DK161491B - PROCEDURE FOR THE PREPARATION OF AN N4-ACYLCYTOSINE ARABINOSIDE PREPARATION WITH IMPROVED CHEMICAL STABILITY AND STORAGE TIME - Google Patents

Description

in DK 161491B

The present invention relates to a process for the preparation of an N 1 -acylcytosine arabinoside composition with improved chemical stability and storage time, and the process of the invention is characterized by the characterizing part of claim 1. The preparation prepared by the method is useful as an anticancer agent.

5

As disclosed in U.S. Patent No. 3,991,045, a 4 N -acylcytosine arabinoside is a useful anticancer agent in that it is particularly effective against leukemia in mice and exhibits resistance to inactivation by the action of deaminase.

However, when an N -acylcytosine arabinoside is stored as it is at room temperature or under elevated temperature for a prolonged period, e.g. at 50 ° C for 30 days, it will decompose to form the corresponding deacylated product, thereby losing its effect. Therefore, when preparing oral medications containing an N -acylcytosine arabinoside, it is necessary to prevent the decomposition reaction.

20

Antioxidants, pH regulators, excipients and the like, commonly used to improve chemical stability, have been found to be unable to prevent the decomposition of an N -acylcytosine arabinoid.

Therefore, it has been desirable to develop a process for the preparation of an N -acylcytosine arabinoside composition having an improved chemical stability and storage time, and this is achieved by the process of the invention.

Thus, it has surprisingly been found that one can stabilize an N -acylcytosine arabinoside which can be used for practical purposes by intimately mixing it with 2

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at least one monoglyceride of an aliphatic acid containing a hydrophobic long chain aliphatic acid group, and / or with a nonionic surfactant containing a hydrophilic polyoxyethylene group as side chain. Hereby a drug is obtained which contains as an active ingredient a 4 very stable N -acylcytosine arabinoside.

In DE Publication No. 2,658,406, injectable compositions for the therapeutic treatment of leukemia 10 and cancer are known in which a suitable water-soluble formulation of an otherwise heavy-soluble N-acylcytosine arabinoside has been provided. This formulation consists of an N - (C 1 -C 2 3) acylcytosine arabinoside, a solubilizing agent and an adjuvant.

In contrast, it is an object of the present invention to improve the stability of N -acylcytosine arabinosides which are known to be unstable over a long period of time and to enable oral administration of such 420 N -acylcytosine arabinosides.

Thus, the process of the invention provides 4 is a medicament containing 100 parts by weight of an N -acylcytosine arabinoside and 10-100 parts by weight of a monoglyceride 25 of an aliphatic acid and / or 5-500 parts by weight of a nonionic surfactant containing a polyoxyethylene group as side chain.

By introducing the nonionic surfactant, which contains a hydrophilic polyoxyethylene group, such as 4 side chain, considerable stabilization of the N -acyl-cytosine arabinoside occurs. Even after 30 days from the start of a storage experiment at 50 ° C, virtually no 4 decomposition of the N -acylcytosine arabinoside is observed. According to the present invention, the nonionic surfactant is used in an amount of 5-500 parts by weight, 4 preferably 10-200 parts by weight, for every 100 parts by weight N - 3.

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acylcytosin arabinoside. If less than 4 parts by weight is used, no stabilization of the N -acyl-cytosine arabinoside is achieved. On the other hand, if quantities greater than 500 parts by weight are used, the powder characteristics required for the practical preparation of oral medications are lost even when excipients are used.

When introducing a monoglyceride of an aliphatic acid containing a hydrophobic long chain aliphatic acid group, a substantially increased stability of the N? -Acylcytosine arabinoside is also obtained. Even after 90 days from the start of a storage experiment at 50 ° C, virtually no decomposition of the N -acylcytosine arabinoside is observed.

If you introduce only small quantities, ie. below 10 parts by weight 15 of the monoglyceride of the aliphatic acid, no stabilizing effect is obtained. On the other hand, the use of large quantities, ie. over 100 parts by weight of monoglyceride does not increase the stabilizing effect, and the use of such large amounts of monoglyceride is thus not preferable from an economic point of view. The monoglyceride of the aliphatic acid is therefore preferably used in an amount of between 10 and 100 parts by weight per 4 parts. 100 parts by weight of N -acylcytosine arabinoside.

Such a monoglyceride of an aliphatic acid is highly effective in stabilizing an N -acylcytosine arabinoside, but at the same time there is a slight decrease in the pharmaceutical effect of the arabinoside. However, it has been found that this disadvantage can be overcome by adding both the nonionic surfactant and the monoglyceride of the aliphatic acid. Thus, it is particularly preferred to introduce both a nonionic surfactant and a monoglyceride of an aliphatic acid, whereby excellent stability can be maintained without any reduction of the pharmaceutical effect, and the amounts of the nonionic surfactant and the monoglyceride of the aliphatic acid. acid can be reduced. When such a 4

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preparation is kept at 50 ° C for 90 days, virtually no decomposition of the N -acylcytosine arabinoside is observed, nor is any reduction of the pharmaceutical effect observed. In this case, 5 is preferred to use between 5 and 50 parts by weight of the monoglyceride of the aliphatic acid and between 5 and 100 parts by weight of the nonionic surfactant for every 100 parts by weight of 4 N -acylcytosine arabinoside.

The monoglyceride of the aliphatic acid used in the process of the invention has heretofore been commonly used as an eluant in foods or as an ointment-like basis for cosmetic and pharmaceutical products. In all cases, such monoglycerides have been used so far for the purpose of stabilizing one. emulsion, but they have never been used before for the purpose of providing a chemical stabilization of a pharmaceutically active component.

The nonionic surfactant containing a polyoxyethylene group as a side chain has found widespread use as a solubilizing agent, emulsifier, suspending agent and the like. However, it has not previously been known that such a surfactant is capable of stabilizing an N -acylcytosine arabinoside; i.e. that the agent is capable of preventing release and transfer of the acyl group of the arabinoside.

. Although anionic surfactants, e.g. sodium dodecyl sulfate, has a stabilizing effect, this is in practice insufficient. Furthermore, since it is a general assumption that water participates in the release and transfer of the acyl group, carriers with low water content and additives having hygroscopic and moisture-encapsulating properties, e.g. mannitol, fine crystalline cellulose, silicic anhydride, methacetic acid magnesium aluminate, synthetic aluminum silicate and the like. It has

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5, however, such compounds have been found to have no positive stabilizing effect on N1-acylcytosine arabinosides.

The stabilizing effect of a monoglyceride of an aliphatic acid and a nonionic surfactant with a polyoxyethylene group as side chain is thus unique.

4 N -acylcytosine arabinosides which can be used as an active ingredient in the process of the invention include such arabinosides which contain an aliphatic acyl group having 3-24 carbon atoms at the N1 position such as 4 N-propionylcytosine arabinoside, N-butryrylcytosine -arabi- 4 4 noside, N -valerylcytosine arabinoside, N -caproylcytosine-4 4 arabinoside, N -heptanoylcytosine-arabinoside, N -caprylyl-4 4 cytosine-arabinoside, N -caprylcytosine-arabinoside, N -lau-4 royloyt -arabinoside, N -myristoylcytosine-arabinoside, 4 4N -pentadecanoylcytosine-arabinoside, N-palmitoylcytosine-4 4 20 arabinoside, N -margaroylcytosine-arabinoside, N -stearoyl-4-cytosine-arabinoside, N-nonadecanoylcytosine -arachidoylcytosine arabinoside, N -heneicosanoylcytosine-4 4 arabinoside, N -behenoylcytosine-arabinoside, N -tricosano-4-ylcytosine-arabinoside, N-lignoceroylcytosine-arabinoside, 4 4 N-palmitooleylcytosine-4 binoside, N -elaidoylcytosine arabinos id, N -vaccenoylcyto- 4 sin-arabinoside, N -linolenoylcytosine-arabinoside, N-linolyl-4-cytosine-arabinoside or N -arachidonoylcytosine-araboside.

30

Monoglycerides of aliphatic acids which can be used in the process of the invention include monoglycerides derived from higher aliphatic acids of 12-18 carbon atoms and glycerol, e.g. stearic acid monoglyceride, palmitic acid monoglyceride, myristic acid monoglyceride, lauric acid monoglyceride and the like. These monoglycerides can be used alone or in combination with each other.

6

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Nonionic surfactants containing a polyoxyethylene group as side chain or side chains which can be used in the process of the invention comprise polyoxyethylene esters of aliphatic acids (preferably compounds added from 20 to 100 moles of oxyethylene units on average , in particular, stearates having an average of from 20 to 55 moles of oxyethylene units), polyoxyethylene castor oil or hydrogenated castor oil (in both cases preferably 10 such to which on average 20 to 100 moles of oxyethylene units are added ), aliphatic acid esters of polyoxyethylene glycerol or polyoxyethylene propylene glycol (especially monostearates or oleate to which an average of 10 to 60 moles of oxyethylene units are added), polyoxyethylene lanolin or beeswax derivatives. (preferably those with an average of from 30 to 100 moles of oxyethylene units), aliphatic acid esters of polyoxyethylene sorbitan or polyoxyethylene sorbxtole, polyoxyethylene alkyl ethers (especially those having an average of 20 to 60 moles of oxyethylene units), polyoxyethylene alkyl phenyl ether (preferably those having an average of from 10 to 60 moles of oxyethylene units), polyoxyethylene-polyoxypropylene alkyl ether (preferably those to which 20 to 25 moles of oxyethylene units and oxypropylene units have been averaged) , polyoxyethylene-polypropylene condensates (preferably those having average molecular weights of between 2,000 and 12,000 and containing from 30 to 90% by weight oxyethylene units) and similar compounds. These non-ionic surfactants can be used alone or in combination with each other.

Of the above compounds, polyoxyethylene / aliphatic acid esters, polyethylene / castor oil, polyoxyethylene / hydrogenated castor oil, polyoxyethylene glycerol / aliphatic acid esters, polyoxyethylene-propylene glycerol / aliphatic acid esters, polyoxyethylene-lanolin

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polyoxyethylene beeswax, polyethylene sorbitan / aliphatic acid esters and polyethylene sorbitol / aliphatic acid esters because they provide a high stabilizing effect when used in relatively small amounts. The most preferred combinations are polyoxyethylene / aliphatic acid esters, polyoxyethylene / castor oil, polyoxyethylene / hydrogenated castor oil, polyoxyethylene glycerol / aliphatic acid esters and polyoxyethylene-propylene glycol / aliphatic acid esters.

When used in combination with monoglycerides of aliphatic acids, they show good results.

When the nonionic surfactant alone is mixed 4 with the N -acylcytosine arabinoside, the acceptable maximum amount of surfactant that can be used is usually 50 parts by weight for every 100 parts by weight of N -acylcytosine arabinoside when the product is to have physical properties. like a powder. When the surfactant is used in quantities greater than 50 parts by weight, it is required that excipients of low water content are added to the resulting oily or waxy mixture of the 4 20 N -acylcytosine arabinoside and the surfactant. mannitol and additives which are subjected to dehydration and drying in advance, e.g. fine crystalline cellulose, silicic anhydride, methacetic acid magnesium aluminate, synthetic aluminum silicate, starch, hydroxypropyl starch or the like. These additives may be added alone or in combination with each other, or they may be pre-added 4 to the N -acylcytosine arabinoside, after which the surfactant may be added to the resulting mixture.

When an improvement in wetting and further stability of the blend is required, anionic and surfactants of the type commonly used for pharmaceutical products may be added. Since these anionic surfactants produce side effects, e.g. irritation of the intestinal system, it is desirable to keep the amount added below 50 by weight 4 8

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parts per 100 parts by weight of N -acylcytosine arabinoside.

Examples of suitable anionic surfactants may be mentioned sodium lauryl sulfate, sodium deoxycholate, sodium dioctysulfosuccinate and the corresponding potassium salts thereof.

The mixing of the constituents can be carried out using known techniques: Thus, a wet method can be used in which the nonionic surfactant and / or the monoglyceride of an aliphatic acid is dissolved in a low boiling solvent, e.g. an alcohol, an ester, a ketone, an ether or the like, if necessary under heating. The resulting solution is added to the N-15 acylcytosine arabinoside or a mixture of arabinoside and an excipient and stirred or kneaded, then the solvent is removed and the resulting solids are pulverized and sieved.

A dry method may also be used in which the nonionic surfactant and / or the monoglyceride of an aliphatic acid is pre-pulverized and added to the N -acylcytosine arabinoside, or to a mixture of the arabinoside with an excipient and if necessary, a lubricant and this mixture is pulverized by means of a crusher, e.g. a ball mill, a vibrating ball mill, a pin mill, an atomizer, a pre-flow means, a mortar or the like. Furthermore, these methods can be used in combination with each other.

30

In order to increase the practical ability of the drug to be used as an oral preparation, excipients, binders, disintegrants, coatings, dispersants, corrective agents, stabilizers, wetting agents, lubricants, dyes, preservatives, flavors and the like can be further added. . The resulting mixture is formed as tablets, 9

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capsules, lozenges, powders, granules, pills or the like. In addition, if a basis of the kind normally used in ointments and suppositories is added to the drug, this can be used for the preparation of 5 preparations for external use, ie. such as ointments or suppositories.

The invention is further illustrated by the following examples.

10

The stability of the preparation as a function of time was measured as follows: The preparations were allowed to stand at 50 ° C for a predetermined period of time, after which the residual N -acylcytosine arabinoside content was determined by high-pressure liquid chromatography and the stability of the preparation as a function. of the time is hereinafter indicated as the weight 4% active ingredient (N-acylcytosine arabinoside) remaining in the composition after the expiry of that time period.

EXAMPLE 1 10

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Three grams of polyoxyethylene (40) monostearate [the number in the parentheses indicates the average number of moles of oxyethylene to be added and hereinafter this number has the same significance] (MYS-40, manufactured by Nikko Chemicals Co., Ltd.) was dissolved in 20 ml of ethanol under heating. The resulting solution was obtained. set. to 10 g of N 2 -stearoyl-cyt'osine arabinoside and the mixture was thoroughly stirred and kneaded in a mortar and then vacuum dried. The 10 solid product thus obtained was pressed through a 250 µm mesh screen.

EXAMPLE 2

A mixture of 1 g of polyoxyethylene (60) / hydrogenated caustic oil (HC0-60, manufactured by Nikko Chemicals Co., 15 Ltd.) and 1 g of polyoxyethylene (40) monostearate (MYS-40) was dissolved in 20 ml of ethanol under warm up. The resulting solution was added to 10 g of N 2 -palmitoylcytosine arabinoside and the mixture was thoroughly stirred and kneaded in a mortar and then vacuum dried. The 20 solid product thus obtained was pressed through a 540 µm mesh screen. A mixture of 5 g of mannitol and 3 g of dried silicic anhydride was then added and the mixture pulverized in a ball mill for one hour.

EXAMPLE T

Two grams of polyoxyethylene (40) monostearate (MYS-40), previously coarsely powdered at low temperature and passed through a 250 µm mesh screen, were added to 10 4 g of N-behenoylcytosine arabinoside and the mixture was powdered in a vibrating ball mill for 30 minutes.

EXAMPLE 4 11

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Ten grams of polyoxyethylene (60) / hydrogenated castor oil (HCO-60) was dissolved in 100 ml of ethanol under heating. The resulting solution was added to a mixture of 10 g of c 4 O N -myristoylcytosine arabinoside and 40 g of mannitol, and the mixture was thoroughly stirred and kneaded in a mortar and then vacuum dried. The solid product thus obtained was pressed through a 540 µm mesh screen and then pulverized in a ball mill for one hour.

EXAMPLE 5

Five grams of polyoxyethylene (40) monostearate (MYS-40) was dissolved in 50 ml of ethanol under heating. The resulting solution was added to 10 g of N 2 -pentadecanoylcytosine arabinoside, and the mixture was stirred and kneaded in a mortar then allowed to stand overnight at room temperature.

To the resulting sticky mixture, which still contained a small amount of solvent, was added 10 g of dry silicic anhydride and thoroughly mixed and pulverized until the resulting mixture became powdery. Then, the mixture was vacuum dried. The resultant solid product was pressed through a 250 µm mesh screen.

The powders obtained according to Examples 1-5 were subjected to a storage experiment at a temperature of 50 ° C for a period of 30 days, the remaining amount of active ingredient 25 being determined thereafter. In comparison, the active ingredients used in Examples 1 to 5 were themselves tested in the same manner as described above. The results are shown in Table 1.

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TABLE 1

Residual amount of active ingredient Sample_ (weight -%) _, _ '

Example 1 99.7 "2 99.0" 3 100.2 "4 99.3" 5 99.6 4 N-Stearoylcytosm arabinoside 92.5

A

N-palmitoylcytosine arabinoside 92., 2.

N 2 -b ehenoylcyt o s in arabinoside 93.0 N 2 -myr st oylcyt o s in- arabinoside 90.3 4 N -pentadecanoylcytosine arabinoside 91.8 EXAMPLES 6-12 13

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The procedure described in Examples 2, 3, 4 and 5 was repeated, altering the N 2 -acylcytosine arabinoside and additives. The resulting solids were subjected to a storage experiment at 50 ° C for 30 days and the residual active ingredient was measured. The results are shown in Table 2. All quantities are by weight.

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DK 161491 B

EXAMPLE 23

Polyoxyethylene (40) monostearate (MYS-40), manufactured by Nikko Chemical Co., Ltd., was added to 100 ml. ethanol in the amounts shown in Table 3 and dissolved under heating. The resulting solution was added to a mixture of 10 g of N 2 -stearoylcytosine arabinoside and 40 g of mannitol, and the mixture was thoroughly stirred and kneaded in a mortar and then vacuum dried. The solid product thus obtained was pressed through a 540 µm mesh screen and pulverized in a ball mill for one hour.

TABLE 5 Amount of polyoxyethyl-residual amount of active ingredient

domain (40) monostearate (g) portion after storage at 50 ° C

for 50 days (%) 0 92.5 0.5 94.1 1.0 98.3 20 99.5 50 99.6 70 * 99.2 see In this case, the mixture did not become powdery and it was impossible to push it through the sieve.

EXAMPLE 24

A mixture of 3.0 g of N 2 -stearoylcytosine arabinoside, 1.5 g of stearic acid monoglyceride and 7.5 g of mannitol (excipient) was triturated in a vibrating ball mill for 3 hours to obtain a powdered drug for oral use. administration.

The residual portion of the active ingredient after storage at 50 ° C for 90 days (i.e., the ratio of residual amount to initial amount) was 99.5%. When you

DK 161491B

On the other hand, N 2 -stearoylcytosine arabonizide itself retained under the same conditions as stated above, the residual portion of the active ingredient was 89.0%.

EXAMPLE 25 4 A mixture of 3.0 g of N -stearoylcytosine arabinoside and 1.5 g of stearic acid monoglyceride was dissolved in 300 ml of ethanol under heating. Then, the ethanol was removed under reduced pressure. To the resulting powder was added 7.50 g of mannitol and the mixture was comminuted in a vibrating ball mill for 3 hours to obtain a powdered oral drug for oral administration.

The residual portion of the active ingredient after storage at 50 ° C for 90 days was 99.6%.

EXAMPLE 26 A mixture of 3.0 g of N 2 -palmitoylcytosine arabinoside, 1.5 g of stearic acid monoglyceride and 7.5 g of mannitol was triturated in a vibrating ball mill for 3 hours to obtain a powdered drug for oral administration.

The residual portion of the active ingredient after storage at 50 ° C for 90 days was 99.4%. When N1-palmitoyl-cytosine arabinoside itself was stored under the same conditions, the residual portion was. active ingredient 88.0%.

EXAMPLE 27 4 A mixture of 10 g of N -stearoylcytosine arabinoside and stearic acid monoglyceride in an amount as indicated in Table 4 was triturated in a vibrating ball mill for 3 hours to obtain a powdered drug for oral administration.

The residual portion of the active ingredient after storage

DK 161491 B

21 durations at 50 ° C for 90 days are shown in Table 4.

TABLE 4 Amount of stearine Residual amount of active ingredient acid monoglyceride after storage at 50 ° C for 90 for £ 1 days (%) - 0 89.0 0.5 89.1 1.0 92.8 5.0 99.5 10.0 99.8 15.0 99.7 Example 28

A mixture of 5 g of N 2 -stearoylcytosine arabinoside, 2.5 g of each of the monoglycerides of aliphatic acids listed in Table 5 or 2.5 g of polyoxyethylene (40) monostearate (MYS-40, manufactured by Nikko Chemicals Co., Ltd.) and 12.5 mannitol were comminuted in a vibrating ball mill for 3 hours to obtain a powdered medicine. The residual portion of the active ingredient after storage at 10 50 ° C for 90 days is shown in Table 5.

DK 161491B

22 TABLE 5

Residual amount of active ingredient (%)

Lauric acid mono-glyceride 99.2

Myristic acid monoglyceride 99.3

Palmitic acid monoglyceride 99.5

Polyoxyethylene Monostearate (MyS-40) 95.2 Example 29

A mixture of 2.5 g of stearic acid monoglyceride, 5.0 g of each of the N 2 -acylcytosine arabinosides and 12.5 g of mannitol was triturated in a vibrating ball mill 5 for 3 hours to obtain a powdery oral administration medication. The residual amount of the active ingredient after storage at 50 ° C for 90 days is shown in Table 6.

\ 23

DK 161491 B

TABLE 6

Residual amount of active ingredient (%) 5 v Preparation 4 4

Type of N - N -acylcytosubstituted by the acylcytosine sin-arabino method arabinoside sid per se of the invention 10 N 2 -propionylcytosine 85.0 95.8 arabinoside N 2 -butyrylcytosine 85.3 96.2 arabinoside 15 N N -caproylcytosine 86.0 97.2 Arabinoside N 3 -Heptanoylcytosine 86.4 97.5 Arabinoside N 2 -Caprylyl Cytosine 86.7 97.8 Arabinoside N β-Caprylic Cytosine 87.1 98.1 Arabinoside N 2 -Lauroyl Cytosine 87.5 98.3 Arabinoside N 2 -Myristoyl Cytosine 88.0 99.0 Arabinoside N 2 -pentadecanoylcytosine 88.5 99.3 Arabinoside N - margaroyl cytosine 89.0 99.6 arabinoside 35, N -nonadecanoyl cytosine 89.2 99.5 arabinoside N 2 -arachidoylcytosine 89.5 99.4 arabinoside 24 TABLE 6 (continued)

DK 16149 TB

Residual amount of active ingredient (%) 5 Preparation 4 4

Type of N - N -acylcyto- positioned by the acylcytosine sin arabino process arabinoside per se of the invention 10 4 N -heneicosanoylcytosine 89.6 99.6 arabinoside 4 N -benzoylcytosin 89.8 99.7 arabinoside N-tricosanoylcytosine 90.0 99.6 arabinoside 4 - N-lignoceroylcytosine 90.2 99.6 arabinoside 4 20 N-palmitoyl oeylcytosine 87.0 97.9 arabinoside 4 N -oleoylcytosine 87.2 98, 1 arabinoside N 1 -elaidoylcytosine 87.1 97.8 arabinoside N 2 -vaccenoylcytosine 87.2 98.0 arabinoside N 1 -linoleylcytosine 86.4 97.4 30 arabinoside 1- / 1-linolenoyl cytosine 86.0 97.2 arabinoside arachidonoylcyte os in- 85.8 97.0 35 arabinoside

DK 161491 B

EXAMPLE 50

A mixture of 10.0 g of N 2 -stearoylcytosine arabinoside and stearic acid monoglyceride and polyoxyethylene stearate (MYS-40, manufactured by Nikko Chemicals Co., Ltd.) in the amounts listed in Table 7 was dissolved in 1500 ml of ethanol under heating. to 50 ° C. The ethanol was removed by evaporation under reduced pressure in a rotary evaporator. The resultant solid product was extracted and pulverized in a mortar. In all cases, a fine powder 10 was obtained which was dissolved and free flowing.

A portion of the fine powder was left at 50 ° C for 3 months and stability as a function of time was measured. To the rest of the powder was added an appropriate amount of water.

And the mixture was kneaded in a mortar to give a dispersion with a concentration of N 2 -stearoylcytosine ara binoside of 30 mg / ml. This dispersion was subjected to a test for anti-cancer activity using mice.

In determining the stability as a function of time, the content of residual N 2 -stearoylcytosine arabinoside was measured after storage at 50 ° C for 3 months, and the stability was reported as the residual amount of active ingredient.

The anti-cancer activity was tested as follows: Each preparation was administered directly into the stomach of mice, using groups of 10 mice of the CDF genus, each of which was mterperitoneally injected with 10 L-1210 mouse leukemia cells. The preparation was injected in an amount of 200 mg be-4 calculated on the N -stearoylcytosine arabinoside per ml. kg of mice once 30 per day for 5 days, using a catheter for injection.

DK 161491 B

26

The mean number of survival days (T) of the mice in the experimental groups and the average number of survival days (C) of the control mice not injected with the active preparation were determined and the anti-cancer activity of the preparation was expressed as the percentage of T based on C (T / C%).

Since it was not possible to prepare an aqueous dispersion of N 2 -stearoylcytosine arabinoside per se, the arabinoside was dispersed in a 0.5% aqueous solution of Tween ^ 10 80 (polyoxyethylene sorbitan monooleate) and administered (only in experiments number 1). The results are shown in Table 7.

Λ -.

27

DK 161491 B

TABLE 7

Residual amount 5 active

stearic acid- Amount of part after re-monogly- MYS-40 50 ° C x 3 T / C

Test No. cerid (g) (g) months (%) (%) 10 - - - - - 10 0 89.0 182 2 0.25 0 89 »° 181 3 0.50 0 89.2 172 4 1, 00 0 92.6 164 15 5 2.50 0 96.4 159 6 5.00 0 99.6 192 7 10.00 0 99.8 136 8 0 1.00 90.7 191 9 0.50 0, 25 89.4 173 10 0.50 0.50 91.4 182 11 0.50 1.00 94.1 190 12 0.50 5.00 96.0 198 13 0.50 10.00 96.7 207 14 0.50 15.00 96.5 211 25 15 2.50 1.00 99.8 183 EXAMPLE 51 4

A mixture of 10.0 g of N -stearoylcytosine arabinoside, 2.5 g of each of the aliphatic acids monoglycerides listed in Table 8, and 1.0 g of polyoxyethylene stearate (MYS-40) were dissolved in 1500 ml of ethanol under heating to 50 Then the ethanol was removed by evaporation under reduced pressure in a rotary evaporator. The solid products thus obtained were extracted and pulverized in a mortar to obtain a fine, very soluble powder.

The fine powder thus obtained was subjected to the same experiment as in Example 30 and the results are shown in Table 8.

Residual amount

Active ingredient monoglyceride

5 Experiment No. aliphatic acid after 50 ° Cx3 months T / C

DK 161491B

28 TABLE 8 (%) (%) 15 Stearic acid 99.8 183 10 monoglyceride 16 Palmitic acid 99.8 182 monoglyceride 17 Myristic acid 99.5 184 15 monoglyceride 18 Lauric acid 99.2 183 monoglyceride 20 EXAMPLE 32 25 10.0 g N 2 -stearoylcytosine arabinoside, 2.5 g of stearic acid monoglyceride, 2.5 g of each of the nonionic surfactants listed in Table 9 containing an oxyethylene unit, and 26.5 g of mannitol (excipient) were mixed and powdered in a vibrating ball mill for a period of 1 30 hours. The powder thus obtained was subjected to the same experiment as in Example 30 and the results are shown in Table 9.

35

Residual amount

Non-ionic overactive ingredient

5 Experiment No. surfactant after 50 ° Cx3 months T / C

DK 161491 B

29 TABLE 9 (%) (%) ^ Polyoxyethylene stearate 99.2 182 10 (MYS-40) ^ Polyoxyethylene / hydrogenated castor oil (HC0-60 manufactured by Nikko Chemicals Co., Ltd.

Polyoxyethylene / Castor 98.9 184 Oil (CO- 60 TX, Manufactured by Nikko Chemicals Co.,

22) Polyoxyethylene glycerol 98.7 183 Monostearate (Nikko Chemicals Co., Ltd.) Polyoxyethylene Propylene 99.0 184 Stearate (TPMS-30) - 94.8 161 30 35

DK 161491 B

EXAMPLE 55

A mixture of 10.0 g of each of the N 1 -acylcytosine arabinosides, 2.5 g of stearic acid monoglyceride and 1.0 g of polyoxyethylene stearate (MYS-40) dissolved in 15.00 ml of ethanol under heating to 50 ° C. The ethanol was then removed by evaporation under reduced pressure in a rotary evaporator. The solid products thus obtained were extracted and pulverized in a mortar to obtain a fine powder.

The fine powder thus obtained was subjected to the same stability test as described in Example 30, and the results are shown in Table 10 together with the results for the N 2 -acylcytosine arabinosides themselves.

TABLE 10 31

DK 161491B

Test Acyl group in N 2 -acylcytosine- Residual amount of active No, arabinoside_ ingredient (th) 25 N 2 -propionyl 85.0 26 "(preparation) 97.2 27 N 2 -butyryl 85.3 28" (preparation) 98.5 29 N 2 -valeryl 85.7 30 "(preparation) 98.8 31 N 2 -caproyl 86.0 32" (preparation) 99.0 33 N 2 -heptanoyl 86.4 34 "(preparation) 99.1 35 N -caprylyl 86.7 36 "(preparation) 99.1 37 N 1 -capryl 87.1 38" (preparation) 99.1 39 N 2 -lauroyl 87.5 40 "(preparation) 99.3 41 N 2 -myristoyl 88.0 42 "(composition) 99.3 43 N 2 -pentadecanoyl 88.5 44" (composition) 99.5 45 N 2 -palmitoyl 88.0 46 "(composition) 99.6 47 N 2 -margaroyl 89, 0 48 "(Preparation) 99.6 (1) ϊΆ-Stearoyl 89.0 (15)" (Preparation) 99.8 49 N + -Nonadecanoyl 89.2 50 "(Preparation) 99.5

DK 161491 B

32 · TATRAT. 10 (continued)

Test Acyl group in N 2 -acylcytosine- Residual amount of active No. arablnoside _; _ component_; (%) 51 N 2 -arachidoyl 89.5 52 "(preparation) 99.8 4 53 N -heneicosanoyl 89.6 54" (preparation) 99.7 55 N 2 -behenoyl -89.8 56 "(preparation) 99 7 4 57 N -tricosanoyl 90.0 58 "(preparation) 99.8 4.59 N-lignoceroyl 90.2 60 11 (preparation) 99.9 - ^ 4 61 N-palmitoyleyl 87.0 62" (preparation) 98.8 63 N ^-oleoyl 87.2 64 "(preparation) 98.5 65 N4-elaidoyl 87.1 66" (preparation) 98.5 67 N ^-linoleyl 86.4 68 "(preparation) 98, 5 69 N 2 "- linolenoyl 86.0 70" (preparation) 98.3 4 71 N -arachidonoyl 85.8 72 "(preparation) 98.6

DK 161491 B

EXAMPLE 54 10.0 g of N₂-palmitate oylcyt os in-arabino acid, 1.5 g of palmitic acid monoglyceride, 1.0 g of polyoxyethylene stearate (MYS-40), 0.5 g of each of the anionic surfactants 5 shown in Table 11 as well as 27.0 g of mannitol (excipient) were mixed and pulverized in a vibrating ball mill over a period of 1 hour.

The powders thus obtained were subjected to the same experiment as described in Example 30 and the results are shown in Table 11.

TABLE 11

Residual amount

Anionic overactive ingredient

Experiment No. surfactant after 50 ° Cx3 months T / C

clothes thaw 73 Sodium lauryl sulphate 99.5 226 74 Sodium deoxycholate 99.7 223 75 Sodium dioctyl sulphosuccinate 99.6 227 76 Sodium dioctyl sulphosuccinate 98.7 201 EXAMPLE 35 10.0 g N 2 -stearoylcytosine arabinoside, 1.5 g stearic acid monogr. 0 g of polyoxyethylene stearate (MYS-40), 0.5 g of each of the anionic surfactants shown in Table 15 12, as well as 27.0 mannitol, were mixed and pulverized in a ball bearing mill over a period of 1 hour.

The powders thus obtained were subjected to the same experiment as described in Example 30 and the results are shown in Table 12.

TABLE 12

DK 161491B

Residual amount

Anionic overactive ingredient

5 Experiment No. surfactant after 50 ° Cx3 months T / C

34 (%) (%) 77 Sodium lauryl sulphate 99.8 203 78 Sodium deoxycholate 99.8 202 10 79 Sodium dioctyl sulphosuccinate 99.8 199 80 - 98.6 187 15 20 25 30 \ 35

Claims (6)

A process for preparing an N -acylcytosine-5 arabinoside composition with improved chemical stability and shelf life, characterized in that intimately 4 mixes 100 parts by weight of an N -acylcytosine arabinoside wherein the acyl group is aliphatic and contains 3-24 carbons. atoms, having 10-100 parts by weight of a monoglyceride of a 10 aliphatic acid and / or 5-500 parts by weight of a nonionic surfactant containing as a side chain a polyoxyethylene group. Process according to claim 1, characterized in that the N -acylcytosine arabinoside is selected from the N - 4 propionylcytosine arabinoside, N -butylrylcytosine arabino-4,4side, N -valerylcytosine arabinoside, N -caproylcytosine araba. - 4 4 binoside, N -heptanoylcytosine arabinoside, N -caprylylcyto- 4 4sin-arabinoside, N -caprylcytosine-arabinoside, N -lauroyl-4 4 cytosine-arabinoside, N -myristoylcytosine-arabinoside, N-4-pentadecanoylcytosine-arabinoside , N -palmitoylcytosine ara 4 4 binoside, N -margaroylcytosine arabinoside, N -stearoylcyto-4 4 sin arabinoside, N -nonadecanoylcytosine arabinoside, N - 4 arachidoylcytosine arabinoside, N -heneicosanoylcytosine -behenoylcytosine arabinoside, N -tricosano-4-ylcytosine-arabinoside, N-lignoceroyl-cytosine-arabinoside, 4 4 -N-palmitoyl-cytosine-arabinoside, N -oleoyl-cytosine-ara-4 4-binoside, N -elaidoyl-cytosine-arabinoside sin-arabinoside, N-linolenoylcytosine-arabinoside, N-linolin cytosine arabinoside and N -arachidonoylcytosine arabinoside. Process according to claim 1 or 2, characterized in that the monoglyceride of an aliphatic acid is at least one monoglyceride selected from stearic acid monoglyceride, palmitic acid monoglyceride, myristic acid monoglyceride and lauric acid monoglyceride. DK 161491B Process according to any one of claims 1-3, characterized in that the nonionic surfactant is at least one compound or system selected from polyoxyethylene / aliphatic acid ester, polyoxyethylene / castor oil, polyoxyethylene glycerol / aliphatic acid ester, polyoxyethylene acid. propylene glycerol / aliphatic acid ester, polyoxyethylene lanolin / polyoxyethylene beeswax, polyoxyethylene sorbitan / aliphatic acid ester, polyoxyethylene sorbitol / aliphatic acid ester, polyoxyethylene alkyl ether, polyoxyethylene alkylene phenyl ether, polyoxyethylene polyethylene polyethylene polyethylene 4 DK 161491 B Patent claims: 5. A process according to any one of claims 1-4, characterized in that the nonionic surfactant is added in an amount of 10-200 parts by weight per day. 100 4 parts by weight of N -acylcytosine arabinoside. Process according to any one of claims 1-5, characterized in that the monoglyceride of an aliphatic acid and the nonionic surfactant is added in amounts of 5-50 parts by weight and 5-100 parts by weight 4, respectively. 100 parts by weight of N -acylcytosine arabinoside. 25 30 \ 35