TWI465442B - Chronic pain therapeutic agent - Google Patents
Chronic pain therapeutic agent Download PDFInfo
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- TWI465442B TWI465442B TW099105621A TW99105621A TWI465442B TW I465442 B TWI465442 B TW I465442B TW 099105621 A TW099105621 A TW 099105621A TW 99105621 A TW99105621 A TW 99105621A TW I465442 B TWI465442 B TW I465442B
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- aripiprazole
- chronic pain
- therapeutic agent
- pain
- acid
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- 239000003814 drug Substances 0.000 title claims description 17
- 229940124597 therapeutic agent Drugs 0.000 title claims description 14
- 208000002193 Pain Diseases 0.000 title description 43
- 208000000094 Chronic Pain Diseases 0.000 title description 30
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims description 35
- 229960004372 aripiprazole Drugs 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 208000027520 Somatoform disease Diseases 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 208000027753 pain disease Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 2
- 230000002085 persistent effect Effects 0.000 claims 3
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
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- 229960004038 fluvoxamine Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
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- 229960005181 morphine Drugs 0.000 description 4
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- 230000000202 analgesic effect Effects 0.000 description 3
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- 229940056213 abilify Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- LFMYNZPAVPMEGP-PIDGMYBPSA-N Fluvoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 LFMYNZPAVPMEGP-PIDGMYBPSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010028836 Neck pain Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000036314 physical performance Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000004800 psychological effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Description
本發明係有關於一種含有阿立哌唑(aripiprazole)作為有效成分之慢性疼痛治療劑。
慢性疼痛係指嚴重不愉快的疼痛持續6個月以上，而造成日常生活障礙之狀態，依照國際疾病分類第10版(ICD-10)，係被賦與稱為「持續性身體表現性疼痛障礙」之病名。對於慢性疼痛的發症或厭惡感，有啟示心理因素具有重要的作用，但是原因未解釋清楚。
經常往返整形外科之慢性疼痛患者之中，有不少患者由於在神經學上的看法無一貫性而有其難治性，在該背景下，被認為具有精神醫學上的問題。因為治療者對未對精神醫學上的問題進行適當的評價而只是重複進行侵襲性的治療，亦存在有患者，其經歷所謂導致更加疼痛的厭惡感之悲慘的經過。
目前，雖然嘗試使用各種藥劑用以減輕慢性疼痛，但是該等就鎮痛效果而言，未必係能夠滿足之物。因此，希望有一種慢性疼痛的有效治療藥。
且說，阿立哌唑係一種治療統合失調症有用的非定型抗精神病藥(例如專利文獻1及2)。
[專利文獻1]美國專利第4734416號說明書
[專利文獻2]美國專利第5006528號說明書
本發明係以提供一種新穎慢性疼痛治療劑作為目的。
為了達成上述課題，本發明者等重複專心研討的結果，確認將阿立哌唑配給慢性疼痛患者時，能夠確認顯著的鎮痛效果，並且發現阿立哌唑作為慢性疼痛的治療藥之有效的。基於此種知識，並進一步研討之結果，完成了本發明。
亦即，本發明係提供一種含有阿立哌唑作為有效成分之慢性疼痛治療劑。
第1項 一種慢性疼痛治療劑，其係含有阿立哌唑作為有效成分。
第2項 如第1項之慢性疼痛治療劑，其係含有阿立哌唑、其酸加成鹽或其溶劑化物作為有效成分。
第3項 如第1或2項之慢性疼痛治療劑，其中進而含有藥學上可容許的載體。
第4項 一種阿立哌唑的使用，其係用以製造慢性疼痛治療劑。
第5項 一種阿立哌唑，其係用以治療慢性疼痛。
第6項 一種治療慢性疼痛之方法，其係包含配給患者有效量的阿立哌唑。
第7項 如第6項之方法，其中，對患者之阿立哌唑的給藥量，係每1天每1 kg體重為0.05～10 mg左右。
第1圖係顯示對慢性疼痛患者持續性配給阿立哌唑等的藥劑時之治療經過之圖。
本發明係含有阿立哌唑作為有效成分之慢性疼痛治療劑。
阿立哌唑係被命名為7-{4-[4-(2,3-二氯苯基)-1-哌基]丁氧基}-3,4-二氫喹諾酮；英文名：7-{4-[4-(2,3-dichlorophenyl)-1-peperazinyl]butoxy}-3,4-dihydrocarbostyril，或是7-{4-[4-(2,3-二氯苯基)-1-哌基]丁氧基}-3,4-二氫-2(1H)-喹啉酮；英文名：7-{4-[4-(2,3-dichlorophenyl)-1-peperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone作為化學名之化合物。
阿立哌唑係不只是游離形態者，亦可以是形成藥學上被容許的酸及酸加成鹽者。作為此種酸，可例示硫酸、硝酸、鹽酸、磷酸、溴化氫酸等的無機酸；乙酸、對甲苯磺酸、甲磺酸、草酸、順丁烯二酸、反丁烯二酸、蘋果酸、酒石酸、檸檬酸、琥珀酸、苯甲酸等的有機酸。該等酸加成鹽亦與游離形態的阿立哌唑同樣地，在本發明能夠使用作為有效成分化合物。
又，阿立哌唑亦可以是溶劑化物(水合物、醇合物等)。
在上述的阿立哌唑之游離形態、酸加成鹽或溶劑化物，亦包含各自的結晶及/或非晶質形態。又，結晶的形態時，係包含各種的結晶多晶型。
對於慢性疼痛疾病(亦包含全身性慢性疼痛疾病之纖維肌痛症等)的患者，阿立哌唑能夠發揮顯著的鎮痛效果而改善症狀。因此，作為慢性疼痛治療劑係非常有用的。具體上，例如實施例1及第1圖所示，對慢性疼痛患者配給鎮痛劑(嗎啡)及抗鬱劑(氟伏沙明(fluvoxamine))時，症狀完全未見改善，但是配給阿立哌唑時，症狀顯著地改善。
在本發明的慢性疼痛治療劑，亦可在上述的阿立哌唑的形態，進而含有藥學上可容許的載體。作為藥學上可容許的載體，可舉出醫藥製劑通常所使用的填料、增量劑、結合劑、賦濕劑、崩潰劑、表面活性劑、潤滑劑等的稀釋劑、賦形劑等。本發明的慢性疼痛治療劑的製劑形態可以是通常的醫藥製劑之形態，可舉出例如錠劑、快速熔化(flash melt)錠劑、丸劑、散劑、液劑、懸浮劑、乳劑、顆粒劑、膠囊劑、栓劑、注射劑(液劑、懸浮劑等)、片劑(troche)、鼻腔內噴霧劑、經皮貼劑等。
本發明的慢性疼痛治療劑之給藥方法沒有特別限制，能夠藉由適應各種製劑形態、患者的年齡、性別及其他條件(疾病程度等)之方法來給藥。例如錠劑、丸劑、液劑、懸浮劑、乳劑、顆粒劑及膠囊劑時，能夠口服給藥。又，注射劑時，能夠單獨或與萄萄糖、胺基酸等通常的補充液混合而靜脈內給藥，或是單獨肌肉內、皮內、皮下或腹腔內給藥。栓劑時係直腸內給藥。
本發明的慢性疼痛治療劑之給藥量能夠依照用法、患者的年齡、性別及其他條件、疾病程度等而適當地選擇，通常阿立哌唑的量係每天每1kg體重為0.05～10 mg左右。又，給藥單位形態的製劑係每單位給藥量含有約1～100 mg的範圍之阿立哌唑，以含有1～30 mg的範圍為更佳。
本申請所引用的文獻係併入本文作為參考。
隨後，使用實施例來具體地說明本發明，但是本發明未限定於此。
實施例
對訴說10年以上持續慢性的後頭頸部疼痛之被診斷為慢性疼痛疾病之患者，在約11個月期間，配給嗎啡(morphine)、氟伏沙明(fluvoxamine)、阿立哌唑(aripiprazole)等的藥劑，並經時性評價患者的後頭頸部(頸)的疼痛強度。第1圖係顯示其治療經過。
疼痛強度的評價係將疼痛設為0～10之11階段，並採用口頭傳達之數值評價量表(numerical rating scale,NRS)。這是將患者能夠想像的最大疼痛設為10，不疼痛設為0，將疼痛程度階段性數值化(定量化)之評價方法。係能夠良好地反映一患者在治療前後的疼痛程度之評價方法。
依照第1圖，首先，對慢性疼痛患者(體重55kg)，將鹽酸嗎啡錠(大日本住友製藥(股)製)以70 mg/日口服給藥，頸的NRS值較高而為8～10，疼痛係未改善。從第1個月的第4週，除了嗎啡以外並且將fluvoxamine(Depromel錠；明治製菓(股)製)以50 mg/日開始口服給藥，並慢慢地增加其給藥量，但是NRS仍然較高而為8～10，疼痛係完全未改善。
因此，從第4個月的第4週，將阿立哌唑(ABILIFY錠；大塚製藥(股)製)以3 mg/日口服給藥時，第5個月的第1週時NRS值係飛躍性地降低成為1，從第6個月的第2週，NRS值係成為0，頸部完全未感到疼痛了。而且，即便從第8個月起停止嗎啡的給藥，同樣地NRS值亦為0。從該結果，能夠確認雖然嗎啡及fluvoxamine係完全無法減輕疼痛，但是阿立哌唑係非常地能夠降低疼痛。
隨後，第9個月的第4週以後，將阿立哌唑(ABILIFY錠；大塚製藥(股)製)的給藥量設為9mg/日，進而從第10個月的第4週以後，即便增量為12 mg/日，NRS值亦為0，未觀察到變化。
從以上，得知阿立哌唑作為慢性疼痛的治療藥係非常有效的。
第1圖係顯示對慢性疼痛患者持續性配給阿立哌唑等的藥劑時之治療經過之圖。
Claims (4)
- 一種阿立哌唑的用途，其係用以製造持續性身體表現性疼痛障礙治療藥。
- 如請求項1之用途，其中該阿立哌唑係阿立哌唑、其酸加成鹽、其結晶多晶型或其溶劑化物。
- 如請求項1之用途，其中前述阿立哌唑係以對持續性身體表現性疼痛障礙患者每1天每1kg體重投予0.05~10mg的方式來使用。
- 一種阿立哌唑及藥學上可容許的載體的用途，其係用以製造持續性身體表現性疼痛障礙治療藥。
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| EP3468540A4 (en) * | 2016-06-13 | 2020-03-18 | Board Of Regents Of the University Of Texas System | PHARMACEUTICAL COMPOSITIONS AND METHOD FOR TREATING PAIN |
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| V. Sushko, "Aripiprazole and addictive properties of opioids painkillers in cancer patients with chronic pain", European Neuropsychopharmacology, 2007, vol. 17, pages S549-S550. * |
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| MY162348A (en) | 2017-06-15 |
| TW201109312A (en) | 2011-03-16 |
| IL218495A0 (en) | 2012-07-31 |
| MX2012002952A (es) | 2012-04-02 |
| JP6025886B2 (ja) | 2016-11-16 |
| RU2012114097A (ru) | 2013-10-20 |
| CO6531434A2 (es) | 2012-09-28 |
| WO2011030575A1 (ja) | 2011-03-17 |
| SG178938A1 (en) | 2012-04-27 |
| BR112012005401A2 (pt) | 2017-02-21 |
| AU2010293647A1 (en) | 2012-03-29 |
| US20120258971A1 (en) | 2012-10-11 |
| UA108862C2 (uk) | 2015-06-25 |
| KR20120065392A (ko) | 2012-06-20 |
| CA2773253A1 (en) | 2011-03-17 |
| KR20160147061A (ko) | 2016-12-21 |
| JP2015129160A (ja) | 2015-07-16 |
| JPWO2011030575A1 (ja) | 2013-02-04 |
| NZ599227A (en) | 2014-02-28 |
| AU2010293647B2 (en) | 2015-06-25 |
| RU2555760C2 (ru) | 2015-07-10 |
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