JP3213471B2 - Method for producing liposome preparation containing medicinal ingredient - Google Patents
Method for producing liposome preparation containing medicinal ingredientInfo
- Publication number
- JP3213471B2 JP3213471B2 JP07475394A JP7475394A JP3213471B2 JP 3213471 B2 JP3213471 B2 JP 3213471B2 JP 07475394 A JP07475394 A JP 07475394A JP 7475394 A JP7475394 A JP 7475394A JP 3213471 B2 JP3213471 B2 JP 3213471B2
- Authority
- JP
- Japan
- Prior art keywords
- liposome preparation
- neocarzinostatin
- liposome
- lipid
- present
- 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.)
- Expired - Fee Related
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
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。BACKGROUND OF THE INVENTION The present invention relates to a medicinal composition in which
The present invention relates to a method for producing a fine liposome preparation containing a pharmaceutically active ingredient having a constant 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 inside particles having a lipid bilayer structure, and as its production method, an ultrasonic dispersion method, a solution method and the like are generally known. The most common of these is the ultrasonic dispersion method, which forms a thin film of lipid on the surface of a container such as a flask, adds a drug dissolved in an aqueous carrier, and applies ultrasonic waves to the thin film. Is dispersed in this aqueous carrier. However, in this method, heat is generated at the time of ultrasonic dispersion, and it is inevitable that the drug is decomposed and deactivated.
【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。[0003] In the solution method, lipids are 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 a liposome. In this method, the heating step is only a 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 has a large particle diameter of the obtained liposome, There was a drawback that the variation in the size was large.
【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 Accordingly, an object of the present invention is to provide a method for producing a fine liposome preparation containing a pharmaceutically active ingredient, which has a uniform particle size without deactivating the pharmaceutically active ingredient.
【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。Means for Solving the Problems In view of this situation, the present inventors have conducted intensive studies on a method for producing a liposome preparation that requires less heating to a medicinal component, and as a result, dissolved lipids in a polyhydric alcohol. The present inventors have found that, if an aqueous solution of a medicinal component is added to an extrusion treatment, the liposome preparation which requires less heating to the medicinal component, has fine particles, and has a high encapsulation rate of the medicinal component, can be obtained. Was completed.
【０００６】すなわち、本発明は、脂質をプロピレング
リコールとグリセリンが重量比で１対１の多価アルコー
ル混合物に溶解せしめ、これに、室温において、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熱により失活する薬効成分を含
有する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 relates to an extrusion method comprising dissolving a lipid in a polyhydric alcohol mixture of propylene glycol and glycerin at a weight ratio of 1: 1 and adding an aqueous carrier solution of a pharmaceutically active ingredient at room temperature. It is intended to provide a method for producing a liposome preparation containing a pharmaceutically active ingredient which is inactivated by heat, characterized by being treated.
【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。[0007] The lipid used in the present invention is not particularly limited as long as it is a lipid capable of forming a liposome, and a fine and uniform liposome can be obtained. Such lipids include:
For example, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol,
Glycerophospholipids such as diphosphatidylglycerol; sphingolipids such as sphingomyelin; cholesterol; These lipids may be used as a mixture of two or more.
【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。[0008] 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 enhanced, and the anticancer effect is remarkably improved. Is preferred. The preferred content of phosphatidylethanolamine in the present invention is 5 to 50% by weight based on the total weight of the lipid. This is not appropriate if the amount is less than 5% by weight based on the total weight of the lipids, since the orientation to cancer is low and does not contribute to the enhancement of the anticancer effect or the improvement of safety. This is because the effect is not appropriate even if it exceeds. A more preferable compounding amount is 10% by weight of the total lipid.
３０30% by weight.
【０００９】[0009]
【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 medicament, but a component which is deactivated by heat is preferred. Of these, anticancer agents are more preferred. Examples of the anticancer agent 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, which has high toxicity and anticancer effect, is most preferred.
【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, a lipid is first dissolved in a polyhydric alcohol. It is preferable that the ratio between the lipid and the polyhydric alcohol be lipid / polyhydric alcohol = 0.03 to 0.3 (weight ratio). The lipid is, for example, 70 to 9
It is preferred 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 of the active ingredient, it is preferable to use various buffers such as phosphate buffered saline (PBS), Ringer's solution, Ringer's lactate and the like. The aqueous carrier of the medicinal component, for 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 holes of a filter using an extruder (for example, one manufactured by Lipex Biomembrane (Canada)) to form liposomes. According to this method, liposomes that are fine and have small size variation can be obtained. However, even if the extrusion treatment is performed without performing the above-mentioned treatment, the filter of the extruder is clogged and liposomes cannot be obtained. The filter used for the extrusion treatment may be appropriately selected according to the purpose, but the filter for forming liposomes that can be administered as an injection is preferably one having a hole diameter of 200 to 50 nm. 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 or intralesional injection, but is preferably further purified by gel filtration, dialysis or the like. In addition, saccharides such as glucose can 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. The extruder filters used in the following examples were all 100 nm pore size filters.
【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 Neocarzinostatin-containing liposomes were 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 (Formulation) (% 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 1ml
【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 A 10-fold amount of dichloromethane was added to A, and after dissolving the components of A, the solvent was distilled off under reduced pressure to form a thin film. I got This was subjected to gel filtration to remove unencapsulated 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 was dissolved by heating at 80 ° C., and B was added thereto to form a solution.
This was extruded to obtain a liposome. This was subjected to gel filtration to remove unencapsulated 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 determined by adding 1% tritone to disrupt the liposomes and then antibacterial activity using Micrococcus luteus, as shown in Table 2 below. Became. Although neocarzinostatin is contained without being decomposed in the solution prepared by the solution-extruder method of the present invention, 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 liposome formulation of neocarzinostatin was obtained by the method 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 / PBS1ml
【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., and B was added thereto to form a solution. The solution was brought to room temperature. C was gradually added to the mixture while gradually stirring to obtain a crude liposome, which was subjected to an extruder to obtain a liposome. This was subjected to gel filtration to remove unencapsulated neocarzinostatin, thereby obtaining a liposome preparation. The amount of neocarzinostatin included in the antibacterial activity was determined to be 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 were produced according to the formulations shown in Table 4 below by the extrusion method only, the solution method only, and the method of the present invention. Table 4 also shows the average particle size of the obtained liposomes.
【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 in the above formulation, 50 times the amount of dichloromethane was added and dissolved, and then the solvent was distilled off under reduced pressure to prepare a thin film. B was added thereto, and the mixture was shaken well to obtain a crude liposome. The mixture was subjected to an extruder. However, in any of the formulations, the filter was clogged and no liposome was 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 Formulation A was dissolved by heating, then cooled to room temperature, and B was gradually added dropwise with stirring to produce liposomes. (3) Method of the Present Invention After dissolving A in the formulation by heating, the mixture was cooled to room temperature, and B was gradually added dropwise with stirring to obtain crude liposomes. This was extruded to obtain liposomes.
【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
Liposome formulation and neocarzinostatin
Acute toxicity was determined using CR mice. That is, BALB
/ C (male, 20 to 25 g) were intraperitoneally administered with the respective diluted saline solutions, and the survival was determined 14 days after administration. The LD 50 value of the liposome preparation of Example 1 was 14
00 units / Kg, the liposome preparation of Example 2 was 8300
Unit / Kg, 2450 units / K for neocarzinostatin
g. This indicates that the use of a liposome preparation containing phosphatidylethanolamine increases safety.
【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 1 × 10 6 C-1300 cells pre-cultured in advance were injected into 7-week-old A / J mice (male) via the tail vein.
Transplanted. Seven days after the transplantation, the liposome preparation of Example 2 or a diluted solution of neocarzinostatin in physiological saline was administered at various doses. On the 14th day after the transplantation, the mice were sacrificed, the liver was removed, and the number of liver metastatic nodules of the cancer was counted. The results are shown in FIG.
This shows that the liposome preparation of Example 2 is superior to neocarzinostatin in the degree of identification and anticancer effect.
【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, a fine liposome preparation containing a pharmaceutically active ingredient can be produced with a uniform particle size without deactivating the pharmaceutically active ingredient.
【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 a liposome preparation containing an anticancer agent obtained by the method of the present invention.
Claims (2)
ンが重量比で１対１の多価アルコール混合物に溶解せし
め、これに、室温において、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
する熱により失活する薬効成分を含有するリポソーム製
剤の製造方法。(1) dissolving a lipid in a polyhydric alcohol mixture of propylene glycol and glycerin in a weight ratio of 1: 1, and subjecting the mixture to an extrusion treatment at room temperature with an aqueous carrier solution of a medicinal ingredient; A method for producing a liposome formulation containing a characteristic heat-inactivated medicinal ingredient.
る請求項１記載の製造方法。2. The method according to claim 1, wherein the pharmaceutically active ingredient is neocarzinostatin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP07475394A JP3213471B2 (en) | 1994-04-13 | 1994-04-13 | Method for producing liposome preparation containing medicinal ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP07475394A JP3213471B2 (en) | 1994-04-13 | 1994-04-13 | Method for producing liposome preparation containing medicinal ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07277956A JPH07277956A (en) | 1995-10-24 |
| JP3213471B2 true JP3213471B2 (en) | 2001-10-02 |
Family
ID=13556350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP07475394A Expired - Fee Related JP3213471B2 (en) | 1994-04-13 | 1994-04-13 | Method for producing liposome preparation containing medicinal ingredient |
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| JP (1) | JP3213471B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005023011A3 (en) * | 2003-09-04 | 2007-02-01 | Bioghurt Biogarde Gmbh & Co Kg | Formulation based on phospholipids |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6262093B1 (en) | 1995-04-12 | 2001-07-17 | The Proctor & Gamble Company | Methods of treating cancer with benzimidazoles |
| US6479526B1 (en) | 1995-04-12 | 2002-11-12 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US6265427B1 (en) | 1995-06-07 | 2001-07-24 | The Proctor & Gamble Company | Pharmaceutical composition for the method of treating leukemia |
| US5900429A (en) * | 1997-01-28 | 1999-05-04 | The Procter & Gamble Company | Method for inhibiting the growth of cancers |
| US6506783B1 (en) | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
| US6245789B1 (en) | 1998-05-19 | 2001-06-12 | The Procter & Gamble Company | HIV and viral treatment |
| US6423734B1 (en) | 1999-08-13 | 2002-07-23 | The Procter & Gamble Company | Method of preventing cancer |
| US6462062B1 (en) | 2000-09-26 | 2002-10-08 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6608096B1 (en) | 2000-09-26 | 2003-08-19 | University Of Arizona Foundation | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6380232B1 (en) | 2000-09-26 | 2002-04-30 | The Procter & Gamble Company | Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof |
| US6407105B1 (en) | 2000-09-26 | 2002-06-18 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US7850990B2 (en) | 2001-10-03 | 2010-12-14 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
| EP1432402B1 (en) * | 2001-10-03 | 2006-11-22 | Celator Pharmaceuticals, Inc. | Compositions for delivery of drug combinations |
| CA2383259A1 (en) | 2002-04-23 | 2003-10-23 | Celator Technologies Inc. | Synergistic compositions |
| JP5771366B2 (en) | 2009-09-02 | 2015-08-26 | 株式会社バイオメッドコア | Liposome production apparatus and method |
| JP6462073B1 (en) * | 2017-09-04 | 2019-01-30 | 一丸ファルコス株式会社 | Method for producing pH-sensitive liposomes |
-
1994
- 1994-04-13 JP JP07475394A patent/JP3213471B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005023011A3 (en) * | 2003-09-04 | 2007-02-01 | Bioghurt Biogarde Gmbh & Co Kg | Formulation based on phospholipids |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07277956A (en) | 1995-10-24 |
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