JPH06254379A - Stable aqueous suspension of liposome - Google Patents
Stable aqueous suspension of liposomeInfo
- Publication number
- JPH06254379A JPH06254379A JP5045610A JP4561093A JPH06254379A JP H06254379 A JPH06254379 A JP H06254379A JP 5045610 A JP5045610 A JP 5045610A JP 4561093 A JP4561093 A JP 4561093A JP H06254379 A JPH06254379 A JP H06254379A
- Authority
- JP
- Japan
- Prior art keywords
- liposome
- aqueous suspension
- ammonium salt
- polyhydric alcohol
- quaternary ammonium
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 33
- 239000007900 aqueous suspension Substances 0.000 title claims description 18
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 12
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 9
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 4
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 3
- 229960001950 benzethonium chloride Drugs 0.000 claims description 3
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical group [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 claims 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 abstract description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 10
- 239000000725 suspension Substances 0.000 abstract description 7
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 abstract description 6
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 4
- 150000002632 lipids Chemical class 0.000 abstract description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 abstract 1
- 238000004821 distillation Methods 0.000 abstract 1
- 230000003311 flocculating effect Effects 0.000 abstract 1
- 239000000787 lecithin Substances 0.000 abstract 1
- 229940067606 lecithin Drugs 0.000 abstract 1
- 235000010445 lecithin Nutrition 0.000 abstract 1
- 230000007774 longterm Effects 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 239000012528 membrane Substances 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 7
- 235000011187 glycerol Nutrition 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000004417 polycarbonate Substances 0.000 description 3
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- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical class CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
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- 229940105990 diglycerin Drugs 0.000 description 2
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- 150000002148 esters Chemical class 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
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- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
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- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 1
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- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 1
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- HVVJCLFLKMGEIY-UHFFFAOYSA-N 2,3-dioctadecoxypropyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOCC(COP([O-])(=O)OCC[N+](C)(C)C)OCCCCCCCCCCCCCCCCCC HVVJCLFLKMGEIY-UHFFFAOYSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-O 2-[[(2r)-2,3-di(tetradecanoyloxy)propoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-O 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
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- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
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- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
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- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
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Landscapes
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】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ームを安定に保存できる技術に
関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a technique for stably storing liposomes even when the liposomes are stored in an aqueous suspension.
【０００２】[0002]
【従来の技術】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ャリア
ーとして用いる試みが数多くなされている。しかしなが
らリポソームは水溶液の状態ではコロイド化学的に不安
定な場合が多く、リポソーム粒子同士の凝集や融合、膜
成分の結晶化による沈澱の生成、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った。
この問題の解決を試みたものとして、特開昭６４−３１
１４号公報記載の技術がある。この技術は多価アルコー
ル及びまたは糖類を用いてリポソームを安定化するもの
である。2. Description of the Related Art Liposomes are closed vesicles composed of lipid bilayers, and because of their excellent biocompatibility, many attempts have been made to retain various drugs in their internal aqueous phase or membranes and use them as drug carriers. Has been done. However, in many cases, liposomes are colloidally chemically unstable in the state of an aqueous solution, and they undergo aggregation or fusion of liposome particles, formation of precipitate due to crystallization of membrane components, increase in particle size, or hydrolysis. The product value was likely to be lost due to changes in efficacy and appearance, such as the formation of lyso bodies.
As an attempt to solve this problem, JP-A-64-31
There is a technique described in Japanese Patent No. 14 publication. This technique uses polyhydric alcohols and / or sugars to stabilize liposomes.
【０００３】[0003]
【発明が解決しようとしている課題】しかしながら前記
技術では、室温で長期間保存する場合、安定性が十分と
は言えなかった。本発明の目的は、室温で長期間保存し
ても、沈澱や凝集、粒径変化がなく、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。However, according to the above technique, the stability was not sufficient when it was stored at room temperature for a long period of time. An object of the present invention is to provide a stable aqueous liposome suspension that does not undergo precipitation, aggregation, or change in particle size even when stored at room temperature for a long period of time, and produces less lyso form.
【０００４】[0004]
【課題を解決するための手段】本発明は、多価アルコー
ル及び第４級アンモニウム塩を添加することを特徴とす
るリポソーム水懸濁液である。本発明において、多価ア
ルコールとしてはグリセリン、ジグリセリン、ポリグリ
セリン、プロピレングリコール、ポリプロピレングリコ
ール、エチレングリコール、ジエチレングリコール、ト
リエチレングリコール、ポリエチレングリコール、ジエ
チレングリコールモノエチルエーテル、１，３−ブチレ
ングリコール、ペンタエリスリトールなどを挙げること
ができるが、好ましくはグリセリン、プロピレングリコ
ール、ポリエチレングリコール４００、ポリエチレング
リコールである。多価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。また、第４級アンモニウム塩と
しては塩化ベンザルコニウム、塩化ベンゼトニウムなど
を用いることができる。第４級アンモニウム塩の添加量
はリポソームの膜成分に対して０．０５〜２０モル％で
ある。アミノ酸とは、ｐＨを６〜７の間で設定して調製
したリポソーム水懸濁液のｐＨ変動を抑える働きを持つ
ものをいい、具体的にはグリシン、α−アラニン、β−
アラニン、バリン、ロイシン、イソロイシン、セリン、
トレオニン、γ−アミノ酪酸、イプシロンアミノカプロ
ン酸、グルタミン、アスパラギン、タウリンなどを挙げ
ることができる。多価アルコール及び第４級アンモニウ
ム塩と共に前記アミノ酸を加えると、室温で長期間保存
した場合、リゾ体の生成がより少なく抑えられるので好
ましい。The present invention is a liposome aqueous suspension characterized by the addition of a polyhydric alcohol and a quaternary ammonium salt. In the present invention, as the polyhydric alcohol, glycerin, diglycerin, polyglycerin, propylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, 1,3-butylene glycol, pentaerythritol, etc. Examples thereof include glycerin, propylene glycol, polyethylene glycol 400, and polyethylene glycol. The amount of the polyhydric alcohol compounded is 0.7 to 7.5% by weight, preferably 1.5.
~ 4.5% by weight. Further, as the quaternary ammonium salt, benzalkonium chloride, benzethonium chloride or the like can be used. The amount of the quaternary ammonium salt added is 0.05 to 20 mol% with respect to the membrane component of the liposome. The amino acid refers to one having a function of suppressing pH fluctuation of a liposome aqueous suspension prepared by setting a pH between 6 and 7, and specifically, glycine, α-alanine, β-
Alanine, valine, leucine, isoleucine, serine,
Examples thereof include threonine, γ-aminobutyric acid, epsilon aminocaproic acid, glutamine, asparagine, taurine and the like. It is preferable to add the amino acid together with the polyhydric alcohol and the quaternary ammonium salt, since the production of lyso form can be further suppressed when stored at room temperature for a long time.
【０００５】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
（後記）を有機溶媒に溶解し、有機溶媒を留去した後、
生成した脂質膜を多価アルコール（及び好ましくはアミ
ノ酸）含有水溶液で水和し、その後、この水溶液に第４
級アンモニウム塩を加えればよいが、特にこの方法に限
定されるわけではない。前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、ジミリストイルフ
ォスファチジルコリン、ジパルミトイルフォスファチジ
ルコリン、ジステアロイ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重量部に対し０．０００５〜０．０２５
重量部好ましくは０．００１〜０．００８重量部であ
る。また、有機溶媒としてはクロロホルム、ジクロルメ
タンなどを用いることができる。The aqueous liposome suspension of the present invention can be prepared, for example, as follows. That is, after dissolving the membrane component (described below) in an organic solvent and distilling off the organic solvent,
The resulting lipid membrane is hydrated with an aqueous solution containing a polyhydric alcohol (and preferably an amino acid), and then a fourth solution is added to this aqueous solution.
It is sufficient to add a graded ammonium salt, but the method is not particularly limited to this method. As the membrane component, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine and the like can be used, and the membrane stabilizer is particularly It is not necessary, but cholesterol etc. may be added. The amount of the membrane component used is usually 0.0005 to 0.025 with respect to 1 part by weight of water.
Parts by weight It is preferably 0.001 to 0.008 parts by weight. Further, as the organic solvent, chloroform, dichloromethane or the like can be used.
【０００６】本発明においてはリポソームの水懸濁液の
ｐＨを水酸化ナトリウム、水酸化カリウム等で中性付近
（６．０〜７．０）に調整することが望ましい。なお、
本発明においては必要に応じてポリカーボネート製メン
ブランフィルターや高圧噴射型ホモジナイザーを用いて
粒径分布をコントロールしてもよい。本発明のリポソー
ム水懸濁液には必要に応じて防腐剤（例えばパラオキシ
安息香酸メチル、パラオキシ安息香酸エチル、パラオキ
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
酸クロルフェニラミンなど）、ビタミン類（例えばビタ
ミンＡ及びそのエステル、活性型ビタミンＢ2、ビタミ
ンＢ6、ビタミンＢ12、ビタミンＥ及びそのエステルな
ど）、局所麻酔剤（例えば、Ｌ−メントール、ボルネオ
ール、カンフル、ハッカ油など）、高分子添加剤（例え
ばポリエチレングリコール、ポリビニルアルコール、ポ
リビニルピロリドン、ヒドロキシエチルセルロース、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、塩化カリウムなど）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。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多価アルコー
ル含有水溶液に溶解して脂質膜に加えて水和させればよ
く、油溶性薬物の場合は薬物と膜成分とをクロロホルム
などの溶媒に溶解し、溶媒を留去した後、多価アルコー
ル含有水溶液で水和すればよい。In the present invention, it is desirable that the pH of the aqueous suspension of liposomes is adjusted to near neutral (6.0 to 7.0) with sodium hydroxide, potassium hydroxide or the like. In addition,
In the present invention, a particle size distribution may be controlled by using a polycarbonate membrane filter or a high-pressure injection type homogenizer, if necessary. The liposome aqueous suspension of the present invention may optionally contain a preservative (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, etc.), antihistamine (eg, diphenhydramine hydrochloride, isothipendyl hydrochloride, chlorpheniramine maleate, etc.). ), Vitamins (for example, vitamin A and its ester, active vitamin B 2 , vitamin B 6 , vitamin B 12 , vitamin E and its ester, etc.), local anesthetics (for example, L-menthol, borneol, camphor, peppermint oil) Etc.), polymer additives (eg polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, etc.), isotonicity agents (eg sodium chloride, potassium chloride, etc.) You may add in the range which does not impair the light effect. The drug to be retained in the liposome aqueous suspension of the present invention is not particularly limited, and in the case of a water-soluble drug, the drug may be dissolved in a polyhydric alcohol-containing aqueous solution and added to a lipid membrane to be hydrated. In the case of a soluble drug, the drug and the membrane component may be dissolved in a solvent such as chloroform, and the solvent may be distilled off, followed by hydration with a polyhydric alcohol-containing aqueous solution.
【０００７】[0007]
【発明の効果】本発明により、室温で２年間以上保存し
ても安定で、かつリポソームが加水分解してリゾ体を生
じることが少ない実用的なリポソーム水懸濁液を提供す
ることが可能となった。Industrial Applicability According to the present invention, it is possible to provide a practical aqueous liposome suspension that is stable even when stored at room temperature for 2 years or more and that is less likely to hydrolyze liposomes to form lyso bodies. became.
【０００８】[0008]
【実施例】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 水素添加大豆レシチン２００ｍｇをナスフラスコにと
り、クロロホルム５０ｍｌ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ムでｐＨを
６．５に調整した２．７％グリセリン水溶液を１０ｍｌ
加え、６０〜７０℃で水和した後、０．８μｍのポリカ
ーボネート製メンブランで１回、０．１μｍのポリカー
ボネート製メンブランで２回加圧濾過によるサイジング
を行った。このうち、５ｍｌをとり、塩化ベンザルコニ
ウムを最終的に０．００５％（Ｗ／Ｖ）（膜成分に対し
て５モル％）となるように加え、さらにｐＨ６．５の
２．７％グリセリン水溶液を加えて、全量５０ｍｌのリ
ポソーム水懸濁液を調製した。EXAMPLES The present invention will be described in more detail below with reference to examples and test examples. Example 1 200 mg of hydrogenated soybean lecithin was placed in an eggplant-shaped flask and dissolved in 50 ml of chloroform, and then chloroform was sufficiently distilled off. To this, 10 ml of 2.7% glycerin aqueous solution whose pH was adjusted to 6.5 with sodium hydroxide
In addition, after hydration at 60 to 70 ° C., sizing was performed by pressure filtration once with a 0.8 μm polycarbonate membrane and twice with a 0.1 μm polycarbonate membrane. Of this, 5 ml was taken, benzalkonium chloride was added so that the final concentration was 0.005% (W / V) (5 mol% based on the membrane components), and 2.7% glycerin at pH 6.5 was added. An aqueous solution was added to prepare a liposome aqueous suspension having a total volume of 50 ml.
【０００９】実施例２ ２．７％グリセリンの代わりに５．４％ジグリセリンを
用いた他は実施例１と同様にしてリポソーム水懸濁液を
調製した。Example 2 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that 5.4% diglycerin was used instead of 2.7% glycerin.
【００１０】実施例３ ２．７％グリセリンの代わりに２．０％グリセリンと
１．０％タウリンを用いた他は実施例１と同様にしてリ
ポソーム水性懸濁液を調製した。Example 3 An aqueous liposome suspension was prepared in the same manner as in Example 1 except that 2.0% glycerin and 1.0% taurine were used instead of 2.7% glycerin.
【００１１】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
にジステアリルフォスファチジルコリン２００ｍｇを用
いた他は実施例１と同様にしてリポソーム水懸濁液を調
製した。Example 4 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that 200 mg of distearylphosphatidylcholine was used instead of 200 mg of hydrogenated soybean lecithin as a membrane component.
【００１２】実施例５ 膜成分として水添大豆レシチン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と同様にしてリポソーム水懸濁液を調製
した。ただし、水和とサイジングは５０〜６０℃で行っ
た。Example 5 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that 200 mg of dipalmitoylphosphatidylcholine was used instead of 200 mg of hydrogenated soybean lecithin as a membrane component. However, hydration and sizing were performed at 50 to 60 ° C.
【００１３】実施例６ 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２００ｍｇを用いた他は実施例
１と同様に調製した。Example 6 The same procedure as in Example 1 was carried out except that 200 mg of hydrogenated egg yolk lecithin was used instead of 200 mg of hydrogenated soybean lecithin as a membrane component.
【００１４】実施例７ 塩化ベンザルコニウム０．００５％（Ｗ／Ｖ）の代わり
に塩化ベンゼトニウム０．０１％（Ｗ／Ｖ）を用いた他
は実施例１と同様にしてリポソーム水懸濁液を調製し
た。Example 7 A liposome aqueous suspension was prepared in the same manner as in Example 1 except that benzethonium chloride 0.01% (W / V) was used instead of benzalkonium chloride 0.005% (W / V). Was prepared.
【００１５】対照例 実施例１において塩化ベンザルコニウムを添加しなかっ
た他は実施例１と同様にしてリポソーム水懸濁液を調製
した。Control Example A liposome aqueous suspension was prepared in the same manner as in Example 1 except that benzalkonium chloride was not added.
【００１６】試験例 実施例１，３及び対照例のリポソーム水懸濁液をアンプ
ルに入れ４０℃に保存し、外観変化を観察し、粒子径を
測定した。その結果を表１に示す。Test Example The liposome aqueous suspensions of Examples 1 and 3 and the control example were placed in an ampoule and stored at 40 ° C., the appearance change was observed, and the particle size was measured. The results are shown in Table 1.
【００１７】[0017]
【表１】 [Table 1]
【００１８】実施例１及び３のリポソーム水懸濁液では
リポソームの凝集・沈澱や粒径の変化も認められなかっ
たが、対照例の場合は実施例の場合に比べ、凝集も多く
粒径も大きくなった。In the aqueous liposome suspensions of Examples 1 and 3, neither aggregation / precipitation of liposomes nor change in particle size was observed, but the control example had more aggregation and a larger particle size than those of the Examples. It got bigger.
【００１９】[0019]
───────────────────────────────────────────────────── フロントページの続き (72)発明者 小山 郁夫 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 根本 正美 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Ikuo Koyama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Masami Nemoto 3-24-1 Takada, Toshima-ku, Tokyo Taisho Inside Pharmaceutical Co., Ltd.
Claims (4)
塩を添加することを特徴とするリポソーム水懸濁液。1. A liposome aqueous suspension, wherein a polyhydric alcohol and a quaternary ammonium salt are added.
塩と共にアミノ酸を添加することを特徴とする請求第１
項記載のリポソーム水懸濁液。2. An amino acid is added together with a polyhydric alcohol and a quaternary ammonium salt.
Item 7. A liposome aqueous suspension according to item.
ニウムまたは塩化ベンゼトニウムである請求項１または
２記載のリポソーム水懸濁液。3. The liposome aqueous suspension according to claim 1, wherein the quaternary ammonium salt is benzalkonium chloride or benzethonium chloride.
記載のリポソーム水懸濁液。4. The pH is in the range of 6 to 7.
The liposome aqueous suspension described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5045610A JPH06254379A (en) | 1993-03-08 | 1993-03-08 | Stable aqueous suspension of liposome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5045610A JPH06254379A (en) | 1993-03-08 | 1993-03-08 | Stable aqueous suspension of liposome |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06254379A true JPH06254379A (en) | 1994-09-13 |
Family
ID=12724144
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5045610A Pending JPH06254379A (en) | 1993-03-08 | 1993-03-08 | Stable aqueous suspension of liposome |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06254379A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003095926A (en) * | 2001-09-26 | 2003-04-03 | Nof Corp | Fatty acid-containing liposome dispersion |
| WO2012117385A2 (en) | 2011-03-03 | 2012-09-07 | WROCŁAWSKIE CENTRUM BADAŃ EIT+ Sp z o.o. | Liposome formulation comprising an anti-tumour active substance, method for its preparation and pharmaceutical compositions comprising it |
-
1993
- 1993-03-08 JP JP5045610A patent/JPH06254379A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003095926A (en) * | 2001-09-26 | 2003-04-03 | Nof Corp | Fatty acid-containing liposome dispersion |
| WO2012117385A2 (en) | 2011-03-03 | 2012-09-07 | WROCŁAWSKIE CENTRUM BADAŃ EIT+ Sp z o.o. | Liposome formulation comprising an anti-tumour active substance, method for its preparation and pharmaceutical compositions comprising it |
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