JPH07277956A - Production of liposome containing medicinal component - Google Patents
Production of liposome containing medicinal componentInfo
- Publication number
- JPH07277956A JPH07277956A JP6074753A JP7475394A JPH07277956A JP H07277956 A JPH07277956 A JP H07277956A JP 6074753 A JP6074753 A JP 6074753A JP 7475394 A JP7475394 A JP 7475394A JP H07277956 A JPH07277956 A JP H07277956A
- Authority
- JP
- Japan
- Prior art keywords
- medicinal component
- liposome
- lipid
- neocarzinostatin
- liposome preparation
- 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.)
- Granted
Links
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
- A61K9/1277—Processes for preparing; Proliposomes
-
- 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
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、薬効成分が失活せず、
粒径が一定で微細な薬効成分含有リポソーム製剤を製造
する方法に関する。FIELD OF THE INVENTION The present invention is directed to the case where the medicinal component is not inactivated,
The present invention relates to a method for producing a fine drug-containing liposome preparation having a uniform particle size.
【０００２】[0002]
【従来の技術】リポソーム製剤は脂質二重構造からなる
粒子の内部に薬物を内包せしめた製剤であり、その製造
法としては、おおよそ超音波分散法、溶液法等が知られ
ている。このうち最も一般的なものが超音波分散法であ
り、これはフラスコ等の容器の表面に脂質の薄膜を作
り、これに水性担体に溶解させた薬物を加え、超音波を
かけることにより、薄膜をこの水性担体中に分散させる
製造法である。しかしながら、この方法では超音波分散
時に発熱が起き、薬物の分解、失活が起こることが避け
られない。2. Description of the Related Art A liposome preparation is a preparation in which a drug is encapsulated in particles having a lipid double structure, and its production method is generally known as an ultrasonic dispersion method or a solution method. The most common of these is the ultrasonic dispersion method, in which a thin film of lipid is made on the surface of a container such as a flask, a drug dissolved in an aqueous carrier is added to this, and ultrasonic waves are applied to form a thin film. Is a production method in which is dispersed in this aqueous carrier. However, in this method, it is unavoidable that heat is generated during ultrasonic dispersion, resulting in decomposition and inactivation of the drug.
【０００３】また、溶液法は脂質を一度グリセリンやプ
ロピレングリコール等の多価アルコールに溶かし込み、
これに生理食塩水等の水性担体に溶解させた薬物を徐々
に加えリポソームを作成する方法である。この方法では
加熱工程は脂質を多価アルコールに溶かし込む際の脂質
を溶解する工程のみであり、直接薬物に熱を与えないと
言う長所が有る反面、得られたリポソームの粒子径が大
きく、粒子の大きさのバラツキも大きいと言う欠点があ
った。In the solution method, the lipid is once dissolved in a polyhydric alcohol such as glycerin or propylene glycol,
In this method, a drug dissolved in an aqueous carrier such as physiological saline is gradually added to form liposomes. In this method, the heating step is only the step of dissolving the lipid when dissolving the lipid in the polyhydric alcohol, and has the advantage of not directly applying heat to the drug, but on the other hand, the particle size of the obtained liposome is large, There was a drawback that there was a large variation in size.
【０００４】[0004]
【発明が解決しようとする課題】従って、本発明の目的
は、薬効成分を失活させず、粒径が一定で微細な薬効成
分含有リポソーム製剤の製造法を提供することにある。SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a method for producing a fine drug-containing liposome preparation having a constant particle size without deactivating drug components.
【０００５】[0005]
【課題を解決するための手段】斯かる実状に鑑み、本発
明者は薬効成分への加熱が少ないリポソーム製剤の製造
法について鋭意研究を重ねた結果、脂質を多価アルコー
ルに溶解せしめ、これに薬効成分の水性担体溶液を加え
たものをエクストルージョン処理すれば、薬効成分への
加熱が少なくて済み、且つ、粒子が細かく薬効成分の内
包率の高いリポソーム製剤が得られることを見出し、本
発明を完成した。In view of such circumstances, the present inventor has conducted earnest research on a method for producing a liposome preparation in which a medicinal component is less heated, and as a result, a lipid is dissolved in a polyhydric alcohol. It has been found that, if an extrusion treatment of an aqueous solution of a medicinal component is carried out, heating to the medicinal component can be reduced, and a liposome preparation having fine particles and a high encapsulation rate of the medicinal component can be obtained. Was completed.
【０００６】即ち、本発明は脂質を多価アルコールに溶
解せしめ、これに薬効成分の水性担体溶液を加えたもの
をエクストルージョン処理することを特徴とする薬効成
分含有リポソーム製剤の製造方法を提供するものであ
る。That is, the present invention provides a method for producing a liposome preparation containing a medicinal component, which comprises dissolving a lipid in a polyhydric alcohol, and adding an aqueous carrier solution of the medicinal component to the solution, and subjecting the mixture to an extrusion treatment. It is a thing.
【０００７】本発明に用いる脂質はリポソームを作成し
うる脂質であれば、特に限定されず、微細で均一なリポ
ソームとすることができる。このような脂質としては、
例えば、フォスファチジルコリン、フォスファチジルイ
ノシトール、フォスファチジルエタノールアミン、フォ
スファチジルセリン、フォスファチジルグリセロール、
ジフォスファチジルグリセロール等のグリセロリン脂
質、スフィンゴミエリン等のスフィンゴリン脂質、コレ
ステロール等が挙げられる。また、これらの脂質は２種
以上を混合して用いてもよい。The lipid used in the present invention is not particularly limited as long as it is a lipid capable of forming liposomes, and it can be a fine and uniform liposome. Such lipids include
For example, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol,
Examples thereof include glycerophospholipids such as diphosphatidylglycerol, sphingophospholipids such as sphingomyelin, and cholesterol. Moreover, you may use these lipids in mixture of 2 or more types.
【０００８】なお、リポソームの脂質二重膜の成分とし
てフォスファチジルエタノールアミンと他の脂質とを併
用することにより、薬効成分として抗癌剤を用いた場合
の安全性が高まり、抗癌効果が著しく向上するので好ま
しい。本発明に於けるフォスファチジルエタノールアミ
ンの好適な含有量は脂質の全重量に対して５〜５０重量
％である。これは、全脂質の重量に対して５重量％未満
では癌への配向性が低く抗癌効果の増強や安全性の向上
に寄与しないため適当ではなく、脂質の全重量に対して
５０重量％を越えても効果が頭打ちの為適当でないから
である。更に好適な配合量は全脂質の重量に対して１０
〜３０重量％である。By using phosphatidylethanolamine in combination with other lipids as a component of the lipid bilayer of the liposome, the safety when an anticancer agent is used as a medicinal component is increased and the anticancer effect is significantly improved. Therefore, it is preferable. The preferred content of phosphatidylethanolamine in the present invention is 5 to 50% by weight based on the total weight of lipid. If the amount is less than 5% by weight based on the total weight of lipids, the orientation to cancer is low and it does not contribute to the enhancement of the anti-cancer effect and the improvement in safety. The reason is that the effect is not reached even if it exceeds the limit, so it is not appropriate. A more preferable blending amount is 10 based on the weight of total lipids.
~ 30% by weight.
【０００９】また、多価アルコールとしては、エチレン
グリコール、プロピレングリコール、グリセリン等が例
示される。Examples of polyhydric alcohols include ethylene glycol, propylene glycol, glycerin and the like.
【００１０】本発明に用いられる薬効成分は、医薬とし
て使用できるものであれば特に限定されないが、熱によ
り失活する成分が好ましい。このうち抗癌剤がより好ま
しい。抗癌剤としては、特に限定はされないが、ネオカ
ルチノスタチン、アドリアマイシン、ブレオマイシン、
アクチノマイシン、マイトマイシンの様な抗癌抗生物
質、フトラフール、テガフール等の代謝拮抗剤、ビンブ
ラスチン、ビンクリスチン等の植物アルカロイド、ナイ
トロジェンマスタード、シクロフォスファミド等のアル
キル化剤等が例示できる。このうち、毒性も抗癌効果も
高いネオカルチノスタチンが最も好適である。The medicinal component used in the present invention is not particularly limited as long as it can be used as a medicine, but a component which is inactivated by heat is preferable. Of these, anticancer agents are more preferable. Anticancer agents include, but are not limited to, neocarzinostatin, adriamycin, bleomycin,
Examples thereof include anticancer antibiotics such as actinomycin and mitomycin, antimetabolites such as futrafur and tegafur, plant alkaloids such as vinblastine and vincristine, and alkylating agents such as nitrogen mustard and cyclophosphamide. Of these, neocarzinostatin is most suitable because of its high toxicity and anticancer effect.
【００１１】本発明方法では、まず脂質を多価アルコー
ルに溶解せしめる。この脂質と多価アルコールとの比
は、脂質／多価アルコール＝０．０３〜０．３（重量
比）とすることが好ましい。また脂質は例えば７０〜９
０℃に加熱溶解してから、多価アルコールを加えること
が好ましい。In the method of the present invention, the lipid is first dissolved in the polyhydric alcohol. The lipid / polyhydric alcohol ratio is preferably lipid / polyhydric alcohol = 0.03 to 0.3 (weight ratio). The lipid is, for example, 70-9
It is preferable to add the polyhydric alcohol after heating and dissolving at 0 ° C.
【００１２】また、薬効成分の水性担体としては、燐酸
緩衝生理食塩水（ＰＢＳ）、リンゲル液、乳酸リンゲル
液等の各種緩衝液を用いることが好ましい。薬効成分の
水性担体は、脂質と多価アルコールの混合物に対して、
１〜３倍程度加えることが好ましい。As the aqueous carrier for the medicinal component, it is preferable to use various buffer solutions such as phosphate buffered saline (PBS), Ringer's solution, lactated Ringer's solution. The aqueous carrier of the medicinal component is a mixture of lipid and polyhydric alcohol,
It is preferable to add about 1 to 3 times.
【００１３】エクストルージョン処理は、エクストルー
ダー（例えば、リペックス・バイオメンブランス社（カ
ナダ）製のもの）を用いて水性担体等の混合物をフィル
ターの微細な穴より押し出し、リポソームとする方法で
ある。この方法によれば微細で且つ大きさのバラツキの
少ないリポソームが得られる。しかしながら、前記の処
理を行わずにエクストルージョン処理を行っても、エク
ストルーダーのフィルターが目づまりをおこしてしまい
リポソームが得られない。エクストルージョン処理に用
いるフィルターは、目的にあわせて適宜選択すればよい
が、注射剤として投与可能なリポソームを作るフィルタ
ーとしては、穴の直径が２００〜５０nmのものが好まし
い。また、押し出しの圧力は最大５０kg／cm2 までかけ
られるが、本発明方法では通常２０〜３０kg／cm2 であ
る。The extrusion treatment is a method in which a mixture of an aqueous carrier and the like is extruded from fine pores of a filter using an extruder (for example, manufactured by Lipex Biomembranes (Canada)) to form liposomes. According to this method, it is possible to obtain liposomes which are fine and have little variation in size. However, even if the extrusion treatment is carried out without the above treatment, the filter of the extruder is clogged and the liposome cannot be obtained. The filter used for the extrusion treatment may be appropriately selected depending on the purpose, but a filter having a hole diameter of 200 to 50 nm is preferable as a filter for producing a liposome that can be administered as an injection. The pressure of the extrusion is subjected to a maximum 50 kg / cm 2, in the present invention a method is usually 20-30 kg / cm 2.
【００１４】かくして得られたリポソーム製剤はそのま
ま静脈注射用、動脈注射用、病巣内注射用の医薬製剤と
して使用することができるが、さらにゲル濾過、透析等
により精製するのが好ましい。また、これにグルコース
などの糖類等を添加することもできる。The liposome preparation thus obtained can be used as it is as a pharmaceutical preparation for intravenous injection, arterial injection and intralesional injection, but it is preferably further purified by gel filtration, dialysis and the like. In addition, sugars such as glucose may be added thereto.
【００１５】[0015]
【実施例】以下に実施例を挙げ、本発明に付いて更に詳
しく説明するが、本発明がこれら実施例に限定を受けな
いことは言うまでもない。なお、以下の実施例で用いた
エクストルーダーのフィルターは全て１００ｎｍのポア
サイズのフィルターを用いた。The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples. In addition, the filters of the extruder used in the following examples were all filters having a pore size of 100 nm.
【００１６】実施例１ 下記の処方に従って超音波分散法及び本発明方法でネオ
カルチノスタチン含有のリポソームを作成した。Example 1 A neocarzinostatin-containing liposome was prepared by the ultrasonic dispersion method and the method of the present invention according to the following formulation.
【００１７】[0017]
【表１】 （処方） （重量％） （Ａ）大豆レシチン ２．５ コレステロール １ （Ｂ）プロピレングリコール ７ グリセリン ７ （Ｃ）燐酸緩衝生理食塩水（ＰＢＳ） ８２．５ ネオカルチノスタチン ５４５５単位／ＰＢＳ１ｍｌ [Table 1] (Prescription) (% by weight) (A) Soy lecithin 2.5 Cholesterol 1 (B) Propylene glycol 7 Glycerin 7 (C) Phosphate buffered saline (PBS) 82.5 Neocarzinostatin 5455 units / PBS 1 ml
【００１８】（１）超音波分散法 Ａにジクロロメタンを１０倍量加え、Ａの成分を溶解し
た後溶媒を減圧溜去し薄膜とし、これにＢとＣを加え超
音波をかけて分散しリポソームを得た。これをゲル濾過
にかけ、内包されていないネオカルチノスタチンを取り
除きリポソーム製剤を得た。(1) Ultrasonic Dispersion Method 10 times the amount of dichloromethane was added to A, the components of A were dissolved, the solvent was evaporated under reduced pressure to form a thin film, and B and C were added to this to disperse by applying ultrasonic waves to liposomes. Got This was subjected to gel filtration to remove non-encapsulated neocarzinostatin to obtain a liposome preparation.
【００１９】（２）本発明方法（溶液−エクストルージ
ョン法） Ａを８０℃で加熱溶解しこれにＢを加え溶液とし、室温
にし、Ｃを徐々に撹拌しながら加え粗リポソームとし、
これをエクストルーダーにかけリポソームを得た。これ
をゲル濾過にかけ、内包されていないネオカルチノスタ
チンを取り除きリポソーム製剤を得た。(2) Method of the present invention (solution-extrusion method) A is heated and dissolved at 80 ° C., B is added to this to make a solution, and the mixture is brought to room temperature, and C is gradually added to obtain a crude liposome.
This was subjected to an extruder to obtain a liposome. This was subjected to gel filtration to remove non-encapsulated neocarzinostatin to obtain a liposome preparation.
【００２０】得られたリポソーム中に含まれるネオカル
チノスタチンの量をトリトーンを１％加えてリポソーム
を破壊した後、マイクロコッカス・ルテウスを用いた抗
菌活性により定量したところ下記の表２に示すようにな
った。本発明の溶液−エクストルーダー法で作成したも
のではネオカルチノスタチンが分解されずに内包されて
いるが、超音波分散では分解されているためネオカルチ
ノスタチンの含有量が低下していることが判る。The amount of neocarzinostatin contained in the obtained liposomes was added to 1% of tritone to destroy the liposomes, and the amount was determined by antibacterial activity using Micrococcus luteus. The results are shown in Table 2 below. Became. In the solution-extruder method of the present invention, neocarzinostatin is encapsulated without being decomposed, but the content of neocarzinostatin is reduced because it is decomposed by ultrasonic dispersion. I understand.
【００２１】[0021]
【表２】 [Table 2]
【００２２】実施例２ 下記処方に従って実施例１の本発明方法によりネオカル
チノスタチンのリポソーム製剤を得た。抗癌効果Example 2 A neocarzinostatin liposome preparation was obtained by the method of the present invention of Example 1 according to the following formulation. Anti-cancer effect
【００２３】[0023]
【表３】 （処方） （重量部） （Ａ）大豆レシチン １．７５ コレステロール ０．８７５ フォスファチジルエタノールアミン ０．８７５ （Ｂ）プロピレングリコール ７ グリセリン ７ （Ｃ）燐酸緩衝生理食塩水 ８２．５ ネオカルチノスタチン ５４５５単位／ＰＢＳ１ｍｌ(Formulation) (Parts by weight) (A) Soybean lecithin 1.75 Cholesterol 0.875 Phosphatidylethanolamine 0.875 (B) Propylene glycol 7 Glycerin 7 (C) Phosphate buffered saline 82.5 Neocarzinostatin 5455 units / PBS 1 ml
【００２４】（製造法）Ａを８０℃で加熱溶解しこれに
Ｂを加え溶液とし、室温にし、Ｃを徐々に撹拌しながら
加え粗リポソームとし、これをエクストルーダーにかけ
リポソームを得た。これをゲル濾過にかけ内包されてい
ないネオカルチノスタチンを取り除き、リポソーム製剤
を得た。抗菌活性で内包されているネオカルチノスタチ
ンの量を定量したところ１４００単位／ｍｌであった。(Manufacturing Method) A was heated and dissolved at 80 ° C., B was added to this to make a solution, and the mixture was brought to room temperature, and C was gradually added with stirring to obtain a crude liposome, which was subjected to an extruder to obtain a liposome. This was subjected to gel filtration to remove non-encapsulated neocarzinostatin to obtain a liposome preparation. When the amount of neocarzinostatin included in the antibacterial activity was quantified, it was 1400 units / ml.
【００２５】実施例３ 下記表４に示す処方でエクストルージョン法のみ、溶液
法のみ及び本発明方法の３つの方法によりリポソームを
製造した。得られたリポソームの平均粒径も表４に示
す。Example 3 Liposomes having the formulations shown in Table 4 below were prepared by the extrusion method only, the solution method only and the method of the present invention. The average particle size of the obtained liposomes is also shown in Table 4.
【００２６】[0026]
【表４】 [Table 4]
【００２７】（１）エクストルージョン法 上記処方のＡに、Ａの５０倍量のジクロロメタンを加え
溶解した後、溶媒を減圧留去し、薄膜を作製した。これ
にＢを加え、よく振盪し粗リポソームを得た。これをエ
クストルーダーにかけたが、何れの処方のものもフィル
ターに目づまりを起こしリポソームは得られなかった。(1) Extrusion Method To A of the above formulation, 50 times the amount of dichloromethane was added and dissolved, and then the solvent was distilled off under reduced pressure to form a thin film. B was added to this and shaken well to obtain a crude liposome. This was put through an extruder, but with any of the formulations, the filter was clogged and liposomes could not be obtained.
【００２８】（２）溶液法 処方Ａを加熱溶解した後、室温に冷却し、撹拌しながら
Ｂを徐徐に滴下して、リポソームを製造した。（３）本
発明方法 処方中のＡを加熱溶解した後、室温に冷却し、撹拌しな
がらＢを徐徐に滴下して、粗リポソームを得た。これを
エクストルーダーにかけ、リポソームを得た。(2) Solution Method After dissolving the formulation A by heating, the solution was cooled to room temperature and B was gradually added dropwise with stirring to produce liposomes. (3) Method of the present invention After A in the formulation was dissolved by heating, it was cooled to room temperature and B was gradually added dropwise with stirring to obtain crude liposomes. This was put through an extruder to obtain a liposome.
【００２９】参考例１ 急性毒性 実施例１（溶液−エクストルージョン法による）及び２
のリポソーム製剤とネオカルチノスタチンについて、Ｉ
ＣＲマウスを用いて急性毒性を求めた。即ち、ＢＡＬＢ
／ｃ（雄性、２０〜２５ｇ）にそれぞれの生理食塩水希
釈溶液を腹腔投与で投与し、投与後１４日後に生死を判
定した。ＬＤ50値は、実施例１のリポソーム製剤が１４
００単位／Ｋｇ、実施例２のリポソーム製剤が８３００
単位／Ｋｇ、ネオカルチノスタチンが２４５０単位／Ｋ
ｇであった。これより、フォスファチジルエタノールア
ミンを含むリポソーム製剤にすることにより安全性が高
まることが判る。Reference Example 1 Acute toxicity Examples 1 (by solution-extrusion method) and 2
Of liposomal preparations of neocarzinostatin and I
Acute toxicity was determined using CR mice. That is, BALB
/ C (male, 20 to 25 g) was intraperitoneally administered with each physiological saline diluted solution, and life or death was determined 14 days after the administration. The LD 50 value of the liposome preparation of Example 1 was 14
00 units / Kg, 8300 for the liposome preparation of Example 2
Unit / Kg, Neocarzinostatin is 2450 Unit / K
It was g. From this, it is understood that the safety is enhanced by using the liposome preparation containing phosphatidylethanolamine.
【００３０】参考例２ 抗癌効果 予め、前培養したＣ−１３００細胞を７週齢のＡ／Ｊマ
ウス（雄性）に、１×１０6個尾静脈より静脈投与し、
移植した。移植後７日目に各種の投与量で実施例２のリ
ポソーム製剤又はネオカルチノスタチンの生理食塩水希
釈溶液を投与した。移植後１４日目に屠殺し、肝臓を取
り出し癌の肝転移結節数を数えた。結果を図１に示す。
これより、実施例２のリポソーム製剤はネオカルチノス
タチンと同定度に抗癌効果に優れていることが判る。Reference Example 2 Anticancer Effect Pre-cultured C-1300 cells were intravenously administered to 7-week-old A / J mice (male) through 1 × 10 6 tail vein,
Transplanted. Seven days after transplantation, various dosages of the liposome preparation of Example 2 or neocarzinostatin diluted with physiological saline were administered. The mice were sacrificed 14 days after the transplantation, the livers were taken out, and the number of liver metastasis nodules of cancer was counted. The results are shown in Fig. 1.
From this, it is understood that the liposome preparation of Example 2 has an excellent anticancer effect in the degree of identification with neocarzinostatin.
【００３１】[0031]
【発明の効果】本発明の溶液−エクストルージョン法に
よれば、薬効成分が失活せず、粒径が一定で微細な薬効
成分含有リポソーム製剤を製造することができる。EFFECT OF THE INVENTION According to the solution-extrusion method of the present invention, it is possible to produce a fine drug-containing liposome preparation having a constant particle size without deactivating the drug.
【図１】本発明方法により得られた抗癌剤含有リポソー
ム製剤の抗癌効果を示す図である。FIG. 1 is a view showing the anticancer effect of an anticancer agent-containing liposome preparation obtained by the method of the present invention.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｂ０１Ｊ 13/02 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI technical display location B01J 13/02
Claims (3)
れに薬効成分の水性担体溶液を加えたものをエクストル
ージョン処理することを特徴とする薬効成分含有リポソ
ーム製剤の製造方法。1. A method for producing a liposome preparation containing a medicinal component, which comprises dissolving a lipid in a polyhydric alcohol and adding an aqueous carrier solution of the medicinal component to the mixture, followed by an extrusion treatment.
る請求項１記載の製造方法。2. The production method according to claim 1, wherein the medicinal component is a component which is inactivated by heat.
る請求項１又は２記載の製造方法。3. The method according to claim 1, wherein the medicinal component is neocarzinostatin.
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| JP07475394A JP3213471B2 (en) | 1994-04-13 | 1994-04-13 | Method for producing liposome preparation containing medicinal ingredient |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP07475394A JP3213471B2 (en) | 1994-04-13 | 1994-04-13 | Method for producing liposome preparation containing medicinal ingredient |
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| JPH07277956A true JPH07277956A (en) | 1995-10-24 |
| JP3213471B2 JP3213471B2 (en) | 2001-10-02 |
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| JP07475394A Expired - Fee Related JP3213471B2 (en) | 1994-04-13 | 1994-04-13 | Method for producing liposome preparation containing medicinal ingredient |
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