JPH0662441B2 - Anti-tumor substance sustained release preparation - Google Patents
Anti-tumor substance sustained release preparationInfo
- Publication number
- JPH0662441B2 JPH0662441B2 JP61033641A JP3364186A JPH0662441B2 JP H0662441 B2 JPH0662441 B2 JP H0662441B2 JP 61033641 A JP61033641 A JP 61033641A JP 3364186 A JP3364186 A JP 3364186A JP H0662441 B2 JPH0662441 B2 JP H0662441B2
- Authority
- JP
- Japan
- Prior art keywords
- antitumor substance
- release preparation
- sustained release
- antitumor
- base
- 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 - Lifetime
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は抗腫瘍物質の徐放性製剤に関し、更に詳細には
抗腫瘍物質を腫瘍部位に投与するための油脂性の抗腫瘍
物質徐放性製剤に関する。Description: TECHNICAL FIELD The present invention relates to a sustained-release preparation of an antitumor substance, and more specifically, a oleaginous antitumor substance sustained-release for administration of an antitumor substance to a tumor site. Sex formulation.
従来多くの抗腫瘍物質が製剤化され、市販されている。
しかしながら、それらの大部分は、経口投与用製剤かあ
るいは静注用製剤であり、これらの抗腫瘍製剤を特定の
臓器腫瘍の治療に使用すると抗腫瘍物質が全身に拡散す
るため、治療効果が低いばかりでなく、生体に対する副
作用が問題となる。そこで特定の臓器腫瘍部位のみに抗
腫瘍物質を集中させる為のターゲツテイング法が種々検
討されているが、未だ実用に供し得ないのが実状であつ
た。Conventionally, many antitumor substances have been formulated and are commercially available.
However, most of them are oral preparations or intravenous preparations, and when these antitumor preparations are used to treat specific organ tumors, the antitumor substance diffuses throughout the body, resulting in low therapeutic effect. Not only that, side effects on the living body become a problem. Therefore, various targeting methods for concentrating the antitumor substance only on the tumor site of a specific organ have been studied, but it has not been practically used yet.
また、最近の腫瘍部治療には、従来の化学療法に併せ
て、ハイパーサーミアと呼ばれる加熱療法で、腫瘍部を
４２℃〜４５℃まで加温することがおこなわれており、
かかる状況下でも効果的に抗腫瘍物質を放出する製剤の
開発が求められていた。In addition, for the recent treatment of the tumor part, in addition to the conventional chemotherapy, the tumor part is heated to 42 ° C. to 45 ° C. by a heat treatment called hyperthermia.
There has been a demand for the development of a formulation that effectively releases antitumor substances even under such circumstances.
本発明者は抗腫瘍物質の徐放性製剤に関し種々研究をお
こなつた結果、基剤として融点の高い油脂性基剤を用い
れば抗腫瘍物質を目的部位に徐々に放出し得る抗腫瘍物
質の徐放性製剤が得られること及び該製剤はハイパーサ
ーミアによつても影響を受けないことを見出した。The present inventor has conducted various studies on a sustained-release preparation of an antitumor substance, and as a result, if an oily base having a high melting point is used as a base, an antitumor substance that can be gradually released to a target site can be obtained. It has been found that a sustained release formulation is obtained and that the formulation is not affected by hyperthermia.
また、上記製剤に更に油溶化助剤を加えればより安定な
製剤とすることができることを見出した。It was also found that a more stable formulation can be obtained by further adding an oil solubilizing aid to the above formulation.
したがつて、本発明は融点が45℃を超える油脂性基剤
に、抗腫瘍物質を内在せしめてなる抗腫瘍性物質徐放性
製剤を提供する第１発明とこの製剤に更にレシチン、ビ
タミンＥ及び非イオン性界面活性剤からなる群より選ば
れる油溶化助剤の一種以上を含有せしめた抗腫瘍物質徐
放性製剤を提供する第２発明よりなるものである。Therefore, the present invention provides a sustained release preparation of an antitumor substance, which comprises an oily base having a melting point of more than 45 ° C. and an antitumor substance incorporated therein, and further comprises lecithin and vitamin E. And a second invention which provides a sustained release preparation of an antitumor substance containing one or more oil solubilizing aids selected from the group consisting of nonionic surfactants.
本発明で用いられる抗腫瘍物質としては、悪性腫瘍を治
療するために用いられるアルキル化剤、代謝拮抗剤、植
物アルカロイド、抗悪性腫瘍性抗生物質及びその他の抗
悪性腫瘍剤が挙げられる。アルキル化剤としては、シク
ロホスフアミド、塩酸ナイトロジエンマスタード−Ｎ−
オキシド、メルフアラン、チオテバ、カルボコン、ピポ
ブロマン、トシル酸インプロスルフアン、プスルフア
ン、ミトブロニトール、塩酸ニムスチンなどが、代謝拮
抗剤としては、メルカプトプリン、メルカプトプリンリ
ボシド、シトシンアラビノシド、フルオロウラシル、テ
ガフール、塩酸サイクロシチジン、メトトレキサート、
カルモフール、エノシタビンなどが、植物アルカロイド
としては、硫酸ビンブラスチン、硫酸ビンクリスチン、
などが、抗悪性腫瘍性抗生物質としては、アクチノマイ
シンＤ、マイトマイシンＣ、塩酸ブレオマイシン、硫酸
ブレオマイシン、クロモマイシンA3、塩酸ダウノルビシ
ン、塩酸ドキソルビシン、ネオカルチノスタチン、硫酸
ペプロマイシン、アクラシノマイシンＡなどが、その他
の抗悪性腫瘍剤としては、プロピオ酸ドロモスタノロ
ン、メピチオスタン、エピチオスタノール、クエン酸タ
モキシフエン、リン酸ジエチルスチルベストロール、Ｌ
−アスパラギナーゼ、グルカロラクトン、塩酸プロカル
バジン、ブロクスクリジン、レンチナン、ベスタチン、
塩酸レバミゾール、シスプラチン、リン酸エストラムス
チンナトリウム等がそれぞれ挙げられる。これらの抗腫
瘍物質は単独または併用して使用される。Examples of the antitumor substance used in the present invention include alkylating agents, antimetabolites, plant alkaloids, antineoplastic antibiotics and other antineoplastic agents used for treating malignant tumors. As the alkylating agent, cyclophosphamide, nitrodiene mustard hydrochloride-N-
Oxide, melphalan, thioteva, carbocon, pipobroman, inprosulfan tosylate, psulfan, mitobronitol, nimustine hydrochloride, etc. Cytidine, methotrexate,
Carmofur, enocitabine, etc., as plant alkaloids, vinblastine sulfate, vincristine sulfate,
However, as antineoplastic antibiotics, actinomycin D, mitomycin C, bleomycin hydrochloride, bleomycin sulfate, chromomycin A 3 , daunorubicin hydrochloride, doxorubicin hydrochloride, neocarzinostatin sulfate, peplomycin sulfate, aclacinomycin A, etc. , And other anti-neoplastic agents include dromostanolone propioate, mepithiostane, epithiostanol, tamoxifen citrate, diethylstilbestrol phosphate, L
-Asparaginase, glucarolactone, procarbazine hydrochloride, broxuridine, lentinan, bestatin,
Levamisole hydrochloride, cisplatin, estramustine sodium phosphate, etc. may be mentioned respectively. These antitumor substances are used alone or in combination.
また本発明で用いられる油脂性基剤としては、融点が４
５℃を超えるものであれば、いかなる組成のものでも用
いることが可能であるが、限定された特定脂肪酸組成を
有し、特定の融点を有する合成あるいは、エステル交換
トリグリセライドが特に好ましい。この場合の特定脂肪
酸組成としては、主に炭素数１２より１８までの脂肪酸
を選択することにより調製する。The oily base used in the present invention has a melting point of 4
Any composition can be used as long as it exceeds 5 ° C., but synthetic or transesterified triglycerides having a limited specific fatty acid composition and a specific melting point are particularly preferable. In this case, the specific fatty acid composition is prepared mainly by selecting a fatty acid having 12 to 18 carbon atoms.
本発明の第１発明の製剤を調製するには、融点以上の温
度で加熱、溶解させた油脂性基剤と抗腫瘍物質を充分に
混合したのち、所望する形状に成型すれば良く、特に調
製法、形状に限定はない。In order to prepare the preparation of the first invention of the present invention, it is sufficient to heat and dissolve the oily base material and the antitumor substance dissolved at a temperature equal to or higher than the melting point, and then mold the mixture into a desired shape. The method and shape are not limited.
この製剤における抗腫瘍物質と油脂性基剤との比率は、
特に限定されない。しかし一般には抗腫瘍物質の種類に
よつても異なるが、抗腫瘍物質１に対し、油脂性基剤
０．５〜５０、好ましくは、１〜２５とすれば良い。The ratio of the antitumor substance and the oily base in this preparation is
There is no particular limitation. However, generally, depending on the type of the antitumor substance, the oil-and-fat base is 0.5 to 50, preferably 1 to 25 with respect to the antitumor substance 1.
さらに本発明の第２発明の製剤においては、レシチン、
ビタミンＥ、非イオン界面活性剤などの油溶化助剤の一
種または二種以上が配合され、その効果を向上せしめる
ことができる。Furthermore, in the formulation of the second invention of the present invention, lecithin,
One or more oil solubilizing aids such as vitamin E and nonionic surfactants may be added to improve the effect.
上記、油溶化助剤のうちレチシンとしては大豆レシチ
ン、卵黄レシチン及びその誘導体等が、非イオン界面活
性剤としては、脂肪酸グリセリンエステル、ソルビタン
脂肪酸エステル、シヨ糖脂肪酸エステル、ポリグリセリ
ン脂肪酸エステル、プロピレングリコール脂肪酸エステ
ル等の多価アルコールエステル型界面活性剤及び高級ア
ルコール酸化エチレン付加物、ポリオキシエチレンアル
キルエーテル、ポリオキシエチレンアルキルアリルエー
テル、ポリオキシエチレン脂肪酸エステル、ポリオキシ
エチレングリセリンモノ脂肪酸エステル等の酸化アルキ
レン付加型界面活性剤が挙げられるがこれらのうちポリ
オキシエチレンアルキルエーテル、シヨ糖脂肪酸エステ
ルが望ましい。Among the above-mentioned oil solubilizing aids, soybean lecithin as lecithin, egg yolk lecithin and derivatives thereof, and the like, as nonionic surfactants, fatty acid glycerin ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyglycerin fatty acid ester, propylene glycol. Polyhydric alcohol ester type surfactant such as fatty acid ester and higher alcohol ethylene oxide adduct, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, polyoxyethylene fatty acid ester, alkylene oxide such as polyoxyethylene glycerin monofatty acid ester Examples of the addition type surfactant include polyoxyethylene alkyl ether and sucrose fatty acid ester.
油溶化助剤が添加された第２発明の製剤の調製は、抗腫
瘍物質が油溶化助剤に常温又は加熱により溶解する場合
は抗腫瘍物質をまず油溶化助剤に溶解させたのち、油脂
性基剤と溶解混合するか、あるいは、三者を同時に混
合、撹拌、溶解することによりおこなわれる。また抗腫
瘍物質が油溶化助剤に溶解しにくい場合あるいは加熱に
より抗腫瘍物質が分解しやすい場合は、抗腫瘍物質と油
溶化助剤、さらには油性基剤を適当な有機溶媒に溶解さ
せた後、溶媒を溜去したものを用いる方法が行なわれ
る。ここで用いる有機溶媒は、上記配合成分を溶解しう
るものであれば特に限定されない。When the antitumor substance is dissolved in the oil solubilizing agent at room temperature or by heating, the antitumor substance is first dissolved in the oil solubilizing agent, and then the oil / fat is added. It is carried out by dissolving and mixing with a base material, or by simultaneously mixing, stirring and dissolving the three. If the antitumor substance is difficult to dissolve in the oil solubilizing agent or if the antitumor substance is easily decomposed by heating, the antitumor substance, the oil solubilizing agent, and further the oily base were dissolved in an appropriate organic solvent. After that, a method using a solvent distilled off is performed. The organic solvent used here is not particularly limited as long as it can dissolve the above-mentioned components.
本発明の第２発明における抗腫瘍物質と油溶化助剤との
比率は油溶化助剤の種類によつて異なるが、抗腫瘍物質
１に対し油溶化助剤０．１〜３０好ましくは、１〜１５
である。The ratio of the antitumor substance and the oil solubilizing agent in the second invention of the present invention varies depending on the type of the oil solubilizing agent, but the antitumor substance 1 to the oil solubilizing agent 0.1 to 30, preferably 1 ~ 15
Is.
斯くして得られた本発明の製剤は、癌摘出手術後に、癌
摘出部位あるいはその周辺に留置、又は縫合糸等により
固定される。また癌摘出部位でなくとも、皮下あるいは
腹腔内に外科的手法を用いて、埋め込み、留置すること
も可能である。The thus-obtained preparation of the present invention is indwelled at or near the site of cancer removal after surgery for cancer removal, or is fixed with a suture or the like. Further, it is also possible to implant and indwell subcutaneously or intraperitoneally using a surgical technique, even if it is not a cancer excision site.
本発明の製剤は、手術後、腫瘍部位、腫瘍摘出部位に埋
め込み留置後長期間にわたり、抗腫瘍物質を接続的に放
出し、治療効果を向上させる作用を有する。The preparation of the present invention has the effect of connectingly releasing an antitumor substance and improving the therapeutic effect for a long period of time after implantation and implantation at the tumor site or tumor excision site after surgery.
従来、癌摘出手術後の抗腫瘍物質の投与は通常、癌摘出
部位付近に留置されたカテーテルを用いて、手術直後よ
り開始されていた。この方法は、投与薬剤が生体内で希
釈され、治療部位に到達する薬剤量が非常に少なく治療
効果が低いばかりでなく、手術後の衰弱した患者を生体
に対する副作用により、さらに衰弱させる原因となつて
いた。Conventionally, administration of an antitumor substance after surgery to remove a cancer has usually been started immediately after the surgery using a catheter placed near the site of cancer removal. This method not only causes the administered drug to be diluted in the body and the amount of the drug reaching the treatment site is very small, resulting in poor therapeutic effect, but also causes the debilitated patient after surgery to be further weakened due to side effects on the living body. Was there.
しかるに、本発明の製剤は、主に腫瘍部位摘出手術後、
手術部位あるいは体内に埋め込み、留置されたのち、抗
腫瘍物質を長期間にわたり徐々に放出されるものである
から持続的薬効と高い安全性が得られるものである。However, the preparation of the present invention is mainly used after surgery to remove the tumor site,
After being implanted and left in the surgical site or body, the antitumor substance is gradually released over a long period of time, so that a sustained drug effect and high safety can be obtained.
次に実施例を挙げ、本発明を具体的に説明する。 Next, the present invention will be specifically described with reference to examples.
実施例１． 次のアルキル鎖組成を有する融点45.2℃及び53.7℃のト
リグリセライドをエステル交換法により合成した。Example 1. Triglycerides having the following alkyl chain compositions and melting points of 45.2 ° C and 53.7 ° C were synthesized by transesterification.
これらの基剤を用い、下に示す処方の直径１cm、重さ１
ｇのペレツトを溶融法により製剤化した。このペレツト
をウイスター系雄性ラツトの腹腔内に麻酔下、開復して
埋め込み、その後一定期間ごとに屠殺、開腹し、埋め込
みんだペレツトの重量変化を測定した。この結果を第１
図に示す。 Using these bases, the formulation shown below has a diameter of 1 cm and a weight of 1
g pellets were formulated by the melt method. The pellets were reopened and embedded in the abdominal cavity of a Wistar male rat under anesthesia, and then sacrificed and abdominated at regular intervals, and the weight change of the implanted pellets was measured. This result is the first
Shown in the figure.
ペレツト１：基剤Ａ １ｇ ペレツト２：基剤Ｂ １ｇ ペレツト３：基剤Ａ 0.98ｇ ポリオキシエチレンソルビタンモノステアリン酸エステ
ル0.02ｇ ペレツト４：基剤Ｂ 0.98ｇ ポリオキシエチレンソルビタンモノステアリン酸エステ
ル0.02ｇ この結果、ペレツトの重量は徐々に減少しており、ペレ
ツトはその表面から徐々に溶解され、生体内に吸収され
ていると推定される。Pellet 1: Base A 1 g Pellet 2: Base B 1 g Pellet 3: Base A 0.98 g Polyoxyethylene sorbitan monostearate 0.02 g Pellet 4: Base B 0.98 g Polyoxyethylene sorbitan monostearate 0.02 g As a result, the weight of the pellet is gradually decreased, and it is presumed that the pellet is gradually dissolved from its surface and absorbed in the living body.
実施例２． 実施例１の基剤Ａ６０ｇをとり、５５℃に加温融解後、
テガフール（１−（２−テトラハイドロフリル）−５−
フロロウラシル）４０ｇを加え、よく混合したのち鋳型
に注入し、０．５ｇのペレツトに製剤化した。このペレ
ツトを体重約４００ｇのウイスター系雄性ラツトの腹腔
内にエーテル麻酔下、埋め込み手術を行なつた。手術後
４〜５日おきに頚動脈より採血し、血中テガフール含量
を高速液体クロマトグラフ法を用いて測定した。結果は
第２図に示す通りテガフールの血中濃度が維持されてお
り、テガフールが基剤から徐々に放出されていると推定
された。Example 2. After taking 60 g of the base A of Example 1 and heating and melting at 55 ° C.,
Tegafur (1- (2-tetrahydrofuryl) -5-
Fluorouracil) (40 g) was added, mixed well, and then poured into a mold to prepare 0.5 g of pellets. The pellet was intraperitoneally injected into a Wistar male rat having a body weight of about 400 g under ether anesthesia, and an implantation operation was performed. Blood was collected from the carotid artery every 4 to 5 days after the operation, and the content of tegafur in the blood was measured by high performance liquid chromatography. As a result, as shown in FIG. 2, the blood concentration of tegafur was maintained, and it was estimated that tegafur was gradually released from the base.
実施例３． 実施例１の基剤Ｂ６９ｇ及びシヨ糖オレイン酸エステル
１ｇをとり、６０℃に加温融解後マイトマイシン３０ｇ
を加え、よく混合したのち、鋳型を用いてペレツト状に
１ｇ宛製剤化する。Example 3. Taking 69 g of the base B of Example 1 and 1 g of sucrose oleate and heating and melting at 60 ° C., 30 g of mitomycin
After adding well and mixing well, 1 g of a pellet is prepared using a mold.
実施例４． 実施例１の基剤Ａ８２ｇ、ポリオキシエチレンラウリル
エーテル１ｇ及びα−トコフエロール２ｇをとり５５℃
に加温融解後アクチマイシンＤ１５ｇを加え、実施例３
と同様に製剤化する。Example 4. 82 g of the base A of Example 1, 1 g of polyoxyethylene lauryl ether and 2 g of α-tocopherol are taken and the temperature is 55 ° C.
After heating and thawing, 15 g of actimicin D was added to
Formulate in the same manner as in.
実施例５． 実施例１の基剤Ｂ７７ｇ、卵黄レシチン１ｇ、ポリオキ
シエチレンオレイルエーテル２ｇをとり、６０℃に加熱
融解後５−フロロウラシル３０ｇを加え、よく混合した
のち、実施例３と同様に製剤化する。Example 5. 77 g of the base B of Example 1, 1 g of egg yolk lecithin, and 2 g of polyoxyethylene oleyl ether are taken, and after heating and melting at 60 ° C., 30 g of 5-fluorouracil is added, mixed well, and then formulated as in Example 3.
第１図は、ラツト腹腔内に設置したペレツトの経時的な
重量変化を示す図面である。 第２図は、ラツト腹腔内にテガフール含有ペレツトを投
与したときのラツト血中テガフール含有の経時変化を示
す図面である。FIG. 1 is a drawing showing the change in weight of a pellet placed in the rat abdominal cavity over time. FIG. 2 is a drawing showing the time course of tegafur content in rat blood when the tegafur-containing pellet was intraperitoneally administered to the rat.
Claims (2)
物質を内在せしめてなる抗腫瘍物質徐放性製剤。1. A sustained-release preparation of an antitumor substance, which comprises an oily base having a melting point of more than 45 ° C. and an antitumor substance incorporated therein.
物質並びにレシチン、ビタミンＥ及び非イオン性界面活
性剤からなる群より選ばれる油溶化助剤の一種以上を内
在せしめてなる抗腫瘍物質徐放性製剤。2. An oily base having a melting point of higher than 45 ° C. and an antitumor substance and one or more oil solubilizing aids selected from the group consisting of lecithin, vitamin E and nonionic surfactants. Sustained release preparation of antitumor substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61033641A JPH0662441B2 (en) | 1986-02-18 | 1986-02-18 | Anti-tumor substance sustained release preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61033641A JPH0662441B2 (en) | 1986-02-18 | 1986-02-18 | Anti-tumor substance sustained release preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62192327A JPS62192327A (en) | 1987-08-22 |
| JPH0662441B2 true JPH0662441B2 (en) | 1994-08-17 |
Family
ID=12392069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61033641A Expired - Lifetime JPH0662441B2 (en) | 1986-02-18 | 1986-02-18 | Anti-tumor substance sustained release preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0662441B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008533A1 (en) | 1996-08-30 | 1998-03-05 | Peptech Limited | Sustained peptide-release formulation |
| GB9824437D0 (en) * | 1998-11-06 | 1999-01-06 | Ylo Herttuala Seppo | Gene therapy |
| KR100482650B1 (en) * | 2002-11-07 | 2005-04-14 | 한국화학연구원 | Locallly implantable anticancer agent using self-microemulsion system |
| WO2006039336A2 (en) * | 2004-10-01 | 2006-04-13 | Ramscor, Inc. | Conveniently implantable sustained release drug compositions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53127819A (en) * | 1977-04-12 | 1978-11-08 | Riken Vitamin Co Ltd | Stabilization of l-asocorbic acid and its salt |
| JPS54109962A (en) * | 1978-02-17 | 1979-08-29 | Riken Vitamin Co Ltd | Pharmaceutical preparation of l-ascorbic acid with high stability |
| JPS58124714A (en) * | 1982-01-20 | 1983-07-25 | Yamanouchi Pharmaceut Co Ltd | Oily composition of antitumor substance |
-
1986
- 1986-02-18 JP JP61033641A patent/JPH0662441B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62192327A (en) | 1987-08-22 |
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