PHARMACEUTICAL COMPOSITION

Abstract: A pharmaceutical composition, particularly when used as an antitumor agent, containing as the active substance, a mixture of 5′-deoxy-5-fluorouridine or a pharmaceutically acceptable salt thereof; and a purine nucleoside or a purine nucleotide.

Description: Pharmaceutical composition This invention is concerned with a novel pharmaceutical composition. More particularly, this invention is concerned with a novel pharmaceutical composition, which contains, as the active substance, a mixture of (a) 5'-deoxy-5-fluorouridine, hereinafter referred to as 5'-DFUR. or a pharmaceutically acceptable salt thereof; and (b) a purine nucleoside or a purine nucleotide; still more particularly with such a composition when used as an antitumor agent. It has been known that 5'-DFUR is useful as an antitumor agent and its therapeutic indices are several times higher than that of 5-fluorouracil. hereinafter referred to as 5-FU. It has now surprisingly been found that the antitumor activity of the mixture of the above mentioned compounds (a) and (b) is remarkably superior to that of 5'-DFUR. without any increase of toxicity. In a preferred embodiment, the pharmaceutical composition provided by the present invention may contain the active substances in the weight ratio of the above mentioned compound (a) to compound (b) of 1:0.1 to 1:20, more pre ferably 1:1 to 1:10. In the present invention, preferred examples of the pharmaceutically acceptable salts of 5'-DFUR are non-toxic' salts such as those formed with acids selected from a group consisting of inorganic mineral acids and organic acids, such as the hydrochloride, hydrobromide. phosphate, sul- - phate, nitrate, acetate. formate, maleate, fumarate and benzoate; and preferred examples of purine nucleosides and purine nucleotides are. for example, guanosine. adenosine, inosine. xanthosine. guanosine-5'-monophosphate, guanosine -5'-diphosphate. guanosine-5'-triphosphate, adenosine-5' -monophosphate, adenosine-5'-diphosphate. adenosine-5l-tri- phosphate, inosine-5'-monophosphate, inosine-5'-diphosphate, inosine-5 '-triphosphate. xanthosine-5'-monophosphate, xanthosine-5'-diphosphate and xanthosine-5 1 -triphosphate. The pharmaceutical composition provided by the present invention can be useful for the treatment of tumors. such as breast cancer, stomach cancer. colorectal cancer, pancreatic cancer. head-and neck cancer, lung cancer and the like. The pharmaceutical composition provided by the present invention may contain the combination of the aforementioned active substancesin association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material suitable for enteral. percutaneous or parenteral administration, such as water. gelatine, gum arabic. lactose. starch, magnesium stearate. talc. vegetable oils, polyalkylene glycols and petroleum jelly. The pharmaceutical composition provided by the present invention can be administered orally, e.g. in form of tablets. capsules. pills. powders, granulates, solu tons, syrups, suspensions or elixirs. The administration can also be carried out parenterally, e.g. in form of sterile solutions, suspensions or emulsions: or locally, e.g. in form of solutions, suspensions, salves, powders or aerosols. The pharmaceutical composition can be sterilized and/or can contain further adjuvants such as preserving, stabilizing, setting, emulsifying agents, flavour-improving agents. salts for variation of the osmotic pressure or substances acting as buffers. The pharmaceutical composition can be prepared in a conventional manner. The dosage of the active substances depends on the route of administration, the age, weight and condition of the patient and the particular disease to be treated. However, a typical dosage for adults is in the range of 100 to 6,000 mg/body/day in he case of oral, rectal or parenteral administration. Rectal administration and intravenous injection are preferred routes of administration of the pharmaceutical composition according to the present invention. The enhanced antitumor activity of the pharmaceutical composition in accordance with the present invention is evident from the tests described hereinafter. (l) Antitumor effects of combination of 50-DFUR with auano- sine 5'-monoPhosphate (hereinafter referred to as GMP) BDF1 male mice weighing 21 to 23 g were used as experimental animals. P388 leukemia cells were implanted intraperitoneally into the mice. Seven days after the implantation. ascites were collected and diluted with saline to prepare the suspension containing 106 P388 leukemia cells in 0.05 ml. The mice were intraperitoneally implanted on day 0 with 106 P388 cells. Each group contained 6 mice. 5'-DFUR and GMP were dissolved in saline, alone or combined with each other. The test compounds were administered intraperitoneally from day 1 to day 5. The antitumor effects were evaluated by the increase in life span over control (ILS) calculated by the following formula: T: Mean survival time (days) in the test drug groups C: Mean survival time (days) in the control group admini stered intraperitoneally with saline alone The safety of the drug was evaluated by the therapeutic ratio; the dose ILSmax / the dose ILS30. As can be seen from Table 1, when the dose of 5'-DFUR was in the range from 2 to 250 mg/kg/day, the higher the dose of 5'-DFUR was. the longer the survival time was, both in the group receiving 5'-DFUR alone and in the group receiving 5'-DFUR combined with GMP at 100 mg/kg/day. The ILSmax was 48% in the 5'-DFUR alone group. while 107% in the 5'-DFUR-GMP combination group. Table 1 Effects of GMP (100 mg/kg/day) on the antitumor activity of 5'-DFUR against P388 leukemia Dose of 5'-DFUR ILS (%) (ms/kg/dav i.p.) 5'-DFUR alone 5'-DFUR+GMP 2 0 31 4 ' 1 56 8 8 61 16 15 73 32 21 76 63 21 82 125 31 101 250 48 107 500 24 71 Note: Mean survival time in the control group: 10.7 days The therapeutic ratio was 2 (250 mg/125 mg) in the 51-DFUR alone group. while 125 (250 mg/2 mg) in the 5'-DFUR -GMP combination group. The therapeutic ratio in the 5'-DFUR-GMP combination group was 63 times as high as in the 5'-DFUR alone group. Moreover. as the dose of GMP was increased. the ILS gob high accordingly (see Table 2) without increasing any toxic effects. With GMP alone, there was no influence observed on ILS (see Table 3). Table 2 Dose examination of GMP on the antitumor activity of 5'-DFUR against P388 leukemia Dose of 5'-DFUR Dose of GMP (mg/kg/day i.p.) (mg/kg/day i.p.) ILS (%) 250 0 48 250 100 107 250 200 112 250 300 120 250 500 125 250 1000 130 Table 3 The antitumor activity of GMP against P388 leukemia Dose of 5'-DFUR Dose of GMP (mg/kg/day i.p.) (mg/kg/day i.p.) ILS (%) 0 100 -3 0 300 5 0 500 8 0 1000 1 The antitumor effects of the combination of 5'-DFUR with GMP have been compared with those of the combination of 5-FU with GMP (Table 4). The therapeutic ratio was 2 with 5'-DFUR alone and 125 with the combination of 5'-DFUR with GMP. 63 times as high as with 5'-DFUR alone, while it was 26.6 with 5-FU alone and 74.0 with the combination of 5-FU with GMP. 2.8 times as high as with 5-FU alone. The therapeutic ratio of the combination of 5'-DFUR with GMP was higher than that. , of the combination of 5-FU with GMP. Accordingly. the combi- nation of 5'-DFUR with GMP is considered very significant for cancer chemotherapy. Table 4 Comparison of the combined effect of GMP (100 mg/kg/day) and 5-FU or 5'-DFUR 5'-DFUR alone 5'-DFUR+GMP 5-FU alone 5-FU+GMP Therapeutic ratio 2 125 26.6 74.0 (dose ILSmax/ (250/125) (250/2) (20/0.75) (20/0.27) dose ILS30) (2) Antitumor effects of combination of 5'-DFUR with purine nucleotides In a manner analogous to that described in (1) above, except that instead of GMP. adenosine-5'-monophosphate or inosine-5 ' -monophosphate (hereinafter respectively referred to as AMP and IMP) was used, the antitumor effects were tested. The results are given in Table 5. Table 5 Compound Change of Survival Dose body weight days (mg/kg/day) on days 6 (mean#SD) (%) (g) 5'-DFUR (250) -2.5 13.1#0.6 139 '-DFUR+GMP (250 + 100) -2.3 16.5#1.4 172 5'-DFUR+AMP (250 + 100) -3.4 16.7i0.5 174 5'-DFUR+IMP (250 + 100) +2.4 16.0#1.8 167 GMP (100) +1.5 8.8+0.8 92 AMP (100) +0.9 9.5i1.9 99 IMP (100) +1.5 9.7j1.8 101 Saline +1.1 9.6i1.6 (3) Antitumor effects of combination of 5'-deoxy-5 fluorocytidine (hereinafter referred to as 5'-DFCR) with GMP In a manner analogous to that described in (1) above except that 5'-DFCR was used instead of 5'-DFUR, the antitumor effects thereof was tested as a referential example. No enhancement of antitumor effects was observed with the combination of 5'-DFCR and GMP, as can be seen from Table 6. Table 6 GMP (100 mg/kg/day) Compound without with Change of Survival Change of Survival Dose body weight days T/C body weight days T/C on days 6 (mean#SD) (%) on days 6 (mean#SD) (%) (mg/kg/day) (g) (g) 5c-DFCR 28 +0.2 10.7#1.5 111 +0.4 10.0#0.6 104 55 +1.0 10.0#1.7 104 +0.9 11.2#1.6 117 110 +0.6 10.3#0.5 107 #0.0 11.0#0.6 115 220 -0.8 12.0#1.7 125 -0.3 12.0#0.0 125 Saline +1.1 9.6#1.6 - +1.5 8.8#0.8 92 Acute toxicity Groups of 5 weeks old male ICR mice were treated intraperitoneally with 5'-DFUR and GMP at the dosage given in thefollowing Table 6. Each mice group contained 5 mice. Two weeks after. the number of died mice were counted. The quotient number of died mice/number of tested mice is given in Table 7. L Table 7 EMI9.1 <tb> <SEP> GMP <tb> <SEP> (mg/kg) <SEP> O <SEP> 2000 <SEP> 4000 <tb> 5'-DFUR <SEP> -DFUR <tb> (mg(kg) <tb> <SEP> 0 <SEP> not <SEP> done <SEP> 0/5 <SEP> 1/5 <tb> <SEP> 2000 <SEP> 0/5 <SEP> not <SEP> done <SEP> 6/6 <tb> <SEP> 4000 <SEP> 0/5 <SEP> 0/5 <SEP> 5/5 <tb> The followings are examples of a typical dosage form: 1. InjectIon in a vial 5'-DFUR 500 mg GMP 2,000 mg 5N NaOH 370 Frl Distilled water 5 ml 2. InjectIon in a vial 5'-DFUR 1,000 mg GMP 2.000 mg 5N NaOH 446 l Distilled water 10 ml

Claims: CLAIMS: 1. A pharmaceutical composition containing as the active. substance, a mixture of 5'-deoxy-5-fluorouridine or a phar- maceutically acceptable salt thereof; and a purine nucleoside or a purine nucleotide. 2. A pharmaceutical composition according to claim 1 as antitumor agent. 3. A pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of 5'-deoxy-5-fluorouridine or the pharmaceutically acceptable salt thereof to the purine nucleoside or the purine nucleotide is 1:0.1 to 1:20. particularly 1:1 to 1:10. 4. A pharmaceutical composition according to claim 1, 2 or 3, which contains a mixture of 5'-deoxy-5-fluorouridine and guanidine-5' -monophosphate. 5. The use of a mixture of 5'-deoxy-5-fluorouridine or a pharmaceutically acceptable salt thereof; and a purine nucleoside or a purine nucleotide, for the manufacture of a pharmaceutical composition according to any one of claims 1-4.

Inventors: IIGO, MASAAKI NATIONAL CANCER CENTER, MIWA, MASANORI, NITTA, KAZUO
Applicants: F. HOFFMANN-LA ROCHE AG
Application year: 1986
Main classification: A61K31
IPC codes: C07H19, A61K31