JPS59163315A - Carmofur-containing liposome - Google Patents
Carmofur-containing liposomeInfo
- Publication number
- JPS59163315A JPS59163315A JP3749683A JP3749683A JPS59163315A JP S59163315 A JPS59163315 A JP S59163315A JP 3749683 A JP3749683 A JP 3749683A JP 3749683 A JP3749683 A JP 3749683A JP S59163315 A JPS59163315 A JP S59163315A
- Authority
- JP
- Japan
- Prior art keywords
- carmofur
- liposome
- cancer
- solubility
- solution
- 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
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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 するリボンームに関する。[Detailed description of the invention] Regarding the ribbon room.
カルモフール、スなわち1−へキシルカルバ大腸癌、乳
癌に対する治療に広く用いられている。Carmofur, ie 1-hexylcarba, is widely used in the treatment of colon cancer and breast cancer.
カルモフールは脂溶性物質でクロロホルム、アセトン、
氷酢酸に溶は易く、ベンゼン、メタノール、無水エタノ
ールにやや溶けにくい。水にはほとんど溶けず、その溶
解度は001係以下である。また、pl44以下の水溶
液中では比較的安定であるが、中性から弱アルカリ性で
は不安定でpHに依存して加水分解を受は易くなり、そ
の半減期(、 t y2)はpH7で約85分、p11
8で約54分、pH12で約20分である。Carmofur is a fat-soluble substance that can be used in chloroform, acetone,
Easily soluble in glacial acetic acid, slightly soluble in benzene, methanol, and anhydrous ethanol. It hardly dissolves in water, and its solubility is less than 001. In addition, it is relatively stable in aqueous solutions with a pl of 44 or less, but is unstable in neutral to weak alkaline conditions and becomes susceptible to hydrolysis depending on the pH, and its half-life (t y2) is approximately 85 at pH 7. min, p11
At pH 8, it takes about 54 minutes, and at pH 12, it takes about 20 minutes.
以上のように、水に対する極めて乏しい溶解度、および
生理的条件下で比較的容易に加水分解するという、製剤
上の欠点を有するカルモフールについて種々検討した結
果、カルモフールをリポソーム中に含有せしめることに
よって前記性質を改善できることを見出し、本発明を完
成するに至った。As mentioned above, as a result of various studies on carmofur, which has the disadvantages of formulations such as extremely poor solubility in water and relatively easy hydrolysis under physiological conditions, we have found that by incorporating carmofur into liposomes, the above-mentioned properties can be improved. The present inventors have discovered that it is possible to improve this, and have completed the present invention.
リポソーム化した薬剤は、薬剤単独に比べかなり少量で
も薬効を現わすだめ、経済的であり、安全でもある。こ
れは、副作用の強く現われる抗悪性IIIII瘍剤に応
用すると特に有益である。壕だ、消化管からは吸収され
ず、静脈、筋肉内、腹腔内への注射剤として優れていて
、しかも血中濃度が持続するため、効果が時間依存性と
されるフルオロウラシル系の薬剤に適している。Liposomal drugs are economical and safe because they exhibit efficacy even in much smaller amounts than drugs alone. This is particularly useful when applied to anti-malignant III tumor drugs that have strong side effects. It is not absorbed from the gastrointestinal tract, making it an excellent choice for intravenous, intramuscular, or intraperitoneal injections, and its blood concentration persists, making it suitable for fluorouracil drugs whose effects are time-dependent. ing.
リポソーム化の使用拐料やリポソームの大きさにより各
種臓器への指向性を調節することができ、これにより希
望する特定部位、例えば肺臓、肝臓、tq%臓、腎臓等
に高濃度に分布させることが可能となる。Directivity to various organs can be adjusted by adjusting the amount used in liposome formation and the size of the liposomes, thereby allowing high concentration distribution to desired specific areas, such as the lungs, liver, tq% organs, kidneys, etc. becomes possible.
仁のようにカルモフールをリポソーム化することにより
、その欠点を補い有用性を高めることができる。By making carmofur into liposomes like Jin, it is possible to compensate for its drawbacks and increase its usefulness.
リポソーム化の方法は公知の薄膜法、溶液注入法、界面
活性剤処理法等によることができる。The liposome formation can be carried out by the known thin film method, solution injection method, surfactant treatment method, etc.
洞料としてはリン脂質、例えばホスファチシルコリン、
ホスファチジルセリン、ホスファチジルエタノールアミ
ン、リゾレシチン捷タハスフィンゴミエリン等の1種捷
だは2種以上の混合物を用いることができ、寸だ安定化
等のだめジセチルホスフエ−1・およびコレステロール
等ヲ添加することもできる。Phospholipids such as phosphatidylcholine,
One type or a mixture of two or more of phosphatidylserine, phosphatidylethanolamine, lysolecithin, terhasphingomyelin, etc. can be used, and dicetylphosphaerine, cholesterol, etc. can also be added for extreme stabilization.
リン脂質、例えば卵黄ホスファチジルコリンとカルモフ
ールの製造時の重量比は卵黄ホスファチジルコリン1に
対しカルモフールが03〜07、好捷しくは04〜06
が良い。The weight ratio of phospholipids, such as egg yolk phosphatidylcholine and carmofur during production, is 1 part egg yolk phosphatidylcholine to 1 part carmofur, preferably 03 to 07, preferably 04 to 06.
is good.
カルモフールを含有するリポソームは、水に対する溶解
度は100倍以上に向上し、寸だ、加水分角イもpl+
9.1のアルカリ性において、これを抑制させることに
成功した。The solubility of liposomes containing carmofur in water is improved by more than 100 times, and the hydrolysis angle is also pl+.
We succeeded in suppressing this at an alkaline level of 9.1.
以上のように、本発明のカルモフール含有リポソームは
、水に対する溶解性および化学的な安定性の向上により
、注射製剤への応用が期待される。As described above, the carmofur-containing liposome of the present invention is expected to be applied to injection preparations due to its improved water solubility and chemical stability.
本発明を実施例により詳細に説明する。The present invention will be explained in detail by examples.
実施例 力ルモフールの薄膜法によるリポソーム化
ナス型フラスコ中において、精製した卵黄ホスファチシ
ルコリン、コレステロールおヨヒカルモフールのそれぞ
れ表1に示した量をクロロホルム4 mlに溶解したの
ち、エバポレーターで溶媒を除去して薄膜を形成させ、
さらに生理食塩水4 mlを加えて薄膜を剥離したのち
超音波照射(25ワット)を1時間行うことにより目的
物を含有する乳白色の液体を得た。カルモフールは」二
記例の如くカルモフールの全量を初めから共存させても
良いし、超音波照射時に1部を結晶の形で徐りに加えな
がら超音波照射しても同様の結果が得られる。Example: Making liposomes using the thin-film method using lumofur In an eggplant-shaped flask, the amounts of purified egg yolk phosphatylcholine, cholesterol phosphatylcholine, and yolkmofur shown in Table 1 were dissolved in 4 ml of chloroform, and then the solvent was removed using an evaporator. forming a thin film,
Furthermore, after adding 4 ml of physiological saline and peeling off the thin film, ultrasonic irradiation (25 watts) was performed for 1 hour to obtain a milky white liquid containing the target product. The entire amount of carmofur may be allowed to coexist from the beginning as in Example 2, or the same result can be obtained by gradually adding a portion of carmofur in the form of crystals during ultrasonic irradiation.
得られた目的物を含有する液体を、さらに限外濾過によ
シ濃縮することも可能であり、才だ、凍結乾燥により粉
末とすることも可能である、。The resulting liquid containing the target product can be further concentrated by ultrafiltration, or alternatively, can be made into a powder by freeze-drying.
得られたリポソームを電子顕微鏡により観察すると、−
多重層リポソームが見られ、その直径はおよそ100
nm〜120 tllnであった。When the obtained liposomes were observed under an electron microscope, -
Multilamellar liposomes are seen, with a diameter of approximately 100
nm to 120 tlln.
リポソーム化したカルモフールの可溶化率は033〜0
72%トナリ、カルモフール単独のおよそ120倍に向
上した。The solubilization rate of liposomal carmofur is 033-0
72%, an improvement approximately 120 times that of carmofur alone.
表1 リポソームの組成
m夕
1 27]、、5 ]、4.32
60 3.0 28.83 2
4 3.4 13.3このものの安定性
について、さらに試験例により詳述する。Table 1 Composition of liposomes 127], 5], 4.32
60 3.0 28.83 2
4 3.4 13.3 The stability of this product will be further explained in detail using test examples.
試験例 リポソーム化によるカルモフールの水溶液中で
の安定性
カルモフールの分解により生成スるヘギンルアミ、とフ
1.ラム(Flura+r卯、。ッッユ)の反応生成物
について、480 n+nにおける螢光強度を測定す
るという新しい測定方法を開発し、水溶液中の安定性を
検討した。すなわち、カルモフール単ぎ虫については、
pH1,7のフ゛リノトンーロヒンソン緩衝液にカルモ
フールを飽和させ、その溶液2. s meを同緩衝液
にて2倍希釈し、さらに0.2 NNaOH3,5m1
1!を加えpl−49,’lとする。以後、経時的に1
meずつサンプリングし、螢光強度を25℃でβり定し
だ。Test Example: Stability of carmofur in aqueous solution by liposome formation. We developed a new measurement method of measuring the fluorescence intensity at 480 n+n for the reaction product of Flura+R, and investigated its stability in an aqueous solution. In other words, for carmofur monoworms,
Carmofur is saturated in a Phylnoton-Rohinson buffer solution of pH 1.7, and the solution 2. sme was diluted 2 times with the same buffer, and further diluted with 0.2 N NaOH3, 5 ml.
1! Add and set it as pl-49,'l. After that, 1 over time
Me samples were taken, and the fluorescence intensity was determined at 25°C.
リポソーム化力ルモフールについては、pl+91のブ
リットンーロヒンソン緩衝液3omlにリボンーム溶液
300μ沼(]、4X10 モル)とフルラム 20
μ石(5XlOモル) f: 加L、以後経時的に1
meずつサンプリングし螢光強度を測定した。但し、
リポソームについては、ブラl−−領域となった150
分経過後にトリトンX −100’ (T
riton X −100■)を用い、リポソーム膜を
破壊した時点の螢光強度を1 +] 0係とした。For the liposome-forming power Lumofur, add 300 μl of Liboome solution (20 μg, 4×10 mol) and Flurum 20
μ stone (5XlO mol) f: Added L, then 1 over time
Me samples were taken and the fluorescence intensity was measured. however,
For liposomes, the region became 150
Triton X -100' (T
riton
結果を表2に示した。The results are shown in Table 2.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3749683A JPS59163315A (en) | 1983-03-09 | 1983-03-09 | Carmofur-containing liposome |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3749683A JPS59163315A (en) | 1983-03-09 | 1983-03-09 | Carmofur-containing liposome |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS59163315A true JPS59163315A (en) | 1984-09-14 |
Family
ID=12499130
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3749683A Pending JPS59163315A (en) | 1983-03-09 | 1983-03-09 | Carmofur-containing liposome |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS59163315A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61158932A (en) * | 1984-10-22 | 1986-07-18 | ネクスター・フアーマシユーテイカルズ・インコーポレイテツド | Method of transporting micell particle enclosing imaging drug or chemical therapy drug to tumor in body |
JPS63208515A (en) * | 1986-12-05 | 1988-08-30 | ザ リポゾム カンパニー インコーポレイテッド | Fine crystal comprising active substance having affinity to phosphatides, at least one phosphatide, manufacture and drug composition |
JPS63503113A (en) * | 1986-04-23 | 1988-11-17 | ニューヨーク ユニバーシィティ | Method for producing contact-inhibitory factors |
US4923854A (en) * | 1986-01-22 | 1990-05-08 | The Liposome Company, Inc. | Solubilization of hydrophobic materials using lysophospholipid |
-
1983
- 1983-03-09 JP JP3749683A patent/JPS59163315A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61158932A (en) * | 1984-10-22 | 1986-07-18 | ネクスター・フアーマシユーテイカルズ・インコーポレイテツド | Method of transporting micell particle enclosing imaging drug or chemical therapy drug to tumor in body |
US4923854A (en) * | 1986-01-22 | 1990-05-08 | The Liposome Company, Inc. | Solubilization of hydrophobic materials using lysophospholipid |
JPS63503113A (en) * | 1986-04-23 | 1988-11-17 | ニューヨーク ユニバーシィティ | Method for producing contact-inhibitory factors |
JPS63208515A (en) * | 1986-12-05 | 1988-08-30 | ザ リポゾム カンパニー インコーポレイテッド | Fine crystal comprising active substance having affinity to phosphatides, at least one phosphatide, manufacture and drug composition |
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