Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-15
2003-09-16
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252060, C514S386000, C514S415000, C514S437000, C514S438000, C514S461000
Reexamination Certificate
active
06620834
ABSTRACT:
TECHNICAL FIELD
The invention relates to a pharmaceutical composition to be administered to the large intestine for treating a colorectal cancer.
BACKGROUND ART
In cancer therapy the surgical treatment is the mainstream at present. However, in order to improve the performance of the surgical treatment further, an ancillary use of chemotherapy is indispensable. Since cases of cancer metastasis to the liver or lung due to a hemokinetic metastasis from, in particular, the colorectal cancer is frequently observed, a postoperative ancillary chemotherapy has become essential. For the chemotherapy aiming to inhibit the postoperative metastasis and recurrence of cancer, usually an oral anticancer agent represented by 5-fluorouracil is mainly used. In case of using such an anticancer agent expecting the metastasis inhibition or recurrence prevention, a medicine-taking period for one year or more is necessary, though the present situation is that the medication is compelled to be abandoned owing to the development of a strong digestive tract disorder or a systemic side effect such as a severe myelosuppression. Therefore, naturally there is limitation for achieving the above object only by the chemotherapy mainly using an anticancer agent.
Further, in case of making the chemotherapy aim to prevent especially the postoperative liver metastasis of colorectal cancer, it is important to carry out a drug delivery from the mesenteric vein to the portal in a metastasis route of cancer cells and to maintain a drug concentration in the portal blood.
From the above viewpoints, it is considered to be effective that a drug with a low side effect except an anticancer agent, which is appropriate for inhibiting the metastasis and can be administered for a long period, is directly administered to the large intestine. As described above, from the above viewpoints of a dosage form which can be administered for a long period at home, a dosage form like an oral preparation is naturally preferable.
At present, among the representative agents being developed as a metastasis inhibitor there are drugs to inhibit the cell adhesion between cancer cells and vascular endothelial cells or their interaction, being antibodies for cell adhesion molecules such as fibronectin, ICAM-1, integrin, selectin, cadherin and laminin, peptide fragments or antisenses (JP, A, 10-147600, etc.). Although these drugs inhibit cell adhesion or metastasis in a specific way, there is only an administration method such as an intravenous administration owing to high molecular oligopepteides or oligonucleotides in all, being not apt to a home treatment because of inferior convenience.
Meanwhile, in drugs of low molecular weight, nonsteroidal antiinflammatory agents represented by aspirin or acetaminophen having a cyclooxygenase inhibitory activity are reported to have action to inhibit carcinogenesis, cancer recurrence and vascularization (Carcinogenesis., 19(12):2195-9, 1998, Inflammation Research., 47 Suppl 2:S112-6, 1998, etc.). Although these drugs can be administered orally because they are low molecular weight drugs, it is necessary to increase the dosage to obtain an expected effect, while a continuous administration produces digestive tract disorders in a high frequency.
Although there is a possibility that a cyclooxygenase inhibitor is put into practice as a medicine for inhibiting the cancer recurrence and cancer metastasis, the present situation is that it is not put into practice owing to its weak activities by itself and problems of side effects against the digestive tract system.
Although various drug developments in which a postoperative ancillary chemotherapy aiming at inhibiting the metastasis and recurrence of cancer are tried as described above, a drug which has a high effectiveness and can be orally administered to make the administration of a long period possible has not been developed to date. Although oral anticancer agents of 5-FU type currently used in the postoperative anchillary chemotherapy could also be administered orally in a simple way, a strong digestive tract disorder or myelosuppression which the anticancer agents have would become problems. Although trials have also made to administer drugs such as a live bacteria preparation or B-carotene low in toxicity aiming at inhibiting the cancer recurrence, it can hardly be said at present that they have a sufficient effect.
DISCLOSURE OF THE INVENTION
Consequently, the object of the invention is to solve the above problems and to provide a medicinal composition for treating colorectal cancer to be administered to the large intestine which is most appropriate for inhibiting the postoperative liver metastasis and recurrence of colorectal cancer using a preparation disintegrating in the large intestine.
The inventors made extensive researches to solve the above problems and consequently found out that the cancer metastasis inhibitory effect was synergistically increased by mixing a cyclooxygenase inhibitor having a little metastasis inhibitory and vascularization inhibitory action with an HMG-CoA reductase inhibitor showing almost no metastasis inhibitory effect by itself, making it possible to improve sharply a surviving rate of prognosis, and accomplished the invention.
Namely, the invention relates to a medicinal composition for treating colorectal cancer, characterized in that a cyclooxygenase inhibitor and an HMG-CoA reductase inhibitor are mixed.
The invention also relates to the above medicinal composition for treating colorectal cancer, characterized in that the mixing ratio of a cyclooxygenase inhibitor and an HMG-CoA reductase inhibitor is 1:0.1-1:5.
The invention also relates to the above medicinal composition for treating colorectal cancer, characterized in that the cyclooxygenase inhibitor is a nonsteroidal antiinflammatory agent.
Further, the invention relates to the above medicinal composition for treating colorectal cancer, characterized in that the nonsteroidal antiinflammatory agent is selected from loxoprofen sodium, ketoprofen, isopropyl antipyrine, antipyrine, phenacetin, tolfenamic acid, mefenamic acid, ethenzamide, sulpyrine, fenbufen, piroxicam, ibprofen, naproxen, meclophenamate, flurbiprofen, diclofenac, sulindac, aspirin, salicylic acid, acetaminophen, meloxicam, nimesulide, etodlac, nabumeton, celecoxib and rofecoxib.
The invention also relates to the above medicinal composition for treating colorectal cancer, characterized in that the HMG-CoA reductase inhibitor is one or more selected from pravastatin, simvastatin, lovastatin, fluvastatin, atrovastatin and cerivastatin.
The invention also relates to a preparation reaching to the large intestine, comprising the above composition.
Further, the invention relates to a preparation disintegrating in the large intestine, comprising the above composition.
BRIEF DESCRIPTION OF DRAWING
FIG. 1
is the graph showing the metastasis inhibitory ratios in each solution when the liver metastasis inhibitory effect in Yoshida's sarcoma rat model bearing a colorectal cancer was evaluated using the drug-mixed solution prepared in the example 1.
Embodiment of the Invention
In the following is explained are embodiments of the invention.
As a preferable embodiment, the mixing ratio of a cyclooxygenase inhibitor and an HMG-CoA reductase inhibitor is 1:0.1-1:5, more preferably 1:0.5-1:2. Namely, the effect of each drug which alone has only a low metastasis inhibitory effect is greatly improved by a synergistic action adjusting the mixing ratio, and it becomes possible to improve remarkably a surviving rate of prognosis by utilizing it as a postoperative ancillary chemotherapy for colorectal cancer.
In the invention, as an HMG-CoA reductase inhibitor preferably used are simvastatin, pravastatin, lovastatin, fluvastatin, atrovastatin and cerivastatin, or the salts thereof.
As a cyclooxygenase inhibitor also preferably used are nonsteroidal antiinflammatory agents represented by loxoprofen sodium, ketoprofen, isopropyl antipyrine, antipyrine, phenacetin, tolfenamic acid, mefenamic acid, ethenzamide, sulpyrine,
Goto Takeshi
Tanida Norifumi
Tomizawa Naoko
Goldberg Jerome D.
Hisamitsu Pharmaceutical Co. Inc.
Licata & Tyrrell P.C.
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