of fatty acids or salts thereof is 0.3% (wZv) or less, or the amount of aliphatic amines is 0.1% (wNv) or less. This is preferred.
  • Stabilizers include, for example, cholesterols in an amount of less than 0.5% (wZV), preferably less than 0.1% (w / V), or 5% (w / V). ) In the following, preferably 1% (w / V) or less of phosphatidic acid and the like are mentioned.
  • Any of the cholesterols and phosphatidic acids can be used as long as they can be used as pharmaceuticals.
  • high molecular substance examples include albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, and hydroxyshethyl starch.
  • PGE polystyrene glycol
  • these may be used in an amount of 0.1 to 5 parts by weight (preferably 0.5 to 1 part by weight) per part by weight.
  • vinyl polymer examples include polyvinylpyrrolidone.
  • nonionic surfactants include polyalkylene glycols (for example, having an average molecular weight of from 1,000 to 10,000, preferably from 4,000 to 6,6). 000 polyethylene glycol) Polyoxyalkylene copolymer (for example, polyoxyethylene having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000) — Polyoxypropylene non-polymer), hydrogenated castor oil polyoxyalkylene derivative [for example, hydrogenated castor oil polyoxyethylene- (20) -ether, same- (40) -ether, same- (100) -ether etc.), castor oil polyoxyalkylene derivative [for example, castor oil polyoxyethylene mono (20) -ether, same- (40) -ether, same (10 0) —ether etc.] can be used.
  • polyalkylene glycols for example, having an average molecular weight of from 1,000 to 10,000, preferably from 4,000 to 6,6).
  • Polyoxyalkylene copolymer for example, polyoxyethylene having an average molecular weight of
  • Examples of the tonicity agent include glycerin and glucose.
  • the amount of PGE, contained in the above-mentioned fat emulsion can be appropriately increased or decreased depending on the form and use of the emulsion, but generally, a very small amount, for example, 0.2 to 100 g Zml is contained in the emulsion. It is enough to let them.
  • compositions of the PGE and other fat emulsions used in the present invention include the following.
  • a total of 1 ml of PGEi-containing fat emulsion can be prepared by various methods. For example, it is produced by the following method.
  • an oil component preferably, soybean oil
  • phospholipid, PGE, and other additives described above are mixed and heated to form a solution, and a conventional homogenizer (for example, a high-pressure spray type) is used.
  • a conventional homogenizer for example, a high-pressure spray type
  • Homogenizer, ultrasonic homogenizer, etc. to produce a water-in-oil dispersion
  • add the required amount of water to the dispersion homogenize again with the homogenizer, and perform oil-in-water dispersion. It can be manufactured by converting it into a type emulsion.
  • additives such as a stabilizer and a tonicity agent may be added after the preparation of the fat emulsion (Japanese Patent Application Laid-Open No. 58-222014).
  • a sterilization treatment may be performed.
  • a usual method is used, and examples thereof include a 0.22 // sterilization filter method, a ⁇ -ray irradiation method, and a high-pressure heat treatment method.
  • the thus-prepared fat emulsion containing PGE or the like may be added as it is or, if desired, with other components added. Accordingly, it is used as the blood triglyceride lowering agent of the present invention.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the blood triglyceride lowering agent of the present invention can be administered parenterally in the form of an injection or the like.
  • Intravenous administration is particularly preferred.
  • the administration is, for example, PGE! It is performed by continuous intravenous infusion once a day at a rate of 1 to 50 ⁇ g, 0.02 to 0.SngZkg.
  • the blood triglyceride lowering agent of the present invention has an effect of lowering blood triglyceride concentration, it can be used for mammals (eg, mice, rats, rabbits, dogs). , Cats, humans, etc.) to prevent or treat hyperlipidemia and improve lipid metabolism. It is also useful for preventing or treating arterial sclerosis and fatty liver caused by hyperlipidemia.
  • the blood triglyceride lowering agent of the present invention is in the form of a fat emulsion, it is excellent in sustained release, sustainability, and local (lesion) concentration in addition to the above-mentioned effects. Good storage stability.
  • This Ma emissions tons - using Gaussian Li down homogenizer Me once 1 2 0 kg / cm 2, was passed through 1 0 times under a pressure of total 5 0 0 kg / cm 2, and emulsified. As a result, a homogenized fat emulsion containing extremely fine PGE was obtained. The average particle size of this emulsion was from 0.2 to 0.4 m, and contained no particles larger than l ⁇ m.
  • the PGE1-containing fat emulsion is used as an agent for lowering blood triglycerides.
  • Example 2 In place of PGE! In Example 1, PGE, ethyl ester (Example 2), PGE, bivaloyloxymethyl ester (Example 3), PGE 1-octyloxycarbonyl methyl ester (Example 4), butyl- 9 — Acetoxy-11 a, 15 S — Dihydroxy 17 S, 20 — Dimethyl prostar 8, 13 E — Gen 1 1 — Ore (except for using Example 5) An emulsion was prepared according to the method of Example 1 to obtain a homogenized and very fine fat emulsion containing PGE and derivatives.
  • the average particle size of the emulsion was from 0.2 to 0.4 m.
  • the PGE thus prepared! Derivative-containing fat emulsion contains blood Medium Used as a triglyceride lowering agent.
  • the emulsion was prepared according to the method of Example 1, except that 5.4 g of the purified yolk lin lipid of Example 1 and 3.6 g of the yolk lin lipid were used instead of 0.72 g of oleic acid. Prepared.
  • the PGE i -containing fat emulsion thus prepared is used as a blood triglyceride lowering agent.
  • the mixture was centrifuged at 10000 rpm at 4 ° C for 10 minutes.
  • the supernatant was subjected to suction filtration with a 1.0-Millipore filter, and the solvent was distilled off to obtain 60 g or more of phospholipid.
  • This purified phospholipid is substantially free of phosphatidylethanolamine (the content is 1% or less).
  • the yolk phospholipid of Example 1 was obtained as described above in place of the phospholipid.
  • An emulsion was prepared according to the method of Example 1 except that the purified phospholipid thus obtained was used.
  • the PGE, containing fat emulsion thus prepared is used as an agent for lowering blood triglycerides.
  • the PGE containing fat emulsion prepared in Example 1 was applied to mice, rats and dogs as PGE! There were no deaths even after heavy intravenous administration, and no serious toxicity occurred.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Diabetes (AREA)
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  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention se rapporte à un agent d'abaissement du niveau de triglycérides dans le sang, qui contient comme principe actif une émulsion de graisses renfermant de la prostaglandine E1 ou un dérivé de celle-ci. Cet agent peut servir à prévenir ou à traiter l'hyperlipidémie chez les mammifères, à améliorer le métabolisme des lipides et à prévenir ou à traiter l'artériosclérose et la stéatose du foie causées par l'hyperlipidémie. Cet agent possède en outre d'excellentes propriétés du point de vue de ses performances de libération prolongée, du point de vue de sa persistance d'action et du point de vue de sa capacité de concentration locale (focale), ainsi qu'une bonne aptitude à la conservation en raison de sa formulation sous forme d'émulsion.
PCT/JP1994/001427 1993-09-01 1994-08-30 Agent d'abaissement du niveau de triglycerides dans le sang WO1995006471A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/217795 1993-09-01
JP5217795A JPH0769897A (ja) 1993-09-01 1993-09-01 血中トリグリセリド低下作用剤

Publications (1)

Publication Number Publication Date
WO1995006471A1 true WO1995006471A1 (fr) 1995-03-09

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PCT/JP1994/001427 WO1995006471A1 (fr) 1993-09-01 1994-08-30 Agent d'abaissement du niveau de triglycerides dans le sang

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JP (1) JPH0769897A (fr)
WO (1) WO1995006471A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777601A (zh) * 2014-12-26 2016-07-20 中国人民解放军第二军医大学 一种前列地尔衍生物及其药物制剂

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007320864A (ja) * 2006-05-30 2007-12-13 Toshihiko Osawa 非アルコール性脂肪肝炎予防・治療用組成物
MY158088A (en) * 2007-07-13 2016-08-30 Mitsubishi Tanabe Pharma Corp Stable lipid emulsion containing prostaglandin e1

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50106941A (fr) * 1974-01-26 1975-08-22
JPS53147045A (en) * 1977-05-26 1978-12-21 May & Baker Ltd Derivative of cyclopentane and its preparation
JPS58222014A (ja) * 1982-06-18 1983-12-23 Taisho Pharmaceut Co Ltd プロスタグランジンｅ↓１脂肪乳剤
JPS59216820A (ja) * 1983-05-20 1984-12-06 Taisho Pharmaceut Co Ltd プロスタグランジン脂肪乳剤
JPS62267231A (ja) * 1986-04-11 1987-11-19 シンテツクス（ユ−・エス・エイ）　インコ−ポレイテツド 脂肪および炭水化物代謝調節剤エンプロスチル型プロスタグランジン類
JPH03163024A (ja) * 1989-07-27 1991-07-15 Ueno Seiyaku Oyo Kenkyusho:Kk 高脂質血症処置・血中脂質成分低下剤
JPH0489430A (ja) * 1990-07-26 1992-03-23 Green Cross Corp:The 低血圧維持剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50106941A (fr) * 1974-01-26 1975-08-22
JPS53147045A (en) * 1977-05-26 1978-12-21 May & Baker Ltd Derivative of cyclopentane and its preparation
JPS58222014A (ja) * 1982-06-18 1983-12-23 Taisho Pharmaceut Co Ltd プロスタグランジンｅ↓１脂肪乳剤
JPS59216820A (ja) * 1983-05-20 1984-12-06 Taisho Pharmaceut Co Ltd プロスタグランジン脂肪乳剤
JPS62267231A (ja) * 1986-04-11 1987-11-19 シンテツクス（ユ−・エス・エイ）　インコ−ポレイテツド 脂肪および炭水化物代謝調節剤エンプロスチル型プロスタグランジン類
JPH03163024A (ja) * 1989-07-27 1991-07-15 Ueno Seiyaku Oyo Kenkyusho:Kk 高脂質血症処置・血中脂質成分低下剤
JPH0489430A (ja) * 1990-07-26 1992-03-23 Green Cross Corp:The 低血圧維持剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777601A (zh) * 2014-12-26 2016-07-20 中国人民解放军第二军医大学 一种前列地尔衍生物及其药物制剂

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Publication number Publication date
JPH0769897A (ja) 1995-03-14

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