WO2012105477A1 - 鎮痛剤 - Google Patents
鎮痛剤 Download PDFInfo
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- WO2012105477A1 WO2012105477A1 PCT/JP2012/051939 JP2012051939W WO2012105477A1 WO 2012105477 A1 WO2012105477 A1 WO 2012105477A1 JP 2012051939 W JP2012051939 W JP 2012051939W WO 2012105477 A1 WO2012105477 A1 WO 2012105477A1
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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
- A61K31/185—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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]
Definitions
- the present invention relates to a novel pharmaceutical use of a fatty acid ester having 10 carbon atoms, and specifically relates to an analgesic containing a fatty acid ester having 10 carbon atoms as an active ingredient.
- the present invention relates to an analgesic containing a fatty acid ester having 10 carbon atoms as an active ingredient.
- fatty acid esters with 10 carbon atoms 10-hydroxy-2-decenoic acid is widely known to be a unique component of royal jelly, has the same action as insulin, and functions to normalize glucose metabolism in the body. It is a substance that is expected to improve lifestyle-related diseases and beauty effects.
- the fatty acid ester having 10 carbon atoms which is an active ingredient of the drug of the present invention, is a compound having a different structure in that the 10-position of the fatty acid chain is substituted with a hydroxy group and that it is not an ester.
- Patent Document 1 discloses that a fatty acid or 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 about having an analgesic action as in the present invention.
- An object of the present invention is to provide an analgesic having an excellent effect.
- the present inventors have found that a fatty acid ester having 10 carbon atoms exhibits an excellent analgesic effect on pain diseases, and has completed the present invention. That is, the present invention is as follows. (1) An analgesic containing a fatty acid ester having 10 carbon atoms as an active ingredient. (2) The analgesic according to (1), wherein the fatty acid in the fatty acid ester is decenoic acid. (3) The analgesic according to (2), wherein the decenoic acid is 2-decenoic acid. (4) The analgesic according to (3), wherein the 2-decenoic acid is trans-2-decenoic acid.
- the analgesic according to (9), wherein the osteoarthritis is knee osteoarthritis or hip osteoarthritis.
- the analgesic according to (11), wherein the demyelinating disease is multiple sclerosis or Guillain-Barre syndrome.
- the analgesic according to any one of (1) to (12), wherein the analgesic is an oral preparation.
- the C10 fatty acid ester related to the analgesic of the present invention is a compound having an excellent analgesic action and is associated with pain due to joint pain such as osteoarthritis, demyelinating diseases such as multiple sclerosis and Guillain-Barre syndrome. It is very useful as a drug for treating various painful diseases such as pain.
- FIG. 1 shows the results of examining the effect of a single administration of the analgesic of the present invention on hyperalgesia in osteoarthritis model rats.
- FIG. 2 shows the results of examining the effect of repeated administration of the analgesic of the present invention on hyperalgesia in osteoarthritis model rats.
- FIG. 3 shows the results of examining the effect of repeated administration of the analgesic of the present invention on joint pain in osteoarthritis model rats.
- FIG. 4 shows the results of examining the effect of repeated administration of the analgesic of the present invention on joint pain in osteoarthritis model rats, as in FIG.
- the present invention relates to an analgesic containing a fatty acid ester having 10 carbon atoms as an active ingredient.
- the fatty acid ester that can be used as an active ingredient of the analgesic of the present invention is a fatty acid ester composed of a C10 fatty acid 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.
- the double bond of the carbon chain such as 2-decenoic acid, 3-decenoic acid and 9-decenoic acid is one unsaturated fatty acid, more preferably these trans isomers, particularly preferably trans-2-decenoic acid. Can be mentioned.
- examples of the alcohol that forms the ester portion of the fatty acid ester in the analgesic of the present invention include alkyl alcohols, alkenyl alcohols, and cycloalkyl alcohols.
- 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 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, cyclohexyl. And cycloalkyl alcohols having 5 or 6 carbon atoms such as
- fatty acid ester having 10 carbon atoms which is an active ingredient of the analgesic of the present invention
- a known compound or a commercial product described in Patent Document 1 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 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 analgesic of the present invention contains a fatty acid ester having 10 carbon atoms as an active ingredient, and is useful as a preventive or therapeutic agent for various pain diseases.
- pain diseases include joint pain such as pain caused by osteoarthritis such as knee osteoarthritis and hip osteoarthritis, and pain caused by rheumatoid arthritis, or demyelinating diseases such as multiple sclerosis or Guillain-Barre syndrome. Accompanying pain etc. are mentioned.
- the fatty acid ester having 10 carbon atoms according to the present invention can be formulated into various dosage forms (oral preparations, injections, external preparations, etc.) in combination with appropriate pharmaceutical carriers and diluents as appropriate.
- the analgesic 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 analgesic of the present invention may be formulated as an inclusion body with cyclodextrin or the like. By doing so, enhancement of pharmacological activity, improvement of stability, sustainability, ease of handling, etc. can 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 C10 fatty acid esters such as excipients, binders, disintegrants, lubricants, bulking agents, wetting agents, buffering agents, Tablets, powders, granules, or capsules can be prepared by combining preservatives, fragrances and the like as appropriate.
- 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 patch a gel, etc., it can be set as the thing using the organogelator, for example.
- 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.
- the desired dose of the analgesic of the present invention can be appropriately increased or decreased in consideration of the usage, patient age, sex, symptom level, etc., but is usually 1 to 1000 mg per day for an adult, preferably 5 to 300 mg once a day or It can be administered in several divided doses.
- Pharmacological test I Analgesic action on osteoarthritis model rats The following studies are conducted to examine the analgesic action of the analgesic of the present invention using sodium monoiodoacetate (MIA) -induced OA rats, a model animal of osteoarthritis (OA). The experiment was conducted.
- MIA sodium monoiodoacetate
- OA osteoarthritis
- test drug Test drug solution (0.1 mg / mL) and LOX suspension (1 mg / mL) using Compound 4 as the test drug are each phosphoric acid containing 0.1 vol% dimethyl sulfoxide (DMSO).
- DMSO dimethyl sulfoxide
- PBS buffered saline
- carboxymethylcellulose aqueous solution prepared with buffered saline (PBS) and 0.5 w / v% carboxymethylcellulose aqueous solution.
- the test drug solution is administered intraperitoneally at a dose of 0.5 mg / kg for the test drug administration group, and the LOX suspension is administered at a dose of 5 mg / kg for the LOX administration group
- the solution was administered once orally.
- PBS containing 0.1 vol% DMSO was administered intraperitoneally once to the normal control group and the onset control group.
- the significant difference test was performed between the normal control group and the onset control group, between the onset control group and the test drug administration group, between the onset control group and the LOX administration group, and between the test drug administration group and the LOX administration group.
- the test (Student's test or Welch test) or Wilcoxon test was used. Analysis was performed using SAS System Version 8.2 (SAS Pre-clinical Package Ver. 5.0, SAS Institute Japan), and p ⁇ 0.05 was considered significant.
- FIG. 1 An example of the test results is shown in FIG.
- the 50% response threshold to mechanical stimulation in the onset control group in which OA was induced by administration of MIA was significantly lower than that in the normal control group.
- the test drug administration group in which the test drug (compound 4) was administered once intraperitoneally after the administration of MIA showed a significantly higher 50% response threshold than the onset control group. It was.
- the LOX administration group administered at a dose of 5 mg / kg did not show a significant hyperalgesia-inhibiting effect, whereas the test drug administration group showed a hyperalgesia-inhibiting effect at a low dose of 0.5 mg / kg.
- Table 3 shows an example of test results obtained by single administration of the analgesic of the present invention as described above. Perform the von Frey test in the same manner as described above, measure the 50% response threshold value for each, and determine the 50% response threshold recovery rate (%) according to the following formula for the 50% response threshold value 1 hour after administration of the test drug. Was calculated.
- 50% response threshold recovery rate (%) [(50% response threshold 1 hour after study drug administration-50% response threshold before study drug administration) ⁇ (normal threshold-50% response threshold before study drug administration) ] ⁇ 100
- the analgesic of the present invention showed an excellent inhibitory effect on OA hyperalgesia induced by MIA administration.
- Trans-2-decenoic acid which is not an ester, did not show a difference in the 50% response threshold before administration of the test drug and 1 hour after administration of the test drug, and no hyperalgesia-inhibiting effect was observed.
- test drug solution and the LOX suspension are as described in 1. above. Prepared in the same manner as (2). Immediately after group formation for 8 days (from 27 days to 34 days after MIA administration), the test drug solution was repeatedly administered intraperitoneally at a dose of 0.5 mg / kg / day for the test drug administration group, and 5 mg / kg for the LOX administration group. The LOX suspension was repeatedly administered orally at a dose of kg / day, and 0.1 vol% DMSO-containing PBS was repeatedly administered intraperitoneally to the normal control group and the onset control group.
- FIG. 2 An example of the results of the above test is shown in FIG.
- the 50% response threshold to mechanical stimulation in the onset control group in which OA was induced by administration of MIA was significantly lower than that in the normal control group.
- the test drug administration group in which the test drug (compound 4) was repeatedly administered intraperitoneally after administration of MIA was significantly higher than the onset control group at 1 and 3 hours after administration.
- a 50% response threshold was indicated.
- the weight load ratio to the hind limbs not administered with MIA was determined by measuring the weight distribution to the left and right hind limbs of the rat using an analgesic evaluation device for small animals (Incapacitance Tester: manufactured by Linton Instrumentation) 1 hour after the final administration of the test drug. It calculated
- MIA non-administration hindlimb weight loading rate (%) [(Weight load on hind limb not administered MIA-weight load on hind limb administered MIA) ⁇ (weight load on hind limb not administered MIA + weight load on hind limb administered MIA)] x 100
- FIG. 3 An example of the test results is shown in FIG.
- the weight loading rate to the non-MIA-administered hind limb was significantly increased compared to the normal control group.
- the test drug compound 4
- the weight load rate to the hind limb not administered with MIA was compared with the onset control group.
- the analgesic of the present invention has an excellent analgesic effect against pain caused by OA induced by MIA administration.
- the analgesic of the present invention showed an excellent inhibitory effect on the hyperalgesia of OA induced by MIA administration.
- FIG. 4 shows an example of test results obtained by measuring the weight load ratio on the hind legs not administered with MIA in the same manner as (5).
- the analgesic of the present invention significantly decreased the weight loading rate, and the weight loading rate of other compounds was also decreased. Therefore, the analgesic of the present invention was induced by administration of MIA. It was confirmed to have an analgesic effect on the pain of OA.
- Pharmacological study II Analgesic effect on multiple sclerosis model rats Using experimental autoimmune encephalomyelitis (EAE) rats, which are multiple sclerosis (MS) model animals that develop chronic pain The following experiment was conducted to examine the analgesic action of the analgesic of the present invention.
- EAE experimental autoimmune encephalomyelitis
- MS multiple sclerosis
- EAE rats were prepared by subcutaneous administration to the left hind limb and immunization.
- test drug Compound 4 was repeatedly intraperitoneally administered once a day from the day of immunization to 28 days after immunization at a dose of 0.25 mg / kg / day or 0.50 mg / kg / day to the test drug administration group.
- the onset control group immunized with the administration of guinea pig myelin basic protein and Freund's complete adjuvant had a 50% response threshold to mechanical stimulation before and after transient onset of paralysis compared to the normal control group. Significantly decreased.
- the test drug administration group in which the test drug (compound 4) was repeatedly administered intraperitoneally after immunization showed an excellent recovery rate of 50% reaction threshold.
- the analgesic of the present invention has an excellent analgesic effect on pain associated with EAE.
- Pharmacological Test III Analgesic Action on Guillain-Barre Syndrome Model Rats Analgesic action of the analgesic of the present invention using experimental autoimmune neuritis (EAN) rats, which are model animals of Guillain-Barre syndrome that develop chronic pain. The following experiment was conducted.
- EAN experimental autoimmune neuritis
- the onset control group immunized with bovine P2 protein-derived peptide and Freund's complete adjuvant had a significant 50% response threshold to mechanical stimulation compared to the normal control group before and after the onset of transient paralysis. Declined.
- the test drug administration group in which the test drug (compound 4) was repeatedly administered intraperitoneally after immunization showed an excellent recovery rate of the 50% reaction threshold.
- the analgesic agent of the present invention has an excellent analgesic effect on pain associated with EAN.
- the analgesics of the present invention used animal models using MIA-induced OA rats, which are OA models, and demyelinating disease model rats such as multiple sclerosis and Guillain-Barre syndrome. In animal experiments, it has excellent analgesic effect and hyperalgesia-suppressing effect. Therefore, the analgesic of the present invention is highly useful as an agent for preventing or treating pain due to various pain diseases such as OA and demyelinating diseases.
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Abstract
Description
(1)炭素数10の脂肪酸エステルを有効成分として含有する鎮痛剤。
(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)記載の鎮痛剤。
(3)前記デセン酸が2-デセン酸である前記(2)記載の鎮痛剤。
(4)前記2-デセン酸がトランス-2-デセン酸である前記(3)記載の鎮痛剤。
(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鎮痛剤。
(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鎮痛剤。
(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鎮痛剤。
(8)前記鎮痛剤が関節痛に対する治療剤である前記(1)乃至(7)のいずれかに記載の鎮痛剤。
(9)前記関節痛が変形性関節症による疼痛である前記(8)記載の鎮痛剤。
(10)前記変形性関節症が変形性膝関節症又は変形性股関節症である前記(9)記載の鎮痛剤。
(11)前記鎮痛剤が脱髄疾患に伴う疼痛に対する治療剤である前記(1)乃至(7)のいすれかに記載の鎮痛剤。
(12)前記脱髄疾患が多発性硬化症又はギランバレー症候群である前記(11)記載の鎮痛剤。
(13)前記鎮痛剤が注射剤である前記(1)乃至(12)のいずれかに記載の鎮痛剤。
(14)前記鎮痛剤が経口剤である前記(1)乃至(12)のいずれかに記載の鎮痛剤。
(15)前記鎮痛剤がシクロデキストリン包接体である前記(13)又は(14)の薬剤。
(16)前記鎮痛剤が外用剤である前記(1)乃至(12)のいずれかに記載の鎮痛剤。
(17)前記外用剤が貼付剤である前記(16)記載の鎮痛剤。
(18)疼痛疾患を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。
(19)疼痛疾患の患者に前記(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、疼痛疾患の治療方法。
(20)疼痛疾患を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。
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。
変形性関節症(Osteoarthritis; OA)のモデル動物であるモノヨード酢酸ナトリウム(MIA)誘発OAラットを用いて、本発明鎮痛剤の鎮痛作用を調べる以下の実験を行った。
(1)MIA誘発OAラットの作製
6週齢雄性Wistar系ラットの機械刺激に対する50%反応閾値(測定方法は後述)を測定して、正常対照群を選別した。正常対照群以外のラットに対し、右膝関節内に生理食塩液で調製したMIAを0.3mg/50μLの用量で単回投与し、左膝関節内には生理食塩液50μLを投与して、MIA誘発OAラットを作製した。また、正常対照群には、両膝の関節内に生理食塩液50μLを投与した。
実験動物の6週齢雄性Wistar系ラットは、正常対照群以外については上記(1)のMIA投与の24日後に、機械刺激に対する50%反応閾値(測定方法は後述)及び体重を測定して、1群6匹として正常対照群、発症対照群、被験薬投与群、ロキソプロフェンナトリウム水和物(LOX)投与群(陽性対照)の4群に群編成を行った。
被験薬として化合物4を用いた被験薬溶液(0.1mg/mL)及びLOX懸濁液(1mg/mL)は、それぞれ0.1vol%のジメチルスルホキシド(DMSO)を含むリン酸緩衝生理食塩液(PBS)及び0.5 w/v%のカルボキシメチルセルロース水溶液で調製した。
群編成直後(MIA投与24日後)に、被験薬投与群には0.5mg/kgの用量で被験薬溶液を腹腔内に単回投与し、LOX投与群には5mg/kgの用量でLOX懸濁液を経口で単回投与した。また、正常対照群及び発症対照群には0.1vol%DMSO含有PBSを腹腔内に単回投与した。
底が金網の透明アクリルゲージに、上記(2)記載の4群のラットを入れ、約3分間馴化させた後に、機械刺激に対する50%反応閾値を、被験薬の投与1、3、5及び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。陽性反応が見られた場合は一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変化した時点を最初の2反応とし、その後4回連続して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を各々の閾値とした。
50%反応閾値の回復率(%)=〔(被験薬投与1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
(1)MIA誘発OAラットの作製
上記1.(1)と同様に、正常対照群の選別及びMIA誘発OAラットの作製を行った。
実験動物の6週齢雄性Wistar系ラットは、正常対照群以外については上記(1)のMIA投与の27日後に、機械刺激に対する50%反応閾値、MIA非投与後肢への重量負荷率(測定方法は後述)及び体重を測定して、1群6匹として正常対照群、発症対照群、被験薬投与群、LOX投与群(陽性対照)の4群に群編成を行った。
被験薬溶液及びLOX懸濁液は、上記1.(2)と同様に調製した。
群編成直後から8日間(MIA投与27日後から34日後まで)、被験薬投与群には0.5mg/kg/日の用量で被験薬溶液を腹腔内に反復投与し、LOX投与群には5mg/kg/日の用量でLOX懸濁液を経口で反復投与し、また、正常対照群及び発症対照群には0.1vol%DMSO含有PBSを腹腔内に反復投与した。
上記1.(4)と同様に、被験薬の最終投与から1、3、5及び24時間後に機械刺激に対する50%反応閾値を測定した。各群の平均値±標準誤差を算出し、有意差の検定は、上記1.(4)と同様に行った。
MIAの投与によりOAを誘発した方のラット後肢は疼痛症状を発症する。従って、ラットはMIA投与後肢への体重の加重を避けるために、痛みのないMIA非投与後肢への体重負荷が上昇する。しかし、被験物質の投与で疼痛症状が改善した場合は、ラットはMIA投与後肢への加重が容易となり、その分MIA非投与後肢への重量負荷率が低下する。このMIA非投与後肢への重量負荷率を指標にして、本発明鎮痛剤の鎮痛作用を測定した。
MIA非投与後肢への重量負荷率は、被験薬の最終投与1時間後に小動物用鎮痛評価装置(Incapacitance Tester:Linton Instrumentation社製)を用いてラットの左右の後肢への重量配分を測定し、以下の式を用いて求めた。また、各群の平均値±標準誤差を算出し、有意差の検定は、上記1.(4)と同様に行った。
MIA非投与後肢への重量負荷率(%)
=〔(MIA非投与後肢への体重負荷-MIA投与後肢への体重負荷)÷(MIA非投与後肢への体重負荷+MIA投与後肢への体重負荷)〕×100
(1)機械刺激に対する50%反応閾値の測定
本発明鎮痛剤をMIA誘発OAラットに反復投与し、上記試験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時間後の50%反応閾値について、上記1.(4)と同様に、50%反応閾値の回復率(%)を算出した。この試験結果の一例を表4に示す。
本発明鎮痛剤を0.5mg/kg/日の用量でMIA誘発OAラットの腹腔内に反復投与し、上記試験2.(5)と同様にMIA非投与後肢への重量負荷率を測定した試験結果の一例を図4に示す。
慢性痛を発症する多発性硬化症(multiple sclerosis; MS)モデル動物である実験的自己免疫性脳脊髄炎(experimental autoallergic encephalomyelitis; EAE)ラットを用いて、本発明鎮痛剤の鎮痛作用を調べる以下の実験を行った。
7週齢雌性Lewis系ラットの機械刺激に対する50%反応閾値を測定して、正常対照群を選別した。正常対照群以外のラットに対し、0.4mg/mLモルモットミエリン塩基性たん白由来ペプチド(MB68-84)溶液とフロイント完全アジュバント(Adjuvant Complete Freund H37Ra)を等量混合したエマルジョン0.1mLを、麻酔したラットの左後肢に皮下投与して免疫し、EAEラットを作製した。
実験動物の7週齢雌性Lewis系ラットは、1群8匹として正常対照群、発症対照群、被験薬0.25mg/kg/日投与群、被験薬0.50mg/kg/日投与群の4群に群編成を行った。
免疫日から28日後まで1日1回、被験薬投与群には0.25mg/kg/日又は0.50mg/kg/日の用量で化合物4を反復腹腔内投与した。
上記薬理試験Iの1.(4)と同様に、フォン・フライ試験を実施し、各群の機械刺激に対する50%反応閾値を経時的に測定し、下記の式により、50%反応閾値の回復率(%)を算出した。有意差の検定は、正常対照群と発症対照群間においては2群の検定(t検定又はWelch検定)を用い、発症対照群と被験薬投与群間においてはノンパラメトリック又はパラメトリックDunnett型多重比較を用いて行った。SAS System Version 8.2(SAS 前臨床パッケージ Ver. 5.0、SAS Institute Japan)を用いて解析を行い、p<0.05を有意差有りとした。
なお、本EAEラットは免疫日から11日後から19日後において、脱髄変性による臨床症状(麻痺)を発症したため、その間の機械刺激に対する50%反応閾値による鎮痛作用の評価は行わなかった。
50%反応閾値の回復率(%)=〔(被験薬投与群の50%反応閾値-発症対照群の50%反応閾値)÷(正常対照群の50%反応閾値-発症対照群の50%反応閾値)〕×100
この試験の結果の一例を表5に示す。
慢性痛を発症するギランバレー症候群モデル動物である実験的自己免疫性神経炎(experimental autoimmune neuritis; EAN)ラットを用いて、本発明鎮痛剤の鎮痛作用を調べる以下の実験を行った。
7週齢雌性Lewis系ラットの機械刺激に対する50%反応閾値を測定して、正常対照群を選別した。正常対照群以外のラットに対し、2mg/mLウシP2たん白由来ペプチド(SP-26)溶液とフロイント完全アジュバント(Adjuvant Complete Freund H37Ra)を等量混合したエマルジョン0.1mLを、麻酔したラットの左後肢に皮下投与して免疫し、EANラットを作製した。
薬理試験IIの(2)及び(3)と同様に、群編成を行い、被験薬を投与した。
上記薬理試験Iの1.(4)と同様に、フォン・フライ試験を実施し、各群の機械刺激に対する50%反応閾値を経時的に測定した。上記薬理試験IIの(4)と同様に有意差の検定を行い、50%反応閾値の回復率(%)を算出した。なお、本EANラットは免疫日から12日後から21日後において、脱髄変性による臨床症状(麻痺)を発症したため、その間の機械刺激に対する50%反応閾値による鎮痛作用の評価は行わなかった。
この試験結果の一例を表6に示す。
Claims (17)
- 炭素数10の脂肪酸エステルを有効成分として含有する鎮痛剤。
- 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記載の鎮痛剤。
- 前記デセン酸が2-デセン酸である請求項2記載の鎮痛剤。
- 前記2-デセン酸がトランス-2-デセン酸である請求項3記載の鎮痛剤。
- 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鎮痛剤。
- 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鎮痛剤。
- 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鎮痛剤。
- 前記鎮痛剤が関節痛に対する治療剤である請求項1乃至7のいずれか一項記載の鎮痛剤。
- 前記関節痛が変形性関節症による疼痛である請求項8記載の鎮痛剤。
- 前記変形性関節症が変形性膝関節症又は変形性股関節症である請求項9記載の鎮痛剤。
- 前記鎮痛剤が脱髄疾患に伴う疼痛に対する治療剤である請求項1乃至7のいずれか一項記載の鎮痛剤。
- 前記脱髄疾患が多発性硬化症又はギランバレー症候群である請求項11記載の鎮痛剤。
- 前記鎮痛剤が注射剤である請求項1乃至12のいずれか一項に記載の鎮痛剤。
- 前記鎮痛剤が経口剤である請求項1乃至12のいずれか一項に記載の鎮痛剤。
- 前記鎮痛剤がシクロデキストリン包接体である請求項13又は14記載の薬剤。
- 前記鎮痛剤が外用剤である請求項1乃至12のいずれか一項に記載の鎮痛剤。
- 前記外用剤が貼付剤である請求項16記載の鎮痛剤。
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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 |
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JP2013139421A (ja) * | 2012-01-04 | 2013-07-18 | Yoichi Akama | 皮膚外用鎮痛剤、皮膚穿刺時疼痛軽減剤および皮下静脈の血管拡張剤 |
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 |
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