WO1993020934A1 - Suspension aqueuse stable contenant des liposomes - Google Patents

Suspension aqueuse stable contenant des liposomes Download PDF

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Publication number
WO1993020934A1
WO1993020934A1 PCT/JP1992/000512 JP9200512W WO9320934A1 WO 1993020934 A1 WO1993020934 A1 WO 1993020934A1 JP 9200512 W JP9200512 W JP 9200512W WO 9320934 A1 WO9320934 A1 WO 9320934A1
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WIPO (PCT)
Prior art keywords
liposome
aqueous suspension
suspension
aqueous
taurine
Prior art date
Application number
PCT/JP1992/000512
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English (en)
French (fr)
Inventor
Katsu Nakamori
Tsuguchika Yoshida
Ikuo Koyama
Toshiaki Nakajima
Mikiko Odawara
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.)
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Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to US08/318,750 priority Critical patent/US5565213A/en
Priority to KR1019940703704A priority patent/KR950701248A/ko
Priority to EP92908351A priority patent/EP0637463A4/en
Priority to AU15488/92A priority patent/AU672579B2/en
Publication of WO1993020934A1 publication Critical patent/WO1993020934A1/ja

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/0004—Preparation of sols
    • B01J13/0021—Preparation of sols containing a solid organic phase
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984—Microcapsule with fluid core [includes liposome]

Definitions

  • the present invention relates to a technique for stably storing liposomes even when liposomes are stored in the form of an aqueous suspension.
  • Liposomes are small vesicles composed of lipid bilayer membranes, and are excellent in biocompatibility. Many attempts have been made to use it. However, ribosomes are aqueous suspensions, and colloids are often chemically unstable in this state, and ribosome particles aggregate and fuse with each other, precipitates are formed by crystallization of membrane components, and the particle size increases. And the loss of commercial value due to changes in potency and appearance, such as the occurrence of lyso-form, which is said to be hemolytic due to hydrolysis.
  • An object of the present invention is to provide a stable aqueous liposome suspension which does not precipitate, aggregate, or change the particle size for 6 months even when stored at 40 ° C., and generates less lyso-form.
  • the present invention is a liposome aqueous suspension characterized by adding taurine and benzalkonium chloride.
  • the amount of taurine to be added is 0.5 to 5.0% by weight based on the total amount of the preparation, and a molar ratio of 1:13 to 1: 133 with respect to the membrane component of C liposome. 1.0 to 3.0% by weight (molar ratio of 1:27 to 1:80 to the ribosome membrane component).
  • the addition amount of Shii-Dani Benzalkonium is 0.05 to 20 mol per mol of the liposome membrane component. — ⁇ _
  • the aqueous liposome suspension of the present invention can be prepared, for example, as follows: a membrane component is dissolved in an organic solvent, and after distilling off the organic solvent, the resulting lipid membrane is washed with 0 taurine. And hydration with an aqueous solution containing benzalkonium, or hydrated with an aqueous solution of taurine, and then benzalkonium chloride may be added, but the method is not particularly limited to this && method.
  • Iil Hydrogenated as self-membrane component fcg lecithin, hydrogenated egg yolk lecithin, dimyris toy, phosphatidylcholine, dihal .: mitoylsfospatidylcholine, distea ⁇ -ylphosphatidylcholine, etc. No film stabilizer is required, but cholesterol may be added.
  • the amount of the membrane component to be used is usually 0.0005 to 0.025 parts by weight, preferably 0.001 to 0.008 parts by weight per one part by weight of water.o
  • chloro-form cyclo-form, dichloromethane, and the like can be used as the organic solvent.
  • ⁇ ⁇ of the liposomal water suspension it is desirable to adjust ⁇ ⁇ of the liposomal water suspension to near neutral ⁇ ( ⁇ ⁇ 6.0 to 7.0) with sodium hydroxide, potassium hydroxide or the like.
  • the particle size distribution of the liposome may be controlled by using a membrane filter made of polycarbonate or a high-pressure injection type homogenizer as necessary.
  • the aqueous ribosome suspension of the present invention may contain, if necessary, a preservative C, such as methyl parahydroxybenzoate, ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate, and antihistamines (eg, diphenhydramine hydrochloride, isotipendyl hydrochloride, maleine). acid-chloro Hue leek Min, etc.), vitamins (e.g. vitamin ⁇ and its ester le, activated vitamin: B 2, vitamin B s, vitamin beta 12, such as vitamin ⁇ and S.
  • a preservative C such as methyl parahydroxybenzoate, ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate, and antihistamines (eg, diphenhydramine hydrochloride, isotipendyl hydrochloride, maleine). acid-chloro Hue leek Min, etc.), vitamins (e.g. vitamin ⁇ and its ester le,
  • lidocaine lidocaine hydrochloride, procaine hydrochloride, dibuforce hydrochloride, etc.
  • freshener for example, ⁇ -menthol, borneol, camphor, potato power oil, etc.
  • polymer additive polyethylene glycol, polyvinyl alcohol) Alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydro Ki And the like, tonicity agents (eg, sodium chloride, chlorinated lime, etc.) may be added as long as the effects of the present invention are not impaired.
  • the drug retained in the aqueous liposome suspension of the present invention is not particularly limited.
  • the drug is dissolved in an aqueous solution containing taurine (and benzalkonium chloride), added to a lipid membrane, and hydrated.
  • the drug and the membrane component are dissolved in a solvent such as porcine and the solvent is distilled off, and then hydrated with an aqueous solution containing taurine (and benzalkonium chloride). .
  • An aqueous ribosomal suspension was prepared in the same manner as in Example 1 except that 200 mg of dipalmitoylphosphatidylcholine was used instead of 200 mg of dimyristylphosphatidylcholine as a membrane component.
  • a liposomal aqueous suspension was prepared in the same manner as in Example 1, except that 200 mg of hydrogenated soybean lecithin was used instead of 200 mg of dimyristoylphosphatidylcholine as a membrane component. However, hydration and sizing were performed at 60-70 ° C.
  • a liposome aqueous suspension was prepared in the same manner as in Example 3, except that m was used.
  • a liposomal water suspension was prepared in the same manner as in Example 3, except that hydrogenated soybean lecithin 200 mg and cholesterol 50 m were used instead of hydrogenated soybean lecithin 200 mg as a membrane component.
  • a ribosome aqueous suspension was prepared in the same manner as in Example 1 except that a 13 mM phosphoric acid and a 140 mM sodium chloride aqueous solution were used in place of the aqueous solution of taurine. '
  • a liposome aqueous suspension was prepared in the same manner as in Example 1 except that benzalkonium chloride was not added.
  • Test example 1 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that benzalkonium chloride was not added.
  • Example 1 The aqueous suspensions of ribosomes of Example 1, Control Example 1 and Reference Example 2 were placed in a transparent sample at 40 ° C. and 65 ° C. Stored in C, temporarily separate phosphatidylcholine by thin-layer chromatography, scrape off this part, and use the E. Gerlach and D. Deu-tiche ⁇ method [Biochemiche Zeitschrift T, Vol. 337 , Page 477 (1963)], and the content of phosphatidylcholine was measured, and the results are shown in Table 1. The lyso-form, a major decomposition product, was produced. Example 1 was less than Controls 1 and 2. Storage temperature () 65 40 Storage period (days) At start 5 20 40 140 Example 1 100 100.0 83.6 72.9 94.5
  • Example 1 placed ribosome water suspension of Reference Example 1 and Reference Example 2 in ampoules, and stored in 40 e C, to observe the appearance change, the particle size was determined. Table 2 shows the results. In the aqueous liposome suspension of Example 1, no aggregation and precipitation of liposomes and no change in particle size were observed.However, in Comparative Examples 1 and 2, aggregation was larger than in Example 1. ⁇ Lots of sediment and large particle size. Second ⁇
  • Particle size unit is n m

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Description

明 細 書 安定なリポソ一ム水懸濁液 技術分野
本発明はリポソームを水懸濁液の状態で保存してもリポソ一厶を安定に保存で きる技術に関する。
背景技術
リポソ―ムは脂質二分子膜よりなる Γォ ϋ小胞であり、 生体適合性に優れてレ る ^めに、 その内水相又は膜中に種々の薬物を保持させて、 ドラッグキヤ リァ一 y して用いる試みが数多くなされている。 し力 しながら、 リボソームは水懸濁液 . 状態ではコロイ ド化学的に不安定な場合が多く、 リボソーム粒子同士の凝集ゃ融 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起こったり、 '加水分 解を受けて溶血性があるといわれているリゾ体を生じるなど効力及び外観変化に よる商品価値の損失となりやすかつた。
これらの課題の解決を試みたものとして、 特開昭 62- 42733号公報記載の技術 がある。 この技術は、 アミノ酸を用いてリポソ一厶を安定ィ匕するものである。
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化であ り、 高温保存での安定化が不十分であった。 また、 リゾ体の生成抑制についても -十分であった。
本発明の目的は、 40°Cの保存でも 6ヶ月間、 沈殿や凝集、 粒径変化がな ：、 ま たリゾ体の生成も少ない安定なリポソーム水懸濁液を提供することにある。
癸明の開示
本発明は、 タウリン及び塩化ベンザルコニゥムを添加することを特徵とするリ ポソ一ム水懸濁液である。
本発明において、 タウリンの添加量は製剤全量に対して 0. 5〜5. 0重量％ C リポ ソ一厶の膜成分に対して 1 : 13〜 1 ： 133のモル比）であり、 好ましくは 1. 0〜 3. 0重量％( リボソームの膜成分に対して 1 : 27〜 1 ： 80のモル比）である。 ま た、 塩ィ匕ベンザルコニゥムの添加量はリポソ一厶の膜成分に対して 0. 05〜20モル —ゥ _
%であり、 好ましくは 2〜8モル％である。
本発明のリポソーム水懸濁液は、 例えば次のようにして調製することができ る すなわち、 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、 0 タウリン及び塩ィ匕ベンザルコニゥム含有水溶液で水和するか、 又は 〉タウリン水溶液で水和した後、 塩化ベンザルコニゥムを加えればよいが、 特 にこの: &法に限定される訳ではない。
Iil己膜成分としては水素添加; fcgレシチン、 水素添加卵黄レシチン、 ジミ リス トイ几.フォスファチジルコリン、 ジハル.：ミ トイルフォスプアチジルコリン、 ジス テア πィルフォスファチジルコリンなどを用いることができ、 また膜安定化剤は 特に必要ないが、 コレステロールなどを入れても構わない。 膜成分の使用量は、 通常水 1重畺部に对し 0. 0005〜0. 025重量部、 好ましくは 0. 001〜0. 008重量部で める o
また、 有機溶媒としてはクロ σホルム、 ジクロルメタンなどを用いることがで きる。
本 明においては、 リポソ一ム水懸濁液の ρ Ηを水酸化ナトリウム、 水酸化力 リウムなどで中性 ί寸近（ ρ Η6. 0〜7. 0 )に調整することが望ましい。
また、 末発明においては必要に応じてポリ力一ボネ一ト製メンブランフィル ターや高圧噴射型ホモジナイザ一を用いてリポソ一厶の粒径分布をコントロー してもよい。
本 のリボソー厶水懸濁液には必要に応じて防腐剤 C例えばパラォキシ安息 香酸メチル、 パラォキシ安息香酸ェチル、 パラォキシ安息香酸プロピルなど 、 抗ヒスタ ミン剤（例えば塩酸ジフェンヒ ドラミン、 塩酸イソチペンジル、 マレイ ン酸クロルフエニラミンなど）、 ビタミン類（例えばビタミン Α及びそのエステ ル、 活性型ビタミン: B 2、 ビタ ミン B s、 ビタ ミン Β 12、 ビタ ミン Ε及びそのエス テリレなど）、 局所麻酔剤（例えばリ ドカイン、 塩酸リ ドカイン、 塩酸プロカイ ン、 塩酸ジブ力インなど）、 清涼化剤（例えば^ —メントール、 ボルネオール、 カンフル、 ハツ力油など）、 高分子添力口剤（ポリエチレングリコール、 ポリビニ ルアルコール、 ポリビニルピロリ 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 リゥムなど）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。
本発明のリポソーム水懸濁液に保持させる薬物としては特に制限はなく、 水溶 性薬物の場合には薬物をタウリン〔及び塩化ベンザルコニゥム）含有水溶液に溶 解して脂質膜に加え、 水和させればよく、 油溶性薬物の場合には薬物と膜成分と をク口口ホルムなどの溶媒に溶解し、 溶媒を留去した後、 タゥリン（及び塩化べ ンザルコニゥ厶）含有水溶液で水和すればよい。
発明を実施するための最良の形態 1；
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。
実施例 1
ジミ リス トィルフォスファチジルコリン 200m と、 脂溶性の薬物であるビタ ミ ン Eアセテート 50m をナスフラスコにとり、 クロ口ホルム 50m に溶解した後、 ク ロロホルムを充分に留去した。 これに水酸化ナトリウ厶で p Hを 6. 5に調整した 3 %タウリン水溶液 10m£を加え、 40〜50。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フィルターで 2回加圧沪過によるサイジングを行った。 この うち、 5 m£をとり、 塩化ベンザルコニゥムを最終的に 0. 005%(W/V〉（膜成分に対 して約 5モル％：)となるように加え、 更に p H6. 5の 3 %タウリン水溶液を加え て、 全畺 50m£のリポソ一ム水懸濁液を調製した。
実施例 2
膜成分としてジミ リ ス トィルフォスファチジルコリン 200mgの代わりにジパル ミ トイルフォスファチジルコ リ ン 200mgを用いた他は実施例 1と同様にしてリボ ソ一ム水懸濁液を調製した。
実施例 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 200mgの代わりに水素添 加大豆レシチン 200mgを用いた他は実施例 1と同様にしてリポソ一ム水懸濁液を 調製した。 ただし、 水和とサイジングは 60〜70°Cで行った。
実施例 4
膜成分として水素添加大豆レシチン 200mgの代わりに水素添加卵黄レシチン 200 m を用いた他は実施例 3と同様にしてリポソーム水懸濁液を調製した。
実施例 5
膜成分として水素添加大豆レシチン 200mgの代わりに水素添加大豆レシ ン 200 mg及びコレステロ一ル 50m を用いた他は実施例 3と同様にしてリポソ一ム水懸濁 液を調製した。
対照例 1
実施例 1において、 タウりン水溶液の代わりに 13mMリン酸及び 140mM塩化 ナトリウム水溶液を用いた他は実施例 Γ·と同様にしてリボソーム水懸濁液を調製 した。 '
対照例 2
実施例 1において、 塩化ベンザルコ二ゥ厶を加えなかった他は実施例 1と同様 にしてリポソ一ム水懸濁液を調製した。 試験例 1
実施例 1、 対照例 1及び对照例 2のリボソ一ム水懸濁液を ni£透明ァンプルに 入れ、 40°C及び 65。Cで保存し、 籙時的に薄層クロマトグラフ —によりフォス ファチジルコリンを分雛し、 この部分をかきとって、 E . Gerlach and D . Deu- ticheの ^法 [ Biochemiche Zeitschrift T第 337巻，第 477ページ（1963年〉 ]によ りリンの定量を行いフォスファチジルコリンの含有量を測定した。 その結果を第 1表丄 す。 主な分解生成物であるリゾ体の生成は実施例 1のほうが対照例 1及 び対照例 2よりも少なかつた。 保存温度 ( 〉 65 40 保存期間（日〉 開始時 5 20 40 140 実施例 1 100 100.0 83.6 72.9 94.5
対照例 1 100 98.9 70.0 55.4 80.1
対照例 2 100 97. 75.4 60.0 84.0 試験例 2
実施例 1、 対照例 1及び対照例 2のリボソーム水懸濁液をアンプルに入れ、 40 eCに保存し、 外観変化を観察し、 粒径を測定した。 その結果を第 2表に示す。 実 施例 1のリポソー厶水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 れなかつたが、 対照例 1及び対照例 2の場合には実施例 1の場合に比べ、 凝集 · 沈殿が多く、 粒径も大きくなつた。 第 2 ά
Figure imgf000007_0001
注）一；凝集 *沈殿なし , +；凝集'沈殿あり
粒径の単位は n m 産業上の糊可無
本祭明により、 高温保存でも長期間安定で、 かつリポソ一厶が加水分解してリ ゾ体を生じることのないリポソーム水懸獨液を提供することが可能となつた。
請求の範囲
( 1 )タウリン及び塩化べンザルコニゥムを添加することを特徴とするリボソーム 水懸濁液。
PCT/JP1992/000512 1990-07-26 1992-04-21 Suspension aqueuse stable contenant des liposomes WO1993020934A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US08/318,750 US5565213A (en) 1990-07-26 1992-04-21 Stable liposome aqueous suspension
KR1019940703704A KR950701248A (ko) 1990-07-26 1992-04-21 안정한 리포좀 수현탁액
EP92908351A EP0637463A4 (en) 1990-07-26 1992-04-21 STABLE, AQUEOUS LIPOSOME SUSPENSION.
AU15488/92A AU672579B2 (en) 1990-07-26 1992-04-21 Stable aqueous suspension of liposome

Applications Claiming Priority (2)

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JP19823690 1990-07-26
JP22376191A JP3218637B2 (ja) 1990-07-26 1991-05-27 安定なリポソーム水懸濁液

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WO1993020934A1 true WO1993020934A1 (fr) 1993-10-28

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EP (1) EP0637463A4 (ja)
JP (1) JP3218637B2 (ja)
KR (1) KR950701248A (ja)
AU (1) AU672579B2 (ja)
CA (1) CA2118487A1 (ja)
WO (1) WO1993020934A1 (ja)

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US6592877B1 (en) * 1995-09-01 2003-07-15 Corixa Corporation Compounds and methods for immunotherapy and diagnosis of tuberculosis
US6458366B1 (en) 1995-09-01 2002-10-01 Corixa Corporation Compounds and methods for diagnosis of tuberculosis
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JP3218637B2 (ja) 2001-10-15
EP0637463A1 (en) 1995-02-08
AU1548892A (en) 1993-11-18
KR950701248A (ko) 1995-03-23
JPH054037A (ja) 1993-01-14

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