Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-12
2003-03-25
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000, C544S310000, C544S313000
Reexamination Certificate
active
06538001
ABSTRACT:
FIELD OF THE ART
The present invention relates to the field of oncology, particularly to polymorphous modifications of anticancer drugs and to complex compounds producing a synergistic antineoplastic effect. The subject of the invention is a new physically stable crystalline modification of ftorafur (INN, tegafur), namely, of 5-fluoro-1-(tetrahydro-2-furyl)uracil, which has an enhanced antineoplastic activity, compared with the modifications known heretofore, as well as new anticancer drugs based thereon, in the form of stable molecular complexes.
PRIOR ART
There is known a large number of medicinal substances and their combinations that are the result of comprehensive investigations of and improvements in antineoplastic substances. Chemotherapeutic substances effective with respect to malignant neoplasms are used in clinical practice. Though the results of such therapy have been improved substantially in recent years, it should be noted that in many cases the efficiency remains insignificant or insufficient for attaining the required degree of inhibiting the tumor growth and an essential extension of the life span of patients. Furthermore, most of the antineoplastic preparations are characterized by high toxicity, and this tells negatively on the process of treatment.
Ftorafur, 5-fluoro-1-(tetrahydro-2-furyl)uracil (INN, tegafur), synthesized by S. A. Giller with coworkers (U.S. Pat. No. 1,168,391) as a precursor of 5-fluorouracil (hereinafter referred to as 5FU) is an effective antineoplastic preparation and is widely used in treating various tumors, particularly, of the gastrointestinal tract and of the mammary gland.
Since tegafur is a sufficiently toxic compound, numerous attempts were made to reduce its toxicity and/or increase its effectiveness.
Pharmacopeial tegafur (corresponding to FS 42-1182-86) is characterized in the x-ray powder diffraction pattern by the following interplanar distances d and the relative intensity of reflections I:
d, Å
I
8.917
64
7.199
13
6.102
14
5.808
69
5.388
25
4.845
43
4.677
90
4.522
100
4.139
13
4.085
48
4.013
24
3.949
48
3.715
17
3.620
26
3.572
75
3.450
86
3.248
32
3.131
84
2.907
25
2.842
17
2.798
34
2.328
17
2.308
15
2.171
19
1.748
71
The differential scanning calorimetry (DSC) curve of the pharmacopeial tegafur, shown in
FIG. 7
, displays two endothermal effects. The first, broad effect is in the range of 84.8-128.1° C.; the second, melting effect is in the range of 172.3-192.0° C. The UV spectrum is shown in FIG.
11
.
In particular, over many years attempts have been made to modernize the very molecule of tegafur. For instance, in Belgian Patent No. 855121 there are described optically active isomers of 2′R- and 2′S-tegafur which is chemically a racemate. However, investigations carried out by different groups of scientists (for instance, by Yasumoto M. et al., “J. Med. Chem.”, 1977, vol. 20, No. 12, 1592-1594 or by Horwitz J. P. et al., “Cancer Res.”, 1975, vol. 35, 1301-1304) showed that the biological activity of both isomers is practically the same and does not differ from the activity of the racemate. The toxicity of one or another isomer does not display substantial differences from the initial substance either.
Furthermore, four crystalline forms of tegafur were produced and investigated (Uchida T. et al., “Chem. Pharm. Bull.”, vol. 41, No. 9, 1632-1635). After treating the initial tegafur (corresponding to JP XII), &agr;-, &bgr;-, &ggr;-, and &dgr;-modifications were isolated. These crystalline modifications differ in their x-ray powder diffraction patterns, IR spectra, and DSC curves. For producing an &agr;-form, tegafur was dissolved in warm acetone and allowed to crystallize at room temperature. Colorless columnar crystals were separated by filtration. Colorless prismatic crystals of the &bgr;-form were prepared from a saturated methanol solution by evaporating the solvent with the help of a rotary evaporator. Crystals of the &ggr;-form were obtained by heating the &bgr;form at 130° C. for 1 hour. Crystals of the &dgr;-form were isolated by recrystallization from a methanol solution (very slow evaporation of methanol) at room temperature. None of the above-cited modifications offers essential therapeutic advantages.
From the above-stated a conclusion can be drawn that the problem of enhancing the tegafur activity by the synthesis or isomers or producing polymorphous modifications is still unsolved.
Concurrently, searches for compositions—synergistic mixtures containing tegafur as the active substance—were carried out.
The discovery of a combination of medicinal substances, consisting of tegafur and uracil, was preceded by an idea that since 5-FU becomes metabolized too rapidly and loses activity in the organism, uracil may be used for inhibiting these processes (U.S. Pat. No. 5,534,513). It turned out that uracil as such does not display an antineoplastic activity, it has the property to potentiate the antineoplastic effect. An investigation of the effectiveness of a mixture of tegafur and uracil (tegafur:uracil molar ratio of 1:4) is discussed, e.g., in the work of Kagawa Y. et al., “Cancer Investigation”, 1955, vol. 13, No. 5, 470-474.
Furthermore, there was produced and investigated a composition containing tegafur, uracil and folic acid (Sanchiz F. and Milla A., “Jpn. Journal Clin. Oncol.”, 1994, vol. 24, No. 6, 322-326).
In such combination preparations an aspect of extreme importance is an optimal dosage of both the active component and of the substance potentiating the activity. It is desirable that the potentiating substance should be used in minimal doses (for reducing its own toxic effect) or that this substance per se should practically have no toxic effect. Presently known synergistic preparations containing tegafur, as the active component, and a potentiator are not always optimized with respect to both the qualitative and quantitative formulation of the components. For instance, uracil (which is usually used for potentiating the activity of tegafur) is a toxic compound, though its toxicity is less pronounced compared with other substances capable of potentiating the action of tegafur:thymine, thymine, thymidine or uridine (Fujita H., Experimental and Clinical Pharmacotherapy, Issue 12, Riga, 1983, p. 205).
Hence, the present-day therapy of neoplasms requires improved preparations used in oncology, as well as developing medicinal preparations displaying high antineoplastic activity along with minimized toxicity.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide physically stable form of tegafur having an enhanced pharmacological activity. As a result of experiments it was unexpectedly found that an enhanced specific activity along with physical stability during a long period of time sufficient for commercial use is displayed by a hitherto-unknown metastable modification of tegafur, hereafter referred to as form V.
A novel form V comprises a light, “airy” white powder.
Form V is characterized in the x-ray powder diffraction pattern by the following interplanar distances d and the relative intensity of reflections I:
d, Å
I
9.035
63
7.237
23
6.149
19
5.839
100
5.413
17
4.704
42
4.551
62
4.104
36
4.041
28
3.966
25
3.730
20
3.626
25
3.588
42
3.473
60
3.437
50
3.255
30
3.143
36
2.915
23
2.382
16
2.336
20
The carried out thermal analysis revealed in the novel form three pronounced peaks on the DSC curve.
The first peak is a transition of &agr;→&bgr; type in the region of 96.6-102° C. The second and third peaks are a superposition of two endothermal effects: a &bgr;→&ggr; transition in the range of 157.1-174.2° C. and an effect of melting of the &ggr;-form with the maximum temperature of 174° C. superposed thereonto. The point of superposition of the second and third effects is in the neighborhood of 167.6° C.
The UV spectrum of form V is shown in FIG.
10
.
Form V of tegafur is prepared by dissolving a pharmacopeial tegafur substance or its individual polymorphous modifications in water, alcohol, or an alcoholic-aqueous mixture. The solvent should pre
Abelman ,Frayne & Schwab
Shah Mukund J.
Truong Tamthom N.
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