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WO2000048611A1 - Preparations de liposomes contenant des medicaments antitumoraux - Google Patents

Preparations de liposomes contenant des medicaments antitumoraux Download PDF

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Publication number
WO2000048611A1
WO2000048611A1 PCT/JP2000/000948 JP0000948W WO0048611A1 WO 2000048611 A1 WO2000048611 A1 WO 2000048611A1 JP 0000948 W JP0000948 W JP 0000948W WO 0048611 A1 WO0048611 A1 WO 0048611A1
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Prior art keywords
ribosome
lipids
composition ratio
preparation according
constituting
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Ceased
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PCT/JP2000/000948
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English (en)
Japanese (ja)
Inventor
Yuji Kasuya
Junichi Okada
Kenji Hanaoka
Shinichi Kurakata
Akira Matsuda
Takuma Sasaki
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Sankyo Co Ltd
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Sankyo Co Ltd
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Priority to AU25746/00A priority Critical patent/AU2574600A/en
Publication of WO2000048611A1 publication Critical patent/WO2000048611A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel 11- (2,1-cyano1-2,1-deoxy-1) 3-D-arabinontofuranosyl) cytosine-containing liposome preparation.
  • CNDAC (2,1-cyano 2′-doxy-1-D-arabinopentofuranosyl) cytosine
  • CNDAC is a compound having excellent antitumor activity (Tanaka et al., Cancer Letter 64, 67- 74 (1992) / Azuma et al., J. Med. Chem. 36, 4183-4189 (1993), Japanese Patent Application Laid-Open No. 4-235182) .
  • CNDAC is water-soluble, it can be used in physiological saline and the like. By dissolving, it can be administered intravenously.
  • water-soluble antitumor drugs are more likely to be degraded in vivo, are excreted faster from the body, and have a non-specific tissue distribution in the body, so that they have better antitumor activity. Formulations are generally desired in order to obtain and reduce side effects.
  • the present invention provides a 1- (2, -cyano 2'-doxy-1] 3-D-arabino-l-pentfuranosyl) cytosine-containing ribosome preparation which solves the above-mentioned problems.
  • the present invention provides a 1- (2, -cyano 2'-doxy-1] 3-D-arabino-l-pentfuranosyl) cytosine-containing ribosome preparation which solves the above-mentioned problems.
  • ⁇ 2> the liposome preparation according to ⁇ 1>, wherein the phospholipid concentration is 50 to 20 O mM, and 3) one of the lipids constituting the ribosome, the sterols being cholesterol.
  • ribosome preparation according to ⁇ 1> to ⁇ 3> further comprising, as a lipid constituting the ribosome, a lipid chemically modified with polyethylene glycols.
  • One of the liposome-forming lipids, lipids chemically modified with polyethylene glycols is composed of N-monomethoxy polyethylene glycol succinylphosphatidylethanolamines, N-monomethoxy polyethylene glycol (2-chloro Mouth 1,3,5-triazine-4,6-diyl) Succinylphosphatidyletano Liposomes as described in ⁇ 4>, characterized in that they are luamines, N-monomethoxy polyethylene glycol carbonyl phosphatidyl ethanolamines or N-mono methoxy polyethylene glycol ethylene phosphatidyl ethanolamines. Formulation,
  • a lipid chemically modified with polyethylene glycol which is one of the lipids constituting the ribosome, is an N-monomethoxypolyethylene glycol succinylphosphatidyl ethanolamine.
  • ⁇ 8> The liposome-constituting lipid, phosphatidylcholine and Z or phosphatidylglycerol, wherein the acyl group is an aliphatic acyl group having 10 to 20 carbon atoms.
  • the liposome-forming lipid, phosphatidylcholine and Z or the acyl group in phosphatidylglycerol is a myristoyl group, palmitoyl group, or stearoyl group.
  • the liposome preparation according to ⁇ 8>, wherein the composition ratio of sterols, which are lipids constituting the ribosome, to the total amount of lipids constituting the ribosome is 1 Omo 1% to 6 Omo 1%.
  • composition ratio of sterols, which are lipids constituting the ribosome, to the total lipid amount constituting the ribosome is 3 Omo 1% to 5 Omo 1%, ⁇ 1> to ⁇ Ribosome preparation according to 10>,
  • composition ratio of N-monomethoxypolyethyleneglycol succinylphosphatidylethanolamines, which are liposome-forming lipids, to the total amount of ribosome-forming lipids should be 1 mo 1% to 1 Omo 1%.
  • composition ratio of phosphatidylcholines, which are lipids constituting ribosomes, to the total amount of lipids constituting ribosomes is 35 mo 1% to 85 mo 1%, and 1> to ⁇ 12.
  • Ribosome preparation according to> ⁇ 14> The composition ratio of phosphatidylcholines, which are lipids constituting ribosomes, to the total amount of lipids constituting ribosomes is 4 Omo 1% to 60 mo 1%, ⁇ 1> to ⁇ 13> Ribosome preparation according to,
  • composition ratio of phosphatidylglycerols, which are lipids constituting ribosomes, to the total amount of lipids constituting liposomes is lmo 1% to 1 Omo 1%.
  • composition ratio of sterols is 10 mol 1% to 60 mol 1%
  • composition ratio of the phosphatidylcholines is 35 mol 1% to 85 mol 1%
  • composition ratio of monomethoxypolyethylene glycol succiniruyl stearoyl phosphatidyl ethanolamines is 1 mo 1% to 10 mo 1%.
  • composition ratio of sterols is 30 mol 1% to 50 mol 1%
  • composition ratio of the phosphatidylcholines is 40 mol 1% to 60 mol 1%
  • composition ratio of monomethoxypolyethylene glycol succinate-lugestearoyl phosphatidylethanolamine is 1 mo 1% to 10 mo 1%, and is described in ⁇ 1> to ⁇ 2>.
  • composition ratio of sterols is 30 mol 1% to 50 mol 1%
  • composition ratio of the phosphatidylcholines is 40 mol 1% to 60 mol 1%
  • ribosome preparation according to ⁇ 1> to ⁇ 20>, wherein the ribosome has a volume average particle diameter of 100 nm to 400 nm.
  • ribosome refers to a liposome, which is well known to those skilled in the art (see DDLasic; “shiposomes: from basic to applications", Elsevier Science Publishers pp. 1-171 (1993)).
  • a closed vesicle composed of lipids and an internal aqueous phase.
  • the surface thereof and polyethylene dalicols are bound by non-covalent bonds such as electrostatic interaction or hydrophobic interaction, or chemically modified with polyethylene glycols described below.
  • Steprols which are essential lipid components constituting the ribosome preparation of the present invention, include, for example, cholesterol, cholesterol monohemisuccinate, 3 / 3- [N- (N ,, N′-dimethinoleamino) Ethane) canoleno moinole] cholesterol, enolegosterone, lanosterol and the like, preferably cholesterol, and sterols are preferably based on the total amount of lipids constituting the ribosome.
  • the ⁇ phosphatidylcholines '' which are essential lipid components constituting the liposome preparation of the present invention include, for example, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine.
  • dimyristoyl phosphatidylcholine, dipamitoyl ⁇ phosphatidinolecholine or distearoylenophosphatidylcholine is preferred.
  • Phosphatidylcholines are used with respect to the total amount of lipids constituting ribosomes.
  • the ribosome contains 35 to 85 mo 1%, more preferably 40 to 6 O mo 1%.
  • the ribosome preparation of the present invention preferably contains "phosphatidylglycerols" or "lipids chemically modified with polyethylenedaricols".
  • phosphatidylglycerols examples include dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoisolephosphatidinoregglycerol, and disteareinolephosphatidinoregglycerol.
  • dimyristoyl phosphatidyl glycerol dipalmitoyl phosphatidyl glycerol
  • distear yl phosphatidyl glycerol Contains 1 to 10 mol% in the ribosome.
  • lipid chemically modified with polyethylene glycols refers to lipids that are covalently bonded to polyethylene dalicols having various molecular weights and lipids, and the lipid is preferably phosphatidylethanolamine.
  • n 10 to 100
  • PE_NH phosphatidylamine
  • n 10 to 100
  • PE—NH phosphatidylamine
  • n 10 to 100
  • PE-NH phosphatidylamin.
  • N-monomethoxypolyethylene glycol carbonyl phosphatidylethanolamines represented by the following formula:
  • n 10 to 100
  • PE-NH represents phosphatidylamine.
  • the molecular weight of the lenglycol moiety is from about 500 to about 500, and most preferably the molecular weight of the polyethylene glycol moiety is from about 100 to about 300, most preferably preferably, the molecular weight of the moiety is from about 2 0 0 0 (DD Lasic, "Liposomes:. from basic to appl icationsj , Elsevier Science Publishers, pp 294- 29o (1993)) 0 to ribosomes formulations of the present invention ,
  • lipids that can be used in ribosome preparations.
  • examples include dilauroylphosphatidylinositol and dimyristoyl Phosphatidylinositols such as phosphatidyluinositol, dipalmitoyl phosphatidyltidylinositol or distearoyl phosphatidylinositol; dilauroyl phosphatidylserine, dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylserine or distearoylphosphatidylphosphatidyl Apatidylserines: dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolanolamine, dipalmitoylphosphatidylethanol Glycero
  • lipids phosphatidylcholines, phosphatidylglycerols, phosphatidylinositols, phosphatidylserines, phosphatidylethanolamines, sulfoxyribosyldiglycerides, digalactosyldiglycerides, galactosyldiglyceride, sulphamine
  • the mouth side, gandarioside, etc. each have two saturated or unsaturated aliphatic acyl chains, and the chain preferably has 14 to 18 carbon atoms (particularly myristoyl, palmi A tyl or stearoyl group).
  • the ribosome of the ribosome preparation of the present invention preferably has a volume average particle size of 100 to 400 nm, and the volume average particle size can be determined based on a principle such as a dynamic light scattering method (DD Lasic ⁇ ). “See iposomes: from basic to applicationsj, Elsevier Science Publishers, pp. 1-171 (1993).”
  • the ribosome preparation of the present invention can be produced according to methods well known to those skilled in the art.
  • the liposomes can be adjusted by the above-mentioned “lipid” and “aqueous phase” by thin-film method, reverse-phase evaporation method, ethanol injection method, ether injection method, dehydration-rehydration method, etc.
  • the volume average particle diameter can be adjusted by a method such as an ultrasonic irradiation method, an ultrasonic irradiation method after freeze-thawing, an extrusion method, a French press method, and a homogenization method.
  • a method such as an ultrasonic irradiation method, an ultrasonic irradiation method after freeze-thawing, an extrusion method, a French press method, and a homogenization method.
  • the “aqueous phase” means an aqueous solution constituting the inside of the ribosome, and is not particularly limited as long as it is a commonly used one. Examples thereof include an aqueous sodium chloride solution, a phosphate buffer, and an acetate buffer. , A glucose aqueous solution, a trehalose aqueous solution and the like, and a mixed aqueous solution thereof.
  • the aqueous phase used in the production is desirably close to isotonic with the extraribosomal solution, that is, body fluid, and has a small osmotic pressure applied to the inside and outside of the ribosome.
  • the extraribosomal solution that is, body fluid
  • lipid used for producing the ribosome preparation of the present invention, a commercially available product and a product that can be easily chemically synthesized from a commercially available product by an ordinary method can be used.
  • lipids having various carbon numbers and Z or unsaturation such as lecithin and soybean lecithin, which can be obtained in a mixed state, can be used without separating and purifying them into a single component.
  • a-tocophere or the like can be added to the liposome preparation for the purpose of antioxidant action and the like.
  • the liposome preparation of the present invention is administered to humans, the liposome is diluted with various aqueous solutions so that the concentration of lipids constituting the liposome calculated from the composition at the time of formulation is 1 to 30 O mM, or And used by concentrating by centrifugation.
  • the aqueous solution used for dilution is not particularly limited as long as it is a commonly used aqueous solution.
  • examples thereof include a phosphate buffer solution, an aqueous saccharide solution such as dalcose and trehalose, an aqueous salt solution such as sodium chloride, and physiological saline.
  • the final liquid volume is 1 to 10 Om1, usually by intravenous injection, and when the final liquid volume is 10 to 100 Oml, by intravenous drip.
  • the storage stability of the ribosome preparation of the present invention that is, the physical stability of the ribosome itself and the chemical stability of the included drug and the lipid forming the ribosome may vary depending on the lipid used and the like.
  • lipids used in the following Examples and Test Examples cholesterol was purchased from Tokyo Kasei, and all other lipids were purchased from Yomoto Yushi Co., Ltd. Further, CNDAC hydrochloride was produced by the method described in JP-A-Hei 4-235182.
  • CNDAC ribosome An appropriate amount of an aqueous phase containing a predetermined amount of solute shown in Table 2 is added to the flask in which the lipid thin layer has been formed, and the lipid per 1 mL of the aqueous phase is adjusted as shown in Table 1, and vortex mixer is used. By shaking, a crude ribosome dispersion was obtained.
  • the obtained liposome is referred to as CNDAC ribosome.
  • PC and PG mean phosphatidylcholines and phosphatidylglycerols, respectively.
  • the chain length of the acyl is S (stearoyl), P (palmitoyl), M (mi). Ristoyl) and L (Lauroyl).
  • SM was described in parentheses of the numbers.
  • Formulation amount of lipid per 1 mL of aqueous phase of CNDAC ribosome dispersion ( ⁇ 1)
  • Formulation example PC Cholesterol PG PEG2000-DSPE
  • the volume average particle diameter of the ribosome was particularly determined by repeating the operation of freezing the crude dispersion of CNDAC ribosome at 160 ° C and thawing at 50 ° C three times.
  • the volume average particle diameter was adjusted by an extrusion method or an ultrasonic irradiation method, and in other production examples, the volume average particle diameter was adjusted by a normal extrusion method or an ultrasonic irradiation method.
  • a crude CND AC ribosome was prepared using an Extorda (Liposofast-Basic, AVESTIN) equipped with a polycarbonate membrane filter (Nomura Microscience) with a pore size of 100 to 200 nm.
  • the dispersion was adjusted by passing through the membrane.
  • passing the crude ribosome dispersion through the membrane using an extruder equipped with a polycarbonate membrane filter having a predetermined pore size is referred to as a predetermined size. Extrusion).
  • an ultrasonic crusher (Model 7600, manufactured by Seiko Instruments Inc.) was used to apply ultrasonic waves to the CNDAC liposome coarse dispersion at an output of 25 W for 1 to 60 minutes. Irradiated.
  • Each of the obtained CNDAC ribosome dispersions whose volume average particle size was adjusted was a uniform emulsion, and was stable at 25 ° C for at least one day with no above change. .
  • the adjusted ribosome volume average particle diameter was measured as follows. That is, after adjusting the ribosome volume average particle diameter (hereinafter referred to as Dv), the obtained CND AC ribosome dispersion is diluted with a 150 mM aqueous sodium chloride solution to adjust the lipid concentration to about 0.1 mM, Particle size analyzer (Nicomp Particle Sizer Model 370, Nicomp Use the Particle Sizing Systems), was measured Dv (Nicomp Particle Sizer Model 370, Nicomp Use the Particle Sizing Systems), was measured Dv (Nicomp Particle Sizer Model 370, Nicomp Use the Particle Sizing Systems), was measured Dv (
  • the dispersion of the volume average particle size CND AC ribosome obtained in Example 1 was diluted with physiological saline, so that the lipid concentration in the dispersion calculated from the formulation at the time of production was 0.5 mM. 100 ⁇ L of this dispersion was used as a sample for measuring the total CND AC concentration contained in the dispersion.
  • CNDAC concentration in the external water phase 100 ml of the supernatant obtained by precipitating the liposome by ultracentrifugation of 1 mL of this dispersion (140,000 g x 20 minutes) does not contain ribosomes in the dispersion.
  • the sample was used to measure the CNDAC concentration (hereinafter, referred to as “CNDAC concentration in the external water phase”).
  • Measuring machine LC-1 OA (manufactured by Shimadzu Corporation)
  • Inclusion rate (%) (A L / A T) X 100 (1)
  • a L is, CNDAC weight of the external aqueous phase from Alpha tau (hereinafter referred to.
  • a s determined by subtracting plug the Can be Therefore, if the volume of lipid in the ribosome dispersion is ignored, equations (2) and (3) hold.
  • C T and C s respectively represent the CND AC concentration in total CND AC concentration and the external phase of the liposome dispersion as measured by the method described above
  • V is, liposome dispersions
  • V represents the ratio of the volume of the aqueous phase (hereinafter referred to as the internal aqueous phase) constituting the ribosome to the volume of the liposome dispersion.
  • the lipid concentration is set to 0.5 mM
  • the lipid concentration is 100 / gZmL or less, and the ratio of the volume of the lipid to the volume of the dispersion is practically negligible.
  • V is proportional to the particle size and the lipid concentration
  • the liposome of the present invention having a particle size of 100 nm to 400 nm is 3 L to 15 L per mole of lipid.
  • V is less than 0.01, so (1 V) in equation (3) can be approximated to 1. That is, equation (3) can be approximated to equation (4) .
  • equation (5) is obtained.
  • the ratio of the total amount of CNDAC in the ribosome dispersion to the prescribed amount of CNDAC was determined as CNDAC recovery.
  • the lipid volume is determined by temporarily setting the lipid ratio to 1.0 (see DD Lasic N, “Liposomes: from basic to applications, Elsevier Science Publishers, p.554 (1993). ), The volume of the ribosome dispersion is It was determined by adding the aqueous phase volume and the lipid volume.
  • the CNDAC concentration in the ribosome in the liposome dispersion was determined by multiplying the CNDAC concentration in the ribosome dispersion, which was calculated from the composition at the time of liposome production, by the CNDAC recovery rate and the inclusion rate.
  • Table 5 shows the DAC concentration. As shown in Table 5, the coverage of CNDAC is high and sufficient for practical use.
  • aqueous phase containing CNDAC in the aqueous phase at the time of prescription is 100 or 200 mg ZmL and a high concentration of CND AC exceeding isotonicity (43.3 mg / mL) is used as the aqueous phase, it is stable.
  • a new ribosome preparation could be produced.
  • the ribosome preparation of the present invention when ribosomes having different total lipid concentrations were produced with the same lipid composition ratio and aqueous phase composition, it was confirmed that the inclusion ratio increased as the total lipid concentration increased. In addition, the inclusion rate was increased by adding a freeze-thaw operation to the CNDAC ribosome crude dispersion.
  • CNDAC retention and release properties of the ribosome were examined as follows. 4.50 mL of a 15 OmM aqueous solution of sodium chloride was added to 50 // L of the CNDAC liposome dispersion prepared in Example 1 and having a controlled volume average particle diameter, followed by ultracentrifugation (l 400 000). g X 20 min) to precipitate the ribosome. The supernatant was removed by decantation, and the phosphate buffer (20 mM sodium dihydrogen phosphate and 150 mM sodium chloride was dissolved, and the pH was adjusted to 7.4 with a 1 M aqueous sodium hydroxide solution.
  • the prepared ribosome was redispersed in 95 mL. In this way, CNDAC that was not included in the liposome was removed, 100 ⁇ L of the purified ribosome dispersion was taken out, and the initial concentration of all CNDACs in the dispersion (including in the ribosome) was determined. It was determined by the method in Test Example 1. The remaining dispersion was shaken at 37 ° C. Two hours later, 100 ⁇ L of the suspension was collected and the total CNDAC concentration in the dispersion (including in the ribosome) was measured. The remaining dispersion (after shaking at 37 ° C.
  • Aqueous solution * 2 22.50 This represents the concentration of the purified or manufactured preparation in the stock solution, and was appropriately diluted and administered with a 150 mM aqueous sodium chloride solution in consideration of the drug dose.
  • MTD maximum tolerated dose
  • the relative tumor volume was calculated as a relative value of the tumor volume with the tumor volume on the day of the first administration taken as 1. The smaller this value is, the stronger the tumor growth inhibitory effect is.
  • the relative tumor volume on day 20 of transplantation was calculated as a measure of the tumor growth inhibitory effect.
  • the mice were bred and the survival days of each mouse were determined.
  • the survival rate of each treatment group was calculated by the following equation: (a_b) / bX100 (%).
  • a and b mean the median value of the number of days alive in the treated group and the untreated group, respectively.
  • Table 8 shows the results of evaluating the antitumor activity near the MTD.
  • the ribosome preparations of Production Examples 12, 13, 18, 18, 23, and 43 are 9 mgZ kg to 44 mg, kg, which are higher than aqueous preparations, even though they are all smaller than aqueous preparations. It showed a tumor growth inhibitory effect and a high survival rate (Table 8).
  • the aqueous solution preparation neither 30 Omg / kg nor 45 Omg / kg provided a tumor growth inhibitory effect and a survival rate lower than those of the ribosome preparation (Table 8). From the above results, it was shown that the ribosome preparation of CNDAC of the present invention has an antitumor activity exceeding that of the aqueous preparation.
  • Test Example 4 Antitumor effect of single administration of CNDAC ribosome preparation The antitumor activity of each of the various preparations of CNDAC shown in Example 1 was examined. The antitumor activity was evaluated in the same manner as in Test Example 3 using the tumor growth inhibitory effect and the survival rate as scales.
  • the drug was appropriately diluted with a 150 mM aqueous sodium chloride solution in consideration of the drug dose and administered.
  • Mouse colon cancer co1on26 was implanted subcutaneously into 5- to 6-week-old female CDF1 mice to engraft and grow tumor tissue.
  • 6 animals per group were randomly divided into groups and administered.
  • the intravenous administration volume of each formulation was 20 mLZkg.
  • the maximum tolerated dose in a single dose is the highest when no fatalities occur due to the side effects of the drug, and the average weight loss rate is less than 20% on the 7th day of transplantation on the 13th day of transplantation, when weight loss is most severe. Made a large amount.
  • the relative tumor volume on the 20th day of transplantation relative to the 7th day of transplantation was calculated as a measure of the tumor growth inhibitory effect.
  • Table 10 shows the results of evaluating the antitumor activity in MTD.
  • the ribosome preparations of Production Examples 53 and 54 showed a high tumor growth inhibitory effect, surpassing that of the aqueous solution, despite the smaller dose of 5 Omg / kg or 10 Omg / kg. And a high survival rate.
  • the tumor growth inhibitory effect and the survival rate were both lower than those of the ribosome preparation.
  • the liposomal preparation showed a high survival rate even with only a single administration.
  • CND AC concentrations in tumors after administration of various CND AC preparations were measured.
  • mice colon cancer co1on26 was implanted subcutaneously in 6-week-old CDF1 mice, and 10 to 14 days later, the preparations shown in Table 11 were treated with 150 mM It was appropriately diluted with an aqueous sodium chloride solution and administered once intravenously. One hour or five hours after the administration, blood was collected. Thereafter, the mice were exsanguinated, the tumor tissue and the kidney were removed, and the weight was measured. To these biological samples, 0.5 to 3 mL of 15 OmL aqueous sodium chloride solution was added and subjected to homogenization.
  • Detection limit is below 0.08 / gZg tissue.
  • the ribosome preparation has high drug transferability to tumor tissues and high retention in tumor tissues, and as a result, is a low-toxicity preparation, and thus is useful as an antitumor agent. is there.

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Abstract

L'invention concerne des préparations de liposomes contenant de la 1-(2'-cyano-2'-désoxy-β-D-arabino-pentofranosyl)cytosine. Ces préparations de liposomes présentent un remarquable pouvoir d'accumulation et de rétention dans un tissu tumoral et, par conséquent, exercent une activité antitumorale favorable.
PCT/JP2000/000948 1999-02-18 2000-02-18 Preparations de liposomes contenant des medicaments antitumoraux Ceased WO2000048611A1 (fr)

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AU25746/00A AU2574600A (en) 1999-02-18 2000-02-18 Liposome preparations containing antitumor drug

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JP3980199 1999-02-18
JP11/39801 1999-02-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007054731A1 (fr) * 2005-11-11 2007-05-18 Cyclacel Limited Produit compose antiproliferatif comprenant cyc-682 et un agent cytotoxique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4330534A (en) * 1979-08-02 1982-05-18 Asahi Kasei Kogyo Kabushiki Kaisha N4 -Acylcytosine arabinoside compositions
JPH0558879A (ja) * 1991-08-30 1993-03-09 Taiho Yakuhin Kogyo Kk 制癌剤含有リポソーム製剤
JPH05214015A (ja) * 1992-02-03 1993-08-24 Nippon Shokubai Co Ltd 新規重合体、その製造方法およびその用途
US5776488A (en) * 1994-03-11 1998-07-07 Yoshitomi Pharmaceutical Industries, Ltd. Liposome preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4330534A (en) * 1979-08-02 1982-05-18 Asahi Kasei Kogyo Kabushiki Kaisha N4 -Acylcytosine arabinoside compositions
JPH0558879A (ja) * 1991-08-30 1993-03-09 Taiho Yakuhin Kogyo Kk 制癌剤含有リポソーム製剤
JPH05214015A (ja) * 1992-02-03 1993-08-24 Nippon Shokubai Co Ltd 新規重合体、その製造方法およびその用途
US5776488A (en) * 1994-03-11 1998-07-07 Yoshitomi Pharmaceutical Industries, Ltd. Liposome preparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007054731A1 (fr) * 2005-11-11 2007-05-18 Cyclacel Limited Produit compose antiproliferatif comprenant cyc-682 et un agent cytotoxique

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