WO2012105476A1 - 抗がん剤による末梢神経障害の予防又は治療剤 - Google Patents
抗がん剤による末梢神経障害の予防又は治療剤 Download PDFInfo
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- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
Definitions
- the present invention relates to a novel pharmaceutical use of a fatty acid ester having 10 carbon atoms, specifically for the prevention or treatment of peripheral neuropathy caused by administration of a drug containing at least one anticancer agent.
- the present invention relates to a drug containing a fatty acid ester having 10 carbon atoms as an active ingredient.
- anticancer agents used in chemotherapy are inherently cytotoxic (cytotoxic) and damage not only cancer cells but also human normal cells. Therefore, it is important to administer to a patient so that a sufficient anticancer effect is exhibited while preventing or reducing such side effects as much as possible.
- neuropathy associated with the administration of anticancer drugs is also observed in sensory organs such as taste.
- the incidence is relatively high and the problems are pain such as stinging and burning, numbness of the extremities, perception abnormalities such as burning sensation, hypersensitivity such as hypersensitivity to cooling sensation, Peripheral nervous system neuropathy such as sensory abnormalities such as loss of sensation, numbness and discomfort, sensory ataxia, and weakness.
- any anticancer agent that causes peripheral neuropathy may be used, but lesions in the peripheral nervous system caused by administration of the anticancer agent are considered to be mainly due to degeneration of nerve axons.
- Microtubules in axons play an important role in maintaining normal cell functions, such as the formation of spindles during cell division and the involvement of intracellular organelles and mass transport.
- Taxane drugs such as paclitaxel and docetaxel
- vinca alkaloid drugs such as vincristine, vinblastine, vindesine, and vinorelbine suppress the growth of cancer cells by acting on these microtubules. It is thought that the tube is often damaged and causes neuropathy.
- platinum preparations such as oxaliplatin, carboplatin, cisplatin, nedaplatin and the like are considered to frequently cause neuropathy due to secondary axonal damage as a result of directly damaging nerve cells.
- vitamin B 12 preparations such as mecobalamin and Kampo-jinki-gan (Kashinki-gan) are used to relieve numbness symptoms, while antidepressants (amitriptyline hydrochloride) are used for pain.
- Antiepileptic drugs carbarbamazepine
- antiarrhythmic drugs mexiletine hydrochloride
- corticosteroids etc. are used, but the effects are limited.
- the present invention relates to a drug for the prevention or treatment of peripheral neuropathy by an anticancer agent containing a fatty acid ester having 10 carbon atoms as an active ingredient (in this application, “peripheral neuropathy” is a synonym) It can be replaced by “neuropathy.” “Prevention” and “treatment” both include “improvement” or “reduction” of peripheral neuropathy by anticancer agents).
- Patent Document 1 discloses that a fatty acid or a fatty acid ester having 8 or 10 to 12 carbon atoms has a neurotrophic factor-like action.
- the neurotrophic factor-like agent of Patent Document 1 is useful as a prophylactic / ameliorating agent for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and mental disorders such as depression and anxiety disorder (neuropathy). It is only described, and there is no description on the effect of preventing or treating peripheral neuropathy that occurs as a side effect of the anticancer drug as in the present invention.
- Non-Patent Document 1 reports that decenoic acid, which is a specific component of royal jelly, has an inhibitory effect on neurite retraction caused by cisplatin, which is an anticancer agent.
- this decenoic acid is 10-hydroxy-2-decenoic acid, and the fatty acid ester having 10 carbon atoms, which is the active ingredient of the drug of the present invention, has 10 It is a compound having a different structure in that it is substituted with a hydroxy group and is not an ester.
- a fatty acid ester having 10 carbon atoms is effective for the prevention or treatment of peripheral neuropathy by administration of an anticancer agent.
- An object of the present invention is to provide a drug effective for the prevention or treatment of peripheral neuropathy that appears as a side effect upon administration of an anticancer drug.
- the present invention is as follows.
- the drug according to (1), wherein the fatty acid in the fatty acid ester is decenoic acid.
- the drug according to (2), wherein the decenoic acid is 2-decenoic acid.
- the drug according to (3), wherein the 2-decenoic acid is trans-2-decenoic acid.
- the drug according to any one of (1) to (4), wherein the ester in the fatty acid ester is an alkyl ester.
- the drug according to any one of (1) to (4), wherein the ester in the fatty acid ester is an alkenyl ester.
- the drug according to any one of (1) to (4), wherein the ester in the fatty acid ester is a cycloalkyl ester.
- the drug according to any one of (1) to (7), wherein the anticancer drug is a microtubule inhibitor.
- the drug according to (8), wherein the microtubule inhibitor is a taxane drug.
- the drug according to (9), wherein the taxane drug is paclitaxel or docetaxel.
- An effective amount of the fatty acid ester having 10 carbon atoms according to any one of (1) to (7) is administered to a patient with peripheral neuropathy caused by administration of a drug containing at least one anticancer drug.
- the carbon number 10 according to any one of (1) to (7) in the manufacture of a medicament for preventing or treating peripheral neuropathy caused by administration of a drug containing at least one anticancer drug Use of fatty acid esters.
- the fatty acid ester having 10 carbon atoms according to the drug of the present invention has an excellent pharmacological action of preventing or treating peripheral neuropathy caused by administration of an anticancer drug, and is extremely useful.
- FIG. 1 shows the results of investigating the effect of prophylactic administration of the drug of the present invention on hyperalgesia caused by paclitaxel administration.
- FIG. 2 shows the results of examining the effect of therapeutic administration of the drug of the present invention on hyperalgesia caused by paclitaxel administration.
- FIG. 3 shows the results of examining the effect of prophylactic administration of the drug of the present invention on hyperalgesia caused by oxaliplatin administration.
- FIG. 4 shows the results of examining the effect of therapeutic administration of the drug of the present invention on hyperalgesia caused by oxaliplatin administration.
- the present invention relates to a drug containing, as an active ingredient, a fatty acid ester having 10 carbon atoms for the prevention or treatment of peripheral neuropathy by administration of a drug containing at least one anticancer drug.
- the fatty acid ester that can be used as an active ingredient of the agent of the present invention is a fatty acid ester composed of a fatty acid having 10 carbon atoms and an alcohol, and these fatty acid esters may be used alone or in combination of two or more.
- the fatty acid having 10 carbon atoms may be any of decanoic acid (capric acid) which is a linear saturated fatty acid, decenoic acid which is a linear unsaturated fatty acid, and geranic acid which is a branched chain unsaturated fatty acid.
- an unsaturated fatty acid having one carbon chain double bond such as 2-decenoic acid, 3-decenoic acid, 9-decenoic acid, more preferably a trans isomer thereof, particularly preferably trans-2-decenoic acid.
- an unsaturated fatty acid having one carbon chain double bond such as 2-decenoic acid, 3-decenoic acid, 9-decenoic acid, more preferably a trans isomer thereof, particularly preferably trans-2-decenoic acid.
- examples of the alcohol that forms the ester portion of the fatty acid ester in the drug of the present invention include alkyl alcohol, alkenyl alcohol, and cycloalkyl alcohol.
- the alkyl alcohol is not particularly limited, but preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl,
- Examples thereof include linear or branched alkyl alcohols having 1 to 12 carbon atoms such as isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, isododecyl and the like.
- the alkenyl alcohol is not particularly limited, but preferably ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, tert-butenyl, pentenyl, isopentenyl, neopentenyl, tert -pentenyl, hexenyl, isohexenyl, Examples thereof include linear or branched alkenyl alcohols having 2 to 12 carbon atoms such as heptenyl, isoheptenyl, octenyl, isooctenyl, nonenyl, isononenyl, decenyl, isodecenyl, undecenyl, isoundecenyl, dodecenyl, isododecenyl, and more preferably nonenyl. And linear or branched alkenyl alcohols having 9 to 11 carbon atoms such as isononenyl
- Cycloalkyl alcohols are not particularly limited, but preferably include cycloalkyl alcohols having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and more preferably cyclopentyl, Examples thereof include cycloalkyl alcohols having 5 or 6 carbon atoms such as cyclohexyl.
- fatty acid ester having 10 carbon atoms which is an active ingredient of the drug of the present invention
- a known compound described in Patent Document 1 or a commercially available product can be used, but it can also be produced by a known method.
- it can also be produced by dehydration condensation of a fatty acid having 10 carbon atoms and an alcohol, and a known method can be used for the dehydration condensation reaction.
- a fatty acid having 10 carbon atoms and an alcohol are mixed with a suitable condensing agent (for example, dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide / HCl).
- a suitable condensing agent for example, dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide / HCl.
- DCC dicyclohexylcarbodiimide
- N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide / HCl can be reacted in the presence of
- the reaction can be usually carried out in a solvent (for example, dichloromethane and the like).
- the amount of alcohol used is usually 0.5 to 2 moles (preferably 1 to 1.5 moles) per mole
- an alcohol can be reacted in the presence or absence of a base.
- a halogenating agent such as thionyl chloride, sulfyryl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, or trichloride phosphate can be used.
- the base include triethylamine, pyridine and the like.
- the amount of alcohol used is usually 0.5 to 2 moles (preferably 1 to 1.5 moles) per mole of linear fatty acid having 10 carbon atoms.
- the amount of the base used is usually about 1 to 5 moles per mole of fatty acid having 10 carbon atoms.
- a fatty acid ester having 10 carbon atoms of the target compound can be obtained by using known purification and isolation operations (for example, extraction, chromatography, distillation, recrystallization, etc.).
- the drug of the present invention contains a fatty acid ester having 10 carbon atoms as an active ingredient and is useful as an agent for preventing or treating peripheral neuropathy caused by administration of an anticancer drug.
- an anticancer agent that develops peripheral neuropathy is an anticancer agent that damages microtubules and causes peripheral neuropathy.
- examples of such drugs include taxane drugs such as paclitaxel and docetaxel, and vinca alkaloid drugs such as vincristine, vinplastin, vindesine, and vinorelbine.
- anticancer agents that cause peripheral neuropathy by causing axonal damage due to nerve cell injury.
- examples of such drugs include platinum preparations such as oxaliplatin, carboplatin, cisplatin, nedaplatin and the like.
- Peripheral neuropathy caused by these anticancer drugs includes pain such as stinging and burning, numbness of the extremities of the limbs, sensory abnormalities such as burning sensation, hypersensitivity such as hypersensitivity to cold stimuli, loss of sensation and sensation Examples include sensory abnormalities such as paralysis and discomfort, sensory ataxia, and weakness of muscles.
- Peripheral neuropathy caused by an anticancer agent that is a subject of prevention or treatment in the present invention is not only peripheral neuropathy caused by monotherapy using one type of anticancer agent, but also a plurality of drugs having different action mechanisms Occurs in multi-drug combination therapy where drugs are administered in combination, or in biochemical modulation therapy where the drug combination and administration method are devised so that drugs with different mechanisms of action can exert their maximum effectiveness Including peripheral neuropathy.
- the fatty acid ester having 10 carbon atoms according to the present invention can be formulated into drugs of various dosage forms (oral preparations, injections, external preparations, etc.) in appropriate combination with appropriate pharmaceutical carriers and diluents.
- the drug of the present invention may be a compounding agent in which a fatty acid ester having 10 carbon atoms is combined with other pharmaceutically active ingredients.
- the drug of the present invention may be formulated as an inclusion body with cyclodextrin or the like. By doing so, enhancement of pharmacological activity, improvement in stability, sustainability, ease of handling, etc. may be obtained.
- the clathrate can be formed, for example, by mixing a fatty acid ester having 10 carbon atoms with ⁇ -, ⁇ -, or ⁇ -cyclodextrin, and, for example, enhanced pharmacological activity upon oral administration is observed. .
- additives suitable for fatty acid esters having 10 carbon atoms such as excipients, binders, disintegrants, lubricants, bulking agents, wetting agents, buffering agents, preservatives
- tablets, powders, granules, or capsules can be prepared by a prescription appropriately combined with fragrances and the like.
- a stabilizer, a preservative, an isotonic agent and the like can be added to a solution or suspension containing a fatty acid ester having 10 carbon atoms to make an injection.
- it can be formulated into external preparations such as patches, gels, ointments and creams.
- a fatty acid ester having 10 carbon atoms is prepared by mixing, melting, emulsifying, and the like in an appropriate base, and in the case of a patch, this is spread-coated on a support.
- a gelling agent, etc. for example, a composition using an organogelling agent can be used.
- preservatives, antioxidants, flavoring agents, pressure-sensitive adhesives and the like that are usually used depending on the dosage form of each external preparation can be appropriately selected and added to the formulation.
- Desirable dosage of the drug of the present invention can be appropriately increased or decreased in consideration of the usage, patient age, sex, degree of symptom, etc., but usually 1 to 1000 mg, preferably 5 to 300 mg per day for an adult is once or several times a day. Can be administered in divided doses.
- Pharmacological test Action against hyperalgesia in rats with anticancer drug-induced peripheral neuropathy
- the effect of the drug of the present invention on peripheral neuropathy that occurs when an anticancer drug is administered was induced by administering an anticancer drug to animals. It was examined by the action of the drug of the present invention on hyperalgesia such as allodynia (pain caused by tactile stimulation that does not usually cause pain).
- Taxol registered trademark
- paclitaxel diluted to 2 mg / mL with physiological saline was intraperitoneally administered every other day at a dose of 2 mg / kg to rats in each group other than the above normal control group to produce paclitaxel-induced peripheral neuropathy rats did.
- Cremophor EL registered trademark, manufactured by Sigma
- Cremophor EL which is a solvent for Taxol (registered trademark) injection solution
- ethanol in an equal volume mixture were diluted 3 times with physiological saline. It administered similarly.
- test drug In the prophylactic administration group of test drug, compound 4 was repeatedly administered intraperitoneally at a dose of 0.25 mg / kg / day or 0.50 mg / kg / day from the start of paclitaxel administration to 13 days later.
- the study drug treatment group and the gabapentin treatment group were administered with Compound 4 at a dose of 0.25 mg / kg / day or 0.50 mg / kg / day from 14 to 27 days after the start of paclitaxel administration, 30 mg / kg / day.
- Each dose of gabapentin was repeatedly administered intraperitoneally.
- von Frey filament North Coast Medical Inc.
- filaments (stimulus load (g): 0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0), start with 2.0 g of filament, and 2 ⁇
- a positive reaction was defined when the hind limb showed an escape reaction when placed perpendicular to the sole for 3 seconds.
- the result was positive. Stimulate in the same way with a lower-strength filament if there is a positive response, or one higher strength if there is no response, and start at the point when the response changes from negative to positive or from positive to negative.
- the two reactions were: Stimulation was performed by the same up-down method four times thereafter. Using the responses to a total of 6 stimuli, the 50% response threshold for mechanical stimuli was measured, and the mean value ⁇ standard error of each group was calculated. In addition, 15.0 g was used when the stimulation was performed up to 15.0 g without any positive reaction, and 0.25 g was used as the 50% reaction threshold when the positive reaction continued to 0.4 g.
- FIGS. 1 An example of the test results is shown in FIGS.
- the 50% response threshold to mechanical stimulation in the onset control group that received four doses of paclitaxel was significantly lower than that in the normal control group from 14 to 42 days after the start of paclitaxel administration.
- FIG. 1 is a graph showing the results of repeated administration of the test drug (Compound 4) intraperitoneally prophylactically immediately after the start of paclitaxel administration until 13 days later.
- the prophylactic administration group of the test drug 0.5 mg / kg / day showed a significantly higher 50% response threshold than the onset control group from 14 to 28 days after the start of paclitaxel administration.
- trans-2-decenoic acid that is not an ester was similarly administered intraperitoneally at a dose of 0.50 mg / kg / day, but the 50% response threshold for mechanical stimulation was not different from the onset control group and was induced by paclitaxel administration. No preventive effect on hyperalgesia was observed.
- FIG. 2 is a graph showing the results of repeated administration of the test drug (compound 4) intraperitoneally from 14 days to 27 days after the start of paclitaxel administration, in which the 50% response threshold is significantly reduced.
- the 50% response threshold is significantly reduced.
- Significantly higher 50% compared to the onset control group in the study drug 0.25 mg / kg / day treatment group 21 days to 35 days after paclitaxel administration and in the test drug 0.5 mg / kg / day treatment group 28 days after paclitaxel administration
- the reaction threshold was shown.
- test drug In the test drug prophylaxis group, the test drug (compound 4) was administered intraperitoneally at a dose of 0.25 mg / kg / day or 0.50 mg / kg / day from the start of oxaliplatin administration to 27 days later. Was repeatedly administered.
- the test drug treatment group or pregabalin treatment administration group was administered intraperitoneally with the test drug (compound 4) at a dose of 0.25 mg / kg / day or 0.50 mg / kg / day from 14 to 27 days after the start of oxaliplatin administration.
- pregabalin was orally repeated at a dose of 10 mg / kg / day during the same period.
- FIGS. 3 is a graph showing the results of repeated administration of the test drug (Compound 4) intraperitoneally from the start of administration of oxaliplatin to 27 days later, from 21 days to 28 days after administration of oxaliplatin.
- the 50% response threshold was significantly higher than the onset control group. Indicated.
- FIG. 4 is a graph showing the results of repeated administration of the test drug (compound 4) intraperitoneally from 14 days to 27 days after the start of oxaliplatin administration, in which the 50% response threshold value significantly decreases.
- the 50% response threshold value significantly decreases.
- the drug of the present invention is compared with the dose of gabapentin (30 mg / kg / day) or the dose of pregabalin (10 mg / kg / day). The effect was shown at a low dose of 0.25 mg / kg / day or 0.50 mg / kg / day.
- Test drug suspension 0.3 mg / kg oral administration group
- Test drug suspension 3 mg / kg oral administration group ⁇ ⁇ -CD clathrate oral administration group containing test drug 0.3 mg / kg
- Test drug 3 mg / kg ⁇ -CD clathrate oral administration group ⁇ -CD oral administration group, test drug 0.3 mg / kg intraperitoneal administration group
- test drug [1]
- test drug equivalent value was 0.3 mg / kg in the test drug suspension oral administration group or the ⁇ -CD clathrate oral administration group containing the test drug
- a single dose was orally administered at a dose of 3 mg / kg, and a single dose was administered intraperitoneally at a dose of 0.3 mg / kg to the test drug intraperitoneal administration group.
- the ⁇ -CD solution was orally administered once at a dose of 15 mg / kg.
- the drug of the present invention has an excellent preventive or therapeutic effect against hyperalgesia due to mechanical stimulation that occurs in an allodynia animal model produced by administering paclitaxel and oxaliplatin, which are anticancer agents. Accordingly, the drug of the present invention is highly useful as a drug for the prevention or treatment of peripheral neuropathy such as sensory abnormalities such as numbness of the extremities of limbs and hyperalgesia such as pain caused by human or animal anticancer agents. .
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Abstract
Description
(1)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の予防又は治療のための炭素数10の脂肪酸エステルを有効成分として含有する薬剤。
(2)前記脂肪酸エステルにおける脂肪酸がデセン酸である前記(1)記載の薬剤。
(3)前記デセン酸が2-デセン酸である前記(2)記載の薬剤。
(4)前記2-デセン酸がトランス-2-デセン酸である前記(3)記載の薬剤。
(5)前記脂肪酸エステルにおけるエステルがアルキルエステルである前記(1)乃至(4)のいずれかに記載の薬剤。
(6)前記脂肪酸エステルにおけるエステルがアルケニルエステルである前記(1)乃至(4)のいずれかに記載の薬剤。
(7)前記脂肪酸エステルにおけるエステルがシクロアルキルエステルである前記(1)乃至(4)のいずれかに記載の薬剤。
(8)前記抗がん剤が微小管阻害剤である前記(1)乃至(7)のいずれかに記載の薬剤。
(9)前記微小管阻害剤がタキサン系薬剤である前記(8)記載の薬剤。
(10)前記タキサン系薬剤がパクリタキセル又はドセタキセルである前記(9)記載の薬剤。
(11)前記タキサン系薬剤がパクリタキセルである前記(9)記載の薬剤。
(12)前記微小管阻害剤がビンアルカロイド系薬剤である前記(8)記載の薬剤。
(13)前記ビンアルカロイド系薬剤がビンクリスチンである前記(12)の薬剤。
(14)前記抗がん剤が白金製剤である前記(1)乃至(7)のいずれかに記載の薬剤。
(15)前記白金製剤がオキサリプラチン又はシスプラチンである前記(14)記載の薬剤。
(16)前記末梢神経障害が急性又は慢性の疼痛、しびれ、知覚異常、知覚過敏又は感覚異常である前記(1)乃至(15)のいずれかに記載の薬剤。
(17)前記薬剤が注射剤である前記(1)乃至(16)のいずれかに記載の薬剤。
(18)前記薬剤が経口剤である前記(1)乃至(16)のいずれかに記載の薬剤。
(19)前記薬剤がシクロデキストリン包接体である前記(17)又は(18)の薬剤。
(20)前記薬剤が外用剤である前記(1)乃至(16)のいずれかに記載の薬剤。
(21)前記外用剤が貼付剤である前記(20)記載の薬剤。
(22)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の予防又は治療するために用いる前記(1)乃至(7)のいずれかに記載の炭素数10の脂肪酸エステル。
(23)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の患者に前記(1)乃至(7)のいずれかに記載の炭素数10の脂肪酸エステルの有効量を投与することを特徴とする、少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の予防又は治療方法。
(24)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害を予防又は治療するための医薬の製造における前記(1)乃至(7)のいずれかに記載の炭素数10の脂肪酸エステルの使用。
アルキルアルコールは特に限定されるものではないが、好ましくはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、tert -ペンチル、ヘキシル、イソヘキシル、ヘプチル、イソヘプチル、オクチル、イソオクチル、ノニル、イソノニル、デシル、イソデシル、ウンデシル、イソウンデシル、ドデシル、イソドデシル等の炭素数1乃至12の直鎖状又は分岐状のアルキルのアルコールが挙げられる。
公知の縮合方法としては、例えば、炭素数10の脂肪酸とアルコールを、適当な縮合剤(例えば、ジシクロヘキシルカルボジイミド(DCC)、N-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド・HCl等)の存在下に反応させることができる。反応は、通常溶媒(例えば、ジクロロメタン等)中で実施することができる。アルコールの使用量は、通常、炭素数10の脂肪酸1モルに対し、0.5~2モル(好ましくは1~1.5モル)である。
上記の反応終了後、公知の精製及び単離操作(例えば、抽出、クロマトグラフィー、蒸留、再結晶等)を用いて、目的化合物の炭素数10の脂肪酸エステルを得ることができる。
抗がん剤を投与した場合に生じる末梢神経障害に対する本発明薬剤の効果を、抗がん剤を動物に投与して惹起されるアロディニア(通常痛みを引き起こさない触覚刺激で惹起される痛み)等の痛覚過敏に対する本発明薬剤の作用によって調べた。
〔1〕パクリタキセル投与による痛覚過敏に対する効果
(1)実験動物の群編成
実験動物の6週齢雄性SD系ラットは、機械刺激に対する50%反応閾値(測定方法は後述)及び体重を測定し、1群8匹として下記の7群に群編成を行った。
・正常対照群
・発症対照群
・被験薬 0.25mg/kg/日予防投与群
・被験薬 0.50mg/kg/日予防投与群
・被験薬0.25mg/kg/日治療投与群
・被験薬0.50mg/kg/日治療投与群
・ガバペンチン30mg/kg/日治療投与群(陽性対照)
パクリタキセルとして6 mg/mLのタキソール(登録商標)注射液30 mg(ブリストル・マイヤーズ社製)を使用した。上記正常対照群以外の各群のラットに対し、生理食塩水で2mg/mLに希釈したパクリタキセルを2mg/kgの用量で1日おきに4回腹腔内投与し、パクリタキセル誘発末梢神経障害ラットを作製した。また、正常対照群には、タキソール(登録商標)注射液の溶媒であるCremophor EL(登録商標、Sigma社製)とエタノールの等量混合液を、生理食塩水で3倍に希釈した溶液にして同様に投与した。
被験薬の予防投与群には、パクリタキセル投与開始直後から13日後まで、0.25mg/kg/日又は0.50mg/kg/日の用量で化合物4を腹腔内に反復投与した。また、被験薬治療投与群及びガバペンチン治療投与群には、パクリタキセル投与開始14日後から27日後まで、0.25mg/kg/日若しくは0.50mg/kg/日の用量で化合物4を、30mg/kg/日の用量でガバペンチンを各々腹腔内に反復投与した。
底が金網の透明アクリルゲージに、上記(1)記載の7群のラットを入れ、約3分間馴化させた後に、右後肢の機械刺激に対する50%反応閾値を、パクリタキセル投与開始から3、7、14、21、28、35及び42日後に測定した。なお、被験薬の投与期間中は、被験薬の最終投与から24時間後に測定した。
測定は、Chaplanら(Journal of Neuroscience Methods、53巻、1号、55-63頁、1994年)及びDixonら(Annual Review of Pharmacology and Toxicology、20巻、441-462頁、1980年)の方法に準じ、フォン・フライフィラメント(von Frey filament、North Coast Medical Inc.製)を用いて行った。8本のフィラメント〔刺激荷重(g):0.4、0.6、1.0、2.0、4.0、6.0、8.0、15.0〕のうち、2.0gのフィラメントより開始し、軽度にフィラメントが湾曲する程度の力で2~3秒間、足底に対し垂直に当て、後肢が逃避反応を示した場合を陽性反応とした。また、フィラメントを除去した瞬間に逃避した場合も陽性とした。陽性反応がみられた場合は1つ下の、反応がなかった場合は1つ上の強さのフィラメントで同様に刺激し、反応が陰性から陽性へ又は陽性から陰性へと変化した時点を最初の2反応とした。その後4回連続して同様のup-down法により刺激を行った。合計6回の刺激に対する反応を用いて、機械刺激に対する50%反応閾値を測定し、各群の平均値±標準誤差を算出した。なお、陽性反応がないまま15.0gの刺激まで行った場合は15.0g、陽性反応が0.4gまで続いた場合は0.25gを各々の50%反応閾値とした。
(1)実験動物の群編成
実験動物の6週齢雄性SD系ラットは、機械刺激に対する50%反応閾値及び体重を測定し、1群8匹として下記の7群に群編成を行った。
・正常対照群
・発症対照群
・被験薬 0.25mg/kg/日予防投与群
・被験薬 0.50mg/kg/日予防投与群
・被験薬0.25mg/kg/日治療投与群
・被験薬0.50mg/kg/日治療投与群
・プレガバリン10mg/kg/日治療投与群(陽性対照)
上記正常対照群以外の各群のラットに対し、ブドウ糖注射液で4mg/mLに溶解したオキサリプラチン溶液を4mg/kgの用量で1週間に2回、4週間にわたり計8回腹腔内投与し、オキサリプラチン誘発末梢神経障害ラットを作製した。また、正常対照群には、ブドウ糖注射液を同様に投与した。
被験薬予防投与群には、オキサリプラチン投与開始直後から27日後まで、0.25mg/kg/日又は0.50mg/kg/日の用量で被験薬(化合物4)を腹腔内に反復投与した。また、被験薬治療投与群又はプレガバリン治療投与群には、オキサリプラチン投与開始14日後から27日後まで、0.25mg/kg/日若しくは0.50mg/kg/日の用量で被験薬(化合物4)を腹腔内に反復投与し、また、同じ間、10mg/kg/日の用量でプレガバリンを経口にて反復投与した。
上記(1)記載の7群のラットを用いて、上記1.〔1〕(4)と同様にフォン・フライ試験を実施した。各群の50%反応閾値を、オキサリプラチンの投与開始前、並びに、投与開始から7、14、21、28、33及び40日後に測定した。各群の平均値±標準誤差を算出し、有意差の検定は、上記1.〔1〕(4)と同様に行った。
(1)パクリタキセル誘発末梢神経障害ラットの作製及び被験薬の投与
実験動物として6週齢雄性SD系ラット(1群6匹)を用い、上記1.〔1〕(2)と同様に、パクリタキセル誘発末梢神経障害ラットを作製した。被験薬は、パクリタキセルの投与開始18~25日後又は20~27日後の間に、いずれも0.3mg/kgとなるように腹腔内に単回投与した。
上記(1)記載のラットを用いて、上記1.〔1〕(4)と同様にフォン・フライ試験を実施し、各々の50%反応閾値を測定した。被験薬投与1時間後又は5時間後の50%反応閾値のうち高い方の50%反応閾値について、下記の式により、50%反応閾値の回復率(%)を算出した。
50%反応閾値の回復率(%)=〔(被験薬投与1時間後又は5時間後の50%反応閾値-被験薬投与前の50%反応閾値)÷(正常閾値-被験薬投与前の50%反応閾値)〕×100
この試験の結果の一例を表3に示す。
(1)本発明化合物のα-シクロデキストリン(CD)包接体の作製
化合物4の懸濁液(2.0mg/L)5mLと1%α-CD水溶液5mLを混ぜ、一晩攪拌し、化合物4のα-CD包接体を作製した。
実験動物の6週齢雄性SD系ラットは、1群6匹として下記の6群に群編成を行った。
・被験薬懸濁液 0.3mg/kg経口投与群
・被験薬懸濁液3mg/kg経口投与群
・被験薬0.3mg/kg を含有するα-CD包接体経口投与群
・被験薬3mg/kgを含有するα-CD包接体経口投与群
・α-CD経口投与群
・被験薬0.3mg /kg腹腔内投与群
上記1.〔1〕(2)と同様に、パクリタキセル誘発末梢神経障害ラットを作製した。被験薬として化合物4を用い、パクリタキセルの投与開始39日後に、被験薬懸濁液経口投与群又は被験薬を含有するα-CD包接体経口投与群に、被験薬換算値が0.3mg/kg又は3mg/kgとなる用量で経口にて単回投与し、被験薬腹腔内投与群には0.3mg /kgの用量で腹腔内に単回投与した。また、α-CD経口投与群には、α-CD溶液を15mg/kgの用量で経口にて単回投与した。
上記(2)記載のラットを用いて、上記1.〔1〕(4)と同様にフォン・フライ試験を実施し、各群の被験薬投与前、1、5、24時間後の50%反応閾値を測定した。また、各群のAUC(50%反応閾値の被験薬投与からの時間経過を表したグラフで描かれる曲線と横軸(時間軸)によって囲まれた部分の面積)を算出し、被験薬0.3mg/kg腹腔内投与群のAUCを100とした場合の各群の相対比を算出した。
この試験結果の一例を表4に示す。
Claims (21)
- 少なくとも1種の抗がん剤を含む薬剤の投与により生じた末梢神経障害の予防又は治療のための炭素数10の脂肪酸エステルを有効成分として含有する薬剤。
- 前記脂肪酸エステルにおける脂肪酸がデセン酸である請求項1記載の薬剤。
- 前記デセン酸が2-デセン酸である請求項2記載の薬剤。
- 前記2-デセン酸がトランス-2-デセン酸である請求項3記載の薬剤。
- 前記脂肪酸エステルにおけるエステルがアルキルエステルである請求項1乃至4のいずれか一項記載の薬剤。
- 前記脂肪酸エステルにおけるエステルがアルケニルエステルである請求項1乃至4のいずれか一項記載の薬剤。
- 前記脂肪酸エステルにおけるエステルがシクロアルキルエステルである請求項1乃至4のいずれか一項記載の薬剤。
- 前記抗がん剤が微小管阻害剤である請求項1乃至7のいずれか一項記載の薬剤。
- 前記微小管阻害剤がタキサン系薬剤である請求項8記載の薬剤。
- 前記タキサン系薬剤がパクリタキセル又はドセタキセルである請求項9記載の薬剤。
- 前記タキサン系薬剤がパクリタキセルである請求項9記載の薬剤。
- 前記微小管阻害剤がビンアルカロイド系薬剤である請求項8記載の薬剤。
- 前記ビンアルカロイド系薬剤がビンクリスチンである請求項12記載の薬剤。
- 前記抗がん剤が白金製剤である請求項1乃至7のいずれか一項記載の薬剤。
- 前記白金製剤がオキサリプラチン又はシスプラチンである請求項14記載の薬剤。
- 前記抗がん剤による末梢神経障害が急性又は慢性の疼痛、しびれ、知覚異常、知覚過敏又は感覚異常である請求項1乃至15のいずれか一項記載の薬剤。
- 前記薬剤が注射剤である請求項1乃至16のいずれか一項記載の薬剤。
- 前記薬剤が経口剤である請求項1乃至16のいずれか一項記載の薬剤。
- 前記薬剤がシクロデキストリン包接体である請求項17又は18記載の薬剤。
- 前記薬剤が外用剤である請求項1乃至16のいずれか一項記載の薬剤。
- 前記外用剤が貼付剤である請求項20記載の薬剤。
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JP2013241408A (ja) * | 2012-04-27 | 2013-12-05 | Nagoya Industrial Science Research Institute | トランス−2−デセン酸誘導体を含有する医薬 |
WO2014142276A1 (ja) * | 2013-03-15 | 2014-09-18 | 岐阜市 | 4-ハイドロパーオキシ-トランス-2-デセン酸誘導体及びこれを含有する医薬 |
US20160075631A1 (en) * | 2014-09-15 | 2016-03-17 | Elevance Renewable Sciences, Inc. | Low-Toxicity Olefinic Ester Compositions and Methods of Using the Same |
WO2017154675A1 (ja) * | 2016-03-11 | 2017-09-14 | 国立大学法人大阪大学 | ファブリー病処置剤、外用鎮痛剤、および発汗増進剤 |
WO2018008973A1 (ko) * | 2016-07-06 | 2018-01-11 | 한국 한의학 연구원 | 연교 추출물을 유효성분으로 함유하는 말초신경병증 예방, 개선 또는 치료용 조성물 |
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KR20130095328A (ko) * | 2011-01-31 | 2013-08-27 | 니폰 조키 세야쿠 가부시키가이샤 | 진통제 |
KR102285938B1 (ko) * | 2018-04-19 | 2021-08-04 | 한양대학교 산학협력단 | 이매티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 화학요법유발 말초신경병증의 예방 또는 치료용 조성물 |
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2012
- 2012-01-30 US US13/979,665 patent/US20130296425A1/en not_active Abandoned
- 2012-01-30 WO PCT/JP2012/051938 patent/WO2012105476A1/ja active Application Filing
- 2012-01-30 EP EP12742127.9A patent/EP2671578A4/en not_active Withdrawn
- 2012-01-30 AU AU2012211854A patent/AU2012211854A1/en not_active Abandoned
- 2012-01-30 CA CA2824735A patent/CA2824735A1/en not_active Abandoned
- 2012-01-30 KR KR1020137020662A patent/KR20130093180A/ko active IP Right Grant
- 2012-01-30 CN CN2012800072297A patent/CN103338761A/zh active Pending
- 2012-01-30 JP JP2012516241A patent/JP5009451B1/ja not_active Expired - Fee Related
- 2012-01-31 TW TW101103019A patent/TW201306835A/zh unknown
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Cited By (7)
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JP2013241408A (ja) * | 2012-04-27 | 2013-12-05 | Nagoya Industrial Science Research Institute | トランス−2−デセン酸誘導体を含有する医薬 |
WO2014142276A1 (ja) * | 2013-03-15 | 2014-09-18 | 岐阜市 | 4-ハイドロパーオキシ-トランス-2-デセン酸誘導体及びこれを含有する医薬 |
JPWO2014142276A1 (ja) * | 2013-03-15 | 2017-02-16 | アピ株式会社 | 4−ハイドロパーオキシ−トランス−2−デセン酸誘導体及びこれを含有する医薬 |
US20160075631A1 (en) * | 2014-09-15 | 2016-03-17 | Elevance Renewable Sciences, Inc. | Low-Toxicity Olefinic Ester Compositions and Methods of Using the Same |
US10358409B2 (en) * | 2014-09-15 | 2019-07-23 | Elevance Renewable Sciences, Inc. | Low-toxicity olefinic ester compositions and methods of using the same |
WO2017154675A1 (ja) * | 2016-03-11 | 2017-09-14 | 国立大学法人大阪大学 | ファブリー病処置剤、外用鎮痛剤、および発汗増進剤 |
WO2018008973A1 (ko) * | 2016-07-06 | 2018-01-11 | 한국 한의학 연구원 | 연교 추출물을 유효성분으로 함유하는 말초신경병증 예방, 개선 또는 치료용 조성물 |
Also Published As
Publication number | Publication date |
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JPWO2012105476A1 (ja) | 2014-07-03 |
TW201306835A (zh) | 2013-02-16 |
KR20130093180A (ko) | 2013-08-21 |
AU2012211854A1 (en) | 2013-08-08 |
EP2671578A4 (en) | 2014-04-02 |
EP2671578A1 (en) | 2013-12-11 |
JP5009451B1 (ja) | 2012-08-22 |
US20130296425A1 (en) | 2013-11-07 |
CA2824735A1 (en) | 2012-08-09 |
CN103338761A (zh) | 2013-10-02 |
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