NO155088B - PROCEDURE FOR AA IMPROVE STORAGE STABILITY OF AN N4 ACYLCYTOSINARABINOSIDE. - Google Patents
PROCEDURE FOR AA IMPROVE STORAGE STABILITY OF AN N4 ACYLCYTOSINARABINOSIDE. Download PDFInfo
- Publication number
- NO155088B NO155088B NO802688A NO802688A NO155088B NO 155088 B NO155088 B NO 155088B NO 802688 A NO802688 A NO 802688A NO 802688 A NO802688 A NO 802688A NO 155088 B NO155088 B NO 155088B
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- Prior art keywords
- arabinoside
- polyoxyethylene
- acylcytosine
- mixture
- added
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- -1 polyoxyethylene group Polymers 0.000 claims description 65
- 125000001931 aliphatic group Chemical group 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 24
- 239000002736 nonionic surfactant Substances 0.000 claims description 17
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 150000008209 arabinosides Chemical class 0.000 description 20
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 17
- 239000000843 powder Substances 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
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- 229930195725 Mannitol Natural products 0.000 description 13
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- 125000006353 oxyethylene group Chemical group 0.000 description 11
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- 238000012360 testing method Methods 0.000 description 7
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- 241000699670 Mus sp. Species 0.000 description 6
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- 239000000243 solution Substances 0.000 description 6
- 230000000087 stabilizing effect Effects 0.000 description 6
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 5
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- QHZLMUACJMDIAE-UHFFFAOYSA-N Palmitic acid monoglyceride Natural products CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 2
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
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- CDONIXJIKOVUIH-AEDHGTSPSA-N (z)-n-[1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]octadec-9-enamide Chemical compound O=C1N=C(NC(=O)CCCCCCC\C=C/CCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 CDONIXJIKOVUIH-AEDHGTSPSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical group CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- DCBSHORRWZKAKO-UHFFFAOYSA-N alpha-glycerol monomyristate Natural products CCCCCCCCCCCCCC(=O)OCC(O)CO DCBSHORRWZKAKO-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical class [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Saccharide Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for å forbedre lagringsstabiliteten for et N 4-acylcytosin-arabinosid, som er nyttig ved behandling av kreft. The present invention relates to a method for improving the storage stability of an N 4-acylcytosine arabinoside, which is useful in the treatment of cancer.
Som vist i US-patent nr. 3.991.045 er et N 4-acylcytosin-arabinosid et nyttig middel ved behandling av kreft, er spesielt effektivt mot leukemi hos mus, og utviser.resi-stens mot inaktivering av deaminase. As shown in US Patent No. 3,991,045, an N 4 -acylcytosine arabinoside is a useful agent in the treatment of cancer, is particularly effective against leukemia in mice, and exhibits resistance to deaminase inactivation.
Imidlertid når et N 4-acylcytosin-arabinosid lagres som det er, ved romtemperatur eller strengere betingelser, spaltes det under dannelse av dets deacylerte produkt og taper sin virkning. Derfor når det fremstilles oralt inntagbare medisiner inneholdende et N 4-acylcytosin-arabinosid, er det nødvendig å forhindre spaltningsreaksjonen. However, when an N 4 -acylcytosine arabinoside is stored as is, at room temperature or more stringent conditions, it breaks down to form its deacylated product and loses its activity. Therefore, when preparing orally ingestible medicines containing an N 4 -acylcytosine arabinoside, it is necessary to prevent the cleavage reaction.
Antioksydanter, pH-regulerende midler, eksipienter etc. som. vanligvis anvendes for å forbedre den kjemiske stabilitet er ikke i stand til å forhindre spaltning av N 4-acylcytosin-arabinosid . Antioxidants, pH-regulating agents, excipients etc. such as. usually used to improve the chemical stability is not able to prevent cleavage of N 4-acylcytosine-arabinoside.
Det er derfor ønskelig å utvikle et medikament inneholdende et N 4-acylcytosin-arabinosid med utmerket lagringsstabilitet. It is therefore desirable to develop a drug containing an N 4 -acylcytosine arabinoside with excellent storage stability.
Det er funnet at det er mulig å stabilisere et N 4-acylcytosin-arabinosid, slik at dette kan utnyttes i praksis, ved å tilføre dette minst et monoglyserid av en alifatisk syre med en hydrofob langkjedet alifatisk syregruppe og et ikke-ionisk overflateaktivt middel med en hydrofil polyoksyetylengruppe som en sidekjede hvorved det erholdes en aktiv blanding hvori N 4-acylcytosin-arabinosidet er stabilisert i vesent-lig grad. It has been found that it is possible to stabilize an N 4-acylcytosine arabinoside, so that this can be utilized in practice, by adding to it at least one monoglyceride of an aliphatic acid with a hydrophobic long-chain aliphatic acid group and a nonionic surfactant with a hydrophilic polyoxyethylene group as a side chain whereby an active mixture is obtained in which the N 4-acylcytosine-arabinoside is stabilized to a significant extent.
100 vektdeler N<4->acylcytosin-arabinosid tilsatt 10 - 100 vektdeler av et monoglyserid av en alifatisk syre og/- 100 parts by weight of N<4->acylcytosine-arabinoside added with 10 - 100 parts by weight of a monoglyceride of an aliphatic acid and/-
eller 5 - 500 vektdeler av et ikke-ionisk overflateaktivt middel med en polyoksyetylgruppe som sidekjede, kan forbedre stabiliteten ved fremgangsmåten ifølge oppfinnelsen. Ved å blande det ikke-ioniske overflateaktive middel med en or 5-500 parts by weight of a non-ionic surfactant with a polyoxyethyl group as side chain, can improve the stability of the method according to the invention. By mixing the nonionic surfactant with a
hydrofil polyoksyetylengruppe som sidekjede vil et N 4-acylcytosin-arabinosid markant stabiliseres, og selv etter 30 døgn fra begynnelsen av et lagringsforsøk ved 50°C kunne det nesten ikke påvises noen spaltning av N 4-acylcytosin-arabinosidet. hydrophilic polyoxyethylene group as a side chain, an N 4-acylcytosine-arabinoside will be markedly stabilized, and even after 30 days from the beginning of a storage experiment at 50°C, almost no cleavage of the N 4-acylcytosine-arabinoside could be detected.
I henhold til oppfinnelsen anvendes det ikke-ioniske overflateaktive middel i en mengde på 5 - 500 vektdeler, fortrinnsvis 10 - 200 vektdeler pr. 100 vektdeler av N 4-acylcytosin-arabinosidet. I mengder på mindre enn 5 vektdeler vil N 4-acylcytosin-arabinosidet ikke stabiliseres. På den annen side vil større mengder enn 500 vektdeler forårsake at de ønskede pulveregenskaper for fremstilling av en oralt inntagbar medisin går tapt. According to the invention, the non-ionic surfactant is used in an amount of 5 - 500 parts by weight, preferably 10 - 200 parts by weight per 100 parts by weight of the N 4 -acylcytosine arabinoside. In amounts of less than 5 parts by weight, the N 4 -acylcytosine arabinoside will not be stabilized. On the other hand, amounts greater than 500 parts by weight will cause the desired powder properties for the production of an orally ingestible medicine to be lost.
Når et monoglyserid åv en alifatisk syre med en hydrofob langkjedet alifatisk syregruppe tilsettes vil et N 4-acylcytosin-arabinosid markant stabiliseres, og selv etter 90 døgn etter påbegynt lagringsforsøk ved 50°C kan det nesten ikke påvises spaltning av N 4-acylcytosin-arabinosidet. Ved tilsetning av mindre mengder av det alifatiske syremonoglyserid så erholdes ingen stabiliserende effekt. På den annen side vil tilsetning av større mengder av monoglyseridet ikke gi noen forøkelse i den stabiliserende effekt og er heller ikke foretrukket fra et økonomisk synspunkt. Det alifatiske syremonoglyseridet tilsettes derfor i en mengde på 10 - 100 vektdeler pr. 100 vektdeler N 4-acylcytosin-arabinosid. When a monoglyceride of an aliphatic acid with a hydrophobic long-chain aliphatic acid group is added, an N 4-acylcytosine-arabinoside is markedly stabilized, and even after 90 days after the initial storage experiment at 50°C, almost no cleavage of the N 4-acylcytosine-arabinoside can be detected . By adding smaller amounts of the aliphatic acid monoglyceride, no stabilizing effect is obtained. On the other hand, the addition of larger amounts of the monoglyceride will not give any increase in the stabilizing effect and is also not preferred from an economic point of view. The aliphatic acid monoglyceride is therefore added in an amount of 10 - 100 parts by weight per 100 parts by weight of N 4-acylcytosine-arabinoside.
Monoglyseridet av denne alifatiske syre er meget effektiv for stabilisering av N 4-acylcytosin-arabinosidet, men senker dets farmasøytiske effekt noe. Det er derfor funnet at denne ulempe kan fjernes ved både å tilsette det ikke-ioniske overflateaktive middel og monoglyseridet av den alifatiske syre. Det er således spesielt foretrukket å iblande både det ikke-ioniske overflateaktive middel og monoglyseridet av den alifatiske syre, hvorved det erholdes utmerket stabilitet uten nedsettelse av den farmasøytiske effekt og meng-dene av det ikke-ioniske overflateaktive middel og monoglyseridet kan reduseres. Nar en slik blanding holdes ved 50 C i 90 døgn kan det nesten ikke påvises noen spaltning av N 4-acylcytosin-arabinosidet og ingen nedsettelse av den farma-søytiske effekt kan observeres. I dette tilfellet er det foretrukket å tilsette 5-50 vektdeler av monoglyseridet av den alifatiske syre og 5 - 100 vektdeler av det ikke-ioniske overflateaktive middel pr. 100 vektdeler av N 4-acylcytosin-arabinosidet . The monoglyceride of this aliphatic acid is very effective in stabilizing the N 4 -acylcytosine-arabinoside, but lowers its pharmaceutical effect somewhat. It has therefore been found that this disadvantage can be removed by both adding the non-ionic surfactant and the monoglyceride of the aliphatic acid. It is thus particularly preferred to mix both the non-ionic surfactant and the monoglyceride of the aliphatic acid, whereby excellent stability is obtained without reducing the pharmaceutical effect and the amounts of the non-ionic surfactant and the monoglyceride can be reduced. When such a mixture is kept at 50 C for 90 days, almost no cleavage of the N 4-acylcytosine-arabinoside can be detected and no reduction in the pharmaceutical effect can be observed. In this case, it is preferred to add 5-50 parts by weight of the monoglyceride of the aliphatic acid and 5-100 parts by weight of the non-ionic surfactant per 100 parts by weight of the N 4-acylcytosine arabinoside.
Monoglyseridet av den alifatiske syre anvendt ved foreliggende oppfinnelse har generelt tidligere vært anvendt som et emulgeringsmiddel for næringsmidler eller kremgrunnlag for kosmetikk eller medisiner. Monoglyseridet av den alifatiske syre har derfor tidligere vært anvendt for stabilisering av en emulsjon men har tidligere ikke vært anvendt for kjemisk stabilisering av en farmasøytisk aktiv bestanddel. The monoglyceride of the aliphatic acid used in the present invention has generally previously been used as an emulsifier for foodstuffs or cream base for cosmetics or medicines. The monoglyceride of the aliphatic acid has therefore previously been used for stabilizing an emulsion but has not previously been used for chemical stabilization of a pharmaceutical active ingredient.
Det ikke-ioniske overflateaktive middel med en polyoksyetylengruppe som sidekjede har bred anvendelse som et oppløse-liggjørende middel, emulgeringsmiddel, suspenderingsmiddel og lignende. Imidlertid er det ikke tidligere kjent at det ikke-ioniske overflateaktive middel bevirker en stabilisering av et N 4-acylcytosin-arabinosid, d.v.s. at det har den virkning å inhibiere frigjørelse og overføring av acylgruppen i N 4-acylcytosin-arabinosidet. The nonionic surfactant with a polyoxyethylene group as a side chain has wide application as a solubilizing agent, emulsifying agent, suspending agent and the like. However, it is not previously known that the nonionic surfactant effects a stabilization of an N 4 -acylcytosine arabinoside, i.e. that it has the effect of inhibiting the release and transfer of the acyl group in the N 4-acylcytosine-arabinoside.
Selv om anioniske overflateaktive midler, så som natriumdode-cylsulfat utviser en stabiliserende effekt er det i praksis utilstrekkelig. Ytterligere,da det generelt er antatt at vann deltar i frigjørelsen og overføringsreaksjonen for acylgruppen, har bærere med lavt vanninnhold og additiver med hygroskopiske og fuktighetsholdende egenskaper så som mannitol, fin krystallinsk cellulose, vannfritt silisiumdioksyd, synte-tisk aluminiumsilikat etc. vært undersøkt. Imidlertid er det funnet at de ikke har noen positiv stabiliseringseffekt for N 4-acylcytosin-arabinosid. N 4-acylcytosin-arabinosider som kan anvendes ifølge oppfinn-elsen som den aktive bestanddel innbefatter de som har. en alifatisk acylgruppe med 3-24 karbonatomer i N 4-stilling-en, så som N 4 -propionylcytosin-arabinosid, N 4-butyrylcyto-sin-arabinosid, N 4 -valerylcytosin-arabinosid, N 4-caproyl-cytosin-arabinosid, N 4 -heptanoylcytosin-arabinosid, N 4-kap-rylylcytosin-arabinosid, - N 4 -kaprylcytosin-arabinosid, N 4-lauroylcytosin-arabinosid, N 4-myristoylcytosin-arabinosid, N 4 -pentadekanoylcytosin-arabinosid, N 4-palmitoylcytosin-arabinosid, N 4 -margaroylcytosin-arabinosid, N 4-stearoylcytosin-arabinosid', N 4 -nonadekanoylcytosin-arabinosid, N 4-arachidoyl-cytosin-arabinosid, N 4 -heneicosanoylcytosin-arabinosid, N 4-behenoylcytosin-arabinosid., N 4-tricosanoylcytosin-arabinosid, N 4 -lignoceroylcytosin-arabinosid, N 4-palmitooleylcytosin-arabinosid, N 4 -oleoylcytosin-arabinosid, N 4-elaidoylcytosin-arabinosid, N 4 -vaccenoylcytosin-arabinosid, N 4-linooleylcyto-sin-arabinosid, N 4 -linoleylcytosin-arabinosid, N 4-rachidon-oylcytosin-arabinosid, etc. Although anionic surfactants such as sodium dodecyl sulfate exhibit a stabilizing effect, it is insufficient in practice. Furthermore, as it is generally believed that water participates in the release and transfer reaction for the acyl group, carriers with a low water content and additives with hygroscopic and moisture-retaining properties such as mannitol, fine crystalline cellulose, anhydrous silicon dioxide, synthetic aluminum silicate etc. have been investigated. However, they have been found to have no positive stabilizing effect for N 4 -acylcytosine arabinoside. N 4-acylcytosine arabinosides which can be used according to the invention as the active ingredient include those which have. an aliphatic acyl group with 3-24 carbon atoms in the N 4 position, such as N 4 -propionylcytosine arabinoside, N 4 -butyrylcytosine arabinoside, N 4 -valerylcytosine arabinoside, N 4 -caproylcytosine arabinoside, N 4 -heptanoylcytosine arabinoside, N 4 -caprylylcytosine arabinoside, - N 4 -caprylcytosine arabinoside, N 4 -lauroylcytosine arabinoside, N 4 -myristoylcytosine arabinoside, N 4 -pentadecanoylcytosine arabinoside, N 4 -palmitoylcytosine arabinoside arabinoside, N 4 -margaroylcytosine arabinoside, N 4 -stearoylcytosine arabinoside', N 4 -nonadecanoylcytosine arabinoside, N 4 -arachidoyl cytosine arabinoside, N 4 -heneicosanoylcytosine arabinoside, N 4 -behenoylcytosine arabinoside., N 4 -tricosanoylcytosine arabinoside, N 4 -lignoceroylcytosine arabinoside, N 4 -palmitoleylcytosine arabinoside, N 4 -oleoylcytosine arabinoside, N 4 -elaidoylcytosine arabinoside, N 4 -vaccenoylcytosine arabinoside, N 4 -linoleylcytosine arabinoside, N 4 4-linoleylcytosine arabinoside, N 4-rachidonoylcytosine arabinoside, etc.
Monoglyserider av alifatiske syrer som kan anvendes i henhold til oppfinnelsen innbefatter de som er avledet fra en høyere alifatisk syre med 12 - 18 karbonatomer og glyserol, så som stearinsyremonoglysérid, palmitinsyremonoglyserid, myristinsyremonoglyserid, laurinsyremonoglyserid, etc. Disse monoglyserider kan anvendes alene eller i kombinasjon med hverandre. Monoglycerides of aliphatic acids that can be used according to the invention include those derived from a higher aliphatic acid with 12 - 18 carbon atoms and glycerol, such as stearic acid monoglyceride, palmitic acid monoglyceride, myristic acid monoglyceride, lauric acid monoglyceride, etc. These monoglycerides can be used alone or in combination with each other.
Eksempler på ikke-ioniske overflateaktive midler med en polyoksyetylengruppe som sidekjede eller -kjeder som kan anvendes i henhold til oppfinnelsen innbefatter polyoksyetylen-alifatiske syreestere (fortrinnsvis de til hvilke gjennomsnittlig er addert 20 - 100 mol oksyetylenenheter og mere foretrukket stearater til hvilke er tilsatt gjennomsnittlig 20 - 55 mol oksyetylenenheter), polyoksyetylenricinusolje eller hydrogenert ricinusolje (i begge tilfeller er de hvor-til er gjennomsnittlig addert 20 - 100 mol oksyetylenenheter), polyoksyetylenglyserolestere av alifatiske syrer eller polyoksyetylenpropylenglykolestere av alifatiske syrer (spesielt foretrukket er monostearater eller oleater til hvilke er addert gjennomsnittlig 10 - 60 mol oksyetylenenheter), poly-oksyetylenlanolin eller bivoksderivater (spesielt foretrukket er de til hvilke er addert gjennomsnittlig 30 - 100 mol oksyetylenenheter), polyoksyetylensorbitanestere av alifatiske syrer og polyoksyetylensorbitolestere av alifatiske. syrer, polyoksyetylenalkyletere (spesielt foretrukket er de til hvilke det gjennomsnittlig er addert 20 - 60 mol oksyetylenenheter) , polyoksyetylenalkylfenyletere (spesielt foretrukket er de til hvilke er addert gjennomsnittlig 10 - 60 mol oksyetylenenheter), polyoksyetylen-polyoksypropylenalkyl-etere (spesielt foretrukne er de til hvilke er addert gjennomsnittlig 20 - 60 mol oksyetylenenheter pluss oksypropyl-enenheter), polyoksyetylen-polyoksypropylenkondensater (spesielt foretrukket er de med en gjennomsnittlig molekyl-vekt på 2 000 - 12 000 og som inneholder 30 - 90 vekt-% oksyetylenenheter), etc. Disse ikke-ioniske overflateaktive midler kan anvendes alene eller i kombinasjon med hverandre. Examples of non-ionic surfactants with a polyoxyethylene group as side chain or chains that can be used according to the invention include polyoxyethylene aliphatic acid esters (preferably those to which an average of 20 - 100 mol of oxyethylene units are added and more preferably stearates to which an average of 20 - 55 mol oxyethylene units), polyoxyethylene castor oil or hydrogenated castor oil (in both cases they are to which 20 - 100 mol oxyethylene units are added on average), polyoxyethylene glycerol esters of aliphatic acids or polyoxyethylene propylene glycol esters of aliphatic acids (especially preferred are monostearates or oleates to which are added on average 10 - 60 mol oxyethylene units), polyoxyethylene lanolin or beeswax derivatives (especially preferred are those to which an average of 30 - 100 mol oxyethylene units have been added), polyoxyethylene sorbitan esters of aliphatic acids and polyoxyethylene sorbitol esters of aliphatic e. acids, polyoxyethylene alkyl ethers (especially preferred are those to which an average of 20 - 60 mol oxyethylene units have been added), polyoxyethylene alkylphenyl ethers (especially preferred are those to which an average of 10 - 60 mol oxyethylene units have been added), polyoxyethylene-polyoxypropylene alkyl ethers (especially preferred are those to to which are added an average of 20 - 60 mol oxyethylene units plus oxypropylene units), polyoxyethylene-polyoxypropylene condensates (especially preferred are those with an average molecular weight of 2,000 - 12,000 and which contain 30 - 90% by weight of oxyethylene units), etc. These non-ionic surfactants can be used alone or in combination with each other.
Av disse forbindelser er polyoksyetylen-alifatiske syreestere, polyoksyetylenricinusolje, polyoksyetylen- hydrogenert ricinusolje, polyoksyetylenglyserolestere av alifatiske syrer, polyoksyetylenpropylenglykolestere av alifatisks syrer, poly-oksyetylenlanolin, polyoksyetylen-bivoks,polyoksyetylensorbitanestere av alifatiske syrer og polyoksyetylensorbitolestere av alifatiske syrer spesielt foretrukket da de gir en meget stor stabiliseringseffekt i relativt små mengder. Of these compounds, polyoxyethylene aliphatic acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene glycerol esters of aliphatic acids, polyoxyethylene propylene glycol esters of aliphatic acids, polyoxyethylene lanolin, polyoxyethylene beeswax, polyoxyethylene sorbitan esters of aliphatic acids and polyoxyethylene sorbitol esters of aliphatic acids are particularly preferred as they give a very great stabilization effect in relatively small quantities.
De mest foretrukne forbindelser er polyoksyetylen-alifatiske syreestere, polyoksyetylenricinusolje, polyoksyetylen-hydrogenert ricinusolje, polyoksyetylenglyserolestere av alifatiske syrer og polyoksyetylen-propylenglykolestere av alifatiske syrer. Når disse anvendes i kombinasjon med alifatiske syremonoglyserider tilveiebringer de gode resultater. The most preferred compounds are polyoxyethylene aliphatic acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene glycerol esters of aliphatic acids and polyoxyethylene propylene glycol esters of aliphatic acids. When these are used in combination with aliphatic acid monoglycerides, they provide good results.
Når de ikke-ioniske overflateaktive midler tilsettes alene til et N 4-acylcytosin-arabinosid er den akseptable maksimale mengde av det overflateaktive middel vanligvis 50 vektdeler When the nonionic surfactants are added alone to an N 4 -acylcytosine arabinoside, the acceptable maximum amount of the surfactant is usually 50 parts by weight
pr. 100 vektdeler N 4-acylcytosin-arabinosid for at blanding- per 100 parts by weight of N 4-acylcytosine-arabinoside so that the mix-
en skal foreligge som et pulver. Når det overflateaktive middel anvendes i større mengder enn 50 vektdeler er det nødvendig å tilsette eksipienter med lavt vanninnhold, eks-empelvis mannitol og additiver som tidligere er dehydrati- one must be present as a powder. When the surfactant is used in larger amounts than 50 parts by weight, it is necessary to add excipients with a low water content, for example mannitol and additives that have previously been dehydrated
sert og tørket, eksempelvis finkrystallinsk cellulose, vann-fri silisiumoksyd, metasilikatsyre-magnesiumaluminat, syn-tetisk aluminiumsilikat, stivelse, hydroksypropylstivelse etc. alene eller i kombinasjon til den erholdte oljeaktige eller voksaktige blanding av N 4-acylcytosin-arabinosid og det overflateaktive middel, eller at disse additiver på for-hånd tilsettes N 4-acylcytosin-arabinosidet hvoretter det overflateaktive middel blandes med den erholdte blanding. hardened and dried, for example fine crystalline cellulose, anhydrous silicon oxide, metasilicic acid-magnesium aluminate, synthetic aluminum silicate, starch, hydroxypropyl starch etc. alone or in combination to the obtained oily or waxy mixture of N 4-acylcytosine-arabinoside and the surfactant, or that these additives are added beforehand to the N 4-acylcytosine-arabinoside, after which the surfactant is mixed with the resulting mixture.
Når en forbedret fukting og ytterligere stabilitet er nød-vendig for blandingen fremstilt i henhold til oppfinnelsen, When an improved wetting and additional stability is necessary for the mixture prepared according to the invention,
kan vanlige anioniske overflateaktive midler tilsettes. Imidlertid da disse anioniske overflateaktive midler forår-saker bieffekter, eksempelvis irritasjon av fordøyelseskana-len er det ønskelig at den tilsatte mengde holdes under 50 vekt-deler pr. 100 vekt-deler N 4-acylcytosin-arabinosid. common anionic surfactants can be added. However, as these anionic surfactants cause side effects, for example irritation of the digestive tract, it is desirable that the added amount be kept below 50 parts by weight per 100 parts by weight N 4-acylcytosine-arabinoside.
Egnede eksempler på slike anioniske overflateaktive midler innbefatter natriumlaurylsulfat, natriumdeoksycholat, nat-riumdioktylsulfosuccinat, samt de tilsvarende kaliumsalter derav. Suitable examples of such anionic surfactants include sodium lauryl sulfate, sodium deoxycholate, sodium dioctyl sulfosuccinate, and the corresponding potassium salts thereof.
Blandemetoden for bestanddelene kan oppnås i henhold til The mixing method for the ingredients can be achieved according to
kjent teknikk eksempelvis en våt metode hvori det ikke-ioniske overflateaktive middel og/eller monoglyseridet av den alifatiske syre oppløses i et lavtkokende oppløsningsmiddel, eksempelvis en alkohol, ester, keton, eter eller lignende, known technique, for example a wet method in which the non-ionic surfactant and/or the monoglyceride of the aliphatic acid is dissolved in a low-boiling solvent, for example an alcohol, ester, ketone, ether or the like,
og om nødvendig under oppvarmning, hvoretter den erholdte oppløsning tilsettes N 4-acylcytosin-arabinosidet eller en blanding derav med en eksipient og deretter omrøres og eltes eller oppløses hvoretter oppløsningsmidlet fjernes og det således erholdte faststoff pulveriseres og siktes. Bestanddel--ene kan føres sammen ved hjelp av en tørr metode hvorved det ikke-ioniske overflateaktive middel og/eller det alifatiske and if necessary during heating, after which the obtained solution is added to the N 4-acylcytosine-arabinoside or a mixture thereof with an excipient and then stirred and kneaded or dissolved, after which the solvent is removed and the thus obtained solid is pulverized and sieved. The components can be brought together using a dry method whereby the nonionic surfactant and/or the aliphatic
syremonoglyserid er forpulverisert og tilsettes N 4-acylcytosin-arabinocidet eller en blanding derav med en eksipient bg om nødvendig tilsettes et smøremiddel hvoretter de blandes og pulveriseres under anvendelse av et måleapparat så som en kulemølle, en vibrerende kulemølle, pinnemølle, atomisør, stråleblander, morter, etc. Ytterligere kan disse metoder også anvendes i kombinasjon. acid monoglyceride is pre-pulverized and the N 4-acylcytosine-arabinocide or a mixture thereof with an excipient bg is added, if necessary, a lubricant is added after which they are mixed and pulverized using a measuring device such as a ball mill, a vibrating ball mill, stick mill, atomizer, jet mixer, mortar , etc. Furthermore, these methods can also be used in combination.
De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Lagringsstabiliteten for blandinger fremstilt i henhold til oppfinnelsen ble målt på følgende måte: blandingen fikk henstå ved 50°C i et forhåndsbestemt tidsrom og det gjenværende N 4-acylcytosin-arabinosid ble bestemt ved hjelp av væske-kromatografi og lagringsstabiliteten er angitt som den gjenværende del (vekt-%) av den aktive bestanddel (N 4-acylcytosin-arabinosid) . The storage stability of mixtures prepared according to the invention was measured in the following way: the mixture was allowed to stand at 50°C for a predetermined period of time and the remaining N 4 -acylcytosine arabinoside was determined by means of liquid chromatography and the storage stability is indicated as the remaining part (% by weight) of the active ingredient (N 4-acylcytosine-arabinoside).
EKSEMPEL 1 EXAMPLE 1
3 g polyoksyetylen (40) monostearat [tallangivelsen i paran-tesen indikerer gjennomsnittlige antall mol oksyetylenenheter som er addert, i det etterfølgende vil tallhenvisningen ha den samme betydning] ("MYS-4 0" fremstilt av Nikko Chemicals Co., Ltd.) ble oppløst i 20 ml etanol under oppvarming. Den erholdte oppløsningen ble satt til 10 g N 4-stearoylcytosin-arabinosid og blandingen ble omhyggelig omrørt og eltet 1 en morter og deretter vakuumtørket. Det således erholdte faststoff ble presset gjennom en 60 mesh sikt. 3 g of polyoxyethylene (40) monostearate [the number in parentheses indicates the average number of moles of oxyethylene units added, hereinafter the number will have the same meaning] ("MYS-40" manufactured by Nikko Chemicals Co., Ltd.) was dissolved in 20 ml of ethanol under heating. The obtained solution was added to 10 g of N 4 -stearoylcytosine-arabinoside and the mixture was carefully stirred and kneaded in a mortar and then vacuum dried. The solid thus obtained was pressed through a 60 mesh sieve.
EKSEMPEL 2 EXAMPLE 2
En blanding av 1 g polyoksyetylen (60) hydrogenert ricinusolje ("HCO-60" fremstilt av Nikko Chemicals Co., Ltd.) og 1 g polyoksyetylen (4 0) monostearat ("MYS-40") ble oppløst i 20 ml etanol under oppvarmning. Den erholdte oppløsning ble satt til 10 g N 4-palmitoylcytosin-arabinosid og deretter omrørt og støtt i en morter og deretter vakuumtørket. Det erholdte faststoff ble presset gjennom en 30 mesh sikt. En blanding av 5 g mannitol og 3 g tørr silisiumoksyd ble tilsatt og blandingen pulverisert i en kulemølle i 1 h. A mixture of 1 g of polyoxyethylene (60) hydrogenated castor oil ("HCO-60" manufactured by Nikko Chemicals Co., Ltd.) and 1 g of polyoxyethylene (40) monostearate ("MYS-40") was dissolved in 20 ml of ethanol under heating. The obtained solution was added to 10 g of N 4 -palmitoylcytosine-arabinoside and then stirred and pounded in a mortar and then vacuum dried. The resulting solid was pressed through a 30 mesh sieve. A mixture of 5 g mannitol and 3 g dry silica was added and the mixture pulverized in a ball mill for 1 h.
EKSEMPEL 3 EXAMPLE 3
2 g polyoksyetylen (40) monostearat ("MYS-40") som var grov-pulverisert ved lav temperatur og ført gjennom en 60 mesh sikt ble satt til 10 g N 4-behenoylcytosin-arabinosid og blandet og pulverisert i en kulemølle i 30 min. 2 g of polyoxyethylene (40) monostearate ("MYS-40") which was coarsely pulverized at low temperature and passed through a 60 mesh sieve was added to 10 g of N 4 -behenoylcytosine arabinoside and mixed and pulverized in a ball mill for 30 min .
EKSEMPEL 4 EXAMPLE 4
10 g polyoksyetylen (60) hydrogenert ricinusolje ("HCO-60") ble oppløst i 100 ml etanol under oppvarmning. Den erholdte oppløsning ble satt til en blanding av 10 g N 4-myrisoyl-cytosin-arabinosid og 40 g mannitol og deretter omrørt og støtt i en morter og deretter vakuumtørket. De erholdte faststoff ble presset gjennom en 30 mesh sikt og pulverisert i en kulemølle i 1 h. 10 g of polyoxyethylene (60) hydrogenated castor oil ("HCO-60") was dissolved in 100 ml of ethanol under heating. The obtained solution was added to a mixture of 10 g of N 4 -myrisoyl-cytosine-arabinoside and 40 g of mannitol and then stirred and pounded in a mortar and then vacuum dried. The solids obtained were pressed through a 30 mesh sieve and pulverized in a ball mill for 1 h.
EKSEMPEL 5 EXAMPLE 5
5 g polyoksyetylen (40) monostearat ("MYS-40") ble oppløst i 50 ml etanol under oppvarmning. Den erholdte oppløsning ble satt til 10 g N 4-pentadekanoylcytosin-arabinosid og deretter omrørt og støtt i en morter og fikk deretter henstå over natten ved romtemperatur. Til denne klebrige blanding hvori en liten mengde av oppløsningsmidlet var tilstede, ble tilsatt 10 g tørr silisiumdioksyd og deretter blandet og pulverisert til det ble erholdt en pulverformig blanding som ble vakuumtørket. Det således erholdte faststoff ble presset gjennom en 60 mesh sikt. 5 g 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 4 -pentadecanoylcytosine-arabinoside and then stirred and pounded in a mortar and then allowed to stand overnight at room temperature. To this sticky mixture in which a small amount of the solvent was present, 10 g of dry silica was added and then mixed and pulverized until a powdery mixture was obtained which was vacuum dried. The solid thus obtained was pressed through a 60 mesh sieve.
Pulvrene erholdt i henhold til eksemplene 1-5 ble underkastet et lagringsforsøk ved en temperatur på 50°C i 30 døgn og den gjenværende del av den aktive bestanddel ble bestemt. For sammenligning ble de aktive bestanddeler anvendt i eksemplene 1-5 alene undersøkt på samme måte. Resultatene er vist i tabell 1. The powders obtained according to examples 1-5 were subjected to a storage test at a temperature of 50°C for 30 days and the remaining part of the active ingredient was determined. For comparison, the active ingredients used in examples 1-5 alone were examined in the same way. The results are shown in table 1.
EKSEMPLENE 6- 22 EXAMPLES 6-22
Fremgangsmåten ifølge eksemplene 2, 3, 4 eller 5 ble gjen-tatt men hvor N 4-acylcytosin-arabinosidet og additivene var forandret. De således erholdte faststoffer ble underkastet lagringsforsøk ved 50°C i 30 døgn og den gjenværende del av den aktive bestanddel ble bestemt. Resultatene er vist i tabell 2. Alle forhold er pr. vekt. The procedure according to examples 2, 3, 4 or 5 was repeated but where the N 4 -acylcytosine arabinoside and the additives were changed. The solids thus obtained were subjected to storage tests at 50°C for 30 days and the remaining part of the active ingredient was determined. The results are shown in table 2. All conditions are per weight.
EKSEMPEL 23 EXAMPLE 23
Polyoksyetylen (40) monostearat ("MYS-40"), fremstilt av Nikko Chemical Co., Ltd) ble satt til 100 ml etanol i mengder som vist i tabell 3 og oppløst ved hjelp av oppvarmning. Polyoxyethylene (40) monostearate ("MYS-40"), manufactured by Nikko Chemical Co., Ltd) was added to 100 ml of ethanol in amounts shown in Table 3 and dissolved by heating.
De således erholdte oppløsninger ble satt til en blanding av 10 g N 4-stearoylcytosin-arabinosid og 40 g mannitol og deretter omrørt og støtt i en morter og vakuumtørket. De erholdte faststoffer ble presset gjennom en 30 mesh sikt og deretter pulverisert i en kulemølle i 1 h. The solutions thus obtained were added to a mixture of 10 g of N 4 -stearoylcytosine-arabinoside and 40 g of mannitol and then stirred and pounded in a mortar and vacuum dried. The solids obtained were pressed through a 30 mesh sieve and then pulverized in a ball mill for 1 h.
EKSEMPEL 24 EXAMPLE 24
En blanding av 3 g N 4-stearoylcytosin-arabinosid, 1,5 g stearinsyre-monoglyserid og 7,5 g mannitol (eksipient) ble malt i en vibrasjonskulemølle i 3 h til å gi et tørt pulver. A mixture of 3 g of N 4 -stearoylcytosine arabinoside, 1.5 g of stearic acid monoglyceride and 7.5 g of mannitol (excipient) was milled in a vibrating ball mill for 3 h to give a dry powder.
Den gjenværende del av den aktive bestanddel etter lagring ved 50°C i 90 døgn, bestemt som den prosentvise andel av den opprinnelige tilstedeværende mengde, var 99,5%. The remaining part of the active ingredient after storage at 50°C for 90 days, determined as the percentage of the original amount present, was 99.5%.
På den annen side nåo r N 4-steorylcytosin-arabinosid som sådant ble lagret under de samme betingelser var den gjenværende andel av den aktive bestanddel 89,0%. On the other hand, when N 4-steorylcytosine-arabinoside as such was stored under the same conditions, the remaining proportion of the active ingredient was 89.0%.
EKSEMPEL 2 5 EXAMPLE 2 5
En blanding av 3,0 g N 4-stearoylcytosin-arabinosid og 1,5 g stearinsyre-monoglyserid ble oppløst i 300 ml etanol under oppvarmning. Deretter ble etanolen fjernet ved nedsatt trykk. Til det erholdte pulver ble tilsatt 7,50 g mannitol og blandingen ble malt i en vibrerende kulemølle i 3 h til å gi et pulver som etter lagring ved 50°C i 90 døgn inneholdt 99,6% av den aktive bestanddel. A mixture of 3.0 g of N 4 -stearoylcytosine arabinoside and 1.5 g of stearic acid monoglyceride was dissolved in 300 ml of ethanol under heating. The ethanol was then removed under reduced pressure. To the powder obtained, 7.50 g of mannitol was added and the mixture was ground in a vibrating ball mill for 3 hours to give a powder which, after storage at 50°C for 90 days, contained 99.6% of the active ingredient.
EKSEMPEL 26 EXAMPLE 26
En blanding av 3,0 g N 4-palmitoylcytosin-arabinosid, 1,5 g stearinsyre-monoglyserid og 7,5 g mannitol ble malt i en vibrerende kulemølle i 3 h til å gi en pulverformig blanding. A mixture of 3.0 g of N 4 -palmitoylcytosine arabinoside, 1.5 g of stearic acid monoglyceride and 7.5 g of mannitol was milled in a vibrating ball mill for 3 h to give a powdery mixture.
Den gjenværende andel av den aktive bestanddel etter lagring ved 50 o C i 90 døgn var 99,4%, mens for N 4-palmitoylcytosin-arabinosid som sådant var den gjenværende andel 88,0%. The remaining proportion of the active ingredient after storage at 50 o C for 90 days was 99.4%, while for N 4-palmitoylcytosine-arabinoside as such the remaining proportion was 88.0%.
EKSEMPEL 27 EXAMPLE 27
En blanding av 10 g N 4-stearoylcytosin-arabinosid og stearinsyre-monoglyserid i de mengder som er vist i tabell 4 ble malt i en vibrerende kulemølle i 3 h til å gi en pulverformig blanding hvis gjenværende andel av den aktive bestanddel etter lagring ved 50°C i 90 døgn er vist i tabell 4. A mixture of 10 g of N 4 -stearoylcytosine arabinoside and stearic acid monoglyceride in the amounts shown in Table 4 was milled in a vibrating ball mill for 3 h to give a powdery mixture whose remaining proportion of the active ingredient after storage at 50 °C for 90 days is shown in table 4.
EKSEMPEL 28 EXAMPLE 28
En blanding av 5 g N 4-stearoylcytosin-arabinosid og 2,5 g av hver av de alifatiske syremonoglyserider vist i tabell 5 eller 2,5 g polyoksyetylen (40) monostearat ("MYS-4 0" fremstilt av Nikko Chemicals Co., Ltd.) og 12,5 g mannitol ble malt i en vibrerende kulemølle i 3 h til å gi et pulverformig produkt. Den gjenværende andel av den aktive bestanddel ved lagring ved 50°C i 90 døgn er vist i tabell 5. A mixture of 5 g of N 4 -stearoylcytosine arabinoside and 2.5 g of each of the aliphatic acid monoglycerides shown in Table 5 or 2.5 g of polyoxyethylene (40) monostearate ("MYS-40" manufactured by Nikko Chemicals Co., Ltd.) and 12.5 g of mannitol were ground in a vibrating ball mill for 3 h to give a powdery product. The remaining proportion of the active ingredient when stored at 50°C for 90 days is shown in table 5.
EKSEMPEL 2 9 EXAMPLE 2 9
En blanding av 2,5 g stearinsyremonoglyserid og 5 g av hver av de N 4-acylcytosinarabinosider som er vist i tabell 6 og 12,5 g mannitol ble malt i en vibrerende kulemølle i 3 h til å gi et pulverformig produkt. Den gjenværende bestanddel av den aktive bestanddel etter lagring ved 50°C i 90 døgn er vist i tabell 6.. A mixture of 2.5 g of stearic acid monoglyceride and 5 g of each of the N 4 -acylcytosine arabinosides shown in Table 6 and 12.5 g of mannitol was milled in a vibrating ball mill for 3 h to give a powdery product. The remaining component of the active component after storage at 50°C for 90 days is shown in table 6.
EKSEMPEL 3 0 EXAMPLE 3 0
En blanding av 10,0 g N 4-stearoylcytosin-arabinosid og stearinsyremonoglyserid og polyoksyetylenstearat ("MYS-40", fremstilt av Nikko Chemicals Co., Ltd.) i de mengder som er vist i tabell 7 ble oppløst i 1 500 ml etanol under oppvarmning til 50°C. Etanolen ble fjernet ved avdampning under nedsatt trykk i en roterende inndamper. Det erholdte faststoff ble pulverisert i en morter og i hvert tilfelle ble et fint pulver med utmerket flyteevne erholdt. En del av det fine pulver fikk henstå ved 50°C i 3 måneder og stabilitet med tiden bestemt. Til den gjenværende del ble tilsatt en passende mengde vann og støtt i en morter til å gi en dispersjon med en konsentrasjon av N 4-stearoylcytosin-arabinosid på 3 0 mg/ml. Denne dispersjonen ble undersøkt med hensyn til anticanceraktivitet under anvendelse av mus som forsøksdyr.. A mixture of 10.0 g of N 4 -stearoylcytosine arabinoside and stearic acid monoglyceride and polyoxyethylene stearate ("MYS-40", manufactured by Nikko Chemicals Co., Ltd.) in the amounts shown in Table 7 was dissolved in 1500 ml of ethanol while heating to 50°C. The ethanol was removed by evaporation under reduced pressure in a rotary evaporator. The solid obtained was pulverized in a mortar and in each case a fine powder with excellent flowability was obtained. A portion of the fine powder was allowed to stand at 50°C for 3 months and stability with time determined. To the remaining portion was added an appropriate amount of water and pounded in a mortar to give a dispersion with a concentration of N 4 -stearoylcytosine arabinoside of 30 mg/ml. This dispersion was investigated with regard to anticancer activity using mice as experimental animals.
For å undersøke stabiliteten med tid ble innholdet av det gjenværende N 4-stearoylcytosin-arabinosid etter lagring ved 50°C i 3 måneder bestemt og stabiliteten ble indikert som den gjenværende del av den aktive bestanddel. To investigate the stability with time, the content of the remaining N 4 -stearoylcytosine-arabinoside after storage at 50°C for 3 months was determined and the stability was indicated as the remaining part of the active ingredient.
Anti-canceraktivitetsforsøk ble utført på følgende måte: Hver blanding ble administrert direkte inn i magen til en gruppe mus k 10 mus av CDF,-linjen hvor hver mus var intra-peritonealt injisert med 10 L-1210 museleukemiceller. N 4-steorylcytosin-arabinose i doser på 200 mg/kg ble innført en gang pr. dag i 5 dager under anvendelse av et kateter. Anti-cancer activity tests were carried out in the following manner: Each mixture was administered directly into the stomach of a group of mice of 10 mice of the CDF line where each mouse was intra-peritoneally injected with 10 L-1210 mouse leukemia cells. N 4-steorylcytosine-arabinose in doses of 200 mg/kg was introduced once per day for 5 days using a catheter.
De gjennomsnittlige overlevelsesdager (T) for mus i forsøksgruppene og de gjennomsnittlige overlevelsesdager (C) for kontrollmus som ikke var tilført den aktive bestanddel ble bestemt og anticanceraktiviteten for blandingen ble uttrykt som prosent-andel av T baser på C (T/C%). The average survival days (T) of mice in the experimental groups and the average survival days (C) of control mice that had not been given the active ingredient were determined and the anticancer activity of the mixture was expressed as a percentage of T bases on C (T/C%).
Da det ikke var mulig å fremstille en vandig dispersjon av N 4-stearoylcytosin-arabinosid som sådant ble det dispergert As it was not possible to prepare an aqueous dispersion of N 4-stearoylcytosine-arabinoside as such, it was dispersed
i en 0,5% "Tween 80" (polyoksyetylensorbitanmonooleat) vandig oppløsning og administrert i denne form (kun i forsøk nr. 1) . in a 0.5% "Tween 80" (polyoxyethylene sorbitan monooleate) aqueous solution and administered in this form (experiment no. 1 only).
Resultatene er vist i tabell 7. The results are shown in table 7.
EKSEMPEL 31 EXAMPLE 31
— 4 — 4
En blanding av 10,0 g N -stearoylcytosin-arabinosid,2,5 g av hver av de alifatiske syremonoglyserider vist i tabell 8 og 1,0 g polyoksyetylenstearat ("MYS-40") ble oppløst i 1 500 ml etanol under oppvarmning ved 50°C. Etanolen ble deretter fjernet ved inndampning under nedsatt trykk i en roterende inndamper. Det erholdte faststoff ble pulverisert i en morter og det ble erholdt et fint pulver med utmerkede flyte-egenskaper. A mixture of 10.0 g of N -stearoylcytosine arabinoside, 2.5 g of each of the aliphatic acid monoglycerides shown in Table 8 and 1.0 g of polyoxyethylene stearate ("MYS-40") was dissolved in 1500 ml of ethanol while heating at 50°C. The ethanol was then removed by evaporation under reduced pressure in a rotary evaporator. The resulting solid was pulverized in a mortar and a fine powder with excellent flow properties was obtained.
Det således erholdte fine pulver ble underkastet samme prøve som i eksempel 30 og resultatene er vist i tabell 8. The thus obtained fine powder was subjected to the same test as in example 30 and the results are shown in table 8.
EKSEMPEL 32 EXAMPLE 32
10,0 g N 4-stearoylcytosin-arabinosid, 2,5 g stearinsyremonoglyserid, 2,5 g av hver av de ikke-ioniske overflateaktive midler inneholdende det antall oksyetylenenheter som er vist i tabell 9, samt 26,5 g mannitol (eksipient) ble blandet og pulverisert i en vibrasjonskulemølle i 1 h. Det således erholdte pulver ble underkastet de samme forsøk som angitt i eksempel 30 og resultatene er vist i tabell 9. 10.0 g of N 4 -stearoylcytosine arabinoside, 2.5 g of stearic acid monoglyceride, 2.5 g of each of the nonionic surfactants containing the number of oxyethylene units shown in Table 9, as well as 26.5 g of mannitol (excipient) was mixed and pulverized in a vibrating ball mill for 1 h. The powder thus obtained was subjected to the same tests as stated in example 30 and the results are shown in table 9.
EKSEMPEL 3 3 EXAMPLE 3 3
En blanding av 10,0 g av hver av de N 4-acylcytosin-arabinosider vist i tabell 10, 2,5 g stearinsyremonoglyserid og 1,0 g polyoksyetylenstearat ("MYS-40") ble oppløst i 1 500 ml etanol ved oppvarmning til 50°C. Etanolen ble fjernet ved inndampning under nedsatt trykk i en roterende inndamper. Det således erholdte faststoff ble pulverisert i en morter til å gi et fint pulver. Det således erholdte fine pulver ble underkastet samme stabilitetsprøve som i eksempel 30 og resultatene er vist i tabell 10 sammen med de aktuelle N 4-acylcytosin-arabinosider som sådanne. A mixture of 10.0 g of each of the N 4 -acylcytosine arabinosides shown in Table 10, 2.5 g of stearic acid monoglyceride and 1.0 g of polyoxyethylene stearate ("MYS-40") was dissolved in 1500 ml of ethanol by heating to 50°C. The ethanol was removed by evaporation under reduced pressure in a rotary evaporator. The solid thus obtained was pulverized in a mortar to give a fine powder. The thus obtained fine powder was subjected to the same stability test as in example 30 and the results are shown in table 10 together with the relevant N 4 -acylcytosine arabinosides as such.
EKSEMPEL 3 4 EXAMPLE 3 4
10,0 g N 4-plamitoylcytosin-arabinosid, 1,5 g palmitinsyre-monoglyserid, 1,0 g polyoksyetylenstearat ("MYS-4 0"), 0,5 g av hver av de anioniske overflateaktive midler som vist i tabell 11 og 27,0 g mannitol (eksipient) ble blandet og pulverisert i en vibrerende kulemølle i 1 h. 10.0 g of N 4 -palmitoylcytosine arabinoside, 1.5 g of palmitic acid monoglyceride, 1.0 g of polyoxyethylene stearate ("MYS-4 0"), 0.5 g of each of the anionic surfactants shown in Table 11 and 27.0 g of mannitol (excipient) was mixed and pulverized in a vibrating ball mill for 1 h.
Det således erholdte pulver ble underkastet de samme prøver som angitt i eksempel 30 og resultatene er vist i tabell 11. The powder thus obtained was subjected to the same tests as stated in example 30 and the results are shown in table 11.
EKSEMPEL 3 5 EXAMPLE 3 5
10,0 g N 4-stearoylcytosin-arabinosid, 1,5 g stearinsyremono- 10.0 g N 4-stearoylcytosine-arabinoside, 1.5 g stearic acid mono-
glyserid, 1,0 g polyoksyetylenstearat ("MYS-40"), 0,5 g av hver av de anioniske overflateaktive midler som vist i tabell 12 og 27,0 g mannitol ble blandet og pulverisert i en vibrerende kulemølle i 1 h. glyceride, 1.0 g of polyoxyethylene stearate ("MYS-40"), 0.5 g of each of the anionic surfactants shown in Table 12 and 27.0 g of mannitol were mixed and pulverized in a vibrating ball mill for 1 h.
Det således erholdte pulver ble underkastet det samme forsøk som angitt i eksempel 30 og resultatene er vist i tabell 12. The powder thus obtained was subjected to the same test as stated in example 30 and the results are shown in table 12.
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11660779A JPS5640606A (en) | 1979-09-11 | 1979-09-11 | Preparation of stable drug |
JP11760779A JPS5640607A (en) | 1979-09-12 | 1979-09-12 | Drug composition |
JP13118879A JPS5655309A (en) | 1979-10-11 | 1979-10-11 | Medical composition |
Publications (3)
Publication Number | Publication Date |
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NO802688L NO802688L (en) | 1981-03-12 |
NO155088B true NO155088B (en) | 1986-11-03 |
NO155088C NO155088C (en) | 1987-02-11 |
Family
ID=27313182
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO802688A NO155088C (en) | 1979-09-11 | 1980-09-10 | PROCEDURE FOR AA IMPROVE STORAGE STABILITY OF AN N4 ACYLCYTOSINARABINOSIDE. |
Country Status (6)
Country | Link |
---|---|
DE (1) | DE3033814C2 (en) |
DK (1) | DK161491C (en) |
IT (1) | IT1145416B (en) |
LU (1) | LU82760A1 (en) |
NL (1) | NL187727C (en) |
NO (1) | NO155088C (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3709861A1 (en) * | 1987-03-25 | 1988-10-06 | Henkel Kgaa | EMULSIFYING SUPPOSITORIES AND MEASURES PRODUCED FROM THEM |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US3991045A (en) * | 1973-05-30 | 1976-11-09 | Asahi Kasei Kogyo Kabushiki Kaisha | N4 -acylarabinonucleosides |
-
1980
- 1980-09-09 DE DE3033814A patent/DE3033814C2/en not_active Expired
- 1980-09-09 IT IT49635/80A patent/IT1145416B/en active
- 1980-09-10 DK DK384580A patent/DK161491C/en active
- 1980-09-10 NO NO802688A patent/NO155088C/en unknown
- 1980-09-10 LU LU82760A patent/LU82760A1/en unknown
- 1980-09-10 NL NLAANVRAGE8005102,A patent/NL187727C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO802688L (en) | 1981-03-12 |
LU82760A1 (en) | 1980-12-15 |
DK161491C (en) | 1992-01-06 |
NO155088C (en) | 1987-02-11 |
IT8049635A0 (en) | 1980-09-09 |
DK384580A (en) | 1981-03-12 |
NL187727C (en) | 1992-01-02 |
IT1145416B (en) | 1986-11-05 |
DK161491B (en) | 1991-07-15 |
NL187727B (en) | 1991-08-01 |
DE3033814A1 (en) | 1981-03-26 |
NL8005102A (en) | 1981-03-13 |
DE3033814C2 (en) | 1983-10-27 |
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