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WO1994011100A1 - Stable aqueous liposome suspension - Google Patents

Stable aqueous liposome suspension Download PDF

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Publication number
WO1994011100A1
WO1994011100A1 PCT/JP1993/001684 JP9301684W WO9411100A1 WO 1994011100 A1 WO1994011100 A1 WO 1994011100A1 JP 9301684 W JP9301684 W JP 9301684W WO 9411100 A1 WO9411100 A1 WO 9411100A1
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WO
WIPO (PCT)
Prior art keywords
liposome suspension
liposome
quaternary ammonium
ammonium salt
sugar alcohol
Prior art date
Application number
PCT/JP1993/001684
Other languages
French (fr)
Japanese (ja)
Inventor
Toshiaki Nakajima
Katsu Nakamori
Mikiko Odawara
Ikuo Koyama
Masami Nemoto
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 AU55335/94A priority Critical patent/AU5533594A/en
Publication of WO1994011100A1 publication Critical patent/WO1994011100A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A61K8/416—Quaternary ammonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to a technique capable of stably storing liposomes even when liposomes are stored in a suspension state.
  • Liposomes are closed vesicles composed of lipid bilayer membranes and are excellent in biocompatibility. I have. However, liposomes are often colloidally unstable in suspension, and when ribosomes are stored in suspension for a long period of time, aggregation and fusion of liposome particles and membrane components may occur. Precipitation was generated by crystallization, and the particle size was increased. This reduced the efficacy of the drug held by the liposome and changed the appearance of the liposome, resulting in a loss of commercial value.
  • the present inventors have conducted intensive studies and found that when sugar alcohol and a quaternary ammonium salt are blended into a liposome suspension, only the sugar alcohol or only the quaternary ammonium salt is added to the ribosome.
  • the present inventors have found that the above-mentioned problems that could not be solved when blended into a suspension can be solved, and thus completed the present invention.
  • the present invention provides that sugar alcohol and a quaternary ammonium salt are blended. Characterized liposome suspension.
  • sugar alcohols include mannitol, sorbitol, xylitol, maltitol, etc., of which mannitol is particularly preferred.
  • the compounding amount of these sugar alcohols is 0.7 to 7.5% by weight, preferably 1.5 to 4.5% by weight based on the total amount of the preparation.
  • the quaternary ammonium salts include benzalkonium chloride and benzennium chloride, and among them, benzalkonium chloride is preferred.
  • the blending amount of the talin is 0.5 to 5.0% by weight.
  • the liposome suspension of the present invention can be prepared, for example, as follows. That is, after dissolving the membrane components of the liposome in an organic solvent and distilling off the organic solvent, the resulting lipid membrane is converted into a sugar alcohol and a quaternary ammonium salt (and, if necessary, a cellulose).
  • the aqueous solution may be hydrated at a temperature not lower than the phase transition temperature of the lipid membrane, but is not particularly limited to this method.
  • the above-mentioned membrane components include hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dimyristo inolev, sphage dimerecolin, and zino.
  • Examples include norremyinolephos fattidinorecoline, distearylfosfate zircoline, phosphatidyleethanol noramine, and sphingoline.
  • a film stabilizer is not particularly required, cholesterol or the like may be added.
  • the amount of these membrane components to be used is generally 0.005 to 0.025 parts by weight, preferably 0.001 to 0.008 parts by weight, per 1 part by weight of water.
  • organic solvent chloroform, dichloromethane and the like can be used.
  • the pH of the liposome suspension it is desirable to adjust the pH of the liposome suspension to around neutral (6.0 to 7.4) with sodium hydroxide, a hydration power rim, or the like. .
  • a polycarbonate membrane filter may be used.
  • the particle size distribution may be controlled using a single or high pressure injection type homogenizer.
  • the liposome suspension of the present invention may contain, if necessary, a preservative (eg, methyl para-hydroxybenzoate, methyl para-hydroxybenzoate, propyl para-hydroxybenzoate), an anti-histamine, etc.
  • Agents for example, difundenhydramine hydrochloride, isotipendyl hydrochloride, chlorfuramide maleate
  • vitamins for example, vitamin A and its ester, active form B) 2, Vita Mi emissions B 2, Vita Mi emissions B 6, Vita Mi emissions B i 2, such as Vita Mi emissions E and S.
  • polymeric additives e.g. port re ethylene les ring recall, port Li Byuruaruko over , Polybutylpyrrolidone, hydroxyshethylcellulose, hydroxypropylmethylcellulose, etc.
  • tonicity agents eg, sodium chloride, lithium chloride, etc.
  • the drug can be retained in the liposome suspension of the present invention.
  • the drug to be retained is not particularly limited.
  • the drug is a sugar alcohol or a quaternary drug. It may be dissolved in an aqueous solution containing an ammonium salt and added to the lipid membrane and hydrated.
  • the drug and the membrane component are dissolved in a solvent such as porcine orifice and the solvent is distilled off Thereafter, hydration may be performed with an aqueous solution containing a sugar alcohol and a quaternary ammonium salt.
  • the ribosome suspension of the present invention includes topical preparations such as eye drops, eye drops, mouthwashes, transdermal preparations such as dermatological preparations, oral preparations such as suspensions, bath preparations, and bath preparations. It can be used as cosmetics such as short-cuts, but is preferably applied in drops or nose drops o
  • Dimyristyl phosphatid Zircoline 200 mg and fat-soluble drug vitamin E-acetate 5 O mg were taken in Nasco. After dissolving in 1, the chloroform was sufficiently distilled off. To this was added 10 ml of a 4.5% aqueous solution of mannitol, the pH of which was adjusted to 6.5 with sodium hydroxide, and the mixture was added to 40 to 50. After hydration with C, the sample is subjected to pressure filtration once with a 0.2 ⁇ m polycarbonate membrane and once with a 0.1 / m polycarbonate membrane. Jing was performed.
  • Example 3 Same as Example 1 except that dipalmitoylphosphatidylzircoline 200 mg was used instead of dimyristylphosphatidylzircoline 200 mg as a membrane component. Thus, a liposome suspension was prepared. However, a mixed aqueous solution of 3.5% mannitol and 1% taurine was used as the hydration solution.
  • Example 3
  • Liposome suspension was performed in the same manner as in Example 1 except that 200 mg of hydrogenated soybean lecithin was used in place of 200 mg of dimyristyl phosphatid zirconine as a membrane component. A liquid was prepared. However, hydration and sizing were performed at 60-70 ° C. Example 4
  • a liposome suspension was prepared in the same manner as in Example 3, except that 200 mg of hydrogenated egg yolk lecithin was used instead of 200 mg of hydrogenated soybean lecithin as a membrane component.
  • Example 5
  • a liposome suspension was prepared in the same manner as in Example 3 except that a 3.3% mannitol aqueous solution and a 1% taurine aqueous solution were used instead of the 4.5% mannitol aqueous solution.
  • Example 7
  • Liposome was prepared in the same manner as in Example 1 except that 0.05% (w / v) of benzene was used instead of 0.05% (w / v) of benzalkonium chloride. A suspension was prepared.
  • a liposome suspension was prepared in the same manner as in Example 3, except that a 4.5% aqueous sorbitol solution was replaced with a 4.5% aqueous sorbitol solution.
  • a liposome suspension was prepared in the same manner as in Example 1 except that benzalkonium chloride was not added. Control 2
  • a liposome suspension was prepared in the same manner as in Example 1 except that physiological saline was used instead of the 4.5% aqueous mannitol solution.
  • Test example 1
  • Example 1 The liposome suspensions of Example 1, Control Example 1 and Control Example 2 were put into an sample, stored at 40 ° C, and observed for changes in appearance. The particle size was measured by an isher. The results are shown in Table 1.
  • Example 1 No aggregation, no sedimentation, +: Aggregation, particle size unit is nm, average value
  • the liposome suspension of Example 1 did not aggregate liposomes. No precipitation or change in particle size was observed However, the ribosome suspension of Control Example 1 had more aggregation and a larger particle size than the case of Example 1.

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Abstract

To provide a stable liposome suspension which does not cause precipitation, coagulation or particle size change and is reduced in the formation of the lyso form. A liposome suspension containing a sugar alcohol and a quaternary ammonium salt.

Description

明 細 書  Specification
安定な リポソーム水性懸濁液  Stable aqueous liposome suspension
技術分野 Technical field
本発明はリポソ一ムを懸濁液の状態で保存してもリ ポソームを安定に保存でき る技術に関する。  The present invention relates to a technique capable of stably storing liposomes even when liposomes are stored in a suspension state.
醫  Doctor
リポソームは脂質二分子膜よりなる閉鎖小胞であり、 生体適合性に優れている ため、 その内水相または膜中に種々の薬物を保持させて ドラ ッグキヤ リア一とし て用いる試みが数多くなされている。 しかしながらリポソ一ムは懸濁液の状態で はコロイ ド化学的に不安定な場合が多く、 長期間リボソームを懸濁液の状態で保 存すると、 リ ボソーム粒子同士の凝集や融合、 膜成分の結晶化による沈殿の生成、 粒子径の増大などがおこ り、 リポソ一ムに保持させる薬物の効力の低下やリ ポソ ームの外観変化をまねいて商品価値の損失を起こしゃすかった。  Liposomes are closed vesicles composed of lipid bilayer membranes and are excellent in biocompatibility. I have. However, liposomes are often colloidally unstable in suspension, and when ribosomes are stored in suspension for a long period of time, aggregation and fusion of liposome particles and membrane components may occur. Precipitation was generated by crystallization, and the particle size was increased. This reduced the efficacy of the drug held by the liposome and changed the appearance of the liposome, resulting in a loss of commercial value.
そのため、 リポソ一ムを使用する場合は懸濁液のまま保存する方法ではなく、 凍結乾燥等の手段により用時溶解して用いる方法が主流であり、 リボソームを懸 濁液のまま保存するための安定化技術の検討例は少なかった。  For this reason, when using liposomes, instead of storing them as suspensions, the mainstream method is to use and dissolve them at the time of use by freeze-drying or other means. There were few studies on stabilization technology.
前記検討例の一つとして、 多価アルコ ール及び/または糖類を配合してリポソ ーム懸濁液を安定化させる方法が報告されている （特開昭 6 4— 3 1 1 4 ) 。  As one of the above-mentioned examination examples, there has been reported a method of stabilizing a liposome suspension by blending a polyhydric alcohol and / or a saccharide (Japanese Patent Application Laid-Open No. S64-31114).
しかしながら、 上記技術で解決したのは室温以下の保存温度での安定性の点で あり、 高温に保存された時の安定性や、 溶血性があるといわれている リゾ体の生 成抑制の点については不十分であった。  However, the above technology solved the problem of stability at a storage temperature below room temperature, and the stability at the time of storage at a high temperature and the suppression of the production of lyso bodies, which are said to be hemolytic. Was insufficient.
本発明の目的は、 4 0 °Cの保存でも 6 ヶ月間、 沈殺や凝集、 粒子怪変化がなく、 またリゾ体の生成も少ない安定なリポソ一ム懸濁液を提供することにある。  It is an object of the present invention to provide a stable liposome suspension which is free from sedimentation, aggregation, and particle change for 6 months even when stored at 40 ° C., and generates less lyso-form.
発明の開示 Disclosure of the invention
本発明者らは鋭意研究した結果、 糖アルコール及び第 4級ア ンモニ ゥ ム塩をリ ポソ一ム懸濁液に配合すると、 糖アルコ ールのみあるいは第 4級ア ンモニゥム塩 のみをリ ボソーム懸濁液に配合した場合には解決できなかつた上記課題を解決で きることを見いだし、 本発明を完成した。  The present inventors have conducted intensive studies and found that when sugar alcohol and a quaternary ammonium salt are blended into a liposome suspension, only the sugar alcohol or only the quaternary ammonium salt is added to the ribosome. The present inventors have found that the above-mentioned problems that could not be solved when blended into a suspension can be solved, and thus completed the present invention.
すなわち、 本発明は糖ァルコール及び第 4級ア ンモニゥム塩を配合したことを 特徴とする リポソーム懸濁液である。 That is, the present invention provides that sugar alcohol and a quaternary ammonium salt are blended. Characterized liposome suspension.
本発明において、 糖アルコールとはマ ンニ トール、 ソ ルビ ト ール、 キ シ リ トー ル、 マルチ トールなどであり、 このうちマンニ トールが特に好ま しい。 これら糖 アルコールの配合量は製剤全量に対して 0. 7〜7. 5重量％であり、 好ま しく は 1. 5 ~ 4. 5重量％である。  In the present invention, sugar alcohols include mannitol, sorbitol, xylitol, maltitol, etc., of which mannitol is particularly preferred. The compounding amount of these sugar alcohols is 0.7 to 7.5% by weight, preferably 1.5 to 4.5% by weight based on the total amount of the preparation.
また、 第 4級ア ンモニ ゥ ム塩とは塩化ベンザルコ ニ ゥ ム、 塩化べンゼ ト ニ ゥ ム などであり、 このうち塩化ベンザルコ ニゥムが好ま しい。 これら第4級ア ンモニ ゥ ム塩の 82合量は、 リ ボ ソームの膜成分 （後述） に対して 0. 0 5〜2 .0モル％、 好ま しく は 2〜 8 モル％である。 Also, the quaternary ammonium salts include benzalkonium chloride and benzennium chloride, and among them, benzalkonium chloride is preferred. 82 total content of the fourth Kyua Nmoni © beam salt, 0.0 5 to 2.0 mol% relative to Li Bo endosomal membrane components (described later), is favored properly is 2-8 mol%.
また、 本発明においては、 タウ リ ンを併せて E合するとより優れた効果が得ら れて好ま しい。 この場合、 前記タゥ リ ンの配合量は、 0. 5 ~ 5. 0重量％であ る o  Further, in the present invention, it is preferable that taurine is combined with E to obtain more excellent effects. In this case, the blending amount of the talin is 0.5 to 5.0% by weight.
本発明のリポソ ーム懸濁液は例えば次にようにして調製することができる。 すなわち リポソ一ムの膜成分を有機溶媒に溶解し、 有機溶媒を留去した後、 生成 した脂質膜を、 糖アルコ ール及び第 4級ア ンモニゥム塩 （並びに必要に応じてタ ゥ リ ン） 含有水溶液で脂質膜の相転移温度以上で水和すればよいが、 特にこ の方 法に限定されるわけではない。  The liposome suspension of the present invention can be prepared, for example, as follows. That is, after dissolving the membrane components of the liposome in an organic solvent and distilling off the organic solvent, the resulting lipid membrane is converted into a sugar alcohol and a quaternary ammonium salt (and, if necessary, a cellulose). The aqueous solution may be hydrated at a temperature not lower than the phase transition temperature of the lipid membrane, but is not particularly limited to this method.
上記膜成分としては水素添加大豆レシチ ン、 水素添加卵黄レ シチ ン、 ジミ リ ス ト イ ノレフ 才 ス フ ァ チ ジメレコ リ ン、 ジノ、。ノレ ミ ト イ ノレフ ォ ス ファチジノレコ リ ン、 ジス テア ロ イ ルフ ォ ス フ ァ チ ジルコ リ ン、 ホ ス フ ァ チ ジルエタ ノ ールァ ミ ン、 ス フ ィ ンゴミ ヱ リ ンなどを挙げることができる。 膜安定化剤は特に必要ないがコレステ ロール等を入れても構わない。 これらの膜成分の使用量は、 通常水 1重量部に対 し 0. 0 0 0 5〜0. 0 2 5重量部好ま しく は 0. 0 0 1〜0. 0 0 8重量部で ある。  The above-mentioned membrane components include hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dimyristo inolev, sphage dimerecolin, and zino. Examples include norremyinolephos fattidinorecoline, distearylfosfate zircoline, phosphatidyleethanol noramine, and sphingoline. Although a film stabilizer is not particularly required, cholesterol or the like may be added. The amount of these membrane components to be used is generally 0.005 to 0.025 parts by weight, preferably 0.001 to 0.008 parts by weight, per 1 part by weight of water.
また、 有機溶媒としてはクロ口ホルム、 ジク ロルメ タ ンなどを用いることがで きる。  Further, as the organic solvent, chloroform, dichloromethane and the like can be used.
本発明においてはリポソ一ムの懸濁液の p Hを水酸化ナ ト リ ウ ム、 水酸化力 リ ゥ ム等で中性付近 （ 6. 0〜7. 4 ) に調整することが望ま しい。  In the present invention, it is desirable to adjust the pH of the liposome suspension to around neutral (6.0 to 7.4) with sodium hydroxide, a hydration power rim, or the like. .
また、 本発明においては必要に応じてポリカーボネ一 ト製メ ンブラ ンフィルタ 一や高圧噴射型ホモジナイザ一を用いて粒径分布をコ ン トロールしてもよい。 本発明のリポソ 一ム懸濁液には必要に応じて防腐剤 （例えばパラォキシ安息香 酸メ チル、 パラ ォキ シ安息香酸ヱチル、 パラ ォキ シ安息香酸プロ ピルなど） 、 抗 ヒ ス タ ミ ン剤 （例えば塩酸ジフ ユ ン ヒ ド ラ ミ ン、 塩酸イ ソチペ ン ジル、 マ レイ ン 酸クロルフ ヱ ユラ ミ ンな ど） 、 ビタ ミ ン類 （例えばビタ ミ ン A及びそのエス テル、 活性型 B 2、 ビタ ミ ン B 2、 ビタ ミ ン B 6、 ビタ ミ ン B i 2、 ビタ ミ ン E及びそのエス テルなど） 、 高分子添加剤 （例えばポ リ エチ レ ング リ コール、 ポ リ ビュルアルコ ール、 ポ リ ビュル ピロ リ ドン、 ヒ ドロキ シェチルセルロース、 ヒ ドロ キ シプロ ピ ルメ チルセルロースなど） 、 等張化剤 （例えば塩化ナ ト リ ウ ム、 塩化力 リ ウ ムな ど） などを本発明の効果を損なわない範囲内で添加してもよい。 In the present invention, if necessary, a polycarbonate membrane filter may be used. The particle size distribution may be controlled using a single or high pressure injection type homogenizer. The liposome suspension of the present invention may contain, if necessary, a preservative (eg, methyl para-hydroxybenzoate, methyl para-hydroxybenzoate, propyl para-hydroxybenzoate), an anti-histamine, etc. Agents (for example, difundenhydramine hydrochloride, isotipendyl hydrochloride, chlorfuramide maleate), vitamins (for example, vitamin A and its ester, active form B) 2, Vita Mi emissions B 2, Vita Mi emissions B 6, Vita Mi emissions B i 2, such as Vita Mi emissions E and S. ether), polymeric additives (e.g. port re ethylene les ring recall, port Li Byuruaruko over , Polybutylpyrrolidone, hydroxyshethylcellulose, hydroxypropylmethylcellulose, etc.) and tonicity agents (eg, sodium chloride, lithium chloride, etc.). Effect of the invention It may be added within a range that does not impair the.
本発明のリポソーム懸濁液には薬物を保持させることもできるが、 薬物を保持 させる場合、 保持させる薬物と しては特に制限はなく、 水溶性薬物の場合は薬物 を糖アルコール及び第 4級ア ンモユウム塩含有水溶液に溶解して脂質膜に加え、 水和させればよく、 油溶性薬物の場合は薬物と膜成分とをク口口ホルムなどの溶 媒に溶解し、 溶媒を留去した後、 糖アルコール及び第 4級ア ンモニゥ ム塩含有水 溶液で水和すればよい。  The drug can be retained in the liposome suspension of the present invention. However, when the drug is retained, the drug to be retained is not particularly limited. In the case of a water-soluble drug, the drug is a sugar alcohol or a quaternary drug. It may be dissolved in an aqueous solution containing an ammonium salt and added to the lipid membrane and hydrated.In the case of an oil-soluble drug, the drug and the membrane component are dissolved in a solvent such as porcine orifice and the solvent is distilled off Thereafter, hydration may be performed with an aqueous solution containing a sugar alcohol and a quaternary ammonium salt.
本発明のリボソーム懸濁液は、 点眼剤、 点募剤、 含嗽洗口剤などの局所投与製 剤、 皮膚用剤などの経皮投与製剤、 懸濁剤などの経口投与製剤、 入浴剤、 ロー シ ヨ ンなどの化粧品として用いることができるが、 好ま しく は点願剤、 点鼻剤であ る o  The ribosome suspension of the present invention includes topical preparations such as eye drops, eye drops, mouthwashes, transdermal preparations such as dermatological preparations, oral preparations such as suspensions, bath preparations, and bath preparations. It can be used as cosmetics such as short-cuts, but is preferably applied in drops or nose drops o
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下、 実施例及び試験例を挙げて、 本発明を更に詳細に説明する。  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
実施例 1 Example 1
ジ ミ リ ス ト ィ ルフ ォ ス フ ァ チ ジルコ リ ン 2 0 0 m g と脂溶性の薬物である ビタ ミ ン E ァセテ一ト 5 O m gをナ スフ ラ ス コ にとりク ロ 口ホルム 5 0 m 1 に溶解し た後クロ 口ホルムを充分に留去した。 これに水酸化ナ ト リ ウムで p Hを 6 . 5 に 調整した 4 . 5 %マ ンニ トール水溶液を 1 0 m 1加え、 4 0〜5 0。Cで水和した 後、 0 . 2〃 mのポ リ カ ーボネー ト製メ ンブラ ンで 1 回， 0 . 1 / mのポ リ カー ボネー ト製メ ンブラ ンで 1 回加圧瀘過によるサイ ジン グを行った。 こ の う ち、 5 m 1 をと り、 塩化ベンザルコ ニ ゥ ムを最終的に 0. 0 0 5 % (WZV) (膜成分 に対して 5モル％) となるように加え、 更に p H 6. 5の 4. 5 %マ ンニ ト ール 水溶液を加えて、 全量 5 0 m l の リ ボソ ーム懸濁液を調製した。 実施例 2 Dimyristyl phosphatid Zircoline 200 mg and fat-soluble drug vitamin E-acetate 5 O mg were taken in Nasco. After dissolving in 1, the chloroform was sufficiently distilled off. To this was added 10 ml of a 4.5% aqueous solution of mannitol, the pH of which was adjusted to 6.5 with sodium hydroxide, and the mixture was added to 40 to 50. After hydration with C, the sample is subjected to pressure filtration once with a 0.2〃m polycarbonate membrane and once with a 0.1 / m polycarbonate membrane. Jing was performed. Of these, 5 m 1, benzalkonium chloride was added to a final concentration of 0.05% (WZV) (5 mol% based on membrane components), and a pH of 4.5 and 4.5 was added. A 50% aqueous solution of mannitol was added to prepare a total of 50 ml of ribosome suspension. Example 2
膜成分としてジミ リ ス ト イ ルフ ォ スフ ァチジルコ リ ン 2 0 0 m gの代わりにジ パル ミ ト イ ルフ ォ ス フ ァ チ ジルコ リ ン 2 0 0 m gを用いた他は実施例 1 と同様に してリポソ一ム懸濁液を調製した。 ただし、 水和液には 3. 5 %マ ンニ トール及 び 1 %タ ウ リ ンの混合水溶液を用いた。 実施例 3  Same as Example 1 except that dipalmitoylphosphatidylzircoline 200 mg was used instead of dimyristylphosphatidylzircoline 200 mg as a membrane component. Thus, a liposome suspension was prepared. However, a mixed aqueous solution of 3.5% mannitol and 1% taurine was used as the hydration solution. Example 3
膜成分としてジ ミ リ ス ト イ ルフ ォ スフ ァ チ ジルコ リ ン 2 0 0 m gの代わりに水 素添加大豆レシチ ン 2 0 0 m gを用いた他は実施例 1 と同様にしてリ ポソーム懸 濁液を調製した。 ただし、 水和とサイ ジ ングは 6 0〜 7 0 °Cで行った。 実施例 4  Liposome suspension was performed in the same manner as in Example 1 except that 200 mg of hydrogenated soybean lecithin was used in place of 200 mg of dimyristyl phosphatid zirconine as a membrane component. A liquid was prepared. However, hydration and sizing were performed at 60-70 ° C. Example 4
膜成分として水素添加大豆レ シチ ン 2 0 0 m gの代わりに水素添加卵黄レ シチ ン 2 0 0 m gを用いた他は実施例 3 と同様にしてリポソーム懸濁液を調製した。 実施例 5  A liposome suspension was prepared in the same manner as in Example 3, except that 200 mg of hydrogenated egg yolk lecithin was used instead of 200 mg of hydrogenated soybean lecithin as a membrane component. Example 5
膜成分として水素添加大豆レ シチ ン 2 0 0 m gの代わり に水素添加大豆レ シチ ン 2 0 0 m g及びコ レス テロール 5 O m gを用いた他は実施例 3 と同様にしてリ ポソーム懸濁液を調製した。 実施例 6  Liposome suspension in the same manner as in Example 3 except that 200 mg of hydrogenated soybean lecithin and 200 mg of cholesterol were used instead of 200 mg of hydrogenated soybean lecithin as a membrane component Was prepared. Example 6
4. 5 %マ ンニ トール水溶液の代わりに 3. 3 %マ ンニ トール水溶液及び 1 % タ ゥ リ ン水溶液を用いた他は実施例 3 と同様にしてリ ポソーム懸濁液を調製した。 実施例 7 A liposome suspension was prepared in the same manner as in Example 3 except that a 3.3% mannitol aqueous solution and a 1% taurine aqueous solution were used instead of the 4.5% mannitol aqueous solution. Example 7
塩化べンザルコ ニゥ ム 0 . 0 0 5 % ( W/ V ) の代わりに塩化べンゼ ト ニ ゥ ム 0 . 0 0 5 % ( W / V ) を用いた他は実施例 1 と同様にしてリポソ一ム懸濁液を 調製した。 実施例 8  Liposome was prepared in the same manner as in Example 1 except that 0.05% (w / v) of benzene was used instead of 0.05% (w / v) of benzalkonium chloride. A suspension was prepared. Example 8
4 . 5 %マ ンニ トール水溶液の代わりに 4 . 5 %ソ ルビトール水溶液を用いた 他は実施例 3 と同様にしてリポソーム懸濁液を調製した。 対照例 1  A liposome suspension was prepared in the same manner as in Example 3, except that a 4.5% aqueous sorbitol solution was replaced with a 4.5% aqueous sorbitol solution. Control Example 1
実施例 1 において、 塩化ベンザルコ二ゥ ムを添加しなかった他は実施例 1 と同 様にして リポソーム懸濁液を調製した。 対照例 2  A liposome suspension was prepared in the same manner as in Example 1 except that benzalkonium chloride was not added. Control 2
実施例 1 において、 4 . 5 %マ ンニ ト ール水溶液の代わりに生理食塩水を用い た他は実施例 1 と同様にしてリポソ一ム懸濁液を調製した。 試験例 1  A liposome suspension was prepared in the same manner as in Example 1 except that physiological saline was used instead of the 4.5% aqueous mannitol solution. Test example 1
実施例 1、 対照例 1及び対照例 2 の リ ボソーム懸濁液をア ンプルに入れ 4 0 °C に保存して外観変化を観察し、 同時に光散乱法に基づくサブミ ク ロ ンパーティ ク ルアナ ラ イ ザ一により粒径を測定した。 その結果を表 1 に示す。 The liposome suspensions of Example 1, Control Example 1 and Control Example 2 were put into an sample, stored at 40 ° C, and observed for changes in appearance. The particle size was measured by an isher. The results are shown in Table 1.
保存期間 （月） 開始時 1 2 3 6 Retention period (month) At the start 1 2 3 6
外観 - 一 ―  Appearance-one-
室施例 1  Room example 1
粒径 1 2 1 1 2 6 1 3 0 1 2 5 1 2 9  Particle size 1 2 1 1 2 6 1 3 0 1 2 5 1 2 9
外観 + +  Appearance + +
対照例 1  Control Example 1
粒径 1 3 1 1 5 0 3 1 2 6 8 7 1 0 9 6  Particle size 1 3 1 1 5 0 3 1 2 6 8 7 1 0 9 6
外観 + + + +  Appearance + + + +
対照例 2  Control 2
粒径 1 3 5 1 5 0 2 1 0 3 5 0 1 6 8 0  Particle size 1 3 5 1 5 0 2 1 0 3 5 0 1 6 8 0
注） 一 ： 凝集、 沈截なし， + ：凝集あり， 粒径の単位は n mで平均値 実施例 1 のリポソ一ム懸濁液ではリポソームの凝集 .沈殿や粒径の変化も認め られなかったが、 対照例 1 のリボソーム懸濁液では実施例 1の場合に比べ、 凝集 も多く粒径も大き くなつた。  Note) 1: No aggregation, no sedimentation, +: Aggregation, particle size unit is nm, average value The liposome suspension of Example 1 did not aggregate liposomes. No precipitation or change in particle size was observed However, the ribosome suspension of Control Example 1 had more aggregation and a larger particle size than the case of Example 1.
産業上の利用可能性 Industrial applicability
本発明により、 高温保存でも長期間安定で、 かつリ ボソームが加水分解してリ ゾ体を生じることの少ないリポソーム懸濁液を提供することが可能となつた。  According to the present invention, it has become possible to provide a liposome suspension that is stable for a long period of time even when stored at high temperature, and that is less likely to hydrolyze ribosomes to form lysosomes.

Claims

( 1 ) 糖アルコール及び第 4級ァンモユウム塩を E合したリ ボソーム懸濁液。 (1) Libosome suspension obtained by combining sugar alcohol and quaternary ammonium salt.
( 2 ) 第 4級ア ンモニゥム塩が塩化ベンザルコニゥムである請求の範囲 （ 1 ) 記 載のリ ポ ソ一ム懸濁液。  (2) The liposome suspension according to (1), wherein the quaternary ammonium salt is benzalkonium chloride.
( 3 ) 糖アルコールがマ ンニ ト ールである請求の範囲 （ 1 ) 記載のリ ボソーム懸 濁液。  (3) The ribosome suspension according to claim (1), wherein the sugar alcohol is mannitol.
( 4 ) 糖アルコールがマ ン- トールであり、 第 4級ア ンモニゥ ム塩が塩化べンザ ルコニゥ ムである請求の範囲 （ 1 ) 記載のリ ボソーム懸濁液。  (4) The ribosome suspension according to claim (1), wherein the sugar alcohol is mannitol, and the quaternary ammonium salt is benzylconium chloride.
( 5 ) 糖アルコールの E合量が製剤全量に対して 0. 7 ~ 7. 5重量％であ り、 第 4級ァンモユウム塩の配合量がリポソ一ムの膜成分に対して 0. 0 5〜2 0モ ル％である請求の範囲 （ 1 ) 記載のリ ボ ソーム懸濁液。  (5) The total E content of the sugar alcohol is 0.7 to 7.5% by weight based on the total weight of the preparation, and the content of the quaternary ammonium salt is 0.05 to the membrane component of the liposome. The liposome suspension according to claim 1, wherein the liposome suspension is at most 20 mol%.
( 6 ) 製剤の p Hが 6. 0〜7. 4である請求の範囲 （ 1 ) 記載のリ ボソーム懸 濁液。  (6) The liposome suspension according to (1), wherein the pH of the preparation is 6.0 to 7.4.
( 7 ) 糖アルコール、 第 4級ァンモユウム塩及び夕ゥ リ ンを配合したリポソーム 懸濁液。  (7) A liposome suspension containing a sugar alcohol, a quaternary ammonium salt, and evening phosphorus.
( 8 ) 糖アルコールがマ ン - ト 一ルであり、 第 4級ァンモニゥ ム塩が塩化べンザ ルコニゥ ムである請求の範囲 （ 7 ) 記載のリボソーム懸濁液。  (8) The ribosome suspension according to claim (7), wherein the sugar alcohol is mantol and the quaternary ammonium salt is benzylconium chloride.
( 9 ) 糖アルコールの 合量が製剤全量に対して 0. 7〜 7. 5重量％であり、 第 4級ァンモユウム塩の配合量がリポソ ームの膜成分に対して 0. 0 5〜 2 0モ ル％であり、 タウ リ ンの E合量が製剤全量に対して 0. 5 ~ 5. 0重量％である 請求の範囲 （ 7 ) 記載のリポソ一ム懸濁液。  (9) The combined amount of the sugar alcohol is 0.7 to 7.5% by weight based on the total amount of the preparation, and the blended amount of the quaternary ammonium salt is 0.05 to 2% based on the membrane component of the liposome. The liposome suspension according to claim 7, wherein the total amount of taurine is 0.5 to 5.0% by weight based on the total amount of the preparation.
( 1 0 ) 製剤の 11が6. 0〜 7. 4である請求の範囲 （ 7 ) 記載のリ ボソ ーム 懸濁液。  (10) The ribosome suspension according to (7), wherein 11 of the preparation is 6.0 to 7.4.
PCT/JP1993/001684 1992-11-18 1993-11-17 Stable aqueous liposome suspension WO1994011100A1 (en)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
FR2734159A1 (en) * 1995-05-17 1996-11-22 Nicolas Francois Michel Compsn. to treat external eye ailments based on sugar, pref. sucrose
EP0799615A4 (en) * 1994-12-19 1999-03-10 Taisho Pharmaceutical Co Ltd DROPS OF EYE DROPS WITH LIPOSOMES
US6316483B1 (en) 1994-02-03 2001-11-13 Schering Corporation Oxymetazoline HCI and/or chlorpheniramine maleate nasal spray compositions
US6890555B1 (en) * 1992-02-05 2005-05-10 Qlt, Inc. Liposome compositions of porphyrin photosensitizers

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JPS60255141A (en) * 1984-05-31 1985-12-16 Shiseido Co Ltd Manufacture of bimolecular film endoplasmic reticulum
JPS62152531A (en) * 1985-12-26 1987-07-07 Dai Ichi Seiyaku Co Ltd Preparation of liposome

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
JPS60255141A (en) * 1984-05-31 1985-12-16 Shiseido Co Ltd Manufacture of bimolecular film endoplasmic reticulum
JPS62152531A (en) * 1985-12-26 1987-07-07 Dai Ichi Seiyaku Co Ltd Preparation of liposome

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6890555B1 (en) * 1992-02-05 2005-05-10 Qlt, Inc. Liposome compositions of porphyrin photosensitizers
US7135193B2 (en) 1992-02-05 2006-11-14 Qlt, Inc. Liposome compositions of porphyrin photosensitizers
US6316483B1 (en) 1994-02-03 2001-11-13 Schering Corporation Oxymetazoline HCI and/or chlorpheniramine maleate nasal spray compositions
US6824762B2 (en) 1994-02-03 2004-11-30 Schering-Plough Healthcare Products Inc. Nasal spray compositions
EP0799615A4 (en) * 1994-12-19 1999-03-10 Taisho Pharmaceutical Co Ltd DROPS OF EYE DROPS WITH LIPOSOMES
US5945121A (en) * 1994-12-19 1999-08-31 Taisho Pharmaceutical Co., Ltd. Liposome eye drops
FR2734159A1 (en) * 1995-05-17 1996-11-22 Nicolas Francois Michel Compsn. to treat external eye ailments based on sugar, pref. sucrose

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