TW202120116A - 纖維肌痛症之治療藥或預防藥 - Google Patents
纖維肌痛症之治療藥或預防藥 Download PDFInfo
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- TW202120116A TW202120116A TW109125944A TW109125944A TW202120116A TW 202120116 A TW202120116 A TW 202120116A TW 109125944 A TW109125944 A TW 109125944A TW 109125944 A TW109125944 A TW 109125944A TW 202120116 A TW202120116 A TW 202120116A
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- oxytocin
- pregabalin
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Abstract
本發明係以提供一種含有催產素作為有效成分的纖維肌痛症之治療藥或預防藥為目的。本發明係提供一種含有催產素作為有效成分的纖維肌痛症之治療藥或預防藥。藉由投予1~500U/Body的催產素或與普加巴林併用,可獲得纖維肌痛症之治療效果或預防效果。
Description
本發明係有關於一種醫藥,其為纖維肌痛症之治療藥或預防藥,尤其係有關於一種含有催產素或者其酸加成鹽或其衍生物作為有效成分的纖維肌痛症之治療藥或預防藥。
催產素為由9個胺基酸所構成的胜肽激素。其於大腦的下視丘室旁核等合成,由腦垂體後葉分泌至血中,對子宮收縮或乳汁分泌產生作用。催產素亦會由樹狀突起等分泌至大腦內,據稱其有與社會互動相關之作用。
以催產素為有效成分的鼻噴劑(製品名:
Syntocinon)已廣為人知。其已確認有誘發分娩等適應症,但對於泛自閉症障礙等適應症仍在臨床試驗中。
纖維肌痛症係以身體的大範圍部位之肌肉骨骼系統的慢性疼痛與僵硬為主要症狀,除了在解剖學上明確的部位確認有壓痛以外,在客觀跡象以及一般臨床檢查結果上均無異常,會伴隨疲勞感、睡眠障礙或抑鬱情緒等各種身體、精神及神經症狀,好發於中年以上的女性之原因不明的風濕性疾病。纖維肌痛症的疼痛非為傷害性,週知是部位的非特定神經失調性或中樞性疼痛,即所謂構成疼痛之中樞性敏感化的中樞性敏感化症候群之一。
目前的治療法有藥物治療及非藥物治療。就藥物治療,係使用神經失調性疼痛緩和藥之普加巴林或抗憂鬱劑之度洛西汀等。而就非藥物治療,則可舉出有氧運動或認知行為療法等。
然而,藉由此等治療,仍常無法充分緩和疼痛。在藥物治療上,對建議用藥物(普加巴林、度洛西汀等)產生抗性的案例極多,且此等藥劑會高頻率發生眩暈、嗜睡、體重增加或末梢性水腫等副作用,而期望開發出新的治療法。
關於催產素與纖維肌痛症,1998年申請之專利文獻1(日本特表2001-527537號公報)中報導投予催產素鼻噴劑(Syntocinon),對部分患者的疼痛及疲勞感的VAS分數有改善效果;但其中患者數偏少而不易判定其效果。近年來2014年之非專利文獻1中報導,即使對患者投予催產素,在VAS量表評估中仍無法看出改善作用。從而,於現階段催產素與纖維肌痛症的關係尚不明確。
[專利文獻1] 日本特表2001-527537號公報
[非專利文獻1] Mameli S等人, Oxytocin nasal spray in fibromyalgic patients. Rheumatol Int. 2014 Aug;34(8):1047-52.
[發明所欲解決之課題]
本發明目的在於提供一種可充分緩和纖維肌痛症之疼痛的治療藥或預防藥。
[解決課題之手段]
本案發明人等為達成上述課題而致力研究的結果發現,藉由單獨投予催產素或併用投予催產素與普加巴林,而有纖維肌痛症之治療或預防效果,終至完成本發明。
亦即,本發明係以下者:
(1)一種醫藥,其為纖維肌痛症之治療藥或預防藥,其係含有催產素或者其酸加成鹽或其衍生物作為有效成分。
(2)如(1)之醫藥,其中催產素或者其酸加成鹽或其衍生物的投予量為1~500U/Body。
(3)如(1)或(2)之醫藥,其中含有催產素或者其酸加成鹽或其衍生物作為有效成分的醫藥為鼻黏膜投予用醫藥。
(4)如(1)至(3)中任一項之醫藥,其係用於與含有普加巴林、米羅加巴林、加巴噴丁或彼等之酸加成鹽作為有效成分的醫藥併用。
(5)如(4)之醫藥,其中催產素或者其酸加成鹽或其衍生物的投予量為1~400U/Body。
(6)一種醫藥,其係(a)與(b)之組合醫藥,且為纖維肌痛症之治療藥或預防藥;
(a)如(1)~(5)中任一項之含有催產素或者其酸加成鹽或其衍生物作為有效成分的醫藥;
(b)含有普加巴林、米羅加巴林、加巴噴丁或彼等之酸加成鹽作為有效成分的醫藥。
(7)如(6)之醫藥,其為(a)與(b)之摻合劑。
(8)如(6)之醫藥,其為(a)與(b)之套組。
(9)如(4)~(8)中任一項之醫藥,其中普加巴林或其酸加成鹽的1日投予量為25~450mg,米羅加巴林或其酸加成鹽的1日投予量為2.5~30mg,或者加巴噴丁或其酸加成鹽的1日投予量為200~2400mg。
[發明之效果]
藉由投予本發明之藥劑,可獲得纖維肌痛症之治療或預防效果。又,本發明之醫藥係具有作為醫藥品的優良效果。
[實施發明之形態]
1.含催產素醫藥
催產素為由9個胺基酸所構成的胜肽激素。其構成為Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly。
本發明中的催產素可為其酸加成鹽。代表性酸加成鹽可舉出乙酸鹽,但不限定於此。催產素衍生物可舉出去胺縮宮素(demoxytocin)、卡貝縮宮素、那卡縮宮素及彼等之酸加成鹽,以及對彼等加成作為連結子之多醣或聚乙二醇而成的衍生物等,但不限定於此等。於本說明書中記載為「催產素類」時,非僅為催產素,亦以包含催產素或者其酸加成鹽或其衍生物之意義記載。
本發明中催產素類單獨的用量係能有效治療或預防本發明之纖維肌痛症的量,且可依據患者的年齡、體重、治療的頻率、期望之效果的種類或者投予法等來設定,惟較佳為1~500U/Body。
2.纖維肌痛症
纖維肌痛症的定義係如「纖維肌痛症診療指南2017」之「1-2 疾病的解說」之「6.診斷」此項所記載(發行日:2017年10月20日,發行所:日本醫事新報公司)。亦即,作為纖維肌痛症的分類基準,國際上係採用美國風濕病學院(ACR)之基準,由身體的大範圍疼痛(3個月以上),以及解剖學上所定義化之身體部位18處中有11處以上確認壓痛點所構成。由2010年ACR所提出之纖維肌痛症的診斷基準(2010年基準),則對疼痛以外的纖維肌痛症積極地導入特徵性臨床徵狀,以基層醫療醫師為對象而作成,並基於纖維肌痛症的症狀嚴重度(symptom severity: SS),作為可隨時間經過而採用之診斷基準使用。
3.催產素類與普加巴林類的併用
普加巴林係指(S)-3-(aminomethyl)-5-methylhexanoic
acid(IUPAC名稱),係使用於神經失調性疼痛的醫藥品。普加巴林會與神經前突觸中之鈣(Ca2+
)通道的α2
δ次單元結合而使Ca2+
的流入減少,抑制興奮性神經傳導物的釋出而發揮鎮痛效果。結合於α2
δ次單元之配體可舉出米羅加巴林、加巴噴丁及彼等之酸加成鹽等,但不限定於此等。於本說明書中記載為「普加巴林類」時,非僅為普加巴林,亦以包含結合於α2
δ次單元之配體及其酸加成鹽等具有鎮痛作用的藥物之意義記載。
普加巴林類亦既已具有纖維肌痛症的適應效果。從而,即使單獨投予普加巴林類時,亦可獲得纖維肌痛症之改善效果,惟已知若併用催產素類而投予,則可進一步提升改善效果。此外,就併用時之催產素類的投予量,若單獨採催產素類時,縱為纖維肌痛症之改善效果較低或無改善效果之程度的低用量,出乎預料的是,透過與普加巴林類併用,可獲得纖維肌痛症之改善效果較普加巴林類單獨時更強的效果。
期望獲得與單獨採普加巴林類時同等程度的纖維肌痛症之改善效果時,透過與本發明之催產素類併用,可減少普加巴林類的投予量。尤其是對於因服用普加巴林類而顯現高副作用,或即使投予高用量亦不易看出效果之對普加巴林類具有抗性的患者,便有可減少普加巴林類投予所產生之副作用的優異效果。再者,對於普加巴林類的用量有其上限的患者,藉由進一步投予催產素類,可望獲得症狀的進一步改善效果。由於催產素類為體內既已具備的胜肽,因此毒性低,容易安全地使用。
與普加巴林類併用時之催產素類的投予量,只要是與單獨投予催產素類時同樣能有效治療或預防本發明之纖維肌痛症的量則不予限定,較佳為1~400U/Body。尤其是與普加巴林類併用時之催產素類可為單獨採催產素類時纖維肌痛症之改善效果較低或無改善效果之程度的用量。
與催產素類併用時之普加巴林類的投予量係能有效治療或預防本發明之纖維肌痛症的量,且可依據患者的年齡、體重、併用療法的種類、治療的頻率、期望之效果的種類或者投予法等來設定。採普加巴林或其酸加成鹽單劑之伴隨纖維肌痛症之疼痛的用法、用量,作為初始用量係將1日150mg分作1日2次進行口服投予,其後過1週以上將1日用量漸增至300mg後,維持於300~450mg。透過與催產素類併用,普加巴林或其酸加成鹽的投予量有可能減少至低於採此等單劑之用法、用量。或者,對於有普加巴林或其酸加成鹽之上限的患者,藉由進一步與催產素類併用,可望獲得進一步改善效果。與催產素類併用時之普加巴林或其酸加成鹽的用量較佳為25mg以上至450mg以下,可視症狀而定。又,併用時的上限值亦可與普加巴林或其酸加成鹽之最大用量的變化一併變更。
與催產素類併用時之普加巴林以外的普加巴林類的投予量能以同樣方式來探討。據此,米羅加巴林或其酸加成鹽的1日投予量較佳為2.5~30mg,或者加巴噴丁或其酸加成鹽的1日投予量較佳為200~2400mg。
所稱併用本發明之催產素類與普加巴林類,係指將催產素類及普加巴林類之任一者對同一患者投予,兩種有效成分可混合同時投予,但亦可舉出將含有各有效成分的醫藥物體個別且於時間上同時或逐次地投予,或者隔開時間個別投予。當投予時非為同時之時,例如可彼此交互投予兩種有效成分,亦可持續投予其中一有效成分後,再投予另一有效成分。
4.製劑
本發明中的藥劑(製劑),作為醫藥組成物之投予路徑不特別限定,可為口服或非口服式投予。劑形亦不特別限定,作為口服投予製劑,可舉出例如錠劑、膠囊劑、顆粒劑、散劑、細粒劑、糖漿、乳化劑、懸浮劑等;作為非口服投予製劑,可舉出例如注射劑、外用劑(滴鼻劑、經皮劑、軟膏等)、塞劑。此等可藉由製劑化步驟中通常一般所採用的方法來製造。
本發明中含有催產素類的製劑不特別限定,較佳為滴鼻劑,亦即鼻黏膜投予用製劑。
併用本發明之催產素類與普加巴林類的治療藥或預防藥可為含有兩種有效成分的摻合劑之構成,亦可為各自獨立的單劑之構成。於此,本發明中的摻合劑係指在一製劑中摻合催產素類與普加巴林類之有效成分;而本發明中的單劑係指在一製劑中含有催產素類或普加巴林類之任一種有效成分者。
當本發明中的兩種有效成分為單劑時,可組合利用可各自單一利用的單劑。從而,含有兩種有效成分的藥劑可為彼此不同的劑型。例如,各劑之形態可互為固體或液體,亦可為固體與液體,不特別限定。又,各者的投予路徑可相同或相異。由於普加巴林類既已以口服錠劑上市,而能以錠劑使用。另外,催產素類則較佳為滴鼻劑。從而,較佳之一樣態係普加巴林類採口服錠劑、催產素類採滴鼻劑而併用投予。當兩種有效成分為單劑時,可採用套組之形態,即備有兩劑一式之狀態。
摻合劑可舉出例如含有兩種有效成分之有效量的錠劑、顆粒劑、散劑、膠囊劑、液劑、鼻噴劑、注射劑等劑形。
本發明中的組合醫藥,為了併用本發明之催產素類與普加巴林類,係具有兩醫藥組合而成之樣態的醫藥。可舉出例如摻合劑或套組之樣態,但不限定於此等。
含有本發明之有效成分的製劑係使用一般製劑化所使用的添加劑來調製。作為該等添加劑,若為固態製劑時,可舉出乳糖、白糖、葡萄糖、玉米澱粉、馬鈴薯澱粉、結晶纖維素、輕質矽酸酐、合成矽酸鋁、鎂鋁矽酸鹽及磷酸氫鈣等賦形劑;結晶纖維素、羧甲基纖維素、羥丙基纖維素、羧甲基纖維素鈉及聚乙烯吡咯啶酮等黏合劑;澱粉、羧甲基纖維素鈉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉及羧甲基澱粉鈉等崩解劑;滑石及硬脂酸類等潤滑劑;羥甲基丙基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯及乙基纖維素等塗覆劑;著色劑;若為半固形製劑時,可舉出白凡士林等基劑;若為液態製劑時,則可舉出乙醇等溶劑、乙醇等增溶劑、對羥基苯甲酸酯類等保存劑、葡萄糖等的等滲壓劑、檸檬酸類等緩衝劑、L-抗壞血酸等抗氧化劑、EDTA等螯合劑及聚山梨醇酯80等懸浮化劑/乳化劑等。
5.投予次數
本發明之醫藥不特別限定,可連日投予或間歇性或者頓服投予;每日的投予次數可為1次或分作2~3次來進行。
併用催產素類與普加巴林類時,兩種有效成分分別為單劑時的投予次數可為相同次數,亦可採不同次數。又,當兩劑為單劑時,亦可組合各自通常投予的次數。
[實施例]
以下根據實施例說明本發明,惟本發明不受此等實施例所限定。
茲利用纖維肌痛症模型之重複寒冷壓力負荷大鼠(系統:Crl:CD(SD),公,購入時5週大,日本Charles River股份有限公司),來探討催產素的疼痛抑制作用。
於施載寒冷壓力的期間,係在飼養籠中鋪設金屬網製底網,將動物以各群6隻、1籠3隻(各群2籠)的方式收容於籠中而飼養。在將溫暖期間溫度設定為23℃、寒冷期間溫度設定為-3℃的附程式恆溫箱(CDB-41A,大和冷機工業股份有限公司)中收容動物120小時(5日),對其施予寒冷壓力之負荷。未施予負荷的Sham動物則是在鋪設有金屬網製底網的飼養籠中收容3隻而進行一般的飼養。寒冷壓力的設定係重複溫暖期間(23℃:2小時)與寒冷期間(-3℃:2小時)1日各5次(合計20小時),其餘的4小時則維持於-3℃。
疼痛的評估係以後肢的疼痛程度為指標,基於使用馮弗雷細絲(von Frey filament)之機械刺激所產生的疼痛反應,利用Dixon之Up-Down法算出50%疼痛閾值,評分與評估項目則採用投予被測物質1及3小時後之左右後肢的疼痛閾值的合計。發病會導致疼痛閾值降低,而就正常值,對於左右後肢的疼痛閾值均定義為6.0g以上。
催產素製劑(TEIJIN PHARMA股份有限公司製)係以微量吸量管量取投予液,以0.0125、0.125及1.25 U/Body(投予容量:25μL/Body)的用量投予至右側鼻腔內。普加巴林(Haoyuan ChemExpress Co., Ltd.製)則使用可撓性口服餵食管,以10mg/kg的用量對胃內強制投予。催產素與普加巴林的併用,係催產素採0.125U/Body及普加巴林採10mg/kg,各用法係依循單獨投予者。
將其結果示於圖1。圖1之記號「*」及「**」係指相對於施予寒冷壓力之負荷的Control群之顯著差異分別為P<0.05、P<0.01(Dunnett檢定或Steel檢定)。記號「++」係指相對於Control群之顯著差異為P<0.01(司徒頓t檢定或Welch-Aspin t檢定)。記號「##」則指相對於普加巴林投予群之顯著差異為P<0.01(司徒頓t檢定)。曲線圖係以平均值+標準誤差(1群6隻)表示。
自投予催產素1.25U/Body投予群過1及3小時後的50%疼痛閾值與Control群相比顯著上升,可看出催產素之疼痛減輕作用。
自投予普加巴林10mg/kg投予群過1及3小時後的50%疼痛閾值與Control群相比顯著上升。透過併用催產素0.125U/Body及普加巴林10mg/kg,與單獨投予普加巴林相比,自投予起過3小時後的50%疼痛閾值顯著上升,確認併用所產生的疼痛減輕相乘效果。投予催產素0.125 U/Body時,與Control群相比雖未看出顯著差異,但與普加巴林併用則出現效果,且其顯著程度出乎預料之外。
[產業上可利用性]
本發明之治療藥或預防藥可作為纖維肌痛症之治療藥或預防藥,或者作為纖維肌痛症之治療方法或預防方法使用。
[圖1]為表示重複寒冷壓力負荷大鼠之催產素、普加巴林、併用催產素與普加巴林之各種投予時的疼痛抑制作用的曲線圖。
Claims (9)
- 一種醫藥,其為纖維肌痛症之治療藥或預防藥,其係含有催產素或者其酸加成鹽或其衍生物作為有效成分。
- 如請求項1之醫藥,其中催產素或者其酸加成鹽或其衍生物的投予量為1~500U/Body。
- 如請求項1或2之醫藥,其中含有催產素或者其酸加成鹽或其衍生物作為有效成分的醫藥為鼻黏膜投予用醫藥。
- 如請求項1至3中任一項之醫藥,其係用於與含有普加巴林、米羅加巴林(Mirogabalin)、加巴噴丁或彼等之酸加成鹽作為有效成分的醫藥併用。
- 如請求項4之醫藥,其中催產素或者其酸加成鹽或其衍生物的投予量為1~400U/Body。
- 一種醫藥,其係(a)與(b)之組合醫藥,且為纖維肌痛症之治療藥或預防藥; (a)如請求項1~5中任一項之含有催產素或者其酸加成鹽或其衍生物作為有效成分的醫藥; (b)含有普加巴林、米羅加巴林、加巴噴丁或彼等之酸加成鹽作為有效成分的醫藥。
- 如請求項6之醫藥,其為(a)與(b)之摻合劑。
- 如請求項6之醫藥,其為(a)與(b)之套組。
- 如請求項4~8中任一項之醫藥,其中普加巴林或其酸加成鹽的1日投予量為25~450mg,米羅加巴林或其酸加成鹽的1日投予量為2.5~30mg,或者加巴噴丁或其酸加成鹽的1日投予量為200~2400mg。
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