WO2018043530A1 - 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット - Google Patents
抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット Download PDFInfo
- Publication number
- WO2018043530A1 WO2018043530A1 PCT/JP2017/031074 JP2017031074W WO2018043530A1 WO 2018043530 A1 WO2018043530 A1 WO 2018043530A1 JP 2017031074 W JP2017031074 W JP 2017031074W WO 2018043530 A1 WO2018043530 A1 WO 2018043530A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- paclitaxel
- tumor
- prodrug
- antitumor
- Prior art date
Links
Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates to an antitumor agent, an antitumor effect enhancer, and an antitumor kit.
- Compound A (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known to be useful as an antitumor agent (Patent Document 1). Compound A is also known to have strong antitumor activity even after oral administration to mice (Non-Patent Documents 1 and 2). Further, a salt of Compound A and a production method thereof are also known (Patent Documents 2 to 4).
- Taxane antitumor agents such as paclitaxel and nabupaclitaxel are also used as useful drugs in chemotherapy for malignant tumors.
- the response rate for tumors with a single taxane antitumor agent is as low as 10 to 25%, and the survival time of cancer patients is short (survival time 12 to 15 months) (Non-patent Document 3). ).
- Non-patent Document 5 the response rate for pancreatic cancer patients with the combination of gemcitabine and nabupaclitaxel is 23%, and the median survival time is 8.5 months (Non-patent Document 4), which cannot be said to be sufficiently high as a therapeutic effect.
- An object of the present invention is to provide an antitumor agent, an antitumor kit, and an antitumor effect potentiator that have an excellent antitumor effect as compared with gemcitabine, paclitaxel and a combination therapy thereof.
- the present invention provides the following.
- An antitumor agent comprising paclitaxel or a salt thereof and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof.
- the amount of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof used is 0.01 to or more than that of paclitaxel or a salt thereof.
- the antitumor agent according to (1) which is 100-fold mol. (3) The antitumor agent according to (1) or (2), wherein the antitumor agent is for pancreatic cancer. (4) The antitumor agent according to any one of (1) to (3), wherein the paclitaxel is a nanoparticle containing paclitaxel and albumin. (5) The antitumor agent according to any one of (1) to (4), wherein the paclitaxel is nabu paclitaxel.
- an antibacterial agent comprising a preparation comprising paclitaxel or a salt thereof and a preparation comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof Tumor kit.
- An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof in combination with paclitaxel or a salt thereof.
- (6-1) The antitumor effect enhancer according to (6), wherein the paclitaxel is a nanoparticle containing paclitaxel and albumin.
- (6-2) The antitumor effect potentiator according to (6) or (6-1), wherein the paclitaxel is nab paclitaxel.
- (7-1) The antitumor kit according to (7), wherein the paclitaxel is a nanoparticle containing paclitaxel and albumin.
- an antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof in combination with paclitaxel or a salt thereof Use of.
- An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof in combination with paclitaxel or a salt thereof use.
- Compound A or a salt or prodrug thereof has a remarkable antitumor effect when used in combination with paclitaxel. That is, the antitumor agent and antitumor kit of the present invention have superior tumor regression and tumor growth inhibitory effects compared to gemcitabine alone, paclitaxel alone, or a combination of gemcitabine and paclitaxel.
- the antitumor effect potentiator of the present invention can enhance the antitumor effect by co-administering in combination with paclitaxel or a salt thereof.
- 2 is a graph showing changes in tumor volume in a human pancreatic cancer strain Capan-1 subcutaneously transplanted tumor-bearing model mouse.
- 2 is a graph showing changes in body weight of human pancreatic cancer strain Capan-1 subcutaneously transplanted tumor-bearing model mice.
- 2 is a graph showing the combined effect on tumor growth suppression in a human pancreatic cancer strain Capan-1 subcutaneously transplanted tumor-bearing model mouse.
- the numerical value represented by “%” is based on mass unless otherwise specified.
- the range represented by “to” includes values at both ends unless otherwise specified.
- the “subject” is a mammal such as a human, a mouse, a monkey, a domestic animal or the like in need of the prevention or treatment, and preferably a human in need of the prevention or treatment.
- Prevention means inhibition of onset, reduction of onset risk or delay of onset.
- Treatment means improvement of a target disease or condition or suppression (maintenance or delay) of progression.
- Treatment means prevention or treatment of various diseases.
- Tuor means benign or malignant tumor.
- “Benign tumor” means a tumor in which the tumor cells and their sequences are close to the normal cells from which they are derived and which are not invasive or metastatic.
- “Malignant tumor” means a tumor that is different from the normal cells from which the morphology and sequence of the tumor cells are derived, and exhibits invasive or metastatic properties.
- the present invention relates to paclitaxel or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the salt”) and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofurano. Sil) cytosine (compound A) or a salt or prodrug thereof.
- the present invention is also an antitumor agent comprising paclitaxel or a salt thereof and compound A or a salt or prodrug thereof in combination.
- salt examples include pharmaceutically acceptable salts, and specific examples include mineral acid salts, organic carboxylate salts, and sulfonate salts.
- Preferred salts include mineral acid salts and sulfonic acid salts.
- Examples of mineral acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, and sulfate, and hydrochloride, hydroiodide, nitrate, and sulfate are preferable. Hydrochloride is more preferable.
- Examples of organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and Examples include trifluoroacetate.
- sulfonate examples include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate, and naphthalenesulfonate, and methanesulfonate is preferable.
- the salt of Compound A may be an anhydride, hydrate or solvate.
- the form may be an anhydride, hydrate or solvate.
- the term “anhydride” as used herein refers to a case in which it is in a state that is neither a hydrate nor a solvate, unless otherwise specified. Originally, even if the substance does not form a hydrate or solvate, the salt of Compound A having no water of crystallization, water of hydration and an interactive solvent is included in the “anhydride” in the present invention. . An anhydride may be referred to as an “anhydrate”.
- the number of hydrated water is not particularly limited, and may be a monohydrate, a dihydrate or the like.
- solvates include methanol solvates, ethanol solvates, propanol solvates and 2-propanol solvates.
- particularly preferable salts of the compound A are as follows.
- a prodrug refers to a compound or a salt thereof, which, after administration, is cleaved by a functional group functioning as a prodrug by a reaction with an enzyme in the body, gastric juice, or the like, and converted into a compound exhibiting a desired pharmacological activity.
- groups that form prodrugs include groups described in Stella VJ et al., Prodrugs: Challenges and Rewards. Parts 1 and 2, 2007, American Association of Pharmaceutical Principles.
- the prodrug of Compound A refers to a compound or a salt thereof that is converted to Compound A or a phosphate compound thereof by a reaction with an enzyme, gastric juice, or the like under physiological conditions in vivo.
- the description in WO2016 / 068341 can be incorporated and referred to, and the contents thereof are incorporated in the present specification. More specifically, for example, a thionucleoside derivative represented by the general formula [1] described in International Publication No. 2016/068341 or a salt thereof is incorporated in the present specification, and a suitable range thereof is also International Publication No. 2016. This is the same as that described in Japanese Patent No. / 068341.
- Compound A or a salt or prodrug thereof may be used alone or in combination of two or more.
- Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, Vol. 64, p7912-7920.
- the salt of compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4.
- a prodrug of Compound A can be produced, for example, by the method described in International Publication No. 2016/068341.
- the compound A or a salt or prodrug thereof according to the present invention can be used as an antitumor agent and as an active ingredient of a pharmaceutical composition.
- Paclitaxel or a salt thereof may be used alone or in combination of two or more.
- Paclitaxel or a salt thereof may be a composition containing them in addition to paclitaxel or a salt thereof.
- the salt include pharmaceutically acceptable salts, and specific examples include salts that are generally known in basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
- Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
- formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
- Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And the salt.
- alkali metals such as sodium and potassium
- salts with alkaline earth metals such as calcium and magnesium
- ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
- composition containing paclitaxel or a salt thereof examples include, for example, nanoparticles containing paclitaxel and albumin (preferably human serum albumin) (a nanoparticle preparation in which paclitaxel is encapsulated with albumin, an albumin-binding paclitaxel injection suspension (nabu paclitaxel, (Trade name “Abraxane”)), a polymer micelle (NK105) in which paclitaxel is encapsulated in a block copolymer of polyethylene glycol and polyaspartic acid, and a prodrug (Taxoprexin) in which fatty acid docosahexaenoic acid (DHA) is combined with paclitaxel.
- albumin preferably human serum albumin
- NK105 polymer micelle
- Taxoprexin fatty acid docosahexaenoic acid
- Prodrugs in which polyglutamic acid is bound to paclitaxel (trade name “Opaxio”), and prodrugs in which a monoclonal antibody targeting tumor cells is bound to paclitaxel. It is.
- paclitaxel nanoparticles containing paclitaxel and albumin are preferable, and nab paclitaxel is more preferable.
- Compound A is an antitumor agent having an excellent DNA synthesis inhibitory action.
- Compound A is used in combination with paclitaxel, it is expected to have an action of enhancing the antitumor effect of paclitaxel without showing a marked increase in toxicity.
- An antitumor agent comprising paclitaxel or a salt thereof and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof; and paclitaxel or a salt thereof
- Antitumor agents comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof used in combination: Is provided.
- the antitumor agent of the present invention is usually used for formulation, excipients, binders, lubricants, disintegrants, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents.
- Additives such as agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
- the antitumor agent of the present invention comprising paclitaxel or a salt thereof and compound A or a salt or prodrug thereof may be a single-form preparation comprising paclitaxel or a salt thereof and compound A or a salt or prodrug thereof. It may be a two-drug preparation containing paclitaxel or a salt thereof and compound A or a salt or prodrug thereof. Preferably, it is a two-part preparation in which paclitaxel or a salt thereof and Compound A or a salt or prodrug thereof are separate preparations.
- each formulation can be administered to a subject simultaneously, separately, sequentially or at intervals.
- the administration means of the composition containing paclitaxel and the administration means of the composition containing Compound A may be the same or different (for example, oral administration and injection).
- the administration route of the antitumor agent of the present invention includes intravenous, intraarterial, intrarectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository. Is mentioned.
- parenteral administration is preferable.
- intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and / or intrathecal injection can be mentioned.
- Examples of the administration method include administration by syringe or infusion.
- the dose or amount of paclitaxel or a salt thereof contained in the antitumor agent of the present invention and compound A or a salt or prodrug thereof is not particularly limited as long as it has a potentiating effect on the antitumor effect, but paclitaxel.
- Compound A or a salt or prodrug thereof may be 0.01 to 100 times mol, preferably 0.1 to 50 times mol, more preferably 1 to 40 times mol, per mol.
- the dose and frequency of administration of paclitaxel or a salt thereof are, for example, 1 to 1000 mg / day per day by oral or parenteral (eg, injection, infusion and rectal administration) administration for adults.
- m 2 can be administered in one to several divided doses.
- the dose and frequency of administration of Compound A or a salt or prodrug thereof can be administered at 1 to 2000 mg / m 2 per day divided into 1 to several times.
- the dose and the number of administration are not limited.
- dosage forms of the antitumor agent of the present invention include tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, suppositories, eye drops, nasal drops, ear drops Although an agent, a patch, an ointment, and an injection are mentioned, an injection is preferable.
- Each of these dosage forms can be produced by conventional formulation methods known to those skilled in the art.
- Antitumor agents of the present invention include, for example, melanoma, liver cancer, glioma, neuroblastoma, sarcoma and lung, colon, breast, bladder, ovary, testis, prostate, neck, pancreas, stomach, small intestine, and others It can be used effectively in the treatment of various types of tumors, including organ tumors.
- the antitumor agent of the present invention is preferably an antineoplastic agent and can be used as an anticancer agent, and is particularly effective for the treatment of pancreatic cancer.
- the antitumor kit of the present invention is a kit comprising a combination of (a) paclitaxel or a salt thereof and (b) compound A or a salt or prodrug thereof.
- (a) paclitaxel or a salt thereof and (b) compound A or a salt or prodrug thereof can be made into various known preparation forms, and various kinds usually used depending on the preparation form. Of containers.
- (a) paclitaxel or a salt thereof and (b) compound A or a salt or prodrug thereof may be contained in separate containers, or may be mixed and accommodated in the same container.
- Paclitaxel or a salt thereof and (b) Compound A or a salt or prodrug thereof are preferably contained in separate containers.
- the antitumor effect potentiator of the present invention is 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof used in combination with paclitaxel or a salt thereof An antitumor agent.
- the antitumor effect potentiator of the present invention is usually an excipient, a binder, a lubricant, a disintegrant, a colorant, a flavoring agent, an emulsifier, a surfactant, a solubilizing agent, a suspension, Additives such as turbidity agents, tonicity agents, buffering agents, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
- the antitumor effect-enhancing agent of the present invention can be administered to a subject simultaneously with paclitaxel or a salt thereof, separately, successively or at intervals.
- parenteral administration is preferable.
- intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection
- administration method include administration by syringe or infusion.
- the dose or amount of compound A or a salt or prodrug thereof contained in the antitumor effect potentiator of the present invention is not particularly limited as long as it exhibits an effect of enhancing the antitumor effect, but it is 1 mol of paclitaxel.
- Compound A or a salt or prodrug thereof may be 0.01 to 100 times mol, preferably 0.1 to 50 times mol, more preferably 1 to 40 times mol.
- the dose and frequency of administration of Compound A or a salt or prodrug thereof contained in the antitumor effect potentiator of the present invention is 1 to 2000 mg / m 2 per day divided into 1 to several doses. be able to. However, the dose and the number of administration are not limited.
- Antitumor effect potentiators of the present invention include, for example, melanoma, liver cancer, glioma, neuroblastoma, sarcoma and lung, colon, breast, bladder, ovary, testis, prostate, cervix, pancreas, stomach, small intestine, It can be used effectively in the treatment of various types of tumors, including tumors of other organs.
- the antitumor effect enhancer of the present invention is preferably an antimalignant effect enhancer, and is particularly effective for the treatment of pancreatic cancer.
- the present invention uses paclitaxel or a salt thereof and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof for the treatment of a tumor.
- a method for use in the treatment of pancreatic cancer comprising the step of administering a therapeutically effective dose to a subject (mammal, including a human) in need of such treatment.
- the present invention also provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof is used in combination therapy, and paclitaxel
- the present invention provides a method for treating a tumor, which comprises administering to a subject a combination with a therapeutically effective dose when the salt is used for combination therapy.
- the present invention relates to a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof is used in combination therapy, and paclitaxel.
- the present invention provides a method for treating a tumor, which comprises administering to a subject a therapeutically effective dose when a salt thereof is used for combination therapy, simultaneously, separately, sequentially or at intervals.
- cytosine or a salt or prodrug thereof can be used for the production of an antitumor agent in combination with paclitaxel or a salt thereof.
- -D-arabinofuranosyl) cytosine or a salt or prodrug thereof can be obtained.
- an anti-antigen comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt or prodrug thereof, used in combination with paclitaxel or a salt thereof.
- a tumor agent can be obtained.
- Example 1 A methanesulfonate salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (Compound A) was synthesized by the method described in International Publication No. 2013/146833 pamphlet. did.
- Test Example 1 Test of combined effect in Capan-1 subcutaneous transplantation tumor-bearing model mouse Gemcitabine (hereinafter also referred to as Gem), Abraxane (hereinafter also referred to as Abx) and methanesulfonate of Compound A were used as test substances.
- gemcitabine gemcitabine hydrochloride (manufactured by TEVA) dissolved in physiological saline was used.
- Abraxane was prepared by dissolving Abraxane (Celgene) in physiological saline.
- Capan-1 cells a human pancreatic cancer cell line, were injected subcutaneously into the posterior flank of 5-6 week old female BALB / cA Jcl-nu mice.
- the test liquid of the Abraxane alone group was prepared to be 30 mg / kg / day as an administration dose.
- the test liquid of the compound A single group was prepared so that it might become 480 mg / kg / day.
- Compound A was administered from the mouse tail vein three times, once a week from day 1, and Abraxane was also administered from the mouse tail vein three times, once a week from day 1.
- Compound A significantly enhanced the antitumor effect of Abraxane.
- 480 mg / kg / day which is a high dose (maximum effect dose) in nude mice, significant tumor reduction was induced by the combined use. The effect was thought to be greater than the existing drug gemcitabine. A more detailed description will be given later.
- body weight (BW) was measured over time as an index of toxicity, and the average rate of change in body weight [day weight change: BWC (%)] up to day 33 relative to day 1 was calculated by the following formula (n: body weight It is a measurement date, and the last measurement date corresponds to day 33, which is the final evaluation date).
- BWC (%) [(BW at Day n) ⁇ (BW at Day 1)] / (BW at Day 1) ⁇ 100 There was no exacerbation of weight loss in the combined administration.
- CI Combination Index: 1
- GC tumor growth inhibitory effect
- the estimated combination GC (%) is 19.8 (%), while the actual combination GC (%) is 3.7 (%), so the remarkable combination exceeds the expected combination effect. It is considered effective.
- the solid arrow in FIG. 3 indicates the combined effect of gemcitabine, and the dotted arrow indicates the combined effect of compound A.
- the estimated combined GC (%) is 3.3 (%), whereas the actual combined GC (%) is -79.0 (%). It is considered that there is a remarkable combined effect exceeding the combined effect. It can be said that the degree is more remarkable than the existing drug gemcitabine.
- the present invention is useful as an antitumor agent and an antitumor kit exhibiting a remarkable antitumor effect, and an antitumor effect enhancer.
Abstract
Description
本発明の課題は、ゲムシタビン、パクリタキセル及びそれらの併用療法と比較して、抗腫瘍効果に優れた抗腫瘍剤及び抗腫瘍用キット、並びに抗腫瘍効果増強剤を提供することにある。
すなわち、本発明は、下記を提供する。
(1)パクリタキセルまたはその塩と、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグとを含む抗腫瘍剤。
(2)上記1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの使用量が、上記パクリタキセルまたはその塩の0.01~100倍モルである、(1)に記載の抗腫瘍剤。
(3)上記抗腫瘍剤が膵臓癌用である、(1)または(2)に記載の抗腫瘍剤。
(4)上記パクリタキセルがパクリタキセル及びアルブミンを含むナノ粒子である、(1)~(3)のいずれか一に記載の抗腫瘍剤。
(5)上記パクリタキセルがナブパクリタキセルである、(1)~(4)のいずれか一に記載の抗腫瘍剤。
(6)パクリタキセルまたはその塩と併用される、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む抗腫瘍効果増強剤。
(7)パクリタキセルまたはその塩を含む製剤と、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む製剤とを含む抗腫瘍用キット。
(8)パクリタキセルまたはその塩と併用される、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む抗腫瘍剤。
(6-1)上記パクリタキセルがパクリタキセル及びアルブミンを含むナノ粒子である、(6)に記載の抗腫瘍効果増強剤。
(6-2)上記パクリタキセルがナブパクリタキセルである、(6)または(6-1)に記載の抗腫瘍効果増強剤。
(7-1)上記パクリタキセルがパクリタキセル及びアルブミンを含むナノ粒子である、(7)に記載の抗腫瘍用キット。
(7-2)上記パクリタキセルがナブパクリタキセルである、(7)または(7-1)に記載の抗腫瘍用キット。
(8-1)上記パクリタキセルがパクリタキセル及びアルブミンを含むナノ粒子である、(8)に記載の抗腫瘍剤。
(8-2)上記パクリタキセルがナブパクリタキセルである、(8)または(8-1)に記載の抗腫瘍剤。
(9)パクリタキセルまたはその塩と、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグとを、腫瘍の処置に用いるための、好ましくは膵臓癌の処置に用いるための方法であって、治療有効用量をそのような処置が必要な対象(ヒトを含む哺乳動物)に投与する工程を含む方法。
(10)1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを併用治療に用いる場合の治療有効用量、及び、パクリタキセルまたはその塩を併用治療に用いる場合の治療有効用量とを組み合わせて、対象に投与することを特徴とする、腫瘍の治療方法。
(11)1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを併用治療に用いる場合の治療有効用量、及び、パクリタキセルまたはその塩を併用治療に用いる場合の治療有効用量を、同時に、別々に、連続して、あるいは間隔をあけて、対象に投与することを特徴とする、腫瘍の治療方法。
(12)1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの、パクリタキセルまたはその塩と組み合わせてなる抗腫瘍剤製造のための使用。
(13)1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの、パクリタキセルまたはその塩と組み合わせてなる抗腫瘍剤のための使用。
(14)パクリタキセルまたはその塩と、一剤型の製剤形態、または別個の製剤形態として投与することにより腫瘍を治療するための、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグ。
「対象」とは、その予防もしくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防もしくは治療を必要とするヒトである。
「予防」とは、発症の阻害、発症リスクの低減または発症の遅延などを意味する。
「治療」とは、対象となる疾患または状態の改善または進行の抑制(維持または遅延)などを意味する。
「処置」とは、各種疾患に対する予防または治療などを意味する。
「腫瘍」とは、良性腫瘍または悪性腫瘍を意味する。
「良性腫瘍」とは、腫瘍細胞およびその配列がその由来する正常細胞に近い形態をとり、浸潤性または転移性のない腫瘍を意味する。
「悪性腫瘍」とは、腫瘍細胞の形態やその配列がその由来する正常細胞と異なっており、浸潤性または転移性を示す腫瘍を意味する。
以下、本発明を詳細に説明する。
本発明は、パクリタキセルまたはその医薬として許容しうる塩(以下、「その塩」ということがある。)と、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシン(化合物A)またはその塩もしくはプロドラッグとを含む抗腫瘍剤である。また本発明は、パクリタキセルまたはその塩と、化合物Aまたはその塩もしくはプロドラッグとを組合わせてなる抗腫瘍剤である。
塩としては、薬学的に許容される塩が挙げられ、具体的には、鉱酸塩、有機カルボン酸塩及びスルホン酸塩が挙げられる。好ましい塩としては、鉱酸塩及びスルホン酸塩が挙げられる。
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンのメタンスルホン酸塩;
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンの塩酸塩;
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンの1/2硫酸塩;
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンの硝酸塩;及び
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンのヨウ化水素酸塩;ならびに上記の塩のいずれかの無水物。
プロドラッグを形成する基としては、例えば、Stella VJら、Prodrugs: Challenges and Rewards. Parts 1 and 2、2007年、American Association of Pharmaceutical Scientistsに記載されている基が挙げられる。
化合物Aのプロドラッグとしては、国際公開第2016/068341号公報の説明を援用及び参酌でき、これらの内容は本願明細書に組み込まれる。
より具体的には、例えば、国際公開第2016/068341号公報に記載の一般式[1]で表わされるチオヌクレオシド誘導体またはその塩が本願明細書に組み込まれ、その好適な範囲も国際公開第2016/068341号公報に記載のものと同一である。
本発明にかかる化合物Aまたはその塩もしくはプロドラッグは、抗腫瘍剤として、また医薬組成物の有効成分として用いることができる。
塩としては、薬学的に許容される塩が挙げられ、具体的には、通常知られているアミノ基などの塩基性基、ヒドロキシル基及びカルボキシル基などの酸性基における塩を挙げることができる。
塩基性基における塩としては、例えば、塩酸、臭化水素酸、硝酸及び硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸及びトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸及びナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
酸性基における塩としては、例えば、ナトリウム及びカリウムなどのアルカリ金属との塩;カルシウム及びマグネシウムなどのアルカリ土類金属との塩;アンモニウム塩;ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、N、N-ジメチルアニリン、N-メチルピペリジン、N-メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、N-ベンジル-β-フェネチルアミン、1-エフェナミン及びN、N'-ジベンジルエチレンジアミンなどの含窒素有機塩基との塩が挙げられる。
パクリタキセルまたはその塩を含む組成物としては、例えば、パクリタキセル及びアルブミン(好ましくはヒト血清アルブミン)を含むナノ粒子(パクリタキセルをアルブミンで封入したナノ粒子製剤のアルブミン結合パクリタキセル注射用懸濁液(ナブパクリタキセル、商品名「アブラキサン」))、ポリエチレングリコールとポリアスパラギン酸のブロック共重合体にパクリタキセルを内包させた高分子ミセル体(NK105)、脂肪酸のドコサヘキサエン酸(DHA)をパクリタキセルと結合させたプロドラッグ(Taxoprexin)、ポリグルタミン酸をパクリタキセルと結合させたプロドラッグ(商品名「Opaxio」)、ならびに腫瘍細胞を標的とするモノクローナル抗体をパクリタキセルと結合させたプロドラッグが挙げられる。
パクリタキセルとしては、パクリタキセル及びアルブミンを含むナノ粒子が好ましく、ナブパクリタキセルがより好ましい。
本発明によれば、
パクリタキセルまたはその塩と、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグとを含む抗腫瘍剤;並びに
パクリタキセルまたはその塩と併用される、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む抗腫瘍剤:
が提供される。
本発明の抗腫瘍剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤及び吸収促進剤などの添加剤を含んでいてもよい。
パクリタキセルまたはその塩と、化合物Aまたはその塩もしくはプロドラッグとが別個の製剤として用いる場合、各製剤は、同時に、別々に、連続して、あるいは間隔をあけて対象に投与することができる。また、パクリタキセルを含む組成物の投与手段と、化合物Aを含む組成物の投与手段は同一であってもよいし、相違していてもよい(例えば、経口投与と注射)。
投与経路としては、非経口投与が好ましい。例えば、点滴等の静脈内注射(静注)、筋肉内注射、腹腔内注射、皮下注射、眼内注射及び/または髄腔内注射を挙げることができる。投与方法としては、シリンジまたは点滴による投与が挙げられる。
化合物Aまたはその塩もしくはプロドラッグの投与量及び投与回数は、1日あたり1~2000 mg/m2を1回から数回に分割して投与することができる。しかし、これらの投与量及び投与回数に制限されるものではない。
本発明の抗腫瘍用キットは、(a)パクリタキセルまたはその塩及び(b)化合物Aまたはその塩もしくはプロドラッグの組み合わせを含むキットである。
また、上記キットでは、(a)パクリタキセルまたはその塩及び(b)化合物Aまたはその塩もしくはプロドラッグは各々公知の各種の製剤形態とすることができ、その製剤形態に応じて、通常用いられる各種の容器に収容される。
さらに、上記キットでは、(a)パクリタキセルまたはその塩及び(b)化合物Aまたはその塩もしくはプロドラッグは各々別の容器に収容されてもよいし、混合されて同じ容器に収容されてもよい。(a)パクリタキセルまたはその塩及び(b)化合物Aまたはその塩もしくはプロドラッグが各々別の容器に収容されていることが好ましい。
本発明の抗腫瘍効果増強剤は、パクリタキセルまたはその塩と併用される、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む抗腫瘍剤である。
本発明の抗腫瘍効果増強剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤及び吸収促進剤などの添加剤を含んでいてもよい。
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシン(化合物A)のメタンスルホン酸塩は、国際公開第2013/146833号パンフレットに記載の方法により合成した。
Capan-1皮下移植担がんモデルマウスでの併用効果試験
被験物質として、ゲムシタビン(以下、Gemともいう)、アブラキサン(以下、Abxともいう)及び化合物Aのメタンスルホン酸塩を用いた。
ゲムシタビンは、ゲムシタビン塩酸塩(TEVA社製)を生理食塩水に溶解させたものを用いた。アブラキサンは、アブラキサン(Celgene社製)を生理食塩水に溶解させたものを用いた。
ヒト膵臓癌細胞株であるCapan-1細胞を生後5~6週齢の雌性BALB/cA Jcl-nuマウスの後部横腹に皮下注射した。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出した。各群の平均TVが均等になるように各群にマウスを割り付け、この群分け(n=8)を実施した日をday 1とした。
アブラキサン単独群の被験液は、投与用量として30 mg/kg/dayとなるよう調製した。また化合物A単独群の被験液は、480 mg/kg/dayとなるよう調製した。化合物Aはday 1から1週間に1度、計3回マウス尾静脈より投与し、アブラキサンも同様に、day 1から1週間に1度、計3回マウス尾静脈より投与した。併用投与群では、化合物Aを480 mg/kg/dayとアブラキサンを30 mg/kg/dayで投与した。
比較実験として、対照薬としてゲムシタビンを用いた。ゲムシタビン単独群の被験液は、240 mg/kg/dayとなるよう調製した。ゲムシタビンはday 1から1週間に1度、計3回マウス尾静脈より投与し、併用投与群では、ゲムシタビンを240 mg/kg/dayとアブラキサンを30 mg/kg/dayで投与した。
本試験では、化合物A及びゲムシタビンの用量設定は、各薬剤のMTDを用いた。アブラキサンは、各薬剤との併用において耐用可能な最大用量を用いた。抗腫瘍剤は最大薬効を示す用量と毒性発現用量が極めて近く、その薬剤が持つ最大抗腫瘍効果を動物モデルで評価するためにはMTD近傍において評価することが一般的であり、本試験例においては、MTDと最大効果発揮用量はほぼ同義である。
TV(mm3)=(長径×短径2)/2
RTV=(Day 33におけるTV)/(Day 1におけるTV)
T/C(%)=[(被験液投与群の平均RTV値)/(対照群の平均RTV値)]×100
BWC(%)=[(Day nにおけるBW)-(Day 1におけるBW)]/(Day 1におけるBW)×100
併用投与において体重減少の増悪は認められなかった。
すなわち、併用する薬剤を薬剤1及び薬剤2とすると、
CI=(併用時のT/C)÷100/{[(薬剤1のT/C)÷100]×[(薬剤2のT/C)÷100]}
CI=1:相加効果
CI>1:拮抗効果
CI<1:相乗効果
アブラキサンとゲムシタビンを併用したときのCIは0.80であり、アブラキサンと化合物Aを併用したときのCIは0.32であった。CI<1であるから、併用による相乗効果が認められ、化合物Aの相乗効果は、既存薬であるゲムシタビンよりもより顕著であると言える。
上記文献に記載の通り、GCは以下の式で算出できる。
[1]RTV>1以上の場合
GC(%)=[(該当薬剤のRTV-1)/(コントロールのRTV-1)]×100
[2]RTV≦1未満の場合
GC(%)=(該当薬剤のRTV-1)×100
アブラキサンと、化合物Aまたはゲムシタビン単剤での薬効から併用効果を以下の算出式で推定した。その結果を図3及び表2に示す。
推定した併用のGC(%)=[アブラキサンのGC(%)×単剤GC(%)]÷100
RTV>1なので、
[(2.03-1)/(4.01-1)]×100=34.2(%)であり、
ゲムシタビンのGC(%)は、RTV>1なので、
[(2.74-1)/(4.01-1)]×100=57.8(%)である。
よって、推定した併用GC(%)は、(34.2×57.8)÷100=19.8(%)
一方、アブラキサンとゲムシタビンの併用の実際のGC(%)は、
RTV>1より、[(1.11-1)/(4.01-1)]×100=3.7(%)である。
これより、推定した併用GC(%)は19.8(%)に対して、実際の併用のGC(%)が3.7(%)であるため、想定される併用効果を超える顕著な併用効果があると考えられる。
化合物Aにおいても同様の計算を行うと、単剤は、RTV>1であるので、
[(1.29-1)/(4.01-1)]×100=9.6(%)
よって、推定した併用GC(%)は、(34.2×9.6÷100=3.3(%)
実際のGC(%)は、RTV≦1より、(0.21-1)×100=-79.0(%)である。図3中の実線の矢印はゲムシタビンの併用効果、点線の矢印は化合物Aの併用効果を示す。
これより、化合物Aにおいても、推定した併用GC(%)は3.3(%)であるのに対し、実際の併用のGC(%)は-79.0(%)であり、想定される併用効果を超える顕著な併用効果があると考えられる。その度合いは、既存薬であるゲムシタビンよりもより顕著であると言える。
Claims (8)
- パクリタキセルまたはその塩と、
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグとを含む抗腫瘍剤。 - 前記1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグの使用量が、前記パクリタキセルまたはその塩の0.01~100倍モルである、請求項1に記載の抗腫瘍剤。
- 前記抗腫瘍剤が膵臓癌用である、請求項1または2に記載の抗腫瘍剤。
- 前記パクリタキセルがパクリタキセル及びアルブミンを含むナノ粒子である、請求項1~3のいずれか一項に記載の抗腫瘍剤。
- 前記パクリタキセルがナブパクリタキセルである、請求項1~4のいずれか一項に記載の抗腫瘍剤。
- パクリタキセルまたはその塩と併用される、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む抗腫瘍効果増強剤。
- パクリタキセルまたはその塩を含む製剤と、
1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む製剤とを含む抗腫瘍用キット。 - パクリタキセルまたはその塩と併用される、1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンまたはその塩もしくはプロドラッグを含む抗腫瘍剤。
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ751051A NZ751051B2 (en) | 2016-08-31 | 2017-08-30 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
AU2017319260A AU2017319260B2 (en) | 2016-08-31 | 2017-08-30 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
EP17846534.0A EP3508205B1 (en) | 2016-08-31 | 2017-08-30 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
JP2018537328A JP7008025B2 (ja) | 2016-08-31 | 2017-08-30 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
CN201780053185.4A CN109641009B (zh) | 2016-08-31 | 2017-08-30 | 抗肿瘤剂、抗肿瘤效果增强剂及抗肿瘤用试剂盒 |
BR112019003946-5A BR112019003946A2 (pt) | 2016-08-31 | 2017-08-30 | agente antitumoral, reforçador do efeito antitumoral e kit antitumoral |
RU2019105574A RU2752172C2 (ru) | 2016-08-31 | 2017-08-30 | Противоопухолевый агент, усилитель противоопухолевого действия и противоопухолевый набор |
KR1020197006023A KR102198656B1 (ko) | 2016-08-31 | 2017-08-30 | 항종양제, 항종양 효과 증강제 및 항종양용 키트 |
SG11201901815WA SG11201901815WA (en) | 2016-08-31 | 2017-08-30 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
MX2019002430A MX2019002430A (es) | 2016-08-31 | 2017-08-30 | Agente antitumoral, mejorador del efecto antitumoral, y kit antitumoral. |
CA3035334A CA3035334C (en) | 2016-08-31 | 2017-08-30 | Combination of paclitaxel and 1-(2-deoxy-2-fluoro-4-thio-beta-d-arabinofuranosyl)-cytosine as anti-tumor agent |
US16/286,930 US11369625B2 (en) | 2016-08-31 | 2019-02-27 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
ZA2019/01563A ZA201901563B (en) | 2016-08-31 | 2019-03-13 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016-169167 | 2016-08-31 | ||
JP2016169167 | 2016-08-31 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/286,930 Continuation US11369625B2 (en) | 2016-08-31 | 2019-02-27 | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018043530A1 true WO2018043530A1 (ja) | 2018-03-08 |
Family
ID=61301073
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2017/031074 WO2018043530A1 (ja) | 2016-08-31 | 2017-08-30 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
Country Status (14)
Country | Link |
---|---|
US (1) | US11369625B2 (ja) |
EP (1) | EP3508205B1 (ja) |
JP (2) | JP7008025B2 (ja) |
KR (1) | KR102198656B1 (ja) |
CN (1) | CN109641009B (ja) |
AU (1) | AU2017319260B2 (ja) |
BR (1) | BR112019003946A2 (ja) |
CA (1) | CA3035334C (ja) |
MX (1) | MX2019002430A (ja) |
RU (1) | RU2752172C2 (ja) |
SG (1) | SG11201901815WA (ja) |
TW (1) | TWI787201B (ja) |
WO (1) | WO2018043530A1 (ja) |
ZA (1) | ZA201901563B (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019176984A1 (ja) * | 2018-03-13 | 2019-09-19 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
WO2019176985A1 (ja) * | 2018-03-13 | 2019-09-19 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
US11141421B2 (en) | 2018-01-29 | 2021-10-12 | Fujifilm Corporation | Antitumor agent for biliary tract cancer and method for treating biliary tract cancer |
WO2023008511A1 (ja) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Bap1およびpbrm1の少なくとも1つの機能低下を有する腫瘍に対する医薬組成物および抗腫瘍剤 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997038001A1 (fr) * | 1996-04-09 | 1997-10-16 | Yamasa Corporation | 1-(2-DESOXY-2-FLUORO-4-THIO-β-D-ARABINOFURANOSYL)CYTOSINES |
WO2013146833A1 (ja) * | 2012-03-28 | 2013-10-03 | 富士フイルム株式会社 | 1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンの塩 |
Family Cites Families (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3116282A (en) | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
US3243425A (en) | 1962-10-29 | 1966-03-29 | Purdue Research Foundation | Novel sulfur-containing compounds |
JPS53119810A (en) | 1977-03-25 | 1978-10-19 | Mitsubishi Chem Ind Ltd | Preparation of aldehyde chloride |
US4211773A (en) | 1978-10-02 | 1980-07-08 | Sloan Kettering Institute For Cancer Research | 5-Substituted 1-(2'-Deoxy-2'-substituted-β-D-arabinofuranosyl)pyrimidine nucleosides |
US4220774A (en) | 1978-10-26 | 1980-09-02 | Omnium Chimique | Vincadifformine synthesis process |
JPS5692239A (en) | 1979-12-27 | 1981-07-25 | Sagami Chem Res Center | Preparation of 5-oxohexyl compound |
US4803272A (en) | 1987-02-24 | 1989-02-07 | E. I. Du Pont De Nemours And Company | S-modified adenosyl-1,8-diamino-3-thiooctane derivatives |
IE74701B1 (en) | 1989-10-04 | 1997-07-30 | Univ Birmingham | Further antiviral pyrimidine nucleosides |
SE9003151D0 (sv) | 1990-10-02 | 1990-10-02 | Medivir Ab | Nucleoside derivatives |
JP3138834B2 (ja) | 1991-12-26 | 2001-02-26 | 生化学工業株式会社 | フコピラノース類縁体の製造方法およびその合成中間化合物 |
GB9218810D0 (en) | 1992-09-04 | 1992-10-21 | Univ Birmingham | Antiviral pyrimidine nucleosides |
WO1996001834A1 (fr) | 1994-07-12 | 1996-01-25 | Yamasa Corporation | 2'-desoxy-2'-(methylidene substitue ou non substitue)-4'-thionucleoside |
JPH0853490A (ja) | 1994-08-09 | 1996-02-27 | Yamasa Shoyu Co Ltd | 2’−デオキシ−2’,2’−ジハロゲノ−4’−チオヌクレオシド |
EP0839813A1 (en) | 1996-04-09 | 1998-05-06 | Yamasa Corporation | 9-(2-deoxy-2-fluoro-4-thio-beta-d-arabinofuranosyl)purine derivatives |
JP4202327B2 (ja) | 1996-04-09 | 2008-12-24 | ヤマサ醤油株式会社 | 1−(2−デオキシ−2−フルオロ−4−チオ−β−D−アラビノフラノシル)シトシン |
HUP9601756A3 (en) | 1996-06-25 | 1999-05-28 | Richter Gedeon Vegyeszet | New anticoagulant glycosides and pharmaceutical compositions containing them |
US7452538B2 (en) * | 1997-01-28 | 2008-11-18 | Human Genome Sciences, Inc. | Death domain containing receptor 4 antibodies and methods |
JP4087471B2 (ja) | 1997-03-31 | 2008-05-21 | 大日本印刷株式会社 | 表面プラズモン共鳴バイオセンサー用測定チップ及びその製造方法 |
HUP9702348A3 (en) | 1997-12-04 | 2000-12-28 | Richter Gedeon Vegyeszet | New anticoagulant glycosides and pharmaceutical conew anticoagulant glycosides and pharmaceutical compositions containing them mpositions containing them |
WO1999043690A1 (fr) | 1998-02-25 | 1999-09-02 | Rational Drug Design Laboratories | Compose de l-4'-arabinofuranonucleoside et composition medicinale le contenant |
JP4719356B2 (ja) | 1998-07-23 | 2011-07-06 | サザン・リサーチ・インスティテュート | 抗ガン剤及びdna複製阻害剤 |
AU2001240098A1 (en) | 2000-03-08 | 2001-09-17 | Southern Research Institute | 4'-thio-l-xylo furanosyl nucleosides, precursors thereof, preparation and use thereof |
KR100426030B1 (ko) | 2000-07-22 | 2004-04-03 | (주) 한켐 | 락톤계 당화합물에서의 키랄성 전환방법 |
TWI247609B (en) | 2001-01-23 | 2006-01-21 | Nihon Mediphysics Co Ltd | Agent for diagnosis of tissue proliferation activity or the treatment of proliferative disease |
US6770653B2 (en) | 2001-03-06 | 2004-08-03 | Bristol-Myers Squibb Company | Method and dosage form for treating tumors by the administration of tegafur, uracil, folinic acid, paclitaxel and carboplatin |
US6949522B2 (en) | 2001-06-22 | 2005-09-27 | Pharmasset, Inc. | β-2′- or 3′-halonucleosides |
JP2003172990A (ja) | 2001-08-03 | 2003-06-20 | Fuji Photo Film Co Ltd | ハロゲン化銀乳剤及びハロゲン化銀写真感光材料 |
NZ532882A (en) | 2001-11-23 | 2007-07-27 | Chugai Pharmaceutical Co Ltd | Method for identification of tumor targeting enzymes |
WO2004014930A1 (ja) | 2002-08-09 | 2004-02-19 | Taisho Pharmaceutical Co., Ltd. | 選択的なアリール5−チオ−β−D−アルドヘキソピラノシドの製造法 |
AU2003200960B2 (en) | 2002-09-18 | 2005-01-06 | Mackinnon, Sebastian Mr | System for Ordering, Tracking and Payment of Goods and Services |
DE602004014485D1 (de) * | 2003-04-07 | 2008-07-31 | Prospect Therapeutics Inc | Zusammensetzung und anwendungen von galectin-antagonisten |
US7312228B2 (en) | 2003-05-12 | 2007-12-25 | Purdue Research Foundation | Cytotoxic indeno and isoindoloisoquinolones |
JPWO2004106280A1 (ja) | 2003-05-28 | 2006-07-20 | 日本たばこ産業株式会社 | CaSRアンタゴニスト |
JPWO2004106352A1 (ja) | 2003-05-29 | 2006-07-20 | 大正製薬株式会社 | アルドヘキソピラノース中間体の製造法 |
GB0317009D0 (en) | 2003-07-21 | 2003-08-27 | Univ Cardiff | Chemical compounds |
JP5379347B2 (ja) | 2003-09-18 | 2013-12-25 | アイシス ファーマシューティカルズ, インコーポレーテッド | 4’−チオヌクレオシドおよびオリゴマー化合物 |
TW200637839A (en) | 2005-01-07 | 2006-11-01 | Taisho Pharmaceutical Co Ltd | 1-thio-d-glucitol derivatives |
SI2301531T1 (sl) | 2005-02-18 | 2018-11-30 | Abraxis Bioscience, Llc | Kombinacije in načini dajanja terapevtskih sredstev in kombinacijska terapija |
US7858788B2 (en) | 2005-02-21 | 2010-12-28 | Shionogi & Co., Ltd. | Bicyclic carbamoylpyridone derivative having HIV integrase inhibitory activity |
JP2006335737A (ja) | 2005-06-03 | 2006-12-14 | Ihara Nikkei Kagaku Kogyo Kk | ベンゾ[c]ヘテロ5員環化合物の製造方法 |
US7888330B2 (en) | 2005-11-09 | 2011-02-15 | Wayne State University | Phosphoramidate derivatives of FAU |
US20090069263A1 (en) | 2005-12-16 | 2009-03-12 | Damha Masad J | 4'-thioarabinonucleotide-containing oligonucleotides, compounds and methods for their preparation and uses thereof |
CN100513395C (zh) | 2006-04-17 | 2009-07-15 | 中国科学院化学研究所 | 一种制备多羟基环状硝酮的方法 |
WO2007130783A2 (en) | 2006-05-03 | 2007-11-15 | Chimerix, Inc. | Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates |
CN101200463B (zh) | 2007-12-11 | 2011-06-22 | 复旦大学 | 全酰化-4-硫代-d-核糖及其制备方法 |
WO2009076170A2 (en) | 2007-12-13 | 2009-06-18 | Novartis Ag | Combinations of therapeutic agents for treating cancer |
US8859589B2 (en) | 2008-03-12 | 2014-10-14 | Southern Research Institute | Use of 4′-thio-2′-deoxynucleosides as anti orthopoxvirus agents |
CN101880287B (zh) | 2009-05-05 | 2012-07-25 | 上海医药工业研究院 | 一类四氢噻吩核苷类似物的中间体化合物及其制备方法 |
SG181745A1 (en) | 2009-12-18 | 2012-07-30 | Libramedicina Inc | PROCESS FOR PREPARING SUBSTITUTED 1-O-ACYL-2-DEOXY-2-FLUORO-4-THIO-ß-D-ARABINOFURANOSES |
GB201016855D0 (en) | 2010-10-06 | 2010-11-17 | Nucana Biomed Ltd | Chemical compounds |
CN102166190B (zh) | 2011-04-14 | 2013-04-10 | 上海市肺科医院 | 一种双重靶向肿瘤的紫杉醇纳米脂质体及其制备方法 |
TWI594986B (zh) | 2011-12-28 | 2017-08-11 | Taiho Pharmaceutical Co Ltd | Antineoplastic agent effect enhancer |
JP5776564B2 (ja) | 2012-01-20 | 2015-09-09 | 日本精工株式会社 | ワーク処理装置、及びワーク処理方法 |
AU2013243873B2 (en) * | 2012-04-04 | 2016-08-25 | Halozyme, Inc. | Combination therapy with an anti - hyaluronan agent and a tumor - targeted taxane |
US20140029864A1 (en) | 2012-07-30 | 2014-01-30 | Dror Reif | Compression encoding and decoding method and apparatus |
SG11201501010QA (en) | 2012-08-10 | 2015-04-29 | Taiho Pharmaceutical Co Ltd | Stable oxaliplatin-encapsulating liposome aqueous dispersion and method for stabilizing same |
LT2883866T (lt) | 2012-08-13 | 2019-05-10 | Fujifilm Corporation | 1-(2-deoksi-2-fluor-4-tio-beta-d-arabinofuranozil)citozino sintezės tarpiniai junginiai, tionukleozido sintezės tarpiniai junginiai ir šių tarpinių junginių gamybos būdai |
WO2015038596A1 (en) | 2013-09-11 | 2015-03-19 | Emory University | Nucleotide and nucleoside compositions and uses related thereto |
WO2015125781A1 (ja) | 2014-02-18 | 2015-08-27 | 富士フイルム株式会社 | チオラン骨格型糖化合物の製造方法およびチオラン骨格型糖化合物 |
JP6204223B2 (ja) | 2014-02-19 | 2017-09-27 | 富士フイルム株式会社 | チオピラノース化合物等の製造方法 |
TWI678373B (zh) | 2014-10-31 | 2019-12-01 | 日商富士軟片股份有限公司 | 硫代核苷衍生物或其鹽及醫藥組合物 |
CN109553651B (zh) | 2015-04-03 | 2021-08-06 | 四川科伦博泰生物医药股份有限公司 | 4’-硫代核苷的新型化合物及其制备方法、药物组合物和应用 |
AU2015418015B2 (en) | 2015-12-23 | 2021-12-09 | NuCana plc | Combination therapy |
JP6450356B2 (ja) | 2016-02-29 | 2019-01-09 | 富士フイルム株式会社 | 液状医薬製剤 |
WO2019146130A1 (ja) | 2018-01-29 | 2019-08-01 | 富士フイルム株式会社 | 胆道がん用抗腫瘍剤および胆道がんの処置方法 |
CA3093794C (en) | 2018-03-13 | 2023-03-14 | Fujifilm Corporation | Antitumor enhancer agent comprising 1-(2-deoxy-2-fluoro-4-thio-b-d-arabinofuranosyl)cytosine and an antitumor platinum complex |
-
2017
- 2017-08-30 KR KR1020197006023A patent/KR102198656B1/ko active IP Right Grant
- 2017-08-30 AU AU2017319260A patent/AU2017319260B2/en active Active
- 2017-08-30 RU RU2019105574A patent/RU2752172C2/ru active
- 2017-08-30 EP EP17846534.0A patent/EP3508205B1/en active Active
- 2017-08-30 CA CA3035334A patent/CA3035334C/en active Active
- 2017-08-30 BR BR112019003946-5A patent/BR112019003946A2/pt unknown
- 2017-08-30 TW TW106129543A patent/TWI787201B/zh active
- 2017-08-30 SG SG11201901815WA patent/SG11201901815WA/en unknown
- 2017-08-30 MX MX2019002430A patent/MX2019002430A/es unknown
- 2017-08-30 WO PCT/JP2017/031074 patent/WO2018043530A1/ja unknown
- 2017-08-30 JP JP2018537328A patent/JP7008025B2/ja active Active
- 2017-08-30 CN CN201780053185.4A patent/CN109641009B/zh active Active
-
2019
- 2019-02-27 US US16/286,930 patent/US11369625B2/en active Active
- 2019-03-13 ZA ZA2019/01563A patent/ZA201901563B/en unknown
-
2020
- 2020-11-20 JP JP2020193081A patent/JP2021014474A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997038001A1 (fr) * | 1996-04-09 | 1997-10-16 | Yamasa Corporation | 1-(2-DESOXY-2-FLUORO-4-THIO-β-D-ARABINOFURANOSYL)CYTOSINES |
WO2013146833A1 (ja) * | 2012-03-28 | 2013-10-03 | 富士フイルム株式会社 | 1-(2-デオキシ-2-フルオロ-4-チオ-β-D-アラビノフラノシル)シトシンの塩 |
Non-Patent Citations (3)
Title |
---|
MIURA, S. ET AL.: "Comparison of 1-(2-deoxy- 2-fluoro-4-thio-beta-d-arabinofuranosyl)cytosine with gemcitabine in its antitumor activity", CANCER LETTERS, vol. 144, 1999, pages 177 - 182, XP055213437, ISSN: 1872-7980, DOI: doi:10.1016/S0304-3835(99)00221-9 * |
See also references of EP3508205A4 * |
VON HOFF, D. D. ET AL.: "Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 369, no. 18, 2013, pages 1691 - 1703, XP055250743, ISSN: 1533-4406, DOI: doi:10.1056/NEJMoa1304369 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11141421B2 (en) | 2018-01-29 | 2021-10-12 | Fujifilm Corporation | Antitumor agent for biliary tract cancer and method for treating biliary tract cancer |
WO2019176984A1 (ja) * | 2018-03-13 | 2019-09-19 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
WO2019176985A1 (ja) * | 2018-03-13 | 2019-09-19 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
JPWO2019176984A1 (ja) * | 2018-03-13 | 2021-02-04 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
JP2022009980A (ja) * | 2018-03-13 | 2022-01-14 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
JP7183371B2 (ja) | 2018-03-13 | 2022-12-05 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
WO2023008511A1 (ja) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Bap1およびpbrm1の少なくとも1つの機能低下を有する腫瘍に対する医薬組成物および抗腫瘍剤 |
KR20240028451A (ko) | 2021-07-29 | 2024-03-05 | 후지필름 가부시키가이샤 | Bap1 및 pbrm1 중 적어도 하나의 기능 저하를 갖는 종양에 대한 의약 조성물 및 항종양제 |
Also Published As
Publication number | Publication date |
---|---|
KR102198656B1 (ko) | 2021-01-05 |
SG11201901815WA (en) | 2019-04-29 |
AU2017319260A1 (en) | 2019-03-21 |
CA3035334A1 (en) | 2018-03-08 |
MX2019002430A (es) | 2019-07-04 |
EP3508205B1 (en) | 2022-05-18 |
RU2019105574A3 (ja) | 2020-10-01 |
EP3508205A1 (en) | 2019-07-10 |
US20190192546A1 (en) | 2019-06-27 |
CA3035334C (en) | 2022-05-10 |
BR112019003946A2 (pt) | 2019-05-21 |
ZA201901563B (en) | 2020-09-30 |
US11369625B2 (en) | 2022-06-28 |
TW201811323A (zh) | 2018-04-01 |
CN109641009A (zh) | 2019-04-16 |
EP3508205A4 (en) | 2019-09-04 |
KR20190034310A (ko) | 2019-04-01 |
RU2019105574A (ru) | 2020-10-01 |
JP7008025B2 (ja) | 2022-01-25 |
JPWO2018043530A1 (ja) | 2019-07-04 |
CN109641009B (zh) | 2021-12-31 |
NZ751051A (en) | 2021-09-24 |
AU2017319260B2 (en) | 2020-01-30 |
RU2752172C2 (ru) | 2021-07-23 |
TWI787201B (zh) | 2022-12-21 |
JP2021014474A (ja) | 2021-02-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2002210993B2 (en) | Medicinal compositions for concominant use as anticancer agents | |
US11369625B2 (en) | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit | |
CN106470696B (zh) | 用于治疗癌症的药物组合 | |
JP2018520352A (ja) | アルギナーゼ活性を阻害するための組成物および方法 | |
CN106488776B (zh) | 包含糖皮质激素和edo-s101的组合 | |
JP2012500180A5 (ja) | ||
JP2015536986A (ja) | 併用療法 | |
JP2022009980A (ja) | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット | |
US11141421B2 (en) | Antitumor agent for biliary tract cancer and method for treating biliary tract cancer | |
WO2022225045A1 (ja) | グレリン抵抗性を伴う悪液質の治療剤又は予防剤 | |
WO2019176985A1 (ja) | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット | |
AU2020402994A1 (en) | Methods of treating cancer | |
TW202000207A (zh) | 膀胱癌用抗腫瘤劑及膀胱癌的處置方法 | |
NZ751051B2 (en) | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit | |
JP6801908B1 (ja) | ベネトクラクスの水溶性高分子誘導体 | |
CN117769416A (zh) | Bak激活剂、药物组合物和在治疗癌症中的用途 | |
JP6851826B2 (ja) | がんの治療のためのpimキナーゼ阻害剤と組み合わせたペプチドエポキシケトンプロテアソーム阻害剤 | |
TW201121547A (en) | Pharmaceutical composition for the treatment of proliferative diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17846534 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2018537328 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 3035334 Country of ref document: CA Ref document number: 20197006023 Country of ref document: KR Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112019003946 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2017319260 Country of ref document: AU Date of ref document: 20170830 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017846534 Country of ref document: EP Effective date: 20190401 |
|
ENP | Entry into the national phase |
Ref document number: 112019003946 Country of ref document: BR Kind code of ref document: A2 Effective date: 20190226 |