JPH0672107B2 - Antitumor agent composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an antitumor agent composition, and more specifically, it is prepared by mixing an antitumor substance with a specific oily base, implanting it in the affected area, and heating it from the outside. The present invention relates to an antitumor agent composition for sustained release of an antitumor substance.

[Conventional technology]

Conventionally, many antitumor substances have been formulated and are commercially available.
However, most of them are limited to formulations for oral administration or formulations for intravenous injection. These antitumor preparations not only have a low therapeutic effect on the living body because the antitumor substance diffuses throughout the body when administered orally or intravenously even when treating a specific organ tumor, for example. Side effects become a serious problem.

Various targeting methods for concentrating the antitumor substance only on the tumor site of a specific organ have been studied in order to eliminate such defects, but in reality, they cannot be put to practical use.

That is, in general, administration of an antitumor substance after surgery to remove cancer is
It is started immediately after surgery using a catheter placed near the site of cancer removal. However, in this method, the administered drug is diluted in vivo, the amount of the drug reaching the treatment site is very small, and the therapeutic effect is low. , Cause further weakness. For example, after surgery to remove gastric cancer,
The catheter is left indwelled and sutured, and injection of mitomycin C injection solution is performed through the indwelling catheter. However, this method is clinically meaningless, and in patients who need to recover their physical strength. In any case, it causes a decrease in physical strength.

[Problems to be Solved by the Present Invention]

Therefore, there has been a demand for the development of a new antitumor substance administration method in place of the conventional targeting method.

[Means for solving problems]

As a result of various studies on the antitumor agent composition and its administration method, the present inventors have placed or implanted an antitumor agent in which an antitumor substance is mixed in a specific oily base at a tumor site,
It has been found that the antitumor substance can be extremely effectively administered to the required site by heating and releasing the drug as needed. Further, they have found that if metal fine particles are further added to the above antitumor agent, heating efficiency is improved and more excellent effects can be obtained.

Therefore, it is an object of the present invention to have an antitumor substance and a melting point of 38.
The invention provides a heat-released antitumor agent composition containing a solid oily base at ˜45 ° C.

Another object of the present invention is to provide a heat-sustained release antitumor agent composition containing, in addition to the above two components, metal fine particles.

Examples of the antitumor substance used in the present invention include alkylating agents, antimetabolites, plant alkaloids, antimalignant tumor antibiotics, and other antimalignant agents used for treating malignant tumors. Examples of the alkylating agent include cyclophosphamide, nitrodiene mustard-N-oxide hydrochloride, melphalan, thiotheba, carbocon, pipobroman, inbrosulfan tosylate, busulfan,
Mitobronitol, nimustine hydrochloride, etc., as antimetabolites, mercaptopurine, mercaptopurine riboside, cytosine arabinoside, fluorouracil, tegafur, cyclocytidine hydrochloride, methotrexate, carmofur, enocitabine, etc., plant alkaloids, vinblastine sulfate, Vincristine sulfate and the like are actinomycin D, mitomycin C, bleomycin hydrochloride, bleomycin sulfate, chromomycin A ₃ , daunorubicin hydrochloride, doxorubicin hydrochloride, neocarzinostatin, peplomycin sulfate, aclacinomycin A as antineoplastic antibiotics. Etc. In addition, as other anti-neoplastic agents, dromostanolone propionate, mepithiostane, epithiostanol, tamoxiphen citrate, diethylstilbestrol phosphate, l-asparaginase, glucarolactone, procarbazine hydrochloride, broxuridine, lentinan, bestatin. , Levamisole hydrochloride, cisplatin, estramustine phosphate phosphate, etc. can be raised. These antitumor substances are used alone or in combination.

Among these antitumor substances, particularly preferable are antitumor substances having low compatibility with solid oily bases, such as carmofur, tegafur, fluorouracil, mitomycin C, and aclacinomycin A.

Further, the solid oily base used in the present invention, 30 ℃
And a solid having a melting point of 38 to 45 ° C., any kind and composition can be used.
Among these, particularly preferable examples include synthetic or transesterified triglycerides, because a certain melting point can be obtained by specifying the composition of fatty acids. The fatty acid composition in this case is mainly selected from fatty acids having 12 to 18 carbon atoms. For example, a solid oily base with a melting point of about 38 ° C. is prepared from a material with a high carbon number of 12,
It has a melting point of around 45 ° C and is prepared from a material with a high carbon number of 18. Also, purified waxes can be used in the same manner.

Further, the fine metal particles used in the second invention of the present invention are added to increase the heating efficiency, and the size and type are not particularly limited as long as they are fine metal particles, but preferably gold,
Silver, platinum, palladium, iridium, aluminum,
Copper, nickel, iron, magnesium, titanium, zirconium, or alloys containing two or more of these metals, as well as derivatives thereof, such as carbonyl iron, ferric hydroxide, iron oxides, ferrites (iron , Cobalt or nickel oxide), and the particle size of these is preferably 0.1 to 1000 μm, particularly preferably 1 to 100 μm.

To prepare the composition of the present invention, the solid oily base dissolved and heated at a temperature above the melting point and the antitumor substance (and the metal fine particles) are thoroughly mixed and then molded into a desired shape. The preparation method and the shape are not particularly limited.

The ratio of the antitumor substance to the solid oily base in the composition of the present invention is not particularly limited, and although it varies depending on the type of the antitumor substance, it is usually the antitumor substance 1 to the solid oily base. Agent
It is 0.5 to 50, preferably 1 to 25.

Further, the ratio of the fine metal particles and the solid oily base is not particularly limited, but is preferably 0.
01 to 2.0.

Furthermore, if necessary, the composition of the present invention may be used in combination with a surfactant, a fatty acid or a salt thereof, a water-soluble organic substance or the like for the purpose of promoting the release of the antitumor substance from the solid oily base. It is also possible to add a solid oily base, a stabilizer for an antitumor substance, an antioxidant and the like.

Administration of the antitumor agent composition thus obtained is carried out as follows.

First, the antitumor composition of the present invention is left 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.

Then, after a certain period of time after implantation, the physical fitness of the patient,
After the condition is restored, externally, hyperthermia (hyperthermia / warming therapy) is performed to melt the composition at a predetermined position and release the drug. For the hyperthermia, it is better to use local hyperthermia rather than whole-body hyperthermia for the composition of the present invention. As a method therefor, microwave, RF (radio freq) is used.
uency) Wave dielectric, ultrasonic wave, hot water perfusion method and the like.

By doing so, the antitumor agent can be administered in a necessary amount at a necessary time.

[Operation and effect of the present invention]

The antitumor agent composition of the present invention is one which, after being implanted in the body and left in place, is subjected to hyperthermia from the outside to melt the solid oily base and release the antitumor substance at the required application site when needed. . Therefore, antitumor substances
When the patient's physical strength was restored, it was possible to administer the drug while minimizing the effects of its toxicity.

〔Example〕

 Next, the present invention will be described with reference to examples.

Example 1. A transesterified triglyceride base having the following alkyl composition and a melting point of 41.5 ° C. was synthesized.

Take 60 g of this base material, heat and melt at 50 ° C, then tegafur (1
40 g of-(2-tetrahydrofuryl) -5-fluorouracil) was added and mixed well and then poured into a mold to prepare 1 g of pellets.

FIG. 1 shows the results of a release test conducted on this pellet containing tegafur using a Toyama suppository release tester.

As is clear from these results, the release of the base of tegafur when the temperature of the eluate was kept at 37 ° C was hardly observed, but it was promptly released when the temperature of the eluate was raised to 42 ° C. Was observed.

Example 2. 0.5 g of pellets obtained in Example 1 (containing 200 mg of tegafur)
Was embedded in the abdominal cavity of a Wistar male rat weighing about 400 g under ether anesthesia. Blood was collected from the carotid artery every 2 to 3 days after the operation, and the tegafur content in blood was measured using a high performance liquid chromatography method. Seven days after the surgery, the skin at the implantation site was refluxed with warm water at 44 ° C for 30 minutes, and then,
Blood tegafur content was measured. The results are shown in FIG.

From these results, it is observed that the blood concentration of tegafur is low for 7 days after implantation, but the blood concentration of tegafur is increased by heating the skin. These results indicate that the base itself gradually releases tegafur, and that tegafur is rapidly released by heating the skin.

Example 3 65 g of the base having the alkyl composition shown in Example 1 was taken, and after heating and melting at 50 ° C., 30 g of mitomycin and 5 g of ferrite having an average particle size of 5 μ were added and mixed well, and then 1 g in a pellet type. To address.

Example 4 A transesterified triglyceride base having the following alkyl composition and a melting point of 42 ° C. was synthesized.

Take 50 g of this base and 20 g of whale wax, heat and melt at 50 ° C, add 30 g of carmofur, mix well, pour into a mold, 1 g
Was prepared into a pellet.

[Brief description of drawings]

1 and 2 are graphs showing the release of tegafur of the antitumor agent of the present invention containing tegafur.

Claims (2)

[Claims] 1. A heat-sustained release antitumor agent composition containing an antitumor substance and a solid oily base having a melting point of 38 to 45 ° C. 2. A heat-sustained release antitumor agent composition containing an antitumor substance, a solid oily base having a melting point of 38 to 45 ° C., and metal fine particles.