WO1991014423A1 - Preparation a base de liposomes - Google Patents

Preparation a base de liposomes Download PDF

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Publication number
WO1991014423A1
WO1991014423A1 PCT/JP1991/000373 JP9100373W WO9114423A1 WO 1991014423 A1 WO1991014423 A1 WO 1991014423A1 JP 9100373 W JP9100373 W JP 9100373W WO 9114423 A1 WO9114423 A1 WO 9114423A1
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WO
WIPO (PCT)
Prior art keywords
mixture
solvent
liposome
added
ribosome
Prior art date
Application number
PCT/JP1991/000373
Other languages
English (en)
Japanese (ja)
Inventor
Masashi Mukai
Yoshihiro Ishizue
Shinichi Ishikawa
Yuzo Kimura
Original Assignee
Otsuka 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 Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Publication of WO1991014423A1 publication Critical patent/WO1991014423A1/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—Liposomes

Definitions

  • the present invention relates to a ribosome preparation, more particularly, a liposome containing an acidic phospholipid as a membrane component or a neutral phospholipid and an acidic phospholipid as a membrane component while retaining a basic drug.
  • a ribosome preparation more particularly, a liposome containing an acidic phospholipid as a membrane component or a neutral phospholipid and an acidic phospholipid as a membrane component while retaining a basic drug.
  • ribosomes which are closed vesicles that have a bilayer composed mainly of lipids and have an aqueous layer inside, are widely used as biomembrane model substances for research on their physicochemical properties.
  • liposomes can hold a variety of drugs in the inner water layer or membrane, so they are used as a drag carrier, and ribosomes containing the drug are administered intravenously and the drug is confined to a limited site.
  • DDS drug delivery systems
  • ribosomes were small and limited, and it was difficult to hold large amounts of drugs.
  • the structure of the ribosome is stable In many cases, vesicles are destroyed due to aggregation and bonding between liposome particles, and the retained drug leaks to the outer layer, and further, precipitates are formed, and insolubles are precipitated. Is known to occur relatively quickly.
  • the present inventors have also attempted to prepare liposomes holding various basic drugs using various phosphatidylcholines, but have been able to obtain liposomes capable of stably maintaining a sufficient trapping rate. Did not.
  • the present invention relates to a liposome preparation containing a basic drug in a ribosome containing an acidic phospholipid as a membrane component or a neutral phospholipid and an acidic phospholipid as a membrane component.
  • the acidic phospholipid in the present invention is defined more narrowly than ordinary acidic phospholipids, and more specifically, dilauroylphosphatidylglycerol (DLPG) dimyristyl.
  • soybean phosphatidylcholine As the neutral phospholipids in the present invention, soybean phosphatidylcholine, egg yolk phosphatidylcholine, hydrogenated soybean phosphatidylcholine, hydrogenated egg yolk phosphatidylcholine, dimyristylphosphatidylcholine (DMPC) , Dipalmitoylphosphatidylcholine (DPPC), dilauroylphosphatidylcholine (DLPC), distearoylphosphine Natural or synthetic phosphatidyl cholesterol such as atizircolin (DSPC), myristol palmitoyl phosphatidylcholine (MPPC), palmitoyl stearyl phosphatidylcholine (PSPC), dioleoyl phosphatidylcholine (D0PC), etc.
  • DSPC atizircolin
  • MPPC myristol palmitoyl phosphatidylcholine
  • PSPC palmitoyl steary
  • PC soybean phosphatidylethanolamine, egg yolk phosphatidylethanolamine, hydrogenated soybean phosphatidylethanolamine, hydrogenated egg yolk phosphatidylethanolamine, dimiristoylphosphatidylethanolamine Min (DMPE), Dipalmitoylphosphatidylethanolamine (DPPE), Dilauroylphosphatidylethanolamine (DLPE), Distearoylphosphatidylethanolamine (DSPE), Myristylvalmitoylphosphamine Jiruetano Rua Mi emissions (MPPE), Nono.
  • DMPE dimiristoylphosphatidylethanolamine Min
  • DPPE Dipalmitoylphosphatidylethanolamine
  • DLPE Dilauroylphosphatidylethanolamine
  • DSPE Distearoylphosphatidylethanolamine
  • MPPE Myristylvalmitoylphosphamine Jiruetano Rua Mi emissions
  • PE Natural or synthetic phosphatidylethanolamines
  • pSPE Lumitoylstearoylphosphatidylethanolamine
  • DOPE dioleoylphosphatidylethanolamine
  • the liposome membrane of the present invention is formed by using the above-mentioned acidic phospholipid alone as a constituent component, or using the above-mentioned neutral phospholipid and an acidic phospholipid in combination according to a conventional method.
  • the combined ratio of acidic phospholipids is about 0.1 to It is preferably about 100 mol%, preferably about 1 to 90 mol%, and more preferably about 10 to 50 mol%.
  • the K ratio of the basic drug and the acidic phospholipid in the liposome dispersion liquid is about 0.5 to 100 equivalents of the basic drug and preferably about 1 to 6 equivalents of the basic drug. It is preferably about 0 equivalents, more preferably about 1.5 to 20 equivalents.
  • the basic drug to be retained conventionally known ones can be widely used as long as the drug is a basic drug.
  • a basic drug such as carteolol, propoterol, buprenorphine and the like and an acid addition salt thereof.
  • the acid addition salt is not particularly limited and can be appropriately selected from a wide range. Representative examples thereof include, for example, inorganic acid salts such as hydrochloride, sulfate and phosphate, and organic acid salts such as oxalate, maleate and citrate.
  • a ribosome dispersion can also be prepared by mixing and stirring with an aqueous drug solution.
  • the drug aqueous solution to be added can be any one as long as the drug is dissolved, and the amount of the drug aqueous solution to be added can be arbitrarily increased or decreased.
  • the particle size distribution of the liposome dispersion obtained in this manner can be controlled by the ultra-permeable membrane method, for example, using a membrane filter made of polycarbonate. . It is also possible to concentrate using a dialysis membrane.
  • a preservative such as a preservative, an isotonic agent, a buffer, a stabilizer, a solubilizer, and an absorption enhancer are appropriately added to the ribosome dispersion as additives necessary for the formulation design. It can be blended, and if necessary, can be diluted with a liquid or water containing these additives.
  • specific examples of the above additives include preservatives that are effective against fungi and bacteria such as benzalkonium chloride, benzethonium chloride, black hexidine, parabens (methylparaben, ethylparaben, etc.), thimerosal, etc.
  • tonicity agents polyhydric alcohols such as D-mannitol, D-sorbitol, D-xylitol, glycerin, glucose, monetose, sucrose, propylene glycol, and sodium chloride
  • Electrolytes such as aluminum, and stabilizers such as tocopherol, butylhydroxyanisole, butylhydroxytoluene, and ethylenediaminetetranate. (EDTA), cysteine, etc., respectively.
  • the liposomal preparation of the present invention exhibits a high trap rate of the drug, which is not found in conventional liposomal preparations, and is excellent as a ribosome preparation which stably maintains its retention ability. It does not use irritating anionic surfactants such as sodium lauryl sulfate (SDS) and dicetyl phosphate, and is also excellent in that it has virtually no irritation. Things.
  • the preparation of the present invention is highly useful as a pharmaceutical agent such as eye drops, nasal drops, injections and inhalants.
  • lipid powder obtained by adding 10 mol% of DMP G (PG purity of 99% or more) to hydrogenated soybean phosphatidylcholine (PC purity of 90% or more) was added.
  • DMP G PG purity of 99% or more
  • PC purity of 90% or more hydrogenated soybean phosphatidylcholine
  • lipid powder obtained by adding 30 mol% of DPPG (PG purity of 9.9% or more) to DPPC (PC purity of 9.9% or more) in advance, add 0.2% 1% buprenorphine hydrochloride aqueous solution. 9.5 (0.04 mmol) was added, and the mixture was heated at ⁇ 0 to sufficiently swell. After sufficiently stirring with vortex while maintaining the temperature at 70, the mixture was cooled to room temperature to obtain a milky white 0.2% buprenorphine hydrochloride isotonic liposome dispersion.
  • the mixture was stirred at 70 ° C. and cooled to room temperature to obtain a milky white liposome dispersion.
  • the solvent was distilled off under reduced pressure to completely remove the solvent.
  • To the obtained residue was added a 0.05% aqueous solution of propoterol hydrochloride containing 2.3% glycerin (20% (0.03 mimol)), and the mixture was heated at 70 to swell to a sufficient extent. While maintaining the temperature at 70, the mixture was stirred and cooled to room temperature to obtain a milky white ribosome dispersion.
  • the mixture was stirred and cooled to room temperature while keeping at 70 to obtain a milky white liposome dispersion.
  • 0.396 g (0.5 mimol) of DSPC and 0.380 g (0.5 mimol) of DSPG were weighed, and the eggplant type flask was weighed. After dissolving 20 ml of the form in the flask, the solvent was distilled off under reduced pressure to completely remove the solvent. To the resulting residue was added a 0.05% aqueous solution of propoterol hydrochloride (0.03 mimol) containing 2.5% glycerin, and the mixture was heated to 70 to swell to a sufficient extent. While maintaining the temperature at 70, the mixture was stirred and cooled to room temperature to obtain a milky white ribosome dispersion.
  • 0.336 g (0.5 mmol) of DPPE and 0.352 g (0.5 mmol) of DPPG were weighed out, dissolved in Cloth Form 2 in an eggplant-shaped flask, and the solvent was removed. Was distilled off under reduced pressure to completely remove the solvent. The resulting supernatant contains 2.5% glycerin 0.05% proproterol hydrochloride aqueous solution 20 (0.03 mimol) was added, and the mixture was heated to 70 ° C to swell sufficiently. While maintaining the temperature at 70, the mixture was stirred and cooled to room temperature to obtain a milky white ribosome dispersion.
  • 0.368 g (0.5 mmol) of DPPC and 0.352 g (0.5 mmol) of DPPG were weighed, and dissolved in black-mouthed form 20 in an eggplant-shaped flask. Thereafter, the solvent was distilled off under reduced pressure to completely remove the solvent. To the obtained residue was added 20% (0.03 mimol) of an aqueous solution of 2.5% glycerin containing 0.05% glycerol, and the mixture was heated to 70% to fill. Swelled. While maintaining the temperature at 70, the mixture was stirred and cooled to room temperature to obtain a milky white ribosome dispersion.
  • the ribosome preparation of the present invention shows that the amount of the ribosome membrane component in the ribosome dispersion, the types of neutral phospholipids and acidic phospholipids in the ribosome membrane component, and the concentration of the acidic phospholipid are different. It can be seen that even when changed, it shows good drug retention ability.
  • the preparations of Control Examples 5 and 6 using phosphatidylserine and phosphatidic acid, respectively still have a lower trapping rate of carteolol hydrochloride than the drug using the acidic phospholipid of the present invention. It turns out to be insufficient.
  • Test Example 2 shows that the liposome preparation of the present invention prepared by various methods exhibits excellent drug-retaining ability even when the drug is proforceterol hydrochloride.
  • Test Example 3 shows that the liposome preparation of the present invention prepared by various methods shows good drug retention ability even when the drug is buprenorphine hydrochloride.
  • Test example 4 shows that the liposome preparation of the present invention prepared by various methods shows good drug retention ability even when the drug is buprenorphine hydrochloride.
  • Test Example 4 shows that the ribosome preparation of the present invention does not show a decrease in drug retention ability over time and is stable over time.o
  • Example 1 The liposome dispersions obtained in Example 1 and Control Example 1 were subjected to steam sterilization under pressure (121, 40 minutes), and the trapping rate of luteolol was measured. Table 5 shows the results. Five
  • Test Example 5 shows that the ribosome preparation of the present invention does not show a decrease in drug retention ability due to pressurized steam sterilization (121, 40 minutes) and is thermodynamically stable.
  • the liposomal preparation containing the acidic phospholipid of the present invention shows a remarkably high trapping rate for basic drugs as compared with the conventional liposome preparations, It is an excellent ribosome preparation that maintains its retention ability over time and thermodynamically.
  • Example 8 200 of each of the liposome dispersion obtained in Example 8 and the aqueous solution of Control 4 were applied to the thigh of a rat (SD strain, male, weight of about 200 g) in each group of 3 animals per group. injected in muscles, the plasma hydrochloride Bupureno Ruch fin density of each rat (n S / M £) was measured over time. The results obtained are shown in Table 8 as the average value of three rats in each group.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Une préparation à base de liposomes comprend un médicament de base incorporé dans un liposome ayant un constituant de membrane comprenant un phospholipide acide ou un mélange de phospholipides neutres et acides, qui peuvent capturer le médicament de base de manière stable et en quantité suffisante.
PCT/JP1991/000373 1990-03-20 1991-03-20 Preparation a base de liposomes WO1991014423A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/70398 1990-03-20
JP7039890 1990-03-20

Publications (1)

Publication Number Publication Date
WO1991014423A1 true WO1991014423A1 (fr) 1991-10-03

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AU (1) AU7496991A (fr)
WO (1) WO1991014423A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006508990A (ja) * 2002-11-26 2006-03-16 エムシーエス マイクロ キャリア システムズ ゲーエムベーハー 自己形成リン脂質ゲル
JP2007517909A (ja) * 2004-01-14 2007-07-05 ギリアード サイエンシーズ， インコーポレイテッド 薬物送達に有用な脂質ベースの分散物
JP2008500297A (ja) * 2004-05-24 2008-01-10 ポリマン サイエンティフィック イミューンバイオロジッシュ フォーシュング ゲゼルシャフト ミット ベシュレンクテル ファフツング 薬剤送達のリポソーム
US8377479B2 (en) * 2007-09-03 2013-02-19 Nanotherapeutics, Inc. Compositions and methods for delivery of poorly soluble drugs
US20150024035A1 (en) * 2014-07-21 2015-01-22 Kimia Zist Parsian Co Method and system for synthesizing nanocarrier based long acting drug delivery system for methadone
US20150024033A1 (en) * 2013-07-21 2015-01-22 Kimia Zist Parsian Co Method and system for synthesizing nanocarrier based long acting drug delivery system for buprenorphine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5287220A (en) * 1976-01-13 1977-07-20 Battelle Memorial Institute Production of liposome
JPS61194024A (ja) * 1985-02-22 1986-08-28 Kuraray Co Ltd 脂質二重膜組成物およびその製造方法
JPS6296431A (ja) * 1985-08-19 1987-05-02 ザ　ボ−ド　オブ　リ−ジエンツ　ユニバ−シテイ　オブ　テキサス　システム 医薬組成物およびその調製に適した混合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5287220A (en) * 1976-01-13 1977-07-20 Battelle Memorial Institute Production of liposome
JPS61194024A (ja) * 1985-02-22 1986-08-28 Kuraray Co Ltd 脂質二重膜組成物およびその製造方法
JPS6296431A (ja) * 1985-08-19 1987-05-02 ザ　ボ−ド　オブ　リ−ジエンツ　ユニバ−シテイ　オブ　テキサス　システム 医薬組成物およびその調製に適した混合物

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006508990A (ja) * 2002-11-26 2006-03-16 エムシーエス マイクロ キャリア システムズ ゲーエムベーハー 自己形成リン脂質ゲル
JP2007517909A (ja) * 2004-01-14 2007-07-05 ギリアード サイエンシーズ， インコーポレイテッド 薬物送達に有用な脂質ベースの分散物
JP2008500297A (ja) * 2004-05-24 2008-01-10 ポリマン サイエンティフィック イミューンバイオロジッシュ フォーシュング ゲゼルシャフト ミット ベシュレンクテル ファフツング 薬剤送達のリポソーム
US8377479B2 (en) * 2007-09-03 2013-02-19 Nanotherapeutics, Inc. Compositions and methods for delivery of poorly soluble drugs
US9554996B2 (en) 2007-09-03 2017-01-31 Nanotherapeutics, Inc. Compositions and methods for delivery of poorly soluble drugs
US20150024033A1 (en) * 2013-07-21 2015-01-22 Kimia Zist Parsian Co Method and system for synthesizing nanocarrier based long acting drug delivery system for buprenorphine
US9326980B2 (en) * 2013-07-21 2016-05-03 Kimia Zist Parsian (Kzp) Method and system for synthesizing nanocarrier based long acting drug delivery system for buprenorphine
US20150024035A1 (en) * 2014-07-21 2015-01-22 Kimia Zist Parsian Co Method and system for synthesizing nanocarrier based long acting drug delivery system for methadone
US9351932B2 (en) * 2014-07-21 2016-05-31 Kimia Zist Parsian (Kzp) Method and system for synthesizing nanocarrier based long acting drug delivery system for methadone

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Publication number Publication date
AU7496991A (en) 1991-10-21

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