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WO2003015753A1 - Preparations de liposomes - Google Patents

Preparations de liposomes Download PDF

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Publication number
WO2003015753A1
WO2003015753A1 PCT/JP2002/008380 JP0208380W WO03015753A1 WO 2003015753 A1 WO2003015753 A1 WO 2003015753A1 JP 0208380 W JP0208380 W JP 0208380W WO 03015753 A1 WO03015753 A1 WO 03015753A1
Authority
WO
WIPO (PCT)
Prior art keywords
ribosome
liposome
phospholipid
preparation
mol
Prior art date
Application number
PCT/JP2002/008380
Other languages
English (en)
Japanese (ja)
Inventor
Yoshitaka Ogata
Hiroshi Gotou
Original Assignee
Terumo Kabushiki Kaisha
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 Terumo Kabushiki Kaisha filed Critical Terumo Kabushiki Kaisha
Priority to JP2003520713A priority Critical patent/JPWO2003015753A1/ja
Publication of WO2003015753A1 publication Critical patent/WO2003015753A1/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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/37—Factors VIII
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to an improved drug-retaining ribosome preparation, and more particularly, to an improved drug-retaining ribosome preparation in which various bioactive substances are encapsulated inside ribosomes (vesicles).
  • Ribosomes are defined as closed vesicles with a membrane composed primarily of lipids. Ribosomes, which are the endoplasmic reticulum of the lipid bilayer membrane, can be used as a drug delivery system because they can encapsulate various substances inside and have excellent biocompatibility because they are formed from biological substances. Ribosomes have been used in many studies as models of biological membranes, but have also been applied to drug delivery systems (DDS). It is also used in the field of genetic engineering as a carrier for genes and antisense. By the way, drug encapsulation changes the biodistribution of the drug and the residence time in the bloodstream. It will also improve accessibility to target organs, reduce side effects of the drug, and allow for sustained release.
  • DDS drug delivery systems
  • ribosomes include low toxicity and antigenicity, and metabolism in vivo because the phospholipid used is a biological component.
  • the size and lipid composition of ribosomes can be easily adjusted, and many things such as water-soluble drugs, fat-soluble drugs, polymers, and proteins can be encapsulated. Surface modification with quality, antibodies, lectins, etc. is also easy.
  • drug capsules for the purpose can be constructed.
  • liposomal preparations can be used to stabilize drugs that are unstable in the living body or to gradually release drugs in the living body, and selectively transfer drugs to specific organs. Use is also considered as a means for this.
  • ribosome preparations containing hemoglobin, insulin, heparin, peroxidase, and various other anticancer and antifungal agents are known as preparations for stabilization and sustained release.
  • a preparation for the purpose of rapidly transferring a drug to ribosomes a ribosome preparation containing ubide force renone, cytosine arabinoside, steroids, and other various anticancer and antifungal agents is known.
  • Phospholipids used as membranes in conventional drug-retaining liposomal preparations include unsaturated lecithin such as egg yolk lecithin or soy lecithin, purified saturated lecithin hydrogenated to these, phosphatidylcholine further separated and purified from these, and phosphatidyl Examples include purified lecithin such as ethanolamine, phosphatidylinositol, phosphatidylserine, and sphingomyelin, and synthetic lecithin such as dimyristoyl lecithin, dipalmityl lecithin, and distearoyl lecithin. These have good affinity to the living body and are used safely in parenteral preparations such as injections.
  • ribosome membrane materials do not always have a sufficient drug retention. That is, the amount of the drug contained in the unit ribosome drug is not sufficient, and a more efficient membrane material is demanded.
  • conventional ribosome membrane materials made from unsaturated lecithin and unsaturated fatty acids Japanese Patent Application Laid-Open No. 60-155109 are stable. The membranes were inadequate, and the membrane was relatively easily destroyed in vitro or in vivo, resulting in short life in vivo and release of drugs.
  • a ribosome preparation using purified lecithin and synthetic lecithin with higher stability is very expensive, and there is a limit in using purified lecithin and synthetic lecithin as a raw material for the preparation.
  • an object of the present invention is, firstly, to provide a drug-retaining liposome preparation having an excellent drug retention rate in the ribosome.
  • a second object of the present invention is to provide an inexpensive membrane agent as a liposome drug material. Disclosure of the invention
  • the present invention provides the following inventions.
  • the membrane agent constituting the ribosome contains a phospholipid and at least one kind of a higher saturated fatty acid having 10 to 20 carbon atoms.
  • a ribosome preparation, wherein the content of the higher saturated fatty acid is 30 raol% to 50 mol% in a molar ratio in the ribosome component.
  • An aggregation inhibitor having a hydrophilic polymer chain portion and a hydrophobic portion is further bound to the ribosome surface, and the aggregation inhibitor has the hydrophobic portion immobilized on the lipid layer in the liposome.
  • the ribosome preparation according to any one of (1) to (3), wherein the hydrophilic polymer chain part extends outward from the liposome surface.
  • FIG. 1 is a graph showing the fatty acid charge ratio and the protein yield.
  • Figure 2 is a graph showing the fatty acid charge ratio and the amount of force-pressed protein per lipid.
  • Figure 3 is a graph showing fatty acid loading ratio and ribosome stability (protein leakage rate).
  • FIG. 4 is a graph showing the carbon number of the fatty acid carbon chain, the protein yield of the liposomal preparation, and the protein amount per lipid amount.
  • a lipid suitable for preparing a liposome is used as a membrane agent used in the drug-retaining ribosome preparation of the present invention.
  • Soy lecithin and yolk lecithin as phospholipids Any phospholipids such as natural unsaturated phospholipids, synthetic phospholipids, and natural hydrogenated phospholipids obtained by hydrogenating natural unsaturated phospholipids can be used. Since all natural phospholipids contain unsaturated fatty acids, hydrogenated phospholipids or synthetic phospholipids in which unsaturated fatty acids of the above natural phospholipids are saturated with hydrogen are required to achieve the object of the present invention to a higher degree. It is more effective to use.
  • phospholipid used in the present invention include lecithin, phosphatidylethanolamine, phosphatidylinosyl], phosphatidylserine, phosphatidylglycerol, sphingomyelin, and cardioribine. Further, there may be mentioned those obtained by hydrogenating them according to a conventional method. In particular, a hydrogenated natural lecithin obtained by hydrogenating soybean lecithin, egg yolk lecithin, corn lecithin, cottonseed oil lecithin, nayu lecithin and the like is preferably used.
  • a higher fatty acid having 10 to 20 carbon atoms is desirable, and examples thereof include ricopric acid, lauric acid, myristin shun, balmitic acid, stearic acid, and eicosanoic acid. .
  • These higher saturated fatty acids can be used alone or as a mixture. Since the hydrophobic carbon chain of the phospholipid suitably used as the ribosome membrane constituent lipid has about 14 to 18 carbon atoms, the higher saturated fatty acid having 14 to 18 carbon atoms can be obtained from the affinity with the phospholipid. More desirable.
  • the molar ratio of the higher saturated fatty acid to the liposome component should be 30 mol% or more, and the molar ratio does not cause micelle formation with the phospholipid. Even when the blending amount of the higher saturated fatty acid is less than 30 mol%, liposomes are formed and the drug has the ability to retain a drug, but in order to improve the drug retention, the blending ratio of the higher saturated fatty acid is 30 mol1 in a molar ratio. This is necessary. Further, when the content is 40 mol% or more, the affinity and stability which are the object of the present invention It is more preferable because it exhibits excellent properties as a drug, a drug retention rate, and an inexpensive film agent.
  • Phospholipids cannot retain drugs as ribosomes unless they are used in a concentration range that results in a lamellar structure.However, if the amount of higher saturated finger acid is excessively increased, micelles formed by higher saturated fatty acid inhibitors are formed. Phospholipids are taken up and do not form liposomes.
  • the blending ratio of the higher saturated fatty acid varies depending on the number of carbon atoms and conditions of the fatty acid, but it is over about 50 mol% in molar ratio. Therefore, higher fatty acids will not form ribosomes unless used at a ratio below this ratio, and the drug retention efficiency will be extremely low or impossible.
  • the molar ratio is 45 mol% or less. Therefore, the molar ratio of the higher saturated fatty acid to the phospholipid is 30 mol to 50 mol%, preferably 40 mol% to 45 mol%.
  • a sterol such as cholesterol or tocopherol can be added to the membrane material of the present invention in order to increase the strength of the membrane.
  • a substance for controlling transfer to a target organ in a living body and sustained release properties can be used. It is also possible to add.
  • the retained substance incorporated and retained in the ribosome preparation of the present invention is not particularly limited as long as it does not inhibit ribosome formation, but it is unstable in vitro or in vivo, and in the bloodstream.
  • a physiologically active substance which is desired to be stably retained in the stomach or a substance which is desired to be rapidly distributed to a specific organ is preferably used. Examples of such substances include hemoglobin, insulin, heparin, perokinase, shrimp dicarenone, methotrexate neomycin, prepomycin, tetracycline, cytochrome C, asparaginase, and cytosine arabinoside. .
  • the drug-carrying ribosome preparation of the present invention is produced by a method known per se.
  • natural phospholipids, hydrogenated natural phospholipids, at least one of the above-mentioned higher saturated fatty acids and, if desired, sterol are dissolved in a suitable solvent such as chloroform or ethanol, and the solvent is distilled off from the resulting solution.
  • a suitable solvent such as chloroform or ethanol
  • aqueous solution of a drug such as a physiologically active substance is added to the obtained lipid mixture, and the obtained mixture is vigorously shaken, stirred or sonicated to uniformly disperse the aqueous drug solution.
  • the drug not taken into the ribosome is removed from the dispersion to obtain a drug-retaining ribosome preparation.
  • the liposomal preparation thus obtained is prepared, if necessary, as a suspension preparation dispersed in a physiologically acceptable aqueous solution, for example, physiological saline.
  • the liposome preparation of the present invention is administered as a parenteral preparation such as an injection.
  • the ribosome of the present invention may be freeze-dried under ordinary conditions.For example, it is preferable to freeze at ⁇ 20 ° C.
  • a ribosome preparation is defined as a preparation in which various substances to be retained are contained inside the ribosome.
  • the ribosome preparation of the present invention may further contain an aggregation inhibitor having a hydrophilic polymer chain portion and a hydrophobic portion.
  • the amount of the aggregation inhibitor can be preferably 0.01 to 5% by mass, more preferably 0.01 to 1% by mass, based on the liposomal preparation.
  • the hydrophobic part is stably inserted into the ribosome surface and fixed to the lipid layer in the liposome, and the hydrophilic polymer chains move outward from the liposome surface. It has the function of elongating and suppressing ribosome aggregation.
  • aggregation inhibitor examples include, as the hydrophobic part, various saturated 'unsaturated fatty acids, sterols, polyoxypropylene alkyl or glycerin fatty acid esters, and phospholipids, and phospholipids are preferable.
  • the hydrophilic polymer chains include polyalkylene glycol, polyvinyl alcohol, alternating copolymer of styrene and maleic anhydride, alternating copolymer of divinyl ether and maleic anhydride, polyglycolic acid, polylactic acid, and dextran and pullula. And polysaccharides such as ficoll, amylose, amylopectin, chitosan, mannan, cyclodextrin, pectin, and carrageenan. Among them, polyethylene glycol is most desirable because of its remarkable effect of improving blood retention. Polyethylene glycol-linked phospholipids and polyethylene glycol-linked cholesterol are preferred.
  • HSPC hydrogenated soybean lecithin
  • cholesterol molecular weight 376
  • stearic acid molecular weight 278
  • Different mixed lipids Table 1 were prepared by dissolving in 10 ml of t-BuOH and freeze-drying to remove t-BuOH. Hemoglobin (45wt%) solution, 20ml was added to this and a high-speed stirrer
  • the concentration of hemoglobin in the liposomal encapsulated hemoglobulin preparations of each formulation ratio obtained in this way was measured by atomic absorption, and the concentrations of HSPC, cholesterol, and stearic acid were measured by high-performance liquid chromatography. did.
  • Protein yield (%) (Amount of protein retained in ribosome Z Amount of protein input at adjustment) X 100
  • the protein yield was about 10% or less, but when the molar ratio was in the range of 30 mol% to 50 mol%, the protein yield was 12% or more. It was found that at a molar ratio of about 40 mol%, the protein yield increased to 16% (Fig. 1).
  • the ribosome-encapsulated hemoglobin preparation at each mixing ratio was placed in a 50-ml centrifuge tube, and at 37 After shaking 60 times per minute for 3 hours, the mixture was centrifuged at 40,000 G for 60 minutes, and the amount of hemoglobin leaked into the supernatant was measured.
  • the value obtained by dividing the amount of leaked hemoglobin by the amount of hemoglobin in the original liposome-encapsulated hemoglobin preparation is shown in FIG. 3 as the protein leakage rate ().
  • the stability of the liposome formulation is improved from a molar ratio to phospholipid of about 12 mol%, and is stable up to a molar ratio of 50 mol%, and is particularly stable in a range of 33 mol% to 46 mol%. Do you get it. It was also found that when the molar ratio exceeds 5 Omol%, the stability of the liposome formulation is adversely affected.
  • HSPC molecular weight: 790
  • cholesterol molecular weight: 376
  • lauric acid molecular weight: 200
  • myristic acid molecular weight: 2248
  • palmitic acid molecular weight: 256
  • stearic acid higher saturated fatty acids 1 g of a mixed lipid containing 33.3 mol of a molecular weight of 278) in a molar ratio to HSPC was prepared in the same manner as in Example 1.
  • a hemoglobin (45w) solution (20 ml) was added thereto, and the mixture was emulsified (15,000 rpm, lmin, 3 times at 20 ° C or lower) using a high-speed stirrer (CLM-0.8S).
  • Hemoglobin concentration in the hemoglobin preparation of each of the thus obtained fatty acid-containing ribosome-produced hemoglobin preparations was measured by atomic absorption, and HSPC concentration, cholesterol concentration and stearic acid concentration were measured by high performance liquid chromatography.
  • the ribosome preparation of the present invention provides a drug-retaining ribosome preparation having an excellent drug retention rate inside the ribosome. Furthermore, they found that ribosomes could be formed by combining fatty acids in amounts previously considered impossible to form ribosomes as higher saturated fatty acids of a specific chain length. Phospholipids are the most frequently incorporated substances in the composition of liposome-constituting membrane materials, and are very expensive compared to fatty acids. According to the present invention, the amount of the inexpensive fatty acid can be increased, and the amount of the phospholipid can be much reduced. Therefore, it is inexpensive as a raw material for ribosome preparations. The present invention provides a film agent having a suitable composition.

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Abstract

L'invention concerne des préparations de liposomes contenant des liposomes et une substance ayant été incorporée dans ceux-ci. Un agent filmogène constituant les liposomes contient un phospholipide et au moins un acide gras saturé supérieur possédant entre 10 et 20 atomes de carbone et le rapport molaire entre l'acide gras saturé supérieur et le phospholipide se situe entre 30 mol % et 50 mol %. Ces préparations, dans lesquelles on utilise un agent filmogène moins cher en tant que matière de liposome, possèdent un excellent rapport de rétention de médicament dans les liposomes.
PCT/JP2002/008380 2001-08-20 2002-08-20 Preparations de liposomes WO2003015753A1 (fr)

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Application Number Priority Date Filing Date Title
JP2003520713A JPWO2003015753A1 (ja) 2001-08-20 2002-08-20 リポソーム製剤

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JP2001248454 2001-08-20
JP2001-248454 2001-08-20

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092388A1 (fr) * 2004-03-26 2005-10-06 Terumo Kabushiki Kaisha Preparation de liposome
JP2006104069A (ja) * 2004-09-30 2006-04-20 Terumo Corp ヘモグロビン含有リポソームの製造方法および包装体
WO2006132388A1 (fr) * 2005-06-06 2006-12-14 Waseda University Materiaux de delivrance de medicament a la moelle osseuse et leurs applications
WO2009114959A1 (fr) * 2008-03-20 2009-09-24 中国人民解放军军事医学科学院毒物药物研究所 Formulation pharmaceutique injectable à libération prolongée et procédé de préparation associé
WO2013047263A1 (fr) * 2011-09-28 2013-04-04 テルモ株式会社 Liposome contenant de l'hémoglobine et son procédé de production
WO2024080371A1 (fr) 2022-10-14 2024-04-18 積水メディカル株式会社 Agent raccourcissant le temps de coagulation sanguine d'un échantillon de sang défaillant en facteur de coagulation ｘｉｉ
WO2024080372A1 (fr) 2022-10-14 2024-04-18 積水メディカル株式会社 Agent modifiant le temps de coagulation sanguine d'un échantillon de sang défaillant en facteur de coagulation ｖｉｉｉ, ｉｘ ou ｘｉ, et réactif pour mesure du temps de thromboplastine partielle activée
WO2024080373A1 (fr) 2022-10-14 2024-04-18 積水メディカル株式会社 Réactif pour mesure du temps de thromboplastine partielle activée, et agent modifiant le temps de coagulation sanguine d'un échantillon de sang positif à l'anticoagulant lupique ou d'un échantillon de sang à teneur en héparine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60155109A (ja) * 1984-01-23 1985-08-15 Terumo Corp リポソ−ム製剤
EP0354855A2 (fr) * 1988-08-11 1990-02-14 Terumo Kabushiki Kaisha Liposomes dont l'adsorption de protéines sur des surfaces est empêchée
JPH05320043A (ja) * 1992-05-20 1993-12-03 Terumo Corp リポポリサッカライド捕捉剤
JPH06183954A (ja) * 1992-12-24 1994-07-05 Kyowa Hakko Kogyo Co Ltd リポソーム製剤
JPH0717874A (ja) * 1993-06-18 1995-01-20 Terumo Corp ヘモグロビン内包リポソーム

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60155109A (ja) * 1984-01-23 1985-08-15 Terumo Corp リポソ−ム製剤
EP0354855A2 (fr) * 1988-08-11 1990-02-14 Terumo Kabushiki Kaisha Liposomes dont l'adsorption de protéines sur des surfaces est empêchée
JPH05320043A (ja) * 1992-05-20 1993-12-03 Terumo Corp リポポリサッカライド捕捉剤
JPH06183954A (ja) * 1992-12-24 1994-07-05 Kyowa Hakko Kogyo Co Ltd リポソーム製剤
JPH0717874A (ja) * 1993-06-18 1995-01-20 Terumo Corp ヘモグロビン内包リポソーム

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1938048B (zh) * 2004-03-26 2010-05-12 泰尔茂株式会社 脂质体制剂
JP4833836B2 (ja) * 2004-03-26 2011-12-07 テルモ株式会社 リポソーム製剤
US8241663B2 (en) 2004-03-26 2012-08-14 Terumo Kabushiki Kaisha Liposome preparation
WO2005092388A1 (fr) * 2004-03-26 2005-10-06 Terumo Kabushiki Kaisha Preparation de liposome
JP2006104069A (ja) * 2004-09-30 2006-04-20 Terumo Corp ヘモグロビン含有リポソームの製造方法および包装体
US8916197B2 (en) 2005-06-06 2014-12-23 The Board Of Regents Of The University Of Texas System Bone marrow-directing drug delivery materials and their applications
WO2006132388A1 (fr) * 2005-06-06 2006-12-14 Waseda University Materiaux de delivrance de medicament a la moelle osseuse et leurs applications
WO2009114959A1 (fr) * 2008-03-20 2009-09-24 中国人民解放军军事医学科学院毒物药物研究所 Formulation pharmaceutique injectable à libération prolongée et procédé de préparation associé
WO2009115053A1 (fr) * 2008-03-20 2009-09-24 中国人民解放军军事医学科学院毒物药物研究所 Formulation pharmaceutique injectable à libération prolongée et son procédé de préparation
WO2013047263A1 (fr) * 2011-09-28 2013-04-04 テルモ株式会社 Liposome contenant de l'hémoglobine et son procédé de production
CN103796668A (zh) * 2011-09-28 2014-05-14 泰尔茂株式会社 含有血红蛋白的脂质体及其制造方法
JPWO2013047263A1 (ja) * 2011-09-28 2015-03-26 テルモ株式会社 ヘモグロビン含有リポソーム及びその製法
CN103796668B (zh) * 2011-09-28 2016-12-28 泰尔茂株式会社 含有血红蛋白的脂质体及其制造方法
WO2024080371A1 (fr) 2022-10-14 2024-04-18 積水メディカル株式会社 Agent raccourcissant le temps de coagulation sanguine d'un échantillon de sang défaillant en facteur de coagulation ｘｉｉ
WO2024080372A1 (fr) 2022-10-14 2024-04-18 積水メディカル株式会社 Agent modifiant le temps de coagulation sanguine d'un échantillon de sang défaillant en facteur de coagulation ｖｉｉｉ, ｉｘ ou ｘｉ, et réactif pour mesure du temps de thromboplastine partielle activée
WO2024080373A1 (fr) 2022-10-14 2024-04-18 積水メディカル株式会社 Réactif pour mesure du temps de thromboplastine partielle activée, et agent modifiant le temps de coagulation sanguine d'un échantillon de sang positif à l'anticoagulant lupique ou d'un échantillon de sang à teneur en héparine

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