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WO2002034250A1 - Emulsions de matieres grasses - Google Patents

Emulsions de matieres grasses Download PDF

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Publication number
WO2002034250A1
WO2002034250A1 PCT/JP2001/009181 JP0109181W WO0234250A1 WO 2002034250 A1 WO2002034250 A1 WO 2002034250A1 JP 0109181 W JP0109181 W JP 0109181W WO 0234250 A1 WO0234250 A1 WO 0234250A1
Authority
WO
WIPO (PCT)
Prior art keywords
fat emulsion
emulsion according
fat
disease
oil
Prior art date
Application number
PCT/JP2001/009181
Other languages
English (en)
Japanese (ja)
Inventor
Shusei Ito
Kenji Yamada
Mari Nakano
Original Assignee
Taisho Pharmaceutical 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.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU2001295973A priority Critical patent/AU2001295973A1/en
Priority to JP2002537304A priority patent/JPWO2002034250A1/ja
Publication of WO2002034250A1 publication Critical patent/WO2002034250A1/fr

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Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a fat emulsion containing a 2-phenoxyaniline derivative, and more particularly, to a fat emulsion containing a high concentration of a 2-phenoxyaniline derivative, having little irritation during intravenous administration, and having a heart after administration.
  • a 2-phenoxyaniline derivative represented by the following formula (1) selectively inhibits the Na + / C a 2 + exchange system, and provides cells after ischemia and reperfusion. It is useful as a drug that suppresses the excessive accumulation of Ca 2+ in cells, which is regarded as an important mechanism of injury, and ischemic heart disease such as myocardial infarction, ischemic brain disease such as cerebral infarction or ischemic We discovered that it could be used as a therapeutic or prophylactic agent for renal diseases, etc., and filed a patent application (Japanese Unexamined Patent Application Publication No. 11-1933263: WO99205998) c
  • R 1 represents a hydrogen atom or a lower alkoxy group
  • R 2 represents a halogen atom or a divalent group
  • R 3 represents a hydrogen atom or a halogen atom.
  • methods for improving the solubility of poorly water-soluble drugs include a method using an acidic salt, an alkaline salt such as an alkaline metal or an amine, a method using a cosolvent, a method involving inclusion with cyclodextrin, and the like.
  • the solubility is generally improved by using one or more of these methods in combination.
  • the solvent amount of propylene glycol or ethanol is large.
  • the pH of the solution was extremely low at 1.6, and there was concern that damage to the injection site tissue and vascular injury due to drug precipitation would occur.
  • a method of dissolving a poorly water-soluble drug in oil and then forming a fat emulsion is known, and it is known that this method can provide an injection containing a high concentration of the drug.
  • oil particles containing a drug are easily trapped in reticuloendothelial cells such as the liver and lungs, and it is considered that the drug naturally accumulates at this site.
  • Like derivatives (1) reach parts other than the liver and lungs, such as the heart and brain It was considered unsuitable for drugs with medicinal effects.
  • An object of the present invention is to provide a means capable of delivering a sufficient amount of the above-mentioned compound to a target tissue by using a base material having a modest effect on a living body. Disclosure of the invention
  • the present inventors have repeatedly studied the properties of the 2-phenoxyaniline derivative (1). As a result, they found that the compound had sufficiently high solubility in oil, but showed higher affinity for blood.
  • the 2-phenoxyanilin derivative (1) is dissolved in oil, and as a fat emulsion, immediately after intravenous administration, it moves from the oil particles into the blood and does not accumulate in the liver, lungs and other parts of the heart. They found that they could reach the brain and completed the present invention.
  • the present invention provides a fat emulsion containing the 2-phenoxyaniline derivative represented by the formula (1).
  • the present invention also provides an agent for treating and preventing ischemic disease and an agent for protecting cells at the time of surgical treatment, comprising the above fatty milk.
  • FIG. 1 is a drawing showing the result of measuring the concentration of SEA 400 in plasma in Test Example 1.
  • FIG. 2 is a drawing showing the results of measuring the concentration of SEA 400 in the heart in Test Example 1.
  • Fig. 3 shows the results of measuring the concentration of SEA 400 in the brain in Test Example 1. It is a drawing showing a result.
  • FIG. 4 is a drawing showing the result of measuring the concentration of SEA 495 in plasma in Test Example 2.
  • FIG. 5 is a drawing showing the results of measuring the concentration of SEA 495 in the heart in Test Example 2.
  • FIG. 6 is a drawing showing the results of measuring the concentration of SEA 495 in the brain in Test Example 2.
  • the fat emulsion of the present invention is prepared by incorporating the 2-phenoxyaniline derivative (1) into the oil particles of the fat emulsion.
  • the 2-phenoxyaniline derivative (1) which is a medicinal component of the present invention, has already been disclosed in Japanese Patent Application Laid-Open No. 11-193263, and should be produced according to the description in the publication. Can be.
  • the fat emulsion of the present invention can be produced by using a pharmaceutically acceptable oil component and a surfactant, and water according to a conventional method.
  • % (Hereinafter simply referred to as “%”), preferably prepared using 1 to 20% of a surfactant and an appropriate amount of water.
  • oils component used in the fat emulsion examples include pharmaceutically acceptable refined products of natural fats and oils and synthetic fats and oils such as medium-chain fatty acid triglycerides. Of these, vegetable oils are preferred. Examples of such vegetable oils include soybean oil, sesame oil, rapeseed oil, cottonseed oil, safflower oil, and cannabis leave oil, and soybean oil and canine leave oil are particularly preferred.
  • a pharmaceutically acceptable surfactant can be used, but a phospholipid is more preferable.
  • This phospholipid is mainly composed of phosphatidylcholine and phosphatidylethanolamine, Other phospholipids also include phosphatidylinositol, phosphatidylserine, sphingomyelin and the like, and preferred examples thereof include soybean lecithin and egg yolk lecithin.
  • a purified phospholipid purified by a known method such as a fractionation method using an organic solvent.
  • the content of 2-full Enoki Xia aniline derivative (1) in the above fat emulsion in the appropriate increase or decrease the dosage form and application of the fat emulsion, can be contained up to a maximum of about 3 O m g / m I However, in general, it is preferably about 1 to 10 mg / ml in a fat emulsion.
  • the fat emulsion of the present invention contains, in addition to the above components, components that can be added to an injection as needed, such as an emulsifying aid, a stabilizer, a polymer, a tonicity agent, and a pH adjuster. Can be added.
  • components that can be added to an injection as needed such as an emulsifying aid, a stabilizer, a polymer, a tonicity agent, and a pH adjuster. Can be added.
  • examples of the emulsifying aid include fatty acids having 12 to 20 carbon atoms or salts thereof, for example, maleic acid, linoleic acid and their sodium salts. Cholesterol, phosphatidic acid and the like can be used as the stabilizer. When phosphatidic acid is used, it is preferably 1% or less in the fat emulsion.
  • examples of the nonionic surfactant include polyoxyethylene sorbitan monooleate and the like, and the blending amount thereof is preferably about 0.5 to 2% in the fat emulsion.
  • examples of the tonicity agent include glycerin, glucose and the like.
  • the fat emulsion of the present invention thus obtained can be used, for example, as an injection for intravenous administration or a formulation for infusion, and is particularly important as a mechanism of cell injury after ischemia / reperfusion. It can be used to suppress the excessive accumulation of Ca 2+ in living cells. More specifically, treatment and prognosis of ischemic heart disease such as myocardial infarction, ischemic brain disease such as cerebral infarction or ischemic renal disease It can be used as a protective agent or as an agent for protecting cells during surgical procedures such as thrombolytic therapy, angioplasty, coronary artery bypass surgery, and organ transplantation.
  • ischemic heart disease such as myocardial infarction, ischemic brain disease such as cerebral infarction or ischemic renal disease
  • It can be used as a protective agent or as an agent for protecting cells during surgical procedures such as thrombolytic therapy, angioplasty, coronary artery bypass surgery, and organ transplantation.
  • the effectiveness of the fat emulsion of the present invention is due to the unique physical properties of the 2-phenoxyaniline derivative (1). That is, a drug that dissolves in the oil component and has high affinity for the oil component remains in the oil particles even in the blood, and as a result, is trapped and accumulated in reticuloendothelial cells such as the liver and lungs.
  • the 2-phenoxyaniline derivative (1) of the present invention has a sufficiently high solubility in the oil component, and can be obtained as a fat emulsion mixed at a high concentration in the oil component. After being administered to a patient, it has a higher affinity for blood, so it is rapidly released into the blood and reaches the target site, the heart or brain, through the circulation of blood.
  • a fat emulsion (injection) containing 1 O mg / ml was obtained.
  • SEA 495 a compound in which R 1 is a hydrogen atom, R 2 is a fluorine atom at the 6-position, and R 3 is a fluorine atom at the 2-position.
  • Example 1 The injection of Example 1 was intravenously administered to the rat at a dose of 1 mg / kg, blood was collected over time, and the concentration of SEA400 in the plasma was measured by LC / MS / MS under the following conditions. .
  • concentration of SEA 400 at the target sites, heart and brain was also measured.
  • SEA 400 showed a favorable plasma concentration transition without precipitation.
  • FIGS. 2 and 3 SEA 400 reached the expected concentration (100 ng / m I) or more in a short period of time in both the target site, heart and brain. (LC / MS / MS conditions)
  • Example 2 6.7.1 69.3
  • the pH of each of the preparations of Examples I and 2 was neutral, their particle diameters were sufficiently small, and it was judged that there was almost no irritation to the living body.
  • SEA 495 was examined in the same manner as in Test Example 1 below.
  • Fig. 4 shows the change in plasma concentration of SEA495, and Figs. 5 and 6 show the concentration of SEA495 in the heart and brain, which are the target sites.
  • the LC / MS / MS conditions were the same as in Test Example 1 except that the precursor ion was mZz328.0 and the daughter ion was mZz107.9 in SRI.
  • Rat middle cerebral artery occlusion reopening model test
  • the pharmacological action of the fat emulsion of the present invention was examined by the following model tests.
  • the SD rats (8 weeks old) were divided into 4 groups, and these rats were anesthetized with 3% isoflurane inhalation, fixed in a supine position, and maintained under 2% isoflurane. Changes in body temperature were monitored by a temperature measurement probe inserted into the rectum, and the temperature during surgery was maintained at around 37 ° C using an incandescent lamp.
  • the catheter was placed in the femoral vein for continuous infusion in the state of frame-bing.
  • the right common carotid artery, external carotid artery and internal carotid artery were exposed, and the common carotid artery and external carotid artery were ligated with a thread. No. 4 nylon thread (obturator), which had been coated with silicon in advance and cut to a length of 19 mm, was inserted from the branch of the external carotid artery and the internal carotid artery to occlude the middle cerebral artery.
  • Brain slices were positioned so that a coronal plane of 4 mm anterior to the anterior vertex (Bregma), 2 mm anterior to the anterior apex, anterior apical, 2 mm posterior to the anterior vertex, and 4 mm posterior to the anterior vertex was obtained.
  • Brain slices are 1% 2,3,5-tritrifluoromethyl chloride
  • the diameter was 20 5.9 nm.
  • the present invention is intended as a therapeutic or preventive agent for ischemic heart disease such as myocardial infarction, ischemic brain disease such as cerebral infarction, or ischemic renal disease, or as thrombolytic therapy, It is extremely useful as a drug for cell protection during surgical procedures such as coronary artery bypass surgery and organ transplantation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Surgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des émulsions de matières grasses contenant des dérivés de 2-phénoxyaniline de la formule générale (I) dans laquelle R1 est hydrogène ou alcoxy inférieur; R2 est halogéno ou nitro; et R3 est hydrogène ou halogéno. Ces émulsions de matières grasses permettent d'acheminer une quantité satisfaisante des dérivés de l'invention vers des tissus cibles du coeur ou du cerveau, sans provoquer des douleurs ni détériorer les vaisseaux sanguins, les sites d'injection ou analogues.
PCT/JP2001/009181 2000-10-26 2001-10-19 Emulsions de matieres grasses WO2002034250A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001295973A AU2001295973A1 (en) 2000-10-26 2001-10-19 Fat emulsions
JP2002537304A JPWO2002034250A1 (ja) 2000-10-26 2001-10-19 脂肪乳剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-326870 2000-10-26
JP2000326870 2000-10-26

Publications (1)

Publication Number Publication Date
WO2002034250A1 true WO2002034250A1 (fr) 2002-05-02

Family

ID=18803988

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/009181 WO2002034250A1 (fr) 2000-10-26 2001-10-19 Emulsions de matieres grasses

Country Status (3)

Country Link
JP (1) JPWO2002034250A1 (fr)
AU (1) AU2001295973A1 (fr)
WO (1) WO2002034250A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061700A1 (fr) * 2002-01-25 2003-07-31 Taisho Pharmaceutical Co.,Ltd. Medicaments servant au traitement de nephropathies chroniques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007964A1 (fr) * 1989-12-01 1991-06-13 Nippon Shinyaku Co., Ltd. Emulsion de graisse
JPH10218844A (ja) * 1997-02-13 1998-08-18 Taisho Pharmaceut Co Ltd ２−フェノキシアニリン誘導体
EP1031556A1 (fr) * 1997-10-20 2000-08-30 Taisho Pharmaceutical Co., Ltd Derives de la 2-phenoxyaniline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007964A1 (fr) * 1989-12-01 1991-06-13 Nippon Shinyaku Co., Ltd. Emulsion de graisse
JPH10218844A (ja) * 1997-02-13 1998-08-18 Taisho Pharmaceut Co Ltd ２−フェノキシアニリン誘導体
EP1031556A1 (fr) * 1997-10-20 2000-08-30 Taisho Pharmaceutical Co., Ltd Derives de la 2-phenoxyaniline

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061700A1 (fr) * 2002-01-25 2003-07-31 Taisho Pharmaceutical Co.,Ltd. Medicaments servant au traitement de nephropathies chroniques

Also Published As

Publication number Publication date
AU2001295973A1 (en) 2002-05-06
JPWO2002034250A1 (ja) 2004-03-04

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