TWI405576B - 疼痛疾病治療劑 - Google Patents
疼痛疾病治療劑 Download PDFInfo
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- TWI405576B TWI405576B TW097104808A TW97104808A TWI405576B TW I405576 B TWI405576 B TW I405576B TW 097104808 A TW097104808 A TW 097104808A TW 97104808 A TW97104808 A TW 97104808A TW I405576 B TWI405576 B TW I405576B
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- pain
- analgesic
- sialic acid
- disease
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Classifications
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
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Description
本發明係關於針對非炎症性疼痛疾病之鎮痛劑，係含唾液酸或其藥學上可容許之鹽作為有效成份。
唾液酸(sialic acid)是神經胺酸之醯基衍生物的總稱，天然界裏有多種類的唾液酸存在，其中尤以N-乙醯基神經胺酸(N-acetylneuraminic acid)為最多，其次以N-羥乙醯基神經胺酸(N-glycolylneuramic acid)的比例為多。唾液酸是作為糖蛋白、糖脂質、醣胜肽等的構成成份而廣汎分佈於生物體內，尤其是存在於動物或細菌之細胞膜表面，關連於細胞的特異性辨認機制等，擔任重要的生物學機能。唾液酸類為與癌、炎症、免疫、病毒感染、細胞分化、激素受體等有關的物質而在醫學上及藥學上受重視，對於唾液酸(sialic acid)及其衍生物正進行種種研究。
本發明者等累積唾液酸的藥理作用之研究中，發現唾液酸具有特殊的鎮痛作用。「痛」大略可分為由於組織之損傷等之發炎，釋放發痛物質而產生的炎症性疼痛，與未伴隨該方式之炎症的生理性痛(侵害性疼痛)以及神經性疼痛。神經性疼痛是起因於中樞神經或末梢神經之損傷或機能異常的疼痛，及藥物治療或放射線治療法引起的神經病變等非炎症性疼痛之總稱而言。神經性疼痛除了自發性之痛外，係產生對於侵害性刺激之疼痛閾值降低的痛覺過敏反應，或通常不會引起痛覺的觸覺刺激所引起的激痛
(allodinia)等的症狀，歷經一次病理完成而變成慢性，與炎症性疼痛不同，是非常難治性的。例如，可列舉三叉神經痛、帶狀疱疹後神經痛、包埋性神經病變(胸廓出口症候群、腕隧道症候群、脊柱管狹窄症等)、複合性局部痛症候群(CRPS)、糖尿病性神經病變，外傷引起的神經障礙、幻肢痛、脊椎損傷後或腦中風後之中樞疼痛等神經性疾病。
現在，針對炎症性疼痛係使用非類固醇性鎮痛藥、非麻藥性鎮痛藥、麻藥性鎮痛藥等，其治療法可說是差不多確立了。但是，對於神經性疼痛等非炎症性疼痛，則雖正進行病理發症機制之解明，但有效的治療藥少，有需要其病態解明及治療法的確立。本發明者等發現，唾液酸對於非炎症性疼痛的病理模型動物有鎮痛作用，而完成本發明。關於唾液酸已有抗炎症作用之報告(專利文獻1及2)，關於其對非炎症性鎮痛作用則無任何揭示，也沒有提示。
[專利文獻1]日本特開昭62-145015號公報
[專利文獻2]日本特開平1-163125號公報
本發明之目的在於提供針對非炎症性疼痛疾病之鎮痛劑，係含唾液酸或其藥學上可容許的鹽作為有效成份。
本發明者由唾液酸對於非炎症性疼痛之病理模型動物表現有鎮痛作用的事實，而發現可做為對於神經性疼痛
等非炎症性疼痛疾病之鎮痛劑，而完成本發明。
本發明藥劑之有效成份之唾液酸，對非炎症性疼痛之病理模型動物表現鎮痛作用。因此本發明鎮痛劑是做為治療神經性疼痛之非炎症性疼痛疾病有用的藥劑。
本發明是有關針對非炎症性疼痛疾病之鎮痛劑，係含有唾液酸或其藥學上可容許之鹽作為有效成分。
本發明鎮痛劑之有效成份之唾液酸，包含其藥學上可容許之鹽，例如與鈉、鉀等鹼金屬，鈣、鎂、鋇等鹼土類金屬或鋁、鋅等金屬、有機胺及銨等之鹽。這些鹽可用公知之方法從游離的唾液酸製造，或可以互相變換。已知有15種以上之唾液酸存在，多數為具有N-乙醯基體或N-羥乙醯基體，以及N-醯基或O-醯基者，在本發明中任一者都可以利用。較佳的是天然界存在最多的，可列舉代表性唾液酸之N-乙醯基神經胺酸及其藥學上可容許之鹽。關於N-乙醯基神經胺酸之急性毒性，揭示於上述專利文獻1，顯示其毒性極低而安全。又，關於N-乙醯基神經胺酸鈉鹽，也由急性毒性試驗之結果顯示毒性極低。(參照日本專利特公昭63-28411號公報實施例8)。
在本發明中，唾液酸之順式-反式體、光學異構物、構型異構物等立體異構物存在的時候，或水合物或配位化合物的狀態存在時，本發明也包含其所有的立體異構物、水合物、配位化合物。
在本發明中之唾液酸可與適當的醫藥用載體或稀釋劑組合成醫藥，以通常的任何方法都可以製劑化，可製劑化為錠劑、膠囊劑、粉末劑、液劑等經口劑，或皮下、靜脈內、肌肉內、直腸內、鼻腔內給藥用的非經口劑。在處方時，可將本發明之唾液酸以其藥學上可容許之鹽的形態使用，也可將本發明之唾液酸單獨或適宜組合使用，又，也可與其他醫藥活性成份做為配合劑。
經口給藥製劑中，可以單獨或加適當的添加劑，例如賦形劑、黏合劑、崩散劑、潤滑劑、增量劑、濕潤化劑、緩衝劑、保存劑、香料等適宜組合成錠劑、散劑、顆粒劑或膠囊劑。又視疾病種類或患者，可製劑化為最適合其治療的上述以外的劑型，例如注射劑、栓劑、吸入劑、氣霧劑、漿劑、點眼劑、軟膏等外用劑等。
本發明之理想的給藥量，可因給藥對象、劑形、給藥方法、給藥期間等而有不同，但為了要得到所期望之效果，一般對成人之有效成份量於一日可經口給藥10至5000mg，理想是50至3000mg。非經口給藥(例如注射劑)時，一般比經口給藥更少量而可期待有效果。
鎮痛效力試驗
使用神經性疼痛模型之Chung模型大鼠，實施鎮痛效力試驗。使用9週齡的Wistar系雄性大鼠作為實驗動物，根據Kim及Chung的方法(Pain，50卷355-363頁，1992年)作成模型大鼠。即，在10週齡大時，以戊巴比妥(40
mg/kg，腹腔給藥)麻醉，露出大鼠L5脊髓神經，將L5後根神經節末梢側以5-0絲紗強力紮緊進行神經損傷。將動物放在以金屬網做底的透明壓克力飼養箱中，使用von Frey纖維(filament)(North Coast Medical Inc.製)，根據Chaplan等之方法(J. Neurosci. Method，53卷，55-63頁，1994年)的方法，以升降法(up-down method)算出50%反應閾值，測定對被驗物質的激痛的效果。測定脊髓神經損傷後之50%反應閾值，而以顯示1g以上且未達4g的安定的閾值降低者用於試驗。這些實驗動物在神經損傷後之50%反應閾做為指標，7隻做為1群，使神經損傷對照群與被驗物質給藥群的平均值幾乎成相等之方式構成群。
以N-乙醯基神經胺酸作為被驗物質而單次在腹腔內給藥(120mg/kg)。
又對神經損傷對照群(控制群)同樣給藥0.5% CMC-Na (w/v)/生理食鹽液，在被驗物質給藥30分鐘後進行痛覺測驗，算出50%反應閾，各群以平均值±標準偏差表示。上述試驗結果之一例示於表1。再者，差異顯著性的檢定，mm使用Dunnett之多重檢定比較法進行神經損傷對照群與被驗物質給藥群之多群間比較，而以P<0.05為有顯著差異。
又，跟上述試驗同樣，將N-乙醯基神經胺酸做為被驗物質，單次經口(300 mg/kg)給藥。神經損傷對照群(控制群)則以注射用水同樣給藥，被驗物質給藥60分鐘後進行痛覺測驗，算出50%反應閾值。但，神經損害對照群與被驗物質給藥群各群的隻數以8隻構成群。試驗結果之一例示於表2。
實施上述鎮痛效力試驗之結果，單次腹腔內給藥及單次經口給藥兩方面而言，關於神經損傷對照群(控制群)，50%反應閾值在CMC-Na/生理食鹽水液或注射用水給藥前後都沒有很大的變化。相對於此，被驗物質(N-乙醯基神經胺酸)給藥群之50%反應閾值，比神經損傷對照群有顯著的反應閾值之上升，可確認本發明化合物之抗激痛作用，即，對神經性疼痛有顯著的鎮痛作用。
如上述鎮痛效力試驗所示，唾液酸於神經性疼痛之病理模型動物具有顯著的鎮痛作用。該神經性疼痛，與因炎症而產生的炎症性疼痛不同，為末梢神經或中樞神經本身之機能異常所引起而不伴隨有炎症疾病的痛。因此，本發
明之鎮痛劑有用於作為用以治療，例如，三叉神經痛、帶狀疱疹後神經痛、包埋性神經病變(胸廓出口症候群、腕隧道症候群、脊柱管狹窄症等)、複合性局部痛症候群(CRPS)，糖尿病性神經病變、外傷引起的神經障礙、幻肢痛、脊椎損傷後或腦中風後之中樞疼痛，以及藥物療法或放射線治療法引起的神經病變性痛等的神經性疼痛等非炎症性疼痛疾病之藥劑。
Claims (5)
- 一種針對神經性疼痛之鎮痛劑，係含有N-乙醯基神經胺酸(N-Acetylneuraminic acid)或其藥學上可容許之鹽作為有效成份。
- 一種針對神經性疼痛之鎮痛劑，係只含有N-乙醯基神經胺酸或其藥學上可容許之鹽作為有效成份。
- 如申請專利範圍第1或2項之鎮痛劑，其中該神經性疼痛係三叉神經痛、帶狀疱疹後神經痛、包埋性神經病變(entrapment neuropathy)、複合性局部痛症候群(CRPS)，糖尿病性神經病變(diabetic neuropathy)、外傷引起的神經障礙、幻肢痛、中樞疼痛、或藥物療法或放射線治療法引起的神經性疼痛。
- 如申請專利範圍第1或2項之鎮痛劑，其係經口劑。
- 如申請專利範圍第3項之鎮痛劑，其係經口劑。
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| CA2677026C (en) | 2014-11-18 |
| CA2677026A1 (en) | 2008-08-14 |
| CN101600438A (zh) | 2009-12-09 |
| KR20090107500A (ko) | 2009-10-13 |
| EP2119444A1 (en) | 2009-11-18 |
| US8492350B2 (en) | 2013-07-23 |
| EP2119444A4 (en) | 2010-06-09 |
| TW200838545A (en) | 2008-10-01 |
| WO2008096775A1 (ja) | 2008-08-14 |
| JP2008189635A (ja) | 2008-08-21 |
| JP4005115B1 (ja) | 2007-11-07 |
| CN101600438B (zh) | 2012-06-27 |
| KR101472431B1 (ko) | 2014-12-12 |
| EP2119444B1 (en) | 2015-07-08 |
| US20100121040A1 (en) | 2010-05-13 |
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| AU2008212250B2 (en) | 2013-07-04 |
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