Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-21
2003-06-10
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06576635
ABSTRACT:
1. FIELD OF INVENTION
The invention relates to a novel composition of matter—trimetrexate ascorbate—and to methods of its preparation and use. The invention is further related to compositions comprising trimetrexate ascorbate, to compositions comprising trimetrexate and ascorbic acid, and to methods for preparing and using such compositions.
2. BACKGROUND OF THE INVENTION
The free base of trimetrexate, chemically named 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline, has the following structure:
Trimetrexate is an inhibitor of dihydrofolate reductase (DHFR), an enzyme which catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, and thus inhibits folate-dependent formyltransferases and interferes with thymidylate and purine biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.
Trimetrexate free base decomposes over time when exposed to oxygen at room temperature. The complete mechanism by which this process occurs is not known, although the formation of 6-aminomethyl-5-methyl-2,4-quinazolinediamine has been observed during trimetrexate degradation. Interestingly, it has been reported that a major decomposition product of the trimetrexate glucuronate salt in solution is (2,4-diamino-5-methyl-6-carboxaldehyde)quinazoline. Stetson, P. L., et al.,
J. Chromatography,
464, 163-171 (1989). Formation of both of these decomposition products is catalyzed by heat and light. Cf. March, J.,
Advanced Organic Chemistry
pp. 1194-1195 (4
th
ed., 1992).
An injectable form of the amorphous glucuronate salt of trimetrexate is sold under the commercial name Neutrexin® by U.S. Bioscience (West Conshohocken, Pa.). Neutrexin® provides trimetrexate glucuronate as a lyophilized powder suitable for reconstitution, which, when reconstituted, is stable for 48 hours at room temperature, 4 days when refrigerated, or 8 days when stored at freezer temperatures.
Physicians' Desk Reference,
53
rd
ed., pp. 3172-3175 (1999).
Neutrexin® has been approved for use in the United States and Canada for the treatment of
Pneumocystis carinii
pneumonia (PCP) in patients with acquired immune deficiency syndrome (AIDS). Id. It is administered in combination with leucovorin (folinic acid), which provides a source of reduced folate necessary for normal cell function. Leucovorin is readily transported into mammalian cells by an active, carrier-mediated process, and can be assimilated into cellular folate pools following its metabolism. Because the
Pneumocystis carinii
organism lacks the reduced folate carrier-mediated transport system, leucovorin is prevented from entering the organism. The adjunctive administration of trimetrexate and leucovorin thus protects normal host cells, but not
Pneumocystis carinii,
from the cytotoxicity of trimetrexate.
Trimetrexate also possesses in vitro and in vivo activity against a range of murine and human tumor cell lines. It shows, for example, in vitro antitumor activity against murine cell lines such as L1210, L5178Y, S-180, W-256, and in vivo utility against murine tumors such as B16 melanoma, colon 26 and 38, L1210 and P388 leukemia and CD8F mammary tumors. Bertino, J. R., et al.,
Biochem. Pharmacol.
28:1983-1987 (1979); Lin, J. T., and Bertino, J. R.,
J. Clin. Oncology
5(12):2032-2040 (1987); O'Dwyer, P. J., et al.,
NCI Monographs
5:105-109 (1987). Trimetrexate also exhibits in vitro activity against human tumor cells lines derived from breast, colon, lung, ovary, renal and melanoma cells. Other possible uses for trimetrexate include the treatment of malaria, psoriasis, and rheumatoid arthritis.
The low water solubility (<0.1 mg/ml) and long term instability of trimetrexate free base diminish its usefulness in the treatment of disease, but the severity of these problems can be lessened if trimetrexate salts are instead used. Examples of some trimetrexate salts are disclosed by: Hempel, A., et al.,
Cancer Biochem. Biophys.,
10, 25-30 (1988); U.S. Pat. Nos. 5,716,968 and 5,716,960, both to Kennedy; and U.S. Pat. No. 4,376,858 to Colbry (“Colbry”). Colbry teaches that a preferred salt is trimetrexate glucuronate because of its superior water solubility (>50 mg/ml), stability, and the low toxicity of glucuronic acid. The synthesis of trimetrexate glucuronate is disclosed both by Colbry and by Hicks, J. L., et al.,
J. Labeled Compounds Radiopharm.
29, 415 (1991).
Although trimetrexate glucuronate oxidizes more slowly than does trimetrexate free base, the solution half-life of trimetrexate glucuronate is reportedly only 51.6±0.8 days at 37° C. Stetson, P. L., et al.,
J. Chromatography
464, 163-171 (1989). There thus remains a need for pharmaceutically acceptable forms of trimetrexate that have formulation advantages such as acceptable solubility and improved stability as solids and/or liquids.
3. SUMMARY OF THE INVENTION
The invention is directed to novel trimetrexate compositions which have advantageous formulation properties, advantageous stability and storage properties, and advantageous therapeutic and prophylactic benefits. These compositions comprise trimetrexate and ascorbate moieties. Particular compositions include trimetrexate ascorbate, solid and liquid compositions comprising trimetrexate ascorbate, and solid and liquid compositions comprising trimetrexate and ascorbic acid.
The trimetrexate compositions of the invention have unexpectedly been found to have improved chemical and physical characteristics as compared to prior trimetrexate compositions. For example, the trimetrexate compositions of this invention evidence little color change and resist degradation when stored over time. Solid trimetrexate compositions of the invention are also highly soluble in aqueous solvents, and may thus be readily reconstituted to form liquid trimetrexate compositions that are free of solid precipitates and are suitable for parenteral administration to patients. The invention thus contributes significantly to the trimetrexate art by providing pharmaceutical products which fully exploit the biological activity of trimetrexate.
A first embodiment of the invention encompasses trimetrexate ascorbate. This novel composition of matter may be crystalline or amorphous.
A second embodiment of the invention encompasses compositions comprising trimetrexate ascorbate. Bulk compositions, pharmaceutical compositions, and pharmaceutically acceptable dosage forms are encompassed by this embodiment, each of which may be solid and liquid. Pharmaceutically acceptable solid trimetrexate ascorbate compositions may be suitable for oral, topical, transdermal, or mucosal delivery. Pharmaceutically acceptable liquid trimetrexate ascorbate compositions may be suitable for parenteral, oral, topical, transdermal, or mucosal delivery.
A third embodiment of the invention encompasses compositions comprising trimetrexate and ascorbic acid. Bulk compositions, pharmaceutical compositions, and pharmaceutically acceptable dosage forms are encompassed by this embodiment. Compositions comprising trimetrexate and ascorbic acid preferably comprise trimetrexate and ascorbic acid in a trimetrexate-to-ascorbic acid molar ratio of from about 1:0.1 to about 1:10, more preferably from about 1:1 to about 1:5, and most preferably from about 1:2 to about 1:4. Compositions encompassed by this embodiment may be solid or liquid.
A particular liquid composition of this invention comprises trimetrexate and ascorbic acid wherein the trimetrexate is present in a concentration of from about 6 to about 18 mg/ml, more preferably from about 8 to about 15 mg/ml, even more preferably from about 9 to about 14 mg/ml, and most preferably from about 10 to about 13 mg/ml. A particularly preferred liquid composition comprises trimetrexate and ascorbic acid wherein the trimetrexate is present in a concentration of about 10 mg/ml. Another liquid composition of the invention comprises trimetrexate and ascorbic acid wherein the ascorbi
Stogniew Martin
Zadei Javad M.
MedImmune Oncology Inc.
Pennie & Edmonds LLP
Raymond Richard L.
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