antitumor agents

Abstract

To provide an anti-tumor agent exhibiting a significantly excellent anti-tumor effect.SOLUTION: An anti-tumor agent for treating cancer which has liposomes including an inner water phase and aqueous solution in which liposomes constituting an outer water phase are dispersed, in which the liposome includes gemcitabine or salt thereof, lipid constituting the liposome at least contains hydrogenated soybean phosphatidyl choline, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol and cholesterol, and gemcitabine or salt thereof included in the liposome is administrated at the dosage of the surface area of 1.0 mg / m2 to the surface area of 240 mg / m2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an antitumor agent comprising a liposome encapsulating gemcitabine or a salt thereof, which is administered in a specific amount and according to a specific schedule. [Background technology]

[0002] Gemcitabine is a useful drug in chemotherapy for malignant tumors. It has an antimetabolic effect that inhibits DNA synthesis. Drugs with an antimetabolic effect only attack a portion of cells undergoing DNA synthesis, so effective cytotoxicity is not achieved if the exposure time is short. For such drugs, if the body's metabolism is rapid after administration, sufficient exposure time in the tumor is not achieved, and the expected efficacy is often not achieved.

[0003] It is known that by encapsulating a drug in a dissolved state in the internal aqueous phase of a liposome and subjecting the liposome composition to hypertonic conditions, it is possible to set the release rate of the drug from the liposome composition at an appropriate rate, thereby achieving more optimal drug delivery (Patent Documents 1 and 2).

[0004] Liposomal compositions in which gemcitabine is encapsulated in liposomes for a sufficient period of time for gemcitabine to be exposed to tumors have been reported in Patent Documents 1, 2, and 3. Furthermore, Patent Documents 4 and 5 have been reported as methods for producing liposomal compositions in which gemcitabine is encapsulated in liposomes. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2015 / 166985 [Patent Document 2] International Publication No. 2015 / 166986 [Patent Document 3] International Publication No. 2015 / 166987 [Patent Document 4] International Publication No. 2015 / 166988 [Patent Document 5] International Publication No. 2017 / 078009 Summary of the Invention [Problem to be solved by the invention]

[0006] To date, there have been no reports on the results of administering liposomes encapsulating gemcitabine or its salts to cancer patients. Therefore, it is unknown what kind of blood kinetics liposomes encapsulating gemcitabine or its salts exhibit. Even those skilled in the art cannot predict what dose would be required for liposomes encapsulating gemcitabine or its salts to exert their therapeutic effect in cancer patients without actually administering the drug to cancer patients. Furthermore, the blood concentration required for liposomes encapsulating gemcitabine or its salts to exhibit antitumor effects has not yet been investigated.

[0007] An object of the present invention is to provide an antitumor agent that exhibits a significantly excellent antitumor effect. [Means for solving the problem]

[0008] As a result of extensive research to solve the above problems, the present inventors have found that particularly excellent antitumor effects can be obtained when administered at a specific dose and schedule, and have completed the present invention.

[0009] That is, the present invention provides the following. <1> An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the gemcitabine or a salt thereof encapsulated in the liposomes is administered at a concentration of 1.0 mg / m2 as gemcitabine per administration. 2 Body surface area ~240mg / m 2Antitumor agents for treating cancer, administered in body surface area doses. <2> The dosage form is a liquid pharmaceutical preparation, and the concentration of gemcitabine or a salt thereof is 0.01 mg / mL to 10 mg / mL as gemcitabine. <1> The antitumor agent according to any one of claims 1 to 4. <3> Repeat one dose every week to every month. <1> or <2> The antitumor agent according to any one of claims 1 to 4. <4> The cancer is an advanced solid tumor, <1> ~ <3> The antitumor agent according to any one of the preceding claims. <5> The solid cancer is at least one selected from pancreatic cancer, uterine cancer, appendix cancer, ovarian cancer, lung cancer, breast cancer, biliary tract cancer, bladder cancer, colorectal cancer, gastric cancer, and non-Hodgkin's lymphoma. <4> The antitumor agent according to any one of claims 1 to 4. <6> The average particle size of the liposome is 5 nm or more and 100 nm or less. <1> ~ <5> The antitumor agent according to any one of the preceding claims. <7> The blending ratio of hydrogenated soybean phosphatidylcholine to the total lipids constituting the liposome is 50% by mass to 90% by mass, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol is 1% by mass to 50% by mass, and cholesterol is 1% by mass to 20% by mass. <1> ~ <6> The antitumor agent according to any one of the preceding claims. <8> the route of administration is intravenous; <1> ~ <7> The antitumor agent according to any one of the preceding claims. <9> A single dose is administered by infusion over 15 to 240 minutes. <1> ~ <8> The antitumor agent according to any one of the preceding claims. <10> An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 15 of a 28-day cycle. 2 Body surface area ~240mg / m 2An antitumor agent administered at a dose based on the body surface area, with a drug-free period from days 2 to 14 and from days 16 to 27, and this cycle is repeated. <11> An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 8 of a 21-day cycle. 2 Body surface area ~240mg / m 2 An antitumor agent administered at a dose of body surface area, with a drug rest period from days 2 to 7 and from days 9 to 20, and this cycle is repeated. <12> An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein one cycle is 28 days, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on the first day. 2 Body surface area ~240mg / m 2 An antitumor agent administered at a dose based on the body surface area, with a break from administration from day 2 to day 27, and this cycle is repeated. <13> An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein one cycle is 21 days, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on the first day.2 Body surface area ~240mg / m 2 An antitumor agent administered at a dose based on the body surface area, with a break from administration from day 2 to day 20, and this cycle is repeated.

[0010] A method for treating cancer, comprising administering to a subject an antitumor agent having liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the gemcitabine or a salt thereof encapsulated in the liposomes is administered at a dose of 1.0 mg / m2 in terms of gemcitabine per administration. 2 Body surface area ~240mg / m 2 A treatment method for treating cancer, wherein the subject is administered a body surface area dose. An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the gemcitabine or a salt thereof encapsulated in the liposomes is administered at a concentration of 1.0 mg / m2 as gemcitabine per administration. 2 Body surface area ~240mg / m 2 An antitumor agent for use in the treatment of cancer, administered in a body surface area dose. <c>1. Use of a composition comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, for the manufacture of an antitumor agent for treating cancer, wherein the liposomes encapsulate gemcitabine or a salt thereof, the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the gemcitabine or a salt thereof encapsulated in the liposomes is administered at a concentration of 1.0 mg / m2 as gemcitabine per administration. 2 Body surface area ~240mg / m 2 Use of compositions administered in body surface area doses.

[0011] <d>A method for treating cancer, comprising administering to a subject an antitumor agent having liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 15 of a 28-day cycle. 2 Body surface area ~240mg / m 2 A treatment method for treating cancer, in which a dose of 100 mg / kg body surface area is administered, followed by a rest period from days 2 to 14 and from days 16 to 27, and this cycle is repeated. <e>An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 15 of a 28-day cycle. 2 Body surface area ~240mg / m 2 1. An anti-tumor agent for use in the treatment of cancer, administered at a dose of body surface area per 100 mg / kg body surface area, with a rest period from days 2 to 14 and from days 16 to 27, the cycle repeating. <f>1. Use of a composition comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase for the manufacture of an antitumor agent for treating cancer, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 15 of a 28-day cycle. 2 Body surface area ~240mg / m 2 Use of the composition, wherein the composition is administered in a dose of body surface area, with a rest period from days 2 to 14 and from days 16 to 27, and the cycle is repeated.

[0012] <g>A method for treating cancer, comprising administering to a subject an antitumor agent having liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 8 of a 21-day cycle. 2 Body surface area ~240mg / m 2 A treatment method for treating cancer, in which a dose of 100 mg / kg body surface area is administered, followed by a rest period from days 2 to 7 and from days 9 to 20, and this cycle is repeated. <h>An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 8 of a 21-day cycle. 2 Body surface area ~240mg / m 2 1. An anti-tumor agent for use in the treatment of cancer, wherein the agent is administered in a dose of body surface area per 100 mg / kg body weight, with a rest period from days 2 to 7 and from days 9 to 20, the cycle being repeated. 1. Use of a composition comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase for the manufacture of an antitumor agent for treating cancer, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 8 of a 21-day cycle. 2 Body surface area ~240mg / m 2 Use of the composition, wherein the composition is administered in a dose of 100 mg / kg body surface area, with a rest period from days 2 to 7 and from days 9 to 20, and the cycle is repeated.

[0013] <j>A method for treating cancer, comprising administering to a subject an antitumor agent having liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes per administration is 1.0 mg / m2 of gemcitabine, with one cycle being 28 days. 2 Body surface area ~240mg / m 2 A treatment method for treating cancer in which a dose of 100 mg / kg body surface area is administered, followed by a rest period from day 2 to day 27, and this cycle is repeated. <k>An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein one cycle is 28 days, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on the first day. 2 Body surface area ~240mg / m 2 An anti-tumor agent for use in the treatment of cancer, administered at a dose of body surface area per 100 mg / kg body surface area, with a rest period from day 2 to day 27, and repeating this cycle. <l>1. Use of a composition comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, for the manufacture of an antitumor agent for treating cancer, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per dose on the first day of a 28-day cycle. 2 Body surface area ~240mg / m 2 Use of the composition, wherein the composition is administered in a dose of 100 mg / kg body surface area, followed by a rest period from day 2 to day 27, and the cycle is repeated.

[0014] <m>A method for treating cancer, comprising administering to a subject an antitumor agent having liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes per administration is 1.0 mg / m2 of gemcitabine, with one cycle lasting 21 days. 2 Body surface area ~240mg / m 2 A treatment method for treating cancer in which a dose of 100 mg / kg body surface area is administered, followed by a rest period from day 2 to day 20, and this cycle is repeated. <n>An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein one cycle is 21 days, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on the first day. 2 Body surface area ~240mg / m 2 An anti-tumor agent for use in the treatment of cancer, administered at a dose of body surface area per 2000 mg / kg body surface area, with a rest period from day 2 to day 20, and repeating this cycle. <o>1. Use of a composition comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase for the manufacture of an antitumor agent for treating cancer, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per dose on the first day of a 21-day cycle. 2 Body surface area ~240mg / m 2 The composition is administered in a dose of 100 mg / kg body surface area, followed by a rest period from day 2 to day 20, and the cycle is repeated. [Effects of the Invention]

[0015] The antitumor agent of the present invention exhibits excellent antitumor effects and is significantly effective in reducing cancer volume. Furthermore, as a result of the antitumor effects obtained by the antitumor agent of the present invention, it is expected that progression-free survival and overall survival will be extended. DETAILED DESCRIPTION OF THE INVENTION

[0016] In the present invention, the ranges expressed with "to" include both end values ​​unless otherwise specified. In the present invention, the term "tumor" is used synonymously with "malignant tumor" and "cancer." A "malignant tumor" refers to a tumor in which the morphology and arrangement of tumor cells differ from those of the normal cells from which they originate, and which exhibits invasive or metastatic properties. "Treatment" refers to treatment for each disease. The "subject" refers to a mammal such as a human, mouse, monkey, or livestock that requires prevention or treatment, and is preferably a human that requires prevention or treatment. "Prevention" means inhibition of onset, reduction of the risk of onset, or delay of onset, or the like. "Treatment" means amelioration of a disease or condition or inhibition (maintenance or delay) of its progression, and the like. "Progression-free survival" refers to the period during (or after) treatment during which cancer does not progress and remains stable. "Overall survival" means the length of time a subject has survived from the date of treatment assignment or initiation date in a clinical trial.

[0017] The present invention will be described in detail below. The present invention provides an antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the gemcitabine or a salt thereof encapsulated in the liposomes is administered at a concentration of 1.0 mg / m2 as gemcitabine per administration. 2 Body surface area ~240mg / m 2 It is an antitumor agent for treating cancer, administered in body surface area doses.

[0018] (liposomes) A liposome is a closed vesicle formed of a lipid bilayer membrane using lipids, and has an aqueous phase (internal aqueous phase) within the space of the closed vesicle. The internal aqueous phase contains water, etc. Liposomes usually exist in a dispersed state in an aqueous solution (external aqueous phase) outside the closed vesicle. Liposomes may be single-lamellar (also called unilamellar or unilamellar, with a single bilayer membrane structure) or multilamellar (also called multilamellar, with a multiple bilayer membrane structure in an onion-like shape, with each layer separated by an aqueous layer), but in the present invention, single-lamellar liposomes are preferred from the viewpoint of safety and stability in pharmaceutical applications.

[0019] The liposome is not particularly limited in its form as long as it is capable of encapsulating a drug. "Encapsulating" means that the liposome is in a form in which the drug is contained in the internal aqueous phase. For example, the liposome may be in a form in which the drug is enclosed in a closed space formed by a membrane, or in which the drug is encapsulated in the membrane itself, or a combination of these may be used.

[0020] The size (average particle diameter) of the liposomes is not particularly limited, but is 2 to 200 nm, preferably 5 to 150 nm, more preferably 5 to 120 nm, and even more preferably 5 to 100 nm. When the enhanced permeation and retention (EPR) effect described below is desired, the size (average particle size) of the liposomes is preferably substantially 50 to 200 nm in diameter, more preferably substantially 50 to 150 nm in diameter, and even more preferably substantially 50 to 100 nm in diameter. The term "substantially" means that at least 75% of the liposomes by number are within the specified diameter range. The aforementioned "at least 75%" is more preferably at least 80%, and even more preferably at least 90%. In the present invention, unless otherwise specified, the term "average particle size" refers to the average particle size measured using a dynamic light scattering method (preferably the cumulant average particle size). The "average particle size" can be measured using an apparatus capable of measuring the average particle size by a light scattering method.

[0021] The components constituting the lipid bilayer membrane of the liposome are selected from lipids, such as hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol.

[0022] The blending ratio of the lipids constituting the liposome of the present invention to the total lipids is preferably 50% by mass to 90% by mass of hydrogenated soybean phosphatidylcholine, 1% by mass to 50% by mass of 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and 1% by mass to 20% by mass of cholesterol, and more preferably 55% by mass to 80% by mass of hydrogenated soybean phosphatidylcholine, 10% by mass to 30% by mass of 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and 1% by mass to 10% by mass of cholesterol.

[0023] (Gemcitabine or its salt) The liposome of the present invention encapsulates gemcitabine or a salt thereof. Gemcitabine, whose chemical name is (+)-2'-deoxy-2',2'-difluorocytidine, is an anticancer drug with antimetabolic activity. In the present invention, gemcitabine may be gemcitabine itself, a pharmaceutically acceptable salt thereof, or a prodrug that releases gemcitabine in vivo. In the present invention, it is preferable to use gemcitabine hydrochloride.

[0024] Gemcitabine encapsulated in the liposomes of the present invention is present in a dissolved state in the internal aqueous phase of the liposomes. Here, the term "dissolved state" refers to when the amount of drug loaded relative to the volume of the liposome is equal to or less than the saturation solubility of the drug in the composition of the internal aqueous phase. Furthermore, even at or above the saturated solubility, if no drug crystals are observed by Cryo-TEM or no diffraction pattern due to the crystal lattice is observed by XRD measurement, gemcitabine is considered to be encapsulated in a dissolved state.

[0025] (Method of manufacturing liposomes) The liposomes of the present invention can be produced by any method that can produce a liposome composition in which gemcitabine is encapsulated in a dissolved state in the liposomes. For example, the method can be carried out by referring to Patent Document 1 (International Publication No. 2015 / 166985) and Patent Document 2 (International Publication No. 2015 / 166986).

[0026] In the liposomes of the present invention, the osmotic pressure of the internal aqueous phase is 2 to 8 times, preferably 2.5 to 6 times, and more preferably 3 to 5 times, that of the external aqueous phase. By making the osmotic pressure of the internal aqueous phase of the liposome 2 to 8 times that of the external aqueous phase, it is possible to obtain liposomes that can achieve both ease of drug release and storage stability.

[0027] The osmotic pressure of the internal and external aqueous phases of liposomes can be measured, for example, as follows, but is not limited to this. In the liposome production process described in Patent Documents 1 and 2, the liquid obtained after the final drug loading step has homogenized solutes in the external and internal aqueous phases. Measuring the osmotic pressure at this point can define the osmotic pressure of the internal aqueous phase of liposomes. However, this is limited to cases where the solutes in the internal aqueous phase are sufficiently retained, for example, by suppressing the heating operation below the lipid phase transition temperature in the subsequent step of replacing the external aqueous phase by dialysis and adjusting the osmotic pressure. The osmotic pressure of the external aqueous phase can also be defined by measuring the osmotic pressure of the dialysate used in the final dialysis step. However, this is limited to cases where sufficient replacement with dialysate has been achieved. Alternatively, the osmotic pressure of the internal and external aqueous phases can be defined by quantifying the composition concentrations of the external and internal aqueous phase solutes using centrifugation or ultrafiltration of the completed liposome solution, and then measuring the osmotic pressure of the resulting composition solution.

[0028] Osmolality can be measured according to the osmolality measurement method described in the 16th Edition of the Japanese Pharmacopoeia. Specifically, osmolality can be determined by measuring the freezing point depression of water. Furthermore, the freezing point depression of water is defined by the solute molar concentration, and osmolality can also be determined from the solute molar concentration.

[0029] The osmotic pressure of the external aqueous phase of the liposome of the present invention has a significant effect on the living body upon administration. If the osmotic pressure is significantly different from that of body fluids, hemolysis and pain may occur due to the movement of water in various tissues. Therefore, the osmotic pressure of the external aqueous phase of the present invention is preferably 200 to 400 mOsmol / L, more preferably 250 to 350 mOsmol / L, and most preferably isotonic with the liposome.

[0030] (Release speed) The release rate refers to the amount of drug (here, gemcitabine) released from the liposome per unit time. In the liposome of the present invention, the release rate in plasma at 37°C is preferably 10% by mass / 24 hr to 70% by mass / 24 hr, more preferably 20% by mass / 24 hr to 60% by mass / 24 hr, and even more preferably 20% by mass / 24 hr to 50% by mass / 24 hr. Since the release rate depends on temperature, it is preferable to measure at a constant temperature. For example, in the case of humans, the temperature is not particularly limited, but it is preferable to measure within the range of body temperature (35°C to 38°C).

[0031] A release rate of less than 10% by mass / 24 hours often results in insufficient exposure time in the body as an antitumor agent, resulting in failure to achieve the expected efficacy. In some cases, liposomes may remain in the body for an unnecessarily long time, resulting in accumulation in tissues where they are difficult to distribute, such as the skin, and thus unexpected toxicity. A release rate of more than 70% by mass / 24 hours is undesirable because the amount of drug exposed per unit time increases, resulting in a higher peak blood concentration and increased toxicity. Furthermore, the leaked drug may be distributed to tissues other than the tumor site or rapidly desorbed, resulting in reduced blood retention.

[0032] (Antineoplastic agent) According to the present invention, an antitumor agent for treating cancer is provided.

[0033] The cancer in the present invention is preferably an aggressive solid cancer. Cancers are basically classified into five stages, from stage 0 to stage IV, depending on the degree of progression. When cancers are referred to as aggressive, they generally refer to stage III or higher, but are not limited thereto. Furthermore, the solid cancer is more preferably at least one selected from pancreatic cancer, uterine cancer, appendix cancer, ovarian cancer, lung cancer, biliary tract cancer, bladder cancer, colorectal cancer, gastric cancer, non-Hodgkin's lymphoma, breast cancer, and sarcoma, even more preferably pancreatic cancer, uterine cancer, appendix cancer, lung cancer, bladder cancer, liposarcoma, malignant melanoma, Hodgkin's lymphoma, renal cell carcinoma, and esophageal cancer, and most preferably pancreatic cancer, lung cancer, bladder cancer, and biliary tract cancer. Lung cancer includes non-small cell carcinoma (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) and small cell carcinoma. Bladder cancer includes urothelial carcinoma, squamous cell carcinoma, or adenocarcinoma.

[0034] The antitumor agent of the present invention is preferably used to treat cancers for which therapy using gemcitabine is effective, and more preferably used to treat cancers that are resistant to gemcitabine. Resistance is when cancer cells show resistance to anticancer drugs, and includes natural resistance, in which anticancer drugs are ineffective from the beginning of treatment, and a state in which an anticancer drug that was initially effective becomes ineffective or less effective as treatment continues. Specifically, it refers to a state in which cells initially responded to anticancer drugs but then showed a decrease in responsiveness during treatment, or did not show an appropriate response to anticancer drugs in that the cells continued to proliferate during treatment with the anticancer drugs.

[0035] The dosage form of the antitumor agent of the present invention is preferably a liquid pharmaceutical preparation, for example, an injection. The concentration of gemcitabine or a salt thereof contained in the liquid pharmaceutical formulation of the present invention is preferably 0.01 mg / mL to 10 mg / mL in terms of gemcitabine, more preferably 0.1 mg / mL to 5 mg / mL, and even more preferably 0.1 mg / mL to 1 mg / mL.

[0036] The liquid pharmaceutical formulation of the present invention may generally contain additives such as emulsifiers, surfactants, solubilizing agents, suspending agents, isotonicity agents, buffers, preservatives, antioxidants, stabilizers, and absorption enhancers.

[0037] Examples of isotonic agents include, but are not limited to, inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; polyols such as glycerol, mannitol, and sorbitol; and sugars such as glucose, fructose, lactose, and sucrose.

[0038] Stabilizers include, but are not limited to, sugars such as glycerol, mannitol, sorbitol, lactose, or sucrose.

[0039] The antioxidant is not particularly limited, but examples thereof include ascorbic acid, uric acid, tocopherol homologues (e.g., vitamin E, four isomers of tocopherol α, β, γ, and δ), cysteine, EDTA, etc. The stabilizers and antioxidants can be used either alone or in combination of two or more.

[0040] Examples of pH adjusters include sodium hydroxide, citric acid, acetic acid, triethanolamine, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

[0041] The liquid pharmaceutical formulation of the present invention may contain a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, gum arabic, casein, gelatin, agar, diglycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, PBS, sodium chloride, sugars, biodegradable polymers, serum-free media, and additives acceptable as pharmaceutical additives.

[0042] In particular, the liquid pharmaceutical preparation of the present invention preferably contains sucrose, L-histidine, sodium chloride, sodium hydroxide, etc. in the external aqueous phase.

[0043] The pH of the external aqueous phase of the liquid pharmaceutical preparation of the present invention is preferably neutral, specifically, about pH 5.5 to 8.5.

[0044] The antitumor agent of the present invention is preferably administered parenterally. Routes of administration include intravenous, intraarterial, intramuscular, intraperitoneal, subcutaneous, intraocular, and intrathecal administration, with intravenous being preferred. Administration methods include administration by syringe or infusion.

[0045] The container for filling the liquid pharmaceutical preparation is not particularly limited, but is preferably made of a material with low oxygen permeability. Examples include plastic containers, glass containers, bags made of aluminum foil, aluminum vapor-deposited film, aluminum oxide vapor-deposited film, silicon oxide vapor-deposited film, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyethylene terephthalate, polyethylene naphthalate, polyvinylidene chloride, or the like, as a gas barrier layer, and if necessary, light can be blocked by using colored glass, bags made of aluminum foil, aluminum vapor-deposited film, or the like.

[0046] In a container filled with a liquid pharmaceutical preparation, it is preferable to replace the gas in the container space and in the pharmaceutical solution with an inert gas such as nitrogen to prevent oxidation due to oxygen present in the space within the container. For example, nitrogen may be bubbled through the injection solution, and the container may be filled under a nitrogen atmosphere.

[0047] The antitumor agent of the present invention can also be used in combination with other active substances or treatment methods useful for treating the target cancer. Examples of treatment methods include physical therapies such as radiation therapy and particle beam therapy, surgical treatments such as surgery, chemotherapy, molecular targeted therapy, and cancer immunotherapy. Other active substances that can be used in combination include chemotherapeutic agents used in chemotherapy, molecular targeted therapeutic agents used in molecular targeted therapy, cell preparations and antibody preparations used in cancer immunotherapy, and immune checkpoint inhibitors. Examples of chemotherapeutic agents include alkylating agents, antimetabolites, antitumor antibiotics, alkaloids, hormone therapy agents, platinum complexes, angiogenesis inhibitors, topoisomerase inhibitors, and microtubule-active agents.

[0048] (Dosage and dosage) The antitumor agent of the present invention has a single dose of gemcitabine or a salt thereof encapsulated in liposomes of 1.0 mg / m2 as gemcitabine. 2 Body surface area ~240mg / m 2 Dose per body surface area. Preferably 6 mg / m 2 Body surface area ~120mg / m 2 Dose per body surface area, more preferably 12 mg / m 2 Body surface area ~100mg / m 2 body surface area, more preferably 30 mg / m 2 Body surface area ~75mg / m 2 The dose is based on the body surface area, and is particularly preferably 40 mg / m 2 Body surface area ~60mg / m 2 Dose per body surface area.

[0049] The antitumor agent of the present invention is preferably administered once every week to once every month multiple times. More preferably, it is administered once every week to four weeks multiple times, even more preferably, it is administered once every two to four weeks multiple times, and particularly preferably, it is administered once every three to four weeks multiple times. It is also preferable to administer a combination of once every two weeks and once a week multiple times.

[0050] The antitumor agent of the present invention is preferably administered by infusion over a period of 15 to 240 minutes in a single administration, more preferably 15 to 180 minutes, even more preferably 30 to 150 minutes, and most preferably 30 to 120 minutes.

[0051] Another aspect of the present invention is an antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 15 of a 28-day cycle. 2 Body surface area ~240mg / m 2 It is an antitumor agent that is administered at a dose based on the body surface area, with a drug-free period from days 2 to 14 and from days 16 to 27, and this cycle is repeated. The preferred embodiment is the same as that described above. The dose of gemcitabine or a salt thereof encapsulated in the liposome per administration is, for example, about 1.0 mg / m as gemcitabine. 2 Body surface area, approximately 1.2mg / m 2 Body surface area, approximately 2.4mg / m 2 Body surface area, approximately 4.8mg / m 2 Body surface area, approximately 8mg / m 2 Body surface area, approximately 12mg / m 2 Body surface area, approximately 17mg / m 2 Body surface area, approximately 23 mg / m 2 Body surface area, approximately 30mg / m 2 Body surface area, approximately 40mg / m 2 Body surface area, approximately 55mg / m 2 Body surface area, approximately 60mg / m 2 Body surface area, approximately 70mg / m 2 Body surface area, approximately 75mg / m 2 Body surface area, approximately 80mg / m 2 Body surface area, approximately 90mg / m 2 Body surface area, approximately 100mg / m 2 Body surface area, approximately 110mg / m 2 Body surface area, approximately 120mg / m 2 Body surface area, approximately 130mg / m 2 Body surface area, approximately 140mg / m 2 Body surface area, approximately 150mg / m 2 Body surface area, approximately 160mg / m 2 Body surface area, approximately 170mg / m 2 Body surface area, approximately 180mg / m 2 Body surface area, approximately 190mg / m 2 Body surface area, approximately 200mg / m 2 Body surface area, approximately 210mg / m 2 Body surface area, approximately 220mg / m 2 Body surface area, approximately 230mg / m 2 Body surface area, approximately 240mg / m 2 Body surface area.

[0052] Yet another embodiment of the present invention is an antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per administration on days 1 and 8 of a 21-day cycle. 2 Body surface area ~240mg / m 2 It is an antitumor agent that is administered at a dose based on the body surface area, with a drug-free period from days 2 to 7 and from days 9 to 20, and this cycle is repeated. The dose of gemcitabine or a salt thereof encapsulated in the liposome per administration is, for example, about 1.0 mg / m as gemcitabine. 2 Body surface area, approximately 1.2mg / m 2 Body surface area, approximately 2.4mg / m 2 Body surface area, approximately 4.8mg / m 2 Body surface area, approximately 8mg / m 2 Body surface area, approximately 12mg / m 2 Body surface area, approximately 17mg / m 2 Body surface area, approximately 23 mg / m 2 Body surface area, approximately 30mg / m 2 Body surface area, approximately 40mg / m 2 Body surface area, approximately 55mg / m 2 Body surface area, approximately 60mg / m 2 Body surface area, approximately 70mg / m 2 Body surface area, approximately 75mg / m 2 Body surface area, approximately 80mg / m 2 Body surface area, approximately 90mg / m 2 Body surface area, approximately 100mg / m 2 Body surface area, approximately 110mg / m 2 Body surface area, approximately 120mg / m 2 Body surface area, approximately 130mg / m 2 Body surface area, approximately 140mg / m 2 Body surface area, approximately 150mg / m 2 Body surface area, approximately 160mg / m 2 Body surface area, approximately 170mg / m 2 Body surface area, approximately 180mg / m 2 Body surface area, approximately 190mg / m 2 Body surface area, approximately 200mg / m 2 Body surface area, approximately 210mg / m 2 Body surface area, approximately 220mg / m 2 Body surface area, approximately 230mg / m 2 Body surface area, approximately 240mg / m 2 Body surface area. The preferred embodiment is the same as that described above.

[0053] Another aspect of the present invention is an antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein one cycle is 28 days, and on the first day, the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per dose. 2 Body surface area ~240mg / m 2 It is an antitumor drug that is administered at a dose based on the body surface area, with a drug-free period from day 2 to day 27, and this cycle is repeated. The preferred embodiment is the same as that described above. The dose of gemcitabine or a salt thereof encapsulated in the liposome per administration is, for example, about 1.0 mg / m as gemcitabine. 2 Body surface area, approximately 1.2mg / m 2 Body surface area, approximately 2.4mg / m 2 Body surface area, approximately 4.8mg / m 2 Body surface area, approximately 8mg / m 2 Body surface area, approximately 12mg / m 2 Body surface area, approximately 17mg / m 2 Body surface area, approximately 23 mg / m 2 Body surface area, approximately 30mg / m 2 Body surface area, approximately 40mg / m 2 Body surface area, approximately 55mg / m 2 Body surface area, approximately 60mg / m 2 Body surface area, approximately 70mg / m 2 Body surface area, approximately 75mg / m 2 Body surface area approx. 80mg / m 2 Body surface area, approximately 90mg / m 2 Body surface area, approximately 100mg / m 2 Body surface area, approximately 110mg / m 2 Body surface area, approximately 120mg / m 2 Body surface area, approximately 130mg / m 2 Body surface area, approximately 140mg / m 2 Body surface area, approximately 150mg / m 2 Body surface area, approximately 160mg / m 2 Body surface area, approximately 170mg / m 2 Body surface area, approximately 180mg / m 2 Body surface area, approximately 190mg / m 2 Body surface area, approximately 200mg / m 2 Body surface area, approximately 210mg / m 2 Body surface area, approximately 220mg / m 2 Body surface area, approximately 230mg / m 2 Body surface area, approximately 240mg / m 2 Body surface area. The dose of gemcitabine or a salt thereof encapsulated in the liposome per administration is preferably about 17 mg / m2 of gemcitabine. 2 Body surface area ~ approx. 60mg / m 2 body surface area, more preferably about 30 mg / m 2 Body surface area~approx. 55mg / m 2 Body surface area.

[0054] Another aspect of the present invention is an antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution dispersing the liposomes constituting an external aqueous phase, wherein the liposomes encapsulate gemcitabine or a salt thereof, and the lipids constituting the liposomes contain at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol, and wherein one cycle is 21 days, and the amount of gemcitabine or a salt thereof encapsulated in the liposomes is 1.0 mg / m2 of gemcitabine per dose on the first day. 2 Body surface area ~240mg / m 2 It is an antitumor agent that is administered at a dose based on the body surface area, with a drug-free period from day 2 to day 20, and this cycle is repeated. The preferred embodiment is the same as that described above. The dose of gemcitabine or a salt thereof encapsulated in the liposome per administration is, for example, about 1.0 mg / m as gemcitabine. 2 Body surface area, approximately 1.2mg / m 2 Body surface area, approximately 2.4mg / m 2 Body surface area, approximately 4.8mg / m 2 Body surface area, approximately 8mg / m 2 Body surface area, approximately 12mg / m 2 Body surface area, approximately 17mg / m 2 Body surface area, approximately 23 mg / m 2 Body surface area, approximately 30mg / m 2 Body surface area, approximately 40mg / m 2 Body surface area, approximately 55mg / m 2 Body surface area, approximately 60mg / m 2 Body surface area, approximately 70mg / m 2 Body surface area, approximately 75mg / m 2 Body surface area approx. 80mg / m 2 Body surface area, approximately 90mg / m 2 Body surface area, approximately 100mg / m 2 Body surface area, approximately 110mg / m 2 Body surface area, approximately 120mg / m 2 Body surface area, approximately 130mg / m 2 Body surface area, approximately 140mg / m 2 Body surface area, approximately 150mg / m 2 Body surface area, approximately 160mg / m 2 Body surface area, approximately 170mg / m 2 Body surface area, approximately 180mg / m 2 Body surface area, approximately 190mg / m 2 Body surface area, approximately 200mg / m 2 Body surface area, approximately 210mg / m 2 Body surface area, approximately 220mg / m 2 Body surface area, approximately 230mg / m 2 Body surface area, approximately 240mg / m 2 Body surface area. The dose of gemcitabine or a salt thereof encapsulated in the liposome per administration is preferably about 17 mg / m2 of gemcitabine. 2 Body surface area ~ approx. 60mg / m 2 body surface area, more preferably about 30 mg / m 2 Body surface area~approx. 55mg / m 2 Body surface area. [Example]

[0055] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[0056] <Preparation of a Liquid Pharmaceutical Preparation Containing Gemcitabine-Encapsulated Liposomes> Referring to Patent Document 1 (International Publication No. 2015 / 166985), a liquid pharmaceutical preparation containing gemcitabine-encapsulated liposomes with the following composition (hereinafter referred to as Preparation A) was prepared. Gemcitabine hydrochloride 0.57 mg / mL Hydrogenated soy phosphatidylcholine 11.3 mg / mL MPEG-DSPE (Note 1) 2.91 mg / mL Cholesterol 1.39 mg / mL Sucrose 94 mg / mL L-Histidine 1.55 mg / mL Sodium chloride 0.188 mg / mL pH adjuster appropriate amount (Note 1) N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl- sn -glycerol-3-phosphoethanolamine sodium salt

[0057] Gemcitabine hydrochloride was obtained from Teva API Co., Ltd., and hydrogenated soy phosphatidylcholine and MPEG-DSPE were obtained from NOF Corporation. Other reagents used were commercially available products conforming to the United States Pharmacopeia.

[0058] <Physical Property Values of Preparation A> The osmotic pressure of the inner aqueous phase of the liposomes was 3.8 times that of the outer aqueous phase. The release rate of gemcitabine from the liposomes was 25% by mass / 24 hours at 37 °C in human plasma, and the average particle size was 77 nm. Preparation A was injected into 10 mL glass vials and used for treatment. The concentration of gemcitabine hydrochloride in the preparation injected into the vials was 0.57 mg / mL, and the pH was 6.5 - 8.0.

[0059] <Reference Example 1: Prediction of Dosage> Formulation A was diluted with 5% glucose solution to 0.1, 0.2, and 0.3 mg / mL, and administered at 1, 2, and 3 mg / kg (6, 12, and 18 mg / mL). 2 ) once a week for 4 weeks to 15 male and 15 female SD rats (Charles River Laboratories, Inc.) (30 rats in total). At 2 mg / kg or less, no deaths were attributed to Formulation A during the test period. At 3 mg / kg, 6 male and female rats (20%) were found dead or sacrificed moribund during the administration period. Causes of death or moribund sacrifice were degeneration, necrosis, or atrophy of the gastrointestinal epithelium, bone marrow suppression, and sepsis resulting from bone marrow suppression. Changes associated with Formulation A in animals subjected to scheduled necropsy included dose-responsive bone marrow suppression and decreased food intake, thymic atrophy, degeneration, necrosis, or atrophy of the gastrointestinal epithelium, and degeneration, necrosis, or atrophy of the spermatogenic epithelium at 1 mg / kg or more, which were considered to correspond to the cell proliferation inhibitory effect of Formulation A. From the above, at 2 mg / kg (12 mg / m), where no deaths were observed, 2 ) is the maximum tolerated dose, and the initial human dose is 1.2 mg / m 2 It was decided.

[0060] Based on the dosage predicted in Reference Example 1, Formulation A was used in the treatments shown in the following Examples 1 and 2. The treatments were conducted at the HonorHealth Research Institute in Scottsdale, Arizona, USA, the Sarah Cannon Research Institute in Denver, Colorado, USA, the University of Texas MD Anderson Cancer Center in Shewston, Texas, USA, and the Sarah Cannon Research Institute in Nashville, Tennessee, USA.

[0061] <Example 1: Administration Test 1> The cancer patients were administered Formulation A once every two weeks in a repeated cycle. Specifically, Formulation A was administered on days 1 and 15 of each 28-day cycle, and this 28-day cycle was repeated.

[0062] The effectiveness of the treatment was judged according to the following criteria: The subjects were identified by diagnostic imaging using CT (Computed Tomography) or MRI (Magnetic Resonance Imaging), and the results were judged according to the following criteria. CR (Complete Response): The tumor has completely disappeared. PR (Partial Response): A state in which the sum of tumor sizes has decreased by 30% or more. SD (Stable Disease): A state in which the size of the tumor does not change PD (Progressive Disease): A state in which the sum of tumor size has increased by 20% or more and the absolute value has increased by 5 mm or more, or a state in which a new lesion has appeared Furthermore, because the purpose of chemotherapy for solid cancers is to alleviate symptoms and prolong life, even if the treatment effect is SD, it is still considered to be effective as a drug.

[0063] (Pancreatic cancer patient 1) Formulation A was administered at a dose of 1.2 mg / m 2 In one patient with pancreatic cancer who received the drug, a tumor shrinkage of over 30% was observed, and SD was maintained for 20 weeks. The patient had received chemotherapy with gemcitabine or a combination of gemcitabine and cisplatin as a prior treatment. The patient was 67 years old and female.

[0064] (Pancreatic cancer patient 2) Formulation A was administered at a dose of 4.8 mg / m 2 In pancreatic cancer patient 2 who received the drug, the tumor shrinkage effect was assessed at 4 and 8 weeks after administration, and the result was PR. The patient had received chemotherapy with a combination of gemcitabine and capecitabine as a prior treatment. The patient was 57 years old and male.

[0065] (Uterine cancer patient 1) Formulation A was administered at a dose of 1.2 mg / m 2 In uterine cancer patient 1, who received 100 mg of riboflavin, the tumor size remained unchanged for 24 weeks, resulting in SD. The patient was 73 years old and female.

[0066] (Pancreatic cancer patient 3) Formulation A was administered at a dose of 12 mg / m 2 In one patient with pancreatic cancer who received the drug, SD was observed, with the tumor size remaining unchanged for eight weeks.

[0067] (Pancreatic cancer patient 4) Formulation A was administered at a dose of 17 mg / m 2 In one patient with pancreatic cancer who received the drug, SD was observed, with no change in tumor size over a period of eight weeks.

[0068] (Liposarcoma patient 1) Formulation A was administered at a dose of 30 mg / m 2 In one sarcoma patient who received this treatment, the tumor size remained unchanged for more than 12 weeks, resulting in SD.

[0069] (Uterine cancer patient 2) Formulation A was administered at a dose of 30 mg / m 2 In one sarcoma patient who received this treatment, the tumor size remained unchanged for more than 8 weeks, resulting in SD.

[0070] <Example 2: Administration Test 2> Formulation A was administered to cancer patients on days 1 and 8 of a 21-day cycle, and this 21-day cycle was repeated. The effect of the treatment was evaluated according to the same criteria as in Example 1.

[0071] (Pancreatic cancer patient 5) Formulation A was administered at a dose of 12 mg / m 2 In five pancreatic cancer patients who received this treatment, the tumor size remained unchanged for more than 10 weeks, indicating SD.

[0072] (Appendix cancer patient 1) Formulation A was administered at a dose of 12 mg / m 2 In appendiceal cancer patient 1, who received the drug, the tumor size remained unchanged for more than 10 weeks, resulting in SD.

[0073] (Lung cancer patient 1) Formulation A was administered at a dose of 23 mg / m 2 The first cycle was administered at 17 mg / m², and then a 13-day rest period was followed from day 1 of the second cycle (day 22 after the first administration). Then, on day 15 of the second cycle (day 36 after the first administration), formulation A was administered at a dose of 17 mg / m² per administration of gemcitabine. 2 In lung cancer patient 1 (non-small cell lung cancer) who received the drug, the tumor size remained unchanged for more than 8 weeks after the first administration, and the patient was judged to have experienced SD.

[0074] <Example 3: Administration Test 3> Cancer patients were administered Formulation A on the first day of each 28-day cycle, and this 28-day cycle was repeated. The effect of the treatment was evaluated according to the same criteria as in Example 1.

[0075] (Biliary tract cancer patient 1) Formulation A was administered at a dose of 40 mg / m 2 In biliary tract cancer patient 1, who received 100 mg of riboflavin, the tumor shrinkage effect was assessed 8 weeks after administration and was determined to be PR. Subsequently, the result was also PR at 16 weeks after administration.

[0076] (Bladder cancer patient 1) Formulation A was administered at a dose of 40 mg / m 2 In one bladder cancer patient who received this treatment, the tumor size remained unchanged for more than 16 days, and the patient was determined to have sustained stable disease.

[0077] <Example 4: Administration Test 4> Cancer patients were administered Formulation A on the first day of each 21-day cycle, and this 21-day cycle was repeated. The effect of the treatment was evaluated according to the same criteria as in Example 1.

[0078] (Pancreatic cancer patient 6) Formulation A was administered at a dose of 40 mg / m 2 In six pancreatic cancer patients who received this treatment, the tumor size remained unchanged for more than six weeks, indicating SD.

[0079] The antitumor agent of the present invention exhibited excellent antitumor effects. Specifically, it reduced the volume of cancer cells and maintained tumor size. Based on these results, the antitumor agent of the present invention is expected to extend the progression-free survival and overall survival of patients, and has a very useful effect in terms of improving patients' quality of life. [Industrial Applicability]

[0080] The antitumor agent of the present invention is useful because it exhibits excellent antitumor effects.< / o> < / n> < / m> < / l> < / k> < / j> < / h> < / g> < / f> < / e> < / d> < / c>

Claims

1. An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution in which the liposomes are dispersed, the aqueous solution constituting an external aqueous phase, The liposome encapsulates gemcitabine or a salt thereof, Lipids constituting the liposomes include at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol; Gemcitabine or a salt thereof encapsulated in liposomes is administered at a dose of 40 mg / m 2 to 60 mg / m 2 of body surface area as gemcitabine per administration; Repeat one dose every 3 to 4 weeks multiple times. An antitumor agent for treating cancer, the subject of administration being a human.

2. 2. The antitumor agent according to claim 1, which is in the form of a liquid pharmaceutical preparation and has a concentration of gemcitabine or a salt thereof of 0.01 mg / mL to 10 mg / mL as gemcitabine.

3. The antitumor agent according to claim 1 or 2, wherein the cancer is an aggressive solid cancer.

4. The antitumor agent according to claim 3, wherein the solid cancer is at least one selected from pancreatic cancer, uterine cancer, appendix cancer, ovarian cancer, lung cancer, breast cancer, biliary tract cancer, bladder cancer, colon cancer, gastric cancer, and non-Hodgkin's lymphoma.

5. The antitumor agent according to any one of claims 1 to 4, wherein the liposome has an average particle size of 5 nm to 100 nm.

6. The antitumor agent according to any one of claims 1 to 5, wherein the blending ratio of hydrogenated soybean phosphatidylcholine to the total lipids constituting the liposome is 50% by mass to 80% by mass, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol to the total lipids constituting the liposome is 1% by mass to 30% by mass, and 1% by mass to 20% by mass of cholesterol.

7. The antitumor agent according to any one of claims 1 to 6, wherein the administration route is intravenous administration.

8. The antitumor agent according to any one of claims 1 to 7, which is administered by infusion over a period of 15 to 240 minutes in a single administration.

9. An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution in which the liposomes are dispersed, the aqueous solution constituting an external aqueous phase, The liposome encapsulates gemcitabine or a salt thereof, Lipids constituting the liposomes include at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol; One cycle is 28 days, and on the first day, gemcitabine or a salt thereof encapsulated in liposomes is administered at a dose of 40 mg / m 2 to 60 mg / m 2 of body surface area per administration, followed by a drug holiday from the second day to the 27th day, and this cycle is repeated to administer the antitumor agent to humans.

10. An antitumor agent comprising liposomes containing an internal aqueous phase and an aqueous solution in which the liposomes are dispersed, the aqueous solution constituting an external aqueous phase, The liposome encapsulates gemcitabine or a salt thereof, Lipids constituting the liposomes include at least hydrogenated soybean phosphatidylcholine, 1,2-distearoyl-3-phosphatidylethanolamine-polyethylene glycol, and cholesterol; One cycle is 21 days, and on the first day, gemcitabine or a salt thereof encapsulated in liposomes is administered at a dose of 40 mg / m 2 to 60 mg / m 2 of body surface area per administration, followed by a drug holiday from the second day to the twentieth day, and this cycle is repeated to administer the antitumor agent to humans.