Antitumor compositions for non-injection administration

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel antitumor compositions which exhibit marked antitumor action by non-injection administration. More specifically, the invention relates to novel antitumor compositions for non-injection administration each of which comprises a pharmacologically effective quantity of an ester of 1-.beta.-D-arabinofuranosylcytosine-5'-phosphate and a vehicle.
2. Prior Art
It has been known that 1-.beta.-D-arabinofuranosyl cytosine (hereinafter referred to as ara-C) is an agent which is indispensable for chemotherapy of cancers, especially leukemias such as acute lymphatic leukemia (ALL), acute myelogenous leukemia (AML) and meningo-leukemia. Recently, ara-C has been often employed in combination with other agents, for example, in DCMP (daunomycin-ara-C-mitomycin-predonisolone) therapy and MFC (mitomycin-5-fluorouracil-ara-C) therapy. Thus, the ara-C has been often used as an essential agent of combined therapeutics in the chemotherapy of leukemias as well as solid cancers such as lymphoma, gastric and intestinal cancers and adenocarcinoma (e.g., reference is made to "Chemotherapeutics of Cancers", Yakuzai Koza Vol. 1, p.p. 75-80, compiled by H. Niitani and H. Kanagami, published by Clinic Magazine Company, Japan, July 1, 1977). At the moment, however, ara-C can only be used for intravenous or intramuscular injection from a viewpoint of pharmacodynamics and actually cannot be used for oral administration. This fact has been an obstacle to further extensive applications of ara-C. Especially, its continuous administration by intravenous injection gives rise to physical and mental pain to a considerable extent in the patients. Thus, the development of forms of ara-C which can be administered orally has been urgently needed in the clinical field.
Hitherto, the syntheses of ara-C derivatives which can be administered orally have been tried (cf. J. Med. Chem. Vol. 19, No. 8, p.p. 1013-1016, 1976). It has also been reported that the oral administration of ara-C is effective in combination with a cytidinedeaminase inhibitor such as tetrahydrouridine (cf. Cancer Research, Vol. 30, p.p. 2166-2172, 1970). However, the effects are not remarkable and there has been no prospect of practical use of this administration.
On the other hand, the present inventors have synthesized alkyl or aryl esters of arabinofuranosylcytosine-5'-phosphate (hereinafter referred to as ara-CMP) in order to study improvement in so-called bioavailability of the ara-C derivatives such as their resistivity to cytidinedeaminase, their effects on ara-C-resistant strains, and their antitumor properties based on selective affinity for organs. These esters were tested with respect to their antitumor properties (cf. Reports on the proceedings of the 35th annual meeting of the Japanese Cancer Association, p. 133, No. 476, issued by Nippon Gan Gakkai, Sept. 1, 1976). The esters of ara-CMP, however, only showed a lower activity than ara-C and ara-CMP in cell proliferation-inhibition effects in vitro using L5178Y cells. Also, in the antitumor tests in vivo using mouse-leukemia cell L1210, the esters tested only showed an increase in life span similar to or lower than ara-CMP when they were administered intraperitoneally. The alkyl esters having 11 or more carbon atoms in the alkyl moiety showed some effectiveness in that the effective doses were decreased but were accompanied by an increase in toxicity. On the whole, in both in vitro experiment and intraperitoneal administration, pharmacologically useful improvements in ara-C or ara-CMP were not observed over the ara-CMP esters.
Hitherto, it has been considered that the most effective administration of a drug is generally attained by intravenous injection (or intraperitoneal injection), and the maintenance of the drug concentration in the blood at a certain level is required for the drug to exhibit effectiveness in the therapy of leukemias such as L1210 leukemia. Consequently, the ara-CMP esters which are not very effective in intraperitoneal administration have not especially been appreciated as antitumor agents.
SUMMARY OF THE INVENTION
The present inventors have carried out extensive research on the derivatives of ara-C in order to develop novel dosage forms of ara-C which will exhibit marked antitumor properties in non-injection administration such as oral administration. The present invention is based on the finding that ara-CMP esters, which have shown no significant effectiveness by parenteral administration, unexpectedly exhibit extremely strong antitumor properties by non-injection administration. According to the present invention, briefly summarized, there are provided antitumor compositions for non-injection administration each comprising a pharmacologically effective quantity of an ester of 1-.beta.-D-arabinofuranosylcytosine-5'-phosphate represented by the following formula and a vehicle. ##STR2## wherein R is a monovalent aliphatic hydrocarbon group having 14 to 23 carbon atoms, and A stands for a hydrogen atom or a pharmaceutically-acceptable alkali cation.
DETAILED DESCRIPTION OF THE INVENTION
The ara-CMP esters, the active component of the present antitumor compositions, are the series of the compounds represented by the above general formula. The substituent R in the formula means a monovalent aliphatic hydrocarbon group having 14 to 23 carbon atoms, which may be saturated or unsaturated and can be branched or substituted with a suitable functional group provided that their effects are equivalent. The symbol A stands for hydrogen atom or a pharmaceutically-acceptable alkali cation, examples of which are alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and ammonium ion.
Examples of the ara-CMP esters are ara-CMP-tetradecyl ester (hereinafter referred to as C14-ara-CMP ester), ara-CMP-pentadecyl ester (hereinafter referred to as C15-ara-CMP ester), ara-CMP-cetyl ester (hereinafter referred to as C16-ara-CMP ester), ara-CMP-heptadecyl ester (hereinafter referred to as C17-ara-CMP ester), ara-CMP-stearyl ester (hereinafter referred to as C18-ara-CMP ester), ara-CMP-nonadecyl ester (hereinafter referred to as C19-ara-CMP ester), ara-CMP-eicosyl ester (hereinafter referred to as C20-ara CMP ester), ara-CMP-heneicosyl ester (hereinafter referred to as C21-ara-CMP ester), ara-CMP-tricosyl ester (hereinafter referred to as C23-ara-CMP ester), ara-CMP-oleyl ester (hereinafter referred to as C18-1-ara-CMP ester), ara-CMP linoleyl ester, ara-CMP palmitoleyl ester, and the alkali salts thereof. Among them C16-ara-CMP ester, C18-ara-CMP ester, C18-1-ara-CMP ester and C20-ara-CMP ester and alkali salts thereof are preferable.
The process for preparing the ara-CMP esters is not especially restricted in the present invention. One of the representative processes for the preparation is, for example, to mix (A) the ara-CMP salt which has been protected at its N.sup.4 -, O.sup.2' - and/or O.sup.3' - positions with an acyl group (e.g., acetyl, butyryl, benzoyl groups) and (B) an alcohol having the desired monovalent aliphatic hydrocarbon group, to condense. The condensation reaction is accelerated by an aryl-sulfonyl chloride in an organic solvent or mixed organic solvents (as disclosed in the specification of Japanese Laid-Open Pat. No. 89681/1977).
Examples of the ara-CMP salts in the above mentioned process are tertiary alkylammonium salts such as triethylammonium salt, tri-n-butylammonium salt, tri-n-octylammonium salt, quaternary alkylammonium hydroxide salts such as methyl-tri-n-butylammonium hydroxide salt, methyl-tri-n-octylammonium hydroxide salt, and amidine salts such as 4-morpholino-N,N'-dicyclohexylcarboxamidine salt. Examples of the organic solvents are N,N-dimethylformamide, N,N-dimethylacetamide, chloroform, pyridine, dioxane, tetrahydrofuran, ethyl acetate, tri-n-butylamine, and mixtures thereof. Examples of the arylsulfonyl chlorides are tri-isopropylbenzenesulfonyl chloride, o-tosyl chloride, p-tosyl chloride, benzenesulfonyl chloride, 2-mesitylenesulfonyl chloride, and the like.
The reaction conditions are, for example, in pyridine, 1 to 2 hours at room temperature when p-tosyl chloride is used as the condensation agent, and 1 to 20 hours at room temperature when tri-isopropyl-benzenesulfonyl chloride is used.
Each of the antitumor compositions of the present invention contains a pharmacologically effective quantity of the ara-CMP ester and a vehicle and is prepared into a dosage form which is suitable for non-injection administrations. The dosage forms for non-injection uses include, depending on the methods and routes of administration, oral preparations such as tablets, capsules, soft capsules, granules, slow-releasing granules, fine granules, powders and syrups; parenteral preparations such as suppositories; and local preparations such as ointments.
Suitable vehicles to be employed for making oral preparations are, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethylcellulose, glycerine, sodium alginate, and gum arabic. As the coating materials for slow-releasing granules, ETHOCEL (trade name, supplied from The Dow Chemical Company, USA), EUDRAGIT (trade name, supplied from Rohm & Haas Company, USA), etc. can be used. As the vehicles for soft capsules, for example, edible oils and fats having a melting point of lower than about 40.degree. C. such as sesame oil, rape seed oil, fatty oils having middle-length carbon chains are used and, if desired, surface active agents, suspending agents and/or silicon dioxide can be added thereto.
Depending on the dosage forms of the pharmaceutical preparations, varieties of binders, disintegrators, lubricants, preservatives, flavoring agents, coloring agents, seasoning agents and the like can be suitably selected and incorporated into the preparations. The pharmaceutical preparations can be prepared according to conventional methods. The pharmacologically-effecitve quantity of the ara-CMP esters in the oral preparations depends upon the kind of the esters, and their daily doses for adult are generally in the range of 30 to 1500 mg (0.5 to 25 mg/kg of body weight). The preferable dosage of the pharmaceutical preparation unit depends on the kind of ara-CMP esters, the dosage forms, and the schedules of administration and is generally in the range of 5 to 500 mg. In each dose of the pharmaceutical preparations, the ester comprises approximately 0.5% by weight or more of the dose.
The base materials for the suppositories are not especially restricted, and conventional base materials such as cacao butter, emulsified cacao butter, laurin fat, and WITEPSOL are used. The suppositories are prepared according to conventional methods. The pharmacologically-effective quantity of an ara-CMP ester in suppositories depends upon the kind of the ester, and its daily dose is generally in the range of 30 to 1500 mg (0.5 to 25 mg/kg of body weight). The dosage of the preparation unit is preferably in the range of 15 to 750 mg.
As the base for ointments to be applied locally, for example, greasy base materials such as liquid paraffin, cetyl alcohol, stearyl alcohol, white vaseline, squalan, lanolin, and cholesterol can be used. A suitable concentration of an ara-CMP ester in the ointments depends on the kind of the ester and is generally in the range of 0.3 to 10% by weight.
The pharmacological activity tests and acute toxicity tests of the ara-CMP esters are described below.
TEST EXAMPLE 1
Therapeutic Test on L1210 Leukemia
The L1210 leukemic cell suspension (1.times.10.sup.5 cells/0.2 ml) was implanted intraperitoneally in BDF.sub.1 mice (males, 18 to 22 g, females, 16 to 20 g) (7 mice per group). From 24 hours after the implantation to the 5th day thereafter, the predetermined doses of the compounds to be tested were orally administered to the mice consecutively once a day. The compounds to be tested were dissolved or suspended in a phosphate-buffered salt solution (PBS) containing 0.5% carboxymethylcellulose, and given at a dose rate of 0.1 ml per 10 g of each mouse's body weight. To a control group, only the same solvent as used for the dissolution of the compounds to be tested was administered in the same way. The mean survival times (MST) for each group were calculated, and the corresponding increase in life span (%ILS) was obtained in accordance with the following formula, the results of which are shown in Table 1. ##EQU1##
TABLE 1______________________________________Tested % ILS at dose (mg/kg/day) ofcompound 6.25 12.5 25 50 100 200 400______________________________________ara-C (hydro- 22 34 67chloride)ara-CMP 8 21 57 73ara-CMP 13 48 65methyl esterara-CMP decyl 0 4 8 36 39esterara-CMP un- 12 27 31 78decyl esterC14-ara-CMP 62 88 105 134esterC15-ara-CMP 70 95 135esterC16-ara-CMP 19 30 73 88 137 >227.sup.1esterC17-ara-CMP 11 32 52 87 123 >154 -15esterC18-ara-CMP 46 52 69 114 >200 53 -7esterC18-1-ara- 20 39 54 81 109 120 >159CMP esterC20-ara-CMP 19 39 60 90 126 >199esterC23-ara-CMP 29 51 65 81 110 128esterara-CMP hexa- 14 23 27 52 86cosyl ester______________________________________ Note: .sup.1 The symbol (>) means that some mice survived the test period (30 days).
TEST EXAMPLE 2
Effectiveness against B16 Melanoma
The B16 melanoma cells (1.times.10.sup.6 cells) were implanted to the right side-abdominal hypoderms of BDF.sub.1 mice (male, 18 to 22 g). From the 13th day after the implantation to death the compounds to be tested were administered orally 3 times a week. The compounds to be tested were dissolved in a phosphate-buffered salt solution (PBS) containing 0.5% carboxymethyl-cellulose to a suitable concentration, and given to the mice at a dose rate of 0.1 ml per 10 g of each mouse's body weight. The increases in life span (%ILS) were calculated in accordance with the same formula as described in Test Example 1. The results are shown in Table 2.
TABLE 2______________________________________ Mean survival Increase in Dose time life spanTested compound (mg/kg) (MST .+-. SE) (% ILS)______________________________________Control -- 22.0 .+-. 2.19 --ara-C (hydro- 100 26.8 .+-. 1.50 22chloride) 200 21.0 .+-. 1.76 -5 400 22.2 .+-. 2.82 15-fluorouracil 25 22.0 .+-. 1.45 0 50 25.0 .+-. 2.26 14 100 19.6 .+-. 0.98 -11C18-ara-CMP ester 50 30.0 .+-. 1.30 36* 100 25.8 .+-. 1.98 17 200 26.8 .+-. 2.20 22______________________________________ *level of significance at 0.05% or lower.
TEST EXAMPLE 3
Effectiveness against experimental tumor proliferation models in the lymph nodes
L1210 leukemic cells (1.times.10.sup.6 cells/0.05 ml) were implanted to the right inner-thigh hypoderms of BDF.sub.1 mice (males, 18 to 22 g). From one day after the transplantation, the compounds to be tested were administered intraperitoneally or orally to the mice once a day consecutively for 6 days. The compounds being tested were dissolved in a phosphate-buffered salt solution (PBS) containing 0.5% carboxymethylcellulose to a suitable concentration, and administered to the mice at a dose rate of 0.1 ml per 10 g of each mouse's body weight. The increases in life span (%ILS) were calculated similarly as in Test Example 1. The results are shown in Table 3.
TABLE 3______________________________________ Route Dose of admin- Mean survival Increase inTested (mg/kg/ istra- time life spancompound day) tion (MST .+-. SE) (% ILS)______________________________________Control -- ip 6.9 .+-. 0.18 --ara-C (hydro- 50 ip 13.9 .+-. 0.59 101chloride) 100 ip 14.5 .+-. 0.62 110C18-ara-CMP 25 ip 17.4 .+-. 0.40 152ester 50 ip 20.2 .+-. 0.53 193 50 po 18.3 .+-. 0.62 165 100 po 19.9 .+-. 0.48 188______________________________________
Furthermore, in a similar manner, each of the test compounds was administered only once on the sixth day after implantation. As the result, anti-tumor effectivenesses as indicated in Table 4 were exhibited.
TABLE 4______________________________________ Route of Mean survival Increase inTested Dose admini- Time life spancompound (mg/kg) stration (MST .+-. SE) (% ILS)______________________________________Control 7.3 .+-. 0.16 --ara-C (hy- 250 ip 9.9 .+-. 0.13 36drochloride) 500 ip 10.9 .+-. 0.23 49C18-ara-CMP 250 po 14.0 .+-. 0.53 92ester 500 po 17.3 .+-. 0.49 137______________________________________
TEST EXAMPLE 4
Acute toxicity test
The C18-ara-CMP ester was dissolved in saline containing 0.5% carboxymethylcellulose, and given orally to ICR-JCL mice (males, 24 to 26 g) at a dose rate of 0.2 ml per 10 g of each mouse's body weight. The mice thus treated were observed for 7 days. The LD.sub.50 value was;
LD.sub.50 (po) 1400(1283-1517) mg/kg (reliability limit 95%).
The C18-ara-CMP ester dissolved in saline was administered intraperitoneally to ICR-JCL mice (males, 24 to 26 g) at a dose rate of 0.2 ml per 10 g of each mouse's body weight. The LD.sub.50 value obtained on the 7th day was;
LD.sub.50 (ip) 137(131-143) mg/kg (reliability limit 95%).
TEST EXAMPLE 5
Acute toxicity test
An ara-CMP ester was neutralized and dissolved in saline containing 0.5% of carboxymethylcellulose, and the resulting solution was orally administered to ICR-JCL mice (males, 24 to 26 g) in a dose of 0.2 ml per 10 g of each mouse's body weight. The LD.sub.50 values calculated on the 14th day after the administration were as set forth in Table 5.
TABLE 5______________________________________ara-CMP ester LD.sub.50 value______________________________________C16-ara-CMP ester 2190 mg/kg (2056-2324*)C18-ara-CMP ester 1050 (981-1919)C18-1-ara-CMP ester 3750 (2990-4510)C20-ara-CMP ester 2720 (2550-2890)______________________________________ *95% reliability limit

Examples of production of the ara-CMP esters which are the effective components of the present antitumor compositions as well as the examples of preparation for the present antitumor compositions will now be described.
PRODUCTION EXAMPLE 1
10 ml of pyridine were added to 10 m mol of N.sup.4, O.sup.2', O.sup.3' -triacetyl ara-CMP (tri-n-butylammonium)salt and 5.4 g (20 m mol) of stearyl alcohol to dissolve them, and then 3.8 g (20 m mol) of p-tosyl chloride was further added thereto. The mixture was caused to react. After 2 hours, 100 ml of water and 50 ml of chloroform were added to the reaction mixture, which was then shaken. The resulting chloroform layer was taken out and 20 ml of ammonia water and 50 ml of ethanol were added thereto to prepare a homogeneous solution. The resulting solution was allowed to stand overnight, and then water was added thereto with stirring, the reaction product thereby being extrated into the water layer. The resulting aqueous solution was adjusted to a pH of 2.0 to 2.5 with concentrated hydrochloric acid to separate out the product (free acid). The separated product was collected by filtration and water was added thereto. The mixture thus obtained was adjusted with sodium hydroxide to a pH of 7 to 8. The resulting solution was again adjusted to a pH of 2.0 to 2.5 with hydrochloric acid to separate out the objective free acid. The separated free acid was collected by filtration, suspended in ethanol and stirred, filtered, and dried to obtain 4.3 g (yield 74.7%) of C18-ara-CMP ester.
Elementary analysis: as C.sub.27 H.sub.50 N.sub.3 O.sub.8 P. Calculated: P (%)=5.38; Found: P (%)=5.23.
Melting point: 224.degree.-226.degree. C. (decomposed) (free acid); 203.degree.-205.degree. C. (decomposed) (sodium salt).
Thin-layer chromatography: (developing solvent: ethanol:n-butanol:1M ammonium acetate (pH 7.5)=2:5:3); Rf=0.79.
PRODUCTION EXAMPLE 2
The process of the preceding Example 1 was employed for various kinds of alcohols in suitable quantities to produce the corresponding ara-CMP esters. The results and the properties of the resulting esters are shown in Table 6.
TABLE 6__________________________________________________________________________ Thin Elementary Melting point layer analysis P (%) .degree.C. (decomposed) chroma-Compounds Alcohols Yield Yield Molecular calcu- free sodium togra-produced kinds g m.mol g % formula lated found acid salt phy Rf__________________________________________________________________________C14-ara-CMP tetra- 6.4 30 4.0 77.0 C.sub.23 H.sub.42 N.sub.3 O.sub.8 P 5.96 5.74 225-227 216- 218 0.75ester decanolC15-ara-CMP penta- 6.8 " 4.5 84.3 C.sub.24 H.sub.44 N.sub.3 O.sub.8 P 5.80 5.69 221-223 197-199 0.76ester decanolC16-ara-CMP cetyl 7.3 " 4.5 82.1 C.sub.25 H.sub.46 N.sub.3 O.sub.8 P 5.66 5.40 226-228 0.77ester alcoholC17-ara-CMP hepta- 5.1 20 4.5 80.1 C.sub.26 H.sub.48 N.sub.3 O.sub.8 P 5.52 5.22 219-221 201-203 0.78ester decanolC18-1-ara- oleyl 5.4 " 4.5 78.4 C.sub.27 H.sub.48 N.sub.3 O.sub.8 P 5.40 5.19 218-220 203-205 0.80CMP ester alcoholC20-ara-CMP eicosa- 6.0 " 4.7 77.8 C.sub.29 H.sub.54 N.sub.3 O.sub.8 P 5.13 4.85 216-218 191-193 0.80ester nolC23-ara-CMP trico- 4.0 11.7 3.6 55.7 C.sub.32 H.sub.60 N.sub.3 O.sub.8 P 5.80 4.73 217-219 204-206 0.80ester sanol__________________________________________________________________________
PREPARATION EXAMPLE 1
A mixture consisting of 10 g of pulverized C18-ara-CAMP ester, 50 g of crystalline cellulose, 3 g of magnesium stearate, 100 g of lactose, and 100 g of potato starch is blended and capsuled, each capsule containing 263 mg of the composition.
PREPARATION EXAMPLE 2
A mixture consisting of 40 g of pulverized C16-ara-CMP ester (sodium salt), 100 g of crystalline cellulose, 6 g of magnesium stearate, and 94 g of lactose is blended and capsuled, each capsule containing 240 mg of the composition.
PREPARATION EXAMPLE 3
A mixture consisting of 20 g of C20-ara-CMP ester, 176 g of crystalline cellulose, 12 g of magnesium stearate, and 40 g of calcium salt of carboxymethyl-cellulose is thoroughly blended and formed into slugs. The resulting slugs are subjected to a granulation treatment by an oscillator equipped with a No. 10 sieve. To the granules is further added 12 g of magnesium stearate, and the resulting material is formed into tablets, each tablet containing 260 mg of the composition. The resulting uncoated tablets are then provided with sugar coating or film coating.
PREPARATION EXAMPLE 4
A mixture consisting of 200 g of C18-1-ara-CMP ester, 5 kg of maize starch, 4 kg of lactose, and 3 kg of sucrose is blended in a fluid-coating apparatus. The resulting fluidized powder is granulated by spraying into the fluidized powder a solution which has been prepared by dissolving 200 g of carboxymethyl-cellulose sodium salt in 15 liters of 30% methanol. After drying, the resulting granules are subjected to a uniforming treatment and formed into preparations which contain 20 mg of C18-1-ara-CMP ester per 1 g of the fine granules.
PREPARATION EXAMPLE 5
A mixture of 200 g of C18-1-ara-CMP (sodium salt) and 4.8 kg of a middle-length chain fatty acid triglyceride is homogeneously blended and is prepared into soft capsules by means of a soft capsule filler, each capsule containing 20 mg of C18-1-ara-CMP (sodium salt).
PREPARATION EXAMPLE 6
A mixture of 2.5 kg of lactose, 1.45 kg of starch, and 100 g of C18-ara-CMP ester is thoroughly blended and is then subjected to a wet granulation treatment with addition of 500 ml of an alcohol solution containing 10% hydroxypropylcellulose. After drying and uniforming, the resulting granules are sprayed with a 1:1 mixed solution of methylene chloride and normal hexane containing 10% Ethocel (ethylcellulose supplied from Dow Chemical Company), to prepare slow-releasing granules.
PREPARATION EXAMPLE 7
About 1.4 kg of WITEPSOL W35 (trade name, supplied from Dynamit Nobel Company, Germany) is heated to 60.degree. C. and melted, and 120 g of C18-ara-CMP ester is added thereto. The mixture is then homogeneously blended. The blended mixture is cooled to 40.degree. C. A specific amount of the mixture is then poured into each of a number of tiny plastic containers by means of a suppository filler, and the filled plastic containers are sealed to prepare suppositories.
PREPARATION EXAMPLE 8
A mixture of 100 g of fluid paraffin, 50 g of cetyl alcohol, and 790 g of vaseline is thoroughly blended with heating to 80.degree. C. Then, 3 g of cholesterol and 50 g of C16-ara-CMP ester are added thereto, after which the mixture is stirred. The resulting mixture is allowed to stand at room temperature to obtain an ointment.
PREPARATION EXAMPLE 9
A mixture consisting of 20 g of C18-1-ara-CMP ester, 100 g of potato starch, 70 g of lactose, 10 g of crystalline cellulose, and 1.0 g of magnesium stearate is blended and is then capsuled, each capsule containing 201 mg of the composition.
PREPARATION EXAMPLE 10
The various preparations of the ara-CMP esters are designed and shown in the following Table 7.
TABLE 7______________________________________ Daily doses (/60 kg of Doses per preparation unit body oralara-CMP esters weight) preparations suppositories______________________________________C18-ara-CMP 30- 5-100 mg 15-150 mgester 300 mgC16-ara-CMP 120- 20-400 mg 60-600 mgester 1200 mgC18-1-ara- 60- 10-200 mg 30-300 mgCMP ester 600 mgC20-ara-CMP 60- 10-200 mg 30-300 mgester 600 mgC14-ara-CMP 150- 25-500 mg 75-750 mgester 1500 mg______________________________________

Antitumor compositions for non-injection administration

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