TWI462696B - 殺外寄生蟲之方法及調配物 - Google Patents
殺外寄生蟲之方法及調配物 Download PDFInfo
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- TWI462696B TWI462696B TW099113998A TW99113998A TWI462696B TW I462696 B TWI462696 B TW I462696B TW 099113998 A TW099113998 A TW 099113998A TW 99113998 A TW99113998 A TW 99113998A TW I462696 B TWI462696 B TW I462696B
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- pharmaceutically acceptable
- dose
- spinetoram
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- administered
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/22—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom rings with more than six members
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Description
體外寄生蟲(諸如跳蚤、蝨子、蒼蠅、蜱及蟎蟲)對人類及動物會造成困擾問題。此等害蟲因會減少體重增加，造成品質不良的皮、毛及肉，且在某些情況下導致死亡，從而嚴重影響家畜之生產率。體外寄生蟲亦在寵物動物中引起疾病及不適。已知體外寄生蟲帶有對人類致病之細菌及病毒。體外寄生蟲會引起的疾病包括(例如)瘧疾、淋巴絲蟲病、沙眼、錐蟲病及盤尾絲蟲病(河盲症)。
控制體外寄生蟲之努力包括使用殺昆蟲劑及農藥。例如，自然產生的發酵產物-多殺菌素(spinosyns)已用作寵物動物之殺體外寄生蟲藥。(Snyder,US 6,664,237)。
多殺菌素之衍生物已用於農業應用中。(DeAmicis等人，US 6,001,981)。乙基多殺菌素(spinetoram)係25至90%(較佳50至90%)之(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-2-(6-脫氧-3-O-乙基-2,4-二-O-甲基-1-α-L-哌喃甘露糖基氧基)-13-[(2R,5S,6R)-5-(二甲胺基)四氫-6-甲基哌喃-2-基氧基]-9-乙基-2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b--十六氫-14-甲基-1H-as-二環戊二烯聯苯并[3,2-d]氧雜環十二烷-7,15-二酮(稱為「二氫-Et-J」，以下式I)、及10至75%(較佳10至50%)之(2R,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-2-(6-脫氧-3-O-乙基-2,4-二-O-甲基-1-α-L-哌喃甘露糖基氧基)-13-[(2R,5S,6R)-5-(二甲胺基)四氫--6-甲基哌喃-2-基氧基]-9-乙基-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-十四氫-4,14-二甲基-1H-as-二環戊二烯聯苯并[3,2-o]氧雜環十二烷-7,15-二酮(稱為「Et-J」，以下式II)之混合物的通用名。
(Podhorez等人，US 2008/0108800A1)。乙基多殺菌素被述為在多種作物中提供廣譜害蟲之長效性控制(Dow AgroSciences Spinetoram Technical Bulletin,2006年11月)。據報導，紐西蘭已將乙基多殺菌素登記作為梨果市場中之殺昆蟲劑(「Dow AgroSciences Receives First Global Registration for Spinetoram Insecticide,」Dow AgroSciences編輯部，公司新聞，2007年8月10日)。
雖然使用多殺菌素及其他殺昆蟲劑及農藥已有效，但是需要另外或改進的調配物及方法。需要之調配物及方法不僅提供另類療法，而且亦克服至少若干個目前療法之限制。此等限制包括毒性及安全性、有效性(效力及持續時間)、及抗性問題。亦影響殺昆蟲劑及農藥之使用效力的係投藥障礙，其包括投與模式及再現性。例如，需要降低投與頻率而同時保持有效性，因為對動物定量給藥經常不便及/或困難。本發明包括用於動物之殺體外寄生蟲之方法及調配物，其提供對抗體外寄生蟲侵擾之另類選擇。此外，其克服目前使用殺昆蟲劑及農藥之至少若干限制，尤其係提供長期有效、安全、全身控制體外寄生蟲。
本發明提供一種控制體外寄生蟲侵擾動物之方法，其係藉由全身性投與動物有效量之乙基多殺菌素(spinetoram)或其醫藥上可接受的鹽，並提供一種醫藥調配物，其係使用乙基多殺菌素或其醫藥上可接受的鹽、及醫藥上可接受的載體全身性控制體外寄生蟲侵擾。本發明亦提供一種控制跳蚤侵擾狗或貓之方法，其藉由給該狗或貓經口或非經腸全身投與有效量之乙基多殺菌素或其醫藥上可接受的鹽，及提供一種單次或脈衝劑量調配物，其係使用乙基多殺菌素或其醫藥上可接受的鹽、及醫藥上可接受的載體形成選自錠片、膠囊、或液體之劑型，依每kg該狗或貓體重使用10至60 mg乙基多殺菌素或其醫藥上可接受的鹽的劑量，供全身性控制狗或貓之體外寄生蟲侵擾。使用乙基多殺菌素之方法及調配物之另一態樣係有能力提供長期全身控制體外寄生蟲侵擾，從而減少重覆對動物投藥，如：不超過每一或兩周，或每月或更久投藥一次。
該寄主動物可為哺乳動物或非哺乳動物，如鳥(火雞、雞)或魚。當該寄主動物為哺乳動物時，其可為人類或非人類哺乳動物。非人類哺乳動物包括畜養動物，如：家畜動物及寵物動物。家畜動物包括牛、駱駝、豬、綿羊、山羊及馬。寵物動物包括與人類所擁有且畜養之關係密切(作為人類-動物關係之一部分)的狗、兔、貓及其他寵物。
體外寄生蟲包括通常侵擾或感染動物之昆蟲及蜱蟎害蟲，且包括其卵、幼蟲、蛹、若蟲及成蟲態。此等害蟲包括跳蚤、蝨子、蚊子、蟎蟲、蜱、及吸血性、咬或滋擾性蠅類。特別目標為跳蚤，且更特別為貓蚤(Ctenocephalides felis
)。
「控制」係指在動物寄主中改善或消除目前之侵擾，或避免侵擾。
「有效量」係指足以控制體外寄生蟲(且包括顯著減少體外寄生蟲侵擾族群數量)之乙基多殺菌素、或其鹽之用量。當害蟲取食或透過驅除或由於乙基多殺菌素或其共軛物或其鹽之全身存在的活體內作用時，此控制可為乙基多殺菌素或其共軛物或鹽進入該害蟲全身之結果。在該等方法及調配物中之乙基多殺菌素或其鹽之範圍為0.01至1000 mg/kg，更佳為0.1至100 mg/kg，且特佳為10至60 mg/kg該動物體重。
在此申請案中使用之「醫藥上可接受的」(例如，當提及鹽及調配物組分(如載體)時)包括「獸醫上可接受的」，且因此獨立地包括人類及動物應用。
醫藥上可接受的鹽及製備其之常用方法係相關技藝已知，參見(例如)P. Stahl等人，Handbook of Pharmaceutical Salts: Properties,Selection and Use,(VCHA/Wiley-VCH,2002)；S.M. Berge等人，「Pharmaceutical Salts,」Journal of Pharmaceutical Sciences,第66卷，第1期，1977年1月。鹽之實例包括(但不限於)由與有機及無機酸之標準反應所形成之鹽，如硫酸、鹽酸、磷酸、醋酸、琥珀酸、檸檬酸、乳酸、馬來酸、富馬酸、膽酸、雙羥萘酸、黏酸、穀胺酸、樟腦酸、戊二酸、乙二醇酸、鄰苯二甲酸、酒石酸、甲酸、月桂酸、硬脂酸、水楊酸、甲磺酸、苯磺酸、山梨醇酸、苦味酸、苯甲酸、肉桂酸及類似酸。
本文使用之術語「載體」係描述調配物中除了活性成分以外之任何成分。載體之選擇很大程度上取決於諸如特定投藥模式、載體對溶解度及安定性之影響、及劑型性質之因素。
可藉由任何適宜途徑全身性投與乙基多殺菌素或其鹽。適宜途徑之實例包括經口、外部(穿皮)、及非經腸投與。該路徑之選擇將取決於該寄主動物之種類及該體外寄生蟲侵擾之性質。該投藥將造成全身分佈在寄主動物體內。全身有效性(藉由寄生蟲吸血，或透過過全身驅蟲或活體內作用)提供不同於非全身性施用殺體外寄生蟲劑(其中該暴露模式係在皮膚表面與該寄生蟲接觸)之暴露模式。相較於非全身性治療(如非穿皮式局部治療)，全身性治療及殺寄生蟲之優點包括：a)減少動物環境(例如，地板、地毯、傢具)中人類施藥者及兒童及物品之暴露；b)無需擔心該動物因暴露在水(例如，湖泊、溪流、沐浴等)中或因摩擦造成之損失；c)無需擔心UV照射及降解；d)不會受到皮膚，等等上油脂氧化之問題；及e)保證投與全部劑量(相較於外部非穿皮式施用法，其中在治療後，立即有一些劑量滴落、擦掉及/或留在配藥管中)。
可將乙基多殺菌素及其鹽調配成用於全身投與之醫藥組合物。此等醫藥組合物及其製備方法係相關技藝已知。參見，例如，Remington：The Science and practice of pharmacy,(A. Gennaro等人合編，第19版,Mack Publishing Co.,1995)。乙基多殺菌素或其鹽在該等調配物中之含量為該調配物的1重量%至90重量%，且更特別為5重量%至60重量%。
術語「單次劑量醫藥調配物」意指該調配物之一次劑量長時間有效控制體外寄生蟲侵擾。術語「長時間」包括至少7天之時期，較佳至少兩周之時期且更佳至少30天。術語「脈衝劑量調配物」意指適於以分次、個別劑量投與目標總量的乙基多殺菌素或其醫藥上可接受的鹽，通常在短期內投與，如一天或兩天。脈衝劑量與單次劑量相反，其中雖然治療效益相同或實質上相當，但是短期內進行之總劑量多於一次劑量。例如，總目標劑量可藉在一或兩天內投與兩次、三次、或四次或更多次個別劑量(通常總和等於目標劑量)脈衝給藥。或者，可藉由總目標劑量的單次投與，然後隨時間釋放完成脈衝給藥。此脈衝給藥方法可藉由使某比例的總劑量隨時間基於動力學(例如，每2、3、4或更多小時)或基於在胃腸道中之位置(例如，50%在胃中，則50%在小腸中)內部釋放而發生。
可藉由膠囊、團劑、錠片、粉劑、錠劑、口嚼片、多微粒及奈米微粒、凝膠、固體溶液、薄膜、噴霧、或液體調配物經口投與。液態型包括懸浮液、溶液、漿液、浸液及酏劑。此等調配物可用作軟或硬膠囊中之填料且通常包括載體(例如，水、乙醇、聚乙二醇、丙二醇、甲基纖維素)、或適宜的油、及一或多種乳化劑及/或懸浮劑。亦可藉由固體(例如，來自藥囊)復水製成液體調配物。通常藉由將活性成分溶於或懸浮於適宜介質中，製備口服浸液。可藉由與動物食物混合、或置於其上完成口服。
可將乙基多殺菌素或其醫藥上可接受的鹽投與至皮膚、黏膜或黏性膜以造成全身性投藥。一種此投藥模式係穿皮式投與。典型載體包括醇、水、礦物油、液體石蠟、白礦脂、甘油、聚乙二醇及丙二醇。可併入滲透促進劑-參見(例如)Finnin及Morgan之J. Pharm Sci,88(10),955-958(1999年10月)。
此外，可非經腸或藉由直接注入血液、肌肉或內臟中投與乙基多殺菌素或其醫藥上可接受的鹽。適宜的非經腸投與途徑包括經靜脈內、動脈內、腹膜內、鞘內、腦室內、尿道內、胸骨內、顱內、肌肉內及皮下。適宜的非經腸投與裝置包括針(包括徵針)注射器、無針注射器、及輸注技術。可採用無菌溶液(其可含有其他物質，例如，可以製成與血液等滲之溶液之足量鹽或葡萄糖)形式製備可注射調配物。可接受的液態載體包括植物油(如，芝麻油)、甘油酯(如，三乙酸甘油酯)、酯類(如，苯甲酸苄酯、豆蔻酸異丙酯)及丙二醇之脂肪酸衍生物、及有機溶劑(如吡咯啶-2-酮及甘油縮甲醛)。藉由將乙基多殺菌素或其醫藥上可接受的鹽溶於或懸浮於該液體中製備該等調配物。此等調配物可係自行防腐或自行殺菌，或可係非無菌(可視情況添加防腐劑)。非經腸調配物通常係可含有賦形劑(如鹽、碳水化合物及緩衝劑(pH值較佳為3至9))之水溶液，但是對若干應用法而言，更適宜將其調配成無菌非水溶液或粉狀或乾燥型，供與適宜介質(如，無菌無熱原水)結合使用。例如，使用熟習此項技術者已熟知之標準醫藥技術可容易在無菌條件下製備非經腸調配物。製備注射溶液時所用之乙基多殺菌素或其醫藥上可接受的鹽之溶解度可藉由使用適當的調配技術(如，併入溶解度增強劑)而增加。
利用活體外及活體內生物分析評估乙基多殺菌素，以測定全身活性。在諸多分析中，多殺菌素(spinsad)用作比較物或歷史陽性對照，同時使用其他標準物(氟蟲腈(fipronil)、苄氯菊酯(permethrin)、吡蟲啉(imidacloprid))。乙基多殺菌素用作技術活性物及用於調配物中。
成年刺蠅或家蠅分析(ASF、AhsF)
。基本上如White,W.H.,S.M. Bauer,X. Zhao等人，Comparison of in vitro and in vivo ectoparasiticide activity of an experimental benzimidazole-carbamate with permethrin及amitraz,J. Med. Entomol. 42,207-211(2005)；及White,W.H.,C.M. McCoy,J.A. Meyer等人，Knockdown and mortality comparisons among spinosad-,imidacloprid-,and methomyl-containing baits against susceptible Musca domestica(Diptera: Muscidae) under laboratory conditions,J. Econ. Entomol. 100,155-163(2007)中所述進行此分析。
在DMSO中調配分析材料成10 mM。在相同溶劑中加倍稀釋，產生10個測試濃度。以牛血清(刺蠅)或5%葡萄糖溶液(家蠅)稀釋材料，獲得200至0.39 μM之所需暴露濃度。將約3 ml之稀釋分析材料放入試管中(每個測試濃度n=3)並用牙線(dental wick)吸收流體。將一條牙線放入100 mm皮氏培養皿內之輕量舟皿中。使用二氧化碳麻醉約10隻性別混合的成蠅並置入皿中。在27℃及50至70%相對濕度下培養此等培養皿。蠅類自麻醉中恢復並吸食已吸收化合物的牙線。24小時後，計數活蠅/死蠅。使用非線性回歸做成劑量-致死率關係模型，並相較於同時期對照組(僅溶劑或苄氯菊酯)，獲得相對效力(LD50
)數據。
以下表1總結乙基多殺菌素(技術活性物)相對於標準物對抗蠅類之活體外特徵。
與多殺菌素相比，乙基多殺菌素顯示明顯更強的活體外對抗成年家蠅之殺蟲活性(效力高出5.5倍)。
給狗經口投與
。考慮以上數據，開始研究狗的口服功效。進行該研究以評估1)在30 mg/kg劑量點，對抗被成年貓蚤，貓櫛頭蚤(Ctenocephalides felis
)；成年階段的美國狗蜱，狗矩頭壁蝨(Dermacentor variabilis
)；及成年階段的狗舍蜱，血色扇頭壁蝨(Rhipicephalus sanguineus
)之實驗性同時侵擾之功效；2)經30 mg/kg處理的狗的血漿濃度；及3)在50 mg/kg或100 mg/kg劑量點，對抗被成年階段的狗舍蜱，血色扇頭壁蝨(R. sanguineus
)之實驗性侵擾之功效。
為兩組選擇十六隻狗，每組八隻狗(4隻雄性：4隻雌性)。一處理組接受乙基多殺菌素，而剩餘另一組未經處理。將該等狗個別安置於內外均混凝土地面的鏈連接狗舍中。研究期間，對該等狗投餵乾狗糧，除了處理日(第0天)接受罐裝食物。該等狗可隨意飲水。
第一組第0天，以30 mg/kg量經口接受一或多個含有乙基多殺菌素粉末之明膠膠囊，而該未處理組接受安慰劑。為評估更高劑量(50及100 mg/kg)對抗血色扇頭壁蝨(R. sanguineus
)之功效，在投與低劑量約2.5個月後，一旦收集跳蚤有效性數據，則以更高濃度再對該30 mg/kg組之狗給藥。
在第-1、5、12、19、28、35及42天，用約100隻成年跳蚤、及50隻各種類的蜱實驗性侵擾每一隻狗，在第49及56天，再進行一次跳蚤侵擾。在給藥24小時後，均評估對蜱及跳蚤之擊倒率。在侵擾48小時後進行所有隨後的計數。對於較高劑量而言，在再次劑量給藥前一天及再次劑量給藥後5天(再一次)，用約50隻血色扇頭壁蝨(R. sanguineus
)蜱侵擾該等狗，在此後約24小時進行梳毛計數。使用給藥24小時後之梳毛計數測定擊倒活性(第1天)。計算所有治療後殘留的蜱數時，在侵擾48小時後計算梳毛計數。在第14、21、28、及35天取血液樣本以確定血漿中之乙基多殺菌素濃度。
表2顯示狗口服30 mg/kg後，乙基多殺菌素對跳蚤之治療及殘留功效(跳蚤減少之幾何平均百分比)。
1
給藥48小時後評估擊倒率
2
表示歷史數據而非同時期對照
3
nd表示未測定
在狗30 mg/kg口服劑量點，相較於多殺菌素對抗成年貓蚤侵擾之歷史數據，乙基多殺菌素顯示相當的擊倒率及卓越的殘留功效。注意該殘留控制(97%)超出8周。在測試劑量下，乙基多殺菌素沒有顯示對抗任一蜱種類之統計學上顯著的活性。一般而言，對抗兩個蜱種類之治療功效難以解釋，因為未經處理的對照動物中保留極低的寄生蟲數。
給狗經口投與的脈衝對單次劑量/貓櫛頭蚤( Ctenocephalides felis )
進行另一項狗的研究，以評估以下對跳蚤侵擾之影響：1)口服60 mg/kg單次點劑量；2)一天每2小時口服20 mg/kg TID之脈衝給藥方案；3)一天每4小時口服20 mg/kg TID之脈衝給藥方案；及4)治療後乙基多殺菌素之血漿濃度。
給四個處理組各8隻狗(4隻雄性：4隻雌性)投與乙基多殺菌素，如下給藥：
處理組1：60 mg/kg，單次劑量
處理組2：60 mg/kg，(每2小時20 mg/kg，三次)
處理組3：60 mg/kg，(每4小時20 mg/kg，三次)
處理組4：0 mg/kg，(陰性對照)
將該等狗個別安置於室內外均混凝土地面的鏈連接狗舍中。研究期間，對該等狗投餵乾狗糧，除了處理前一天及處理當天(第0天)兩天接受罐裝食物。該等狗可隨意飲水。
處理組的狗經口接受一或多個含有本發明活性乙基多殺菌素粉末之明膠膠囊，其中處理組4接受安慰劑。在試驗第-1、5、12、19、28、35、42、49及56天，用約100隻跳蚤實驗性侵擾各狗。在劑量給藥24小時後，評估擊倒率，在每下一次侵擾48小時後，隨後評估殘留功效。以第1天梳毛計數決定最初/擊倒功效，在投與60 mg/kg劑量後約24小時，或該脈衝劑量第一次給藥時。取血液樣本以確定血漿中之乙基多殺菌素濃度。
表3顯示相較於未經處理對照組，活成年蠅計數的幾何平均減少百分比。結果顯示，不論投與單次60 mg/kg劑量或多次20 mg/kg劑量，所引起之功效無實質差異。
Claims (8)
- 一種乙基多殺菌素(spinetoram)或其醫藥上可接受的鹽之用途，其係用於製備用以控制狗或貓之跳蚤侵擾的藥物，其中該乙基多殺菌素係將藉由口服投藥以全身性方式投與。
- 如請求項1之用途，其中該跳蚤係貓櫛頭蚤(Ctenocephalides felis )。
- 如請求項1之用途，其中該投藥係將以單次或脈衝劑量，不超過每兩周一次投藥。
- 如請求項1之用途，其中該投藥係不超過每月一次投與。
- 如請求項1之用途，其中該乙基多殺菌素投藥之量以該狗或貓體重計為10mg/kg至60mg/kg。
- 一種用於以全身性方式控制狗或貓之體外寄生蟲侵擾之單次或脈衝劑量調配物，其包含乙基多殺菌素或其醫藥上可接受的鹽，及醫藥上可接受的載體，其係選自錠片、膠囊、或液體之口服劑型，劑量為以該狗或貓之體重計每kg 10至60mg乙基多殺菌素或其醫藥上可接受的鹽。
- 如請求項6之調配物，其中該劑型為錠片或膠囊，且該乙基多殺菌素或其醫藥上可接受的鹽的含量為該調配物的5至60重量%。
- 如請求項6之調配物，其呈可咀嚼的治療型式。
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| EA019278B1 (ru) | 2014-02-28 |
| IL216060A0 (en) | 2012-01-31 |
| JP2012526122A (ja) | 2012-10-25 |
| CA2760578C (en) | 2014-12-30 |
| WO2010129491A1 (en) | 2010-11-11 |
| SG175911A1 (en) | 2011-12-29 |
| CO6460763A2 (es) | 2012-06-15 |
| TW201105236A (en) | 2011-02-16 |
| NZ595798A (en) | 2014-03-28 |
| ZA201107635B (en) | 2014-03-26 |
| CA2760578A1 (en) | 2010-11-11 |
| JP5734959B2 (ja) | 2015-06-17 |
| AU2010246096A1 (en) | 2011-11-03 |
| CL2011002793A1 (es) | 2012-08-24 |
| KR20120012971A (ko) | 2012-02-13 |
| EP2427055B1 (en) | 2014-02-26 |
| TW201444563A (zh) | 2014-12-01 |
| CN102421289B (zh) | 2014-12-10 |
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