Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-04
2004-08-03
Krass, Frederick F. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S249000, C514S449000, C514S492000, C514S836000, C514S922000
Reexamination Certificate
active
06770653
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the administration to a warm blooded animal of the combination of tegafur, uracil, folinic acid, paclitaxel and carboplatin for the treatment of tumors.
BACKGROUND OF THE INVENTION
5-Fluorouracil (5-FU) is a known anti-tumor agent. The combination of 5-fluorouracil and folinic acid is a known treatment for colorectal cancer. Tegafur (1-(2-tertrahydrofuryl)-5-fluorouracil) is a prodrug of 5-fluorouracil. In vivo, 5-fluorouracil is rapidly inactivated by the enzyme dihydropyridine dehydrogenase (DPD). Uracil competitively inhibits DPD metabolism of 5-FU generated from tegafur. Thus, coadministration of uracil with tegafur results in higher exposures of active 5-FU as compared to tegafur alone. It is known that 5-fluorouracil cannot be administered orally.
U.S. Pat. No. 4,328,229 discloses an anti-cancer composition containing 1-(2-tetrahydrofuryl)-5-fluorouracil (“tegafur”) and uracil. The composition is used for delivery of 5-fluorouracil to a tumor sensitive to 5-fluorouracil in a warm-blooded animal. It is disclosed that the composition can be administered in a variety of dosage forms including an oral dosage form.
U.S. Pat. No. 5,534,513 discloses an anti-tumor composition containing tegafur and uracil in a molar ratio of 1:4. This anti-tumor composition is stated to be further potentiated by the administration of folinic acid or a pharmaceutically acceptable salt thereof. It is disclosed in the '513 patent that the combination can be administered in a variety of dosage forms including an oral dosage form.
Paclitaxel (TAXOL®), a diterpene taxane compound, is a natural substance extracted from the bark of the Pacific yew tree,
Taxus brevifolia.
In studies, it has been shown to possess excellent antitumor activity against a range of tumors in in vivo animal models including ovarian and breast, for example. Paclitaxel is an antimitotic agent which preferentially binds to microtubules. The stabilization of microtubules by paclitaxel inhibits reorganization of the microtubule network. Paclitaxel is typically administered by intravenous injection or infusion.
Carboplatin (PARAPLATIN®) is a known anti-tumor agent which induces both protein and non-protein associated DNA cross-links. This effect is observed to be cell-cycle nonspecific. Carboplatin is typically administered by intravenous infusion or injection.
It has been observed by Applicants that 5-fluorouracil can enhance the activity of paclitaxel and carboplatin. However, because 5-fluorouracil cannot be administered orally, the mode of administration for this combination therapy requires a more invasive form of administration such as through intravenous injection, and therefore typically requires administration by trained medical personnel.
It would be an advance in the art of treating tumors, especially tumors of the esophagus, gastroesophageal junction, and stomach, if a therapy could be developed employing the intravenous administration of paclitaxel and carboplatin, and oral administration of 5-fluorouracil to a warm-blooded animal for the effective treatment of such tumors.
SUMMARY OF THE INVENTION
The present invention is generally directed to the administration of tegafur, uracil, folinic acid or a pharmaceutically acceptable salt thereof, paclitaxel and carboplatin in suitable dosage forms to warm-blooded animals for the treatment of tumors, especially tumors of the esophagus, gastroesophageal junction, and stomach. In a particular aspect of the present invention, tegafur, uracil and folinic acid or a pharmaceutically acceptable salt thereof are administered in oral dosage form(s) to a warm-blooded animal having a tumor, and paclitaxel and carboplatin are intravenously administered to the warm-blooded animal. In a preferred embodiment of the invention, tegafur and uracil are present in respective amounts sufficient for tegafur to effectively and efficiently convert to 5-fluorouracil. In a particularly preferred embodiment of the invention tegafur and uracil are present in a molar ratio of about 1:4 (hereinafter referred to as “UFT”).
There is also disclosed a method of treating cancer by orally administering an anti-tumor effective amount of the combination of tegafur and uracil, preferably as UFT, and folinic acid or a pharmaceutically acceptable salt thereof to a warm-blooded animal having a tumor who is undergoing paclitaxel and carboplatin combination therapy.
REFERENCES:
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patent: 5534513 (1996-07-01), Junji et al.
patent: 5919816 (1999-07-01), Hausheer et al.
patent: 6239167 (2001-05-01), Bissery
Database HCAPLUS on ACS, Accession No. 2000:103596, Langer, The role of tegafur/uracil in pulmonary maligancy, Abstract, 1999, 58 (3), pp. 71-75.
Database HCAPLUS on ACS, Accession No. 2000:131659, Hoff et al., Tegafur/uracil +calcium folinate in colorectal cancer: Double modulation of fluorouracil. Abstract, 1999, 58 (3), pp. 77-83.
Database HCAPLUS on ACS, Accession No. 2000:103599, Brockstein et al., Oral chemotherapy in head and neck cancer, Abstract, 1999, 58 (3) pp. 91-97.
Database MEDLINE on ACS, Accession No. 94189518, Grau et al., Carboplatin plus ftorafur as a palliative treatment in locally advanced cancer on the oral cavity and lip., Apr. 1994, 17(2) pp. 134-136.
Ajani Jafferhusen Abdulhusen
Benner Steven E.
Dugan Terry S.
Bristol--Myers Squibb Company
Gibbons Maureen S.
Krass Frederick F.
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