TWI484958B - 用於戒菸之口腔吸收尼古丁組成物 - Google Patents
用於戒菸之口腔吸收尼古丁組成物 Download PDFInfo
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- TWI484958B TWI484958B TW100117543A TW100117543A TWI484958B TW I484958 B TWI484958 B TW I484958B TW 100117543 A TW100117543 A TW 100117543A TW 100117543 A TW100117543 A TW 100117543A TW I484958 B TWI484958 B TW I484958B
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Description
本發明係關於一種組成物，其可提供尼古丁之口腔吸收，使尼古丁進入全身循環並分布至中央神經系統，藉以提供非吸菸之尼古丁替代，以協助戒菸。
由吸菸者及非吸菸者所進行之廣泛統計研究以證明吸菸對於人體之影響。一天抽一包菸的吸菸者每日攝入系統循環的尼古丁量為20至30毫克(Benowitz NL et al.,Clin. Pharmacol. Ther. 44(1988) 23-28)。尼古丁吸收十分迅速，吸入後十至二十秒即會抵達腦部(Benowitz NL et al.,Annu.Rev.Pharmacol.Toxicol. 36(1996) 597-613)。許多證據顯示尼古丁會影響腦部多巴胺受體，導致腦部對尼古丁之耐受增加及成癮(Hoffman D et al.,Am. J. Health 73(1983) 1050-1053)。戒菸之道在於棄除尼古丁成癮，為一種菸鹼中毒療法。戒菸過程往往是一場成功率不高的長期抗戰(Cummings KM，Hyland A,Ann. Rev. Pub. Health 26(2005) 583-599)。
戒菸治療中會利用各種不同施用途徑的尼古丁製劑。為方便使用及達成充分之尼古丁生物利用度，最常見之吸收方式為經由口腔粘膜吸收。吸菸者所欲達成的血液中尼古丁濃度為每公升30至50微克(Lawson GM et al.,J. Clin. Pharmacol. 38(1998) 510-516)。由於成癮是對於立即達成血液中尼古丁高峰值之藥理反應，因此尼古丁緩釋並無助益(Henningfield JE，Keenan RM,J. Consult. Clin. Psychol. 61(1993) 743-750)。
包含2毫克或4毫克尼古丁的口香糖其生物利用度(Shiffman S et al.,Addiction 97(2002) 505-516)約為50%(Benowitz NL，Jacob P III,Savanapridi C,Clin. Pharmacol. Ther. 41(1987) 467-473)。在穩定度方面，由於口香糖係使尼古丁緩慢持續釋入口腔，因此其於血液中造成尼古丁濃度隨時間變化之情形與吸菸產生者有所不同(Henningfield JE et al，Drug Alcohol Depend. 33(1993) 23-29)。尼古丁之生物利用度主要取決於口中酸鹼度，嚼食口香糖前後15分鐘不建議飲用過酸飲料(Henningfield JE et al.,JAMA 264(1990) 1560-1564)，因為其離子化型態鹽會降低透黏膜吸收。此種使用型態亦會於口腔與喉嚨造成令人不快的熱燙感(Henningfield JE et al.,CA Cancer J. Clin. 55(2005) 281-299)。尼古丁釋出率難以確實控制，某些製造商建議避免過度集中嚼食以免尼古丁過量(美國專利第6,344,222)。
口香糖及其他錠劑型態產品係使尼古丁緩慢溶解於口中(美國專利第4,967,773號)，遠較吸菸釋出速度為慢(Russel MAH et al.,Lancet 2(1985) 1370)。前案專利已揭露更快速溶出尼古丁之組成物(美國專利第6,280,761號)。為達成較高之生物利用度，建議之酸鹼度為7至9，藉由碳酸緩衝液控制酸鹼度可使組成物具有充分之穩定性(美國專利第6,280,761號)。將酸鹼值增加為7.4至8.5可使非離子化型態之釋出率從30%提高至80%，且生物利用度可增加3.8倍(美國專利第6,110,495號)。錠劑因尼古丁劑量較低，效率亦較低。因此美國核准劑量較高，從1毫克至2毫克和4毫克(Shiffman S et al.,Arch. Intern. Med. 162(2002) 1267-1276)。尼古丁釋放緩慢，生物利用度高於口香糖25%(Choi JH et al.,Nicotine Tob. Res. 5(2003) 635-644)。另一種較為少見之型態為舌下錠。此種藥劑體積極小，可溶於水，使用時係放置在舌下。單次劑量之尼古丁生物利用度與口香糖相仿(Molander L，Lunell E,Eur. J. Clin. Pharmacol. 56(2001) 813-819)。
鼻用噴劑為尼古丁製劑之另一種型態。此種製劑在美國僅限持有醫療處方者使用(Henningfield JE et al.,CA Cancer J. Clin. 55(2005) 281-299)。使用時係於每側鼻腔投用含0.5毫克尼古丁劑量之50微升溶劑。尼古丁吸收十分迅速，噴劑之優點在於可根據病患之成癮程度設定尼古丁劑量(Schneider NG et al.,Clin. Pharmacokinet. 31(1996) 65-80)。此種製劑使用初期常會引起鼻粘膜過敏。
WO/1997/038662及EP 0 904 055專利之口腔噴劑是以有效物質之酒精、水或聚乙二醇溶液和風味添加劑組成，經由幫浦將尼古丁及其鹽、吡喀醇胺和類固醇激素噴出。其他專利技術還包括利用幫浦噴灑器將尼古丁製劑施用於口腔(美國專利第5,186,925號)；含尼古丁微球體之口腔噴劑亦為前案專利所保護(美國專利第5,939,100號)。
所謂的電子菸係時下最新穎且為廣受歡迎之尼古丁製劑產品型態(歐洲專利申請第1618803號)。尼古丁攝入後為口腔及肺部所吸收。世界健康組織則以正式聲明表示質疑此種產品之安全性及功效，並宣稱不建議以其做為戒菸輔助手段(Anon.,Marketers of electronic cigatettes should halt unproved therapy claims. World Health Organization，2008-09-19)。
呼出尼古丁煙霧濃度於交通工具之封閉空間中對於非吸菸者的健康影響時為令人憂心的問題，尤其孩童對於尼古丁的解毒能力遠不如成人，因此所受影響更大。
尼古丁為一種高效率的天然物質，屬於生物鹼類。其效果發揮十分迅速，對於多種器官皆有影響，尤以心臟、血管及腦部為最。致命劑量(LD 50)為30至60毫克(Gosselin RE，Clinical toxicology of commercial products,VI. Ed.,Williams & Wilkins,Baltimore 1988,pp 311-313)，但4至8毫克便可能使非吸菸者產生嚴重毒性反應，對於孩童而言危險劑量門檻更低。目前對此物質尚未發現有效的解毒劑。
包括尼古丁在內，所有生物鹼以非離子化型態溶液施用時較易通過生物屏障，亦即酸鹼度超過pKa值愈多愈好。pKa值為一參數，其用以表達當一物質其離子化與非離子化型態之濃度為相等時之pH值。施用生物活性物質時，也須考量生理條件。生理上最佳pH值(異位酸溶液)與最利穿透屏障pH值兩者間之折衷值即是所謂之適當酸性(euacid)溶液。此適當酸性pH值確保在同時適合於生物環境及施用物質兩者之pH值下的充分生物利用度。所述之生物利用度為一參數，其表達施用物質總量中進入系統循環或目標組織或結構之比率。
在許多物質中，此適當酸性pH值之達成係藉由將一物質之酸或鹼型態與及其鹽以適當比例混合。在本發明則是利用菸鹼(尼古丁鹼)結合其添加適量酸而形成的菸鹼鹽為尼古丁來源。
為提升物質之生物利用度，除了以增加非離子化型態之比例為手段外，另一種特別適用於口腔施用物質的方法為減少黏蛋白之屏障功能。黏蛋白為一種高分子量糖蛋白，特徵為高水溶液黏度。化痰劑則可降低其黏度。許多目前常用之化痰劑分子中所包含的巰基可減少二硫基，進而減少黏蛋白分子之交聯。反應結果係使溶液黏度之大幅降低，因此可利用於解決肺病及呼吸系統疾病之大小症狀。此為胺基酸胱胺酸、蛋胺酸及其酯和醚之功效(Takatsuka S et al.,Int. J. Pharm. 349(2008) 94-100)。
尚有其他許多非巰基類之化痰劑，各以相異之機制作用。多種酶對於黏蛋白均有解聚作用(Rubin B K，Respiratory Care,52(2007) 859-865)。治療實務傳統上使用如氯化銨及氯化鈉等電解質溶液來造成黏蛋白之大分子覆蓋層部分脫水，藉以降低其溶液之黏度。將處理後之海水用為浮質型態化痰劑即為前案專利揭露之技術(美國專利第7097852號)。傳統及替代醫學中，以小兒科為主，則常採用醣類(蜂蜜、無花果等等)或多元醇(甘露醇、山梨醇、木糖醇、季戊四醇)之高張溶液與電解質之組合。
治療實務中亦廣泛使用許多取自植物各部份萃取物之植物複合物。黃花九輪草或高報春花等植物的花朵或根部萃取物長期為人所用，此等植物包含三萜皂苷和酚醛配糖(Anon.: Assessment report on Primula veris,Primula elatior(L.),radix. EMEA(HPMC/144474/2006)。皂苷於水溶液中因表面活性機制而有顯著效果。利用植物皂苷及皂苷元降低人類唾液黏度以利微生物學分析係一前案專利技術(美國專利第4053363號)。常春藤葉中所含三萜皂苷亦有類似效果(Kraft K,Zeitschr. Phytotherap. 25(2004) 179-181；Fazio S et al.,Phytomedicine 16(2009) 17-24)。尤加利精油主要包含桉葉素(1,8-cineol)及其他多種物質，如萜、倍半萜及倍半萜醇，各以不同機制作用，其中亦包含化痰效果(Tibballs J,Med. J. Aust. 163(1995) 177-180)。甘草根亦提供多種表面活性物質，其去除甘草素後可發揮化痰效果(Guslandi M,Int. J. Clin. Parmacol. Ther. Toxicol.,23(1985) 398-402)。冰島苔和藥蜀葵內含物質與局部麻醉劑之組合為WO/2006/032364之揭露。款冬種及毛蕊花屬的花朵包含多種物質，尤其是類黃酮和皂苷類，亦特別具有化痰效果(Newall C A,Anderson L A,Phillipson J D,Herbal Medicines,Pharmaceutical Press,London 1996)。許多其他植物複合物亦以據稱之化痰效果用於治療實務，如碎雪草、牛至、茴芹、麝香草和三葉草等等。
尼古丁為相對穩定物質，暴露於空氣中時會為氧所分解，且會因受光加速分解。電子之強大受體可催化反應，而物質捕獲基則會抑制反應。分解反應中主要產生烷基吡咯烷之氮氧化合物(Suffredini HB et al.,Anal. Letters 38(2005) 1587-1599)及類似含量之吡咯烷酮(Beckwith ALJ et al.,Austral. J. Chem. 36(1983) 719-739)。各種纖維素中所吸收之尼古丁中並含有可丁尼、甲酮-(1-甲基-3-吡咯烷基)-3-吡啶基及其他降解產物(Mihranyan A,Andersson S-B,Ek R,Eur. J. Pharm. Sci. 22(2004) 279-286)。穩定尼古丁之一種方法為以藻類、細菌或真菌之纖維素吸收尼古丁(WO/2005/023227)。尼古丁在人體中主要代謝部位為肺部，現已知會產生數十種代謝物(Moyer TP et al.,Clin. Chem. 48(2002) 1460-1471)。為穩定尼古丁，必須添加水可溶性抗氧化劑。
發明內容
一種使尼古丁經口腔吸而收進入系統循環並分布於中央神經系統之組成物，目的為戒菸或為免除吸菸之尼古丁替代，其特徵在於包含濃度0.01至8.00%重量比，更佳者為0.10至4.00%重量比，最佳者為0.20至1.00%重量比之尼古丁溶液，其型態為鹼及/或鹼與有機酸產生之鹽；其進一步包含具有化痰效果之物質，該具化痰效果之物質係為3.0至30.0%重量比之乙醯化胱胺酸及/或0.50至15.00%重量比之具化痰效果植物複合物，所述具化痰效果之植物複合物係萃取自黃花九輪草、高報春花、常春藤、尤加利或甘草。
組成物可進一步包含0.05至1.50%重量比之具抗氧化效果植物複合物，抗氧化效果植物複合物係該選自以下群組：黃酮、類黃酮、黃烷酮、黃酮醇、異黃酮、新黃酮、花青素、原花青素及其寡聚物以及萃取自綠茶、薑黃、迷迭香、水飛薊、葡萄、銀杏、巴西莓、山桑子、檄樹、西印度櫻桃等植物之聚合物。
該組成物較佳地可進一步包含緩衝液或酸性調整物質，以將其pH值範圍調整為6.0至9.5，更佳者為7.0至9.0，最佳者為8.5。
該組成物包含一溶劑，該溶劑為50至99%重量比之水，或水與2至50%重量比之多元醇之混合物，其中所述多元醇為甘油、丙烯乙二醇及/或醣類，且所述醣類係選自以下群組：甘露醇、木糖醇、葡萄糖、左旋糖及蔗糖。
該組成物亦宜包含以下物質中之至少一種：調整味覺感知之物質、調整嗅覺感知之物質、抗菌劑、隔離劑、抗氧化劑、助溶劑及可濕性提升劑、改善施用組成物物理參數(黏度及表面張力)之物質，以及改善口腔表面(黏膜或牙齒)條件之物質。
本發明之組成物係以膠狀體型態或經噴灑裝置產生之非均質空氣散佈施用於口腔，且該組成物之單次使用劑量為50微升至2000微升，較佳者為150微升至500微升。
該組成物之單次使用劑量包含之尼古丁為0.05至3.00毫克，更佳者為0.10毫克至2.00毫克，最佳者為0.25毫克至1.00毫克。
一種使尼古丁經口腔吸而收進入系統循環並分布於中央神經系統之組成物，目的為戒菸或為免除吸菸之尼古丁替代，其特徵在於包含濃度0.01至8.00%重量比，更佳者為0.10至4.00%重量比，最佳者為0.20至1.00%重量比之尼古丁溶液，其型態為鹼及/或鹼與有機酸產生之鹽；其進一步包含具有化痰效果之物質，該具化痰效果之物質係為3.0至30.0%重量比之乙醯化胱胺酸及/或0.50至15.00%重量比之具化痰效果植物複合物，所述具化痰效果之植物複合物係萃取自黃花九輪草、高報春花、常春藤、尤加利或甘草。
組成物可進一步包含0.05至1.50%重量比之具抗氧化效果植物複合物，抗氧化效果植物複合物係該選自以下群組：黃酮、類黃酮、黃烷酮、黃酮醇、異黃酮、新黃酮、花青素、原花青素及其寡聚物以及萃取自綠茶、薑黃、迷迭香、水飛薊、葡萄、銀杏、巴西莓、山桑子、檄樹、西印度櫻桃等植物之聚合物。
該組成物較佳地可進一步包含緩衝液或酸性調整物質，以將其pH值範圍調整為6.0至9.5，更佳者為7.0至9.0，最佳者為8.5。
該組成物包含一溶劑，該溶劑為50至99%重量比之水，或水與2至50%重量比之多元醇之混合物，其中所述多元醇為甘油、丙烯乙二醇及/或醣類，且所述醣類係選自以下群組：甘露醇、木糖醇、葡萄糖、左旋糖及蔗糖。
該組成物亦宜包含以下物質中之至少一種：調整味覺感知之物質、調整嗅覺感知之物質、抗菌劑、隔離劑、抗氧化劑、助溶劑及可濕性提升劑、改善施用組成物物理參數(黏度及表面張力)之物質，以及改善口腔表面(黏膜或牙齒)條件之物質。
本發明之組成物係以膠狀體型態或經噴灑裝置產生之非均質空氣散佈施用於口腔，且該組成物之單次使用劑量為50微升至2000微升，較佳者為150微升至500微升。
該組成物之單次使用劑量包含之尼古丁為0.05至3.00毫克，更佳者為0.10毫克至2.00毫克，最佳者為0.25毫克至1.00毫克。
本發明之組成物除了以尼古丁及其鹽為活性物質以外，尚包含化痰劑，如乙醯化胱胺酸及/或具化痰效果之植物複合物，該具化痰效果之植物複合物係萃取自植物，作用為提高尼古丁生物利用度。本發明之組成物可進一步包含取自天然植物之抗氧化劑，以提高尼古丁之穩定性，防止其氧化，該組成物中並以水做為溶劑。本發明組成物中亦可包含各類穩定劑，如抗菌劑、隔離劑、自由基淬滅劑；亦可加入感官特性調整物質。本發明之組成物亦可包含改善組成物施用時之黏度及表面張力等物理參數的物質，以及改善黏膜或牙齒等口腔表面條件的物質。
尼古丁為極有效之生物鹼，在水至強鹼性溶液中皆可輕易溶解。口腔黏膜對其容受性良好，且其可經口腔黏膜吸收後充分進入全身循環，尼古丁溶液之pH值以低於9.0且高於7.0為佳。藉由加入如檸檬酸、蘋果酸、酒石酸、乳酸、乙醇酸或磷酸等等酸類之鹽，可輕易降低尼古丁水溶液之pH值。溶液中尼古丁之濃度係取決於施用之劑量；可為0.01%至8.00%，更佳者為0.10%至4.00%，最佳者為0.20%至1.00%。單次施用之尼古丁劑量可為0.05毫克至3.00毫克，更佳者為0.10毫克至2.00毫克，最佳者為0.25毫克至1.00毫克。
化痰劑為可降低黏蛋白黏度之高度親水性物質，所述黏蛋白包含黏蛋白類物質。降低黏蛋白之黏度可使尼古丁分子更快擴散至黏膜屏障之表面，因此加速並且加強尼古丁之吸收。乙醯化胱胺酸即為一種高度親水性物質。羧基能與尼古丁之吡咯烷環的鹼性氮相互作用。其具有抗氧化效果，巰基可為電子施體。其為重要之化痰劑，可與二硫化物鍵交互作用而降低黏蛋白水溶液黏度。
能夠增加本發明組成物之尼古丁生物利用度的天然植物來源化痰劑與傳統上用於促進於排痰之化痰劑相同，此種物質尤其常見用於小兒科。適用者為萃取自藥用植物之複合物，如黃花九輪草或高報春之花朵或根部的水或醇萃取物，其包含三萜皂苷及酚醛配糖。常春藤葉片中所含之三萜皂苷亦具有類似功效。本發明之組成物亦可包含取自尤加利樹葉之精油，其特別含有桉葉素(1,8-cineol)及其他多種物質，如萜、倍半萜及倍半萜醇。自甘草根萃取而得之植物複合物可提供表面活性物質，在除去甘草素後具有化痰效果。另一適用於本發明組成物之成分為冰島苔和藥蜀葵所含物質之組合，以及款冬種及毛芯屬植物內所含物質。尚有許多其他植物複合物可提供所需之化痰效果，如碎雪草、牛至、茴芹、麝香草、三葉草等等。具化痰效果之植物複合物用為本案組成物之成分時，其濃度係為0.5%重量比至15%重量比，更佳者為0.5%重量比至5%重量比，最佳者為1%重量比至2%重量比。
本案組成物中之抗氧化劑對於維持溶液中尼古丁之穩定性甚為重要，可防止尼古丁產生氧化反應，且抗氧化劑對於口腔黏膜亦具正面作用。本發明之組成物中可包含產自天然植物之物質或其可溶於水之混合物，如抗壞血酸及其鹽、各種類黃酮，如黃酮、類黃酮、黃烷酮、黃酮醇、異黃酮、新黃酮、花青素、原花青素及其寡聚物和聚合物。在諸多萃取自含有已知種類物質之植物原料的植物複合物中，含兒茶素之綠茶葉萃取物屬於黃烷醇類，水飛薊萃取物含有水飛薊複合物，薑黃萃取物包含薑黃複合物，迷迭香萃取物包含迷迭香酸，葡萄萃取物包含原花青素和其他各種聚酚醛物質，之銀杏葉含類黃酮，而山桑子果實和巴西莓都含有花青素。除了綠茶中所含的表兒茶素以外，黃酮醇類之槲皮素及多酚類之白藜蘆醇為最常用於食品者。法國海岸松碧蘿芷之萃取物包含許多生物類黃酮類兒茶素、寡聚合體前花青素及具抗氧化能力之酚醛果酸的混合物。檄樹及西印度櫻桃等植物之萃取物為抗壞血酸及其鹽之主要來源。在本發明組成物濃度中，包含各種抗氧化劑且萃取自植物之植物複合物其濃度約為0.05%重量比至1.5%重量比，更佳者為0.25%重量比至1.5%重量比，最佳者為0.50%重量比至1.0%重量比。水在本案組成物中為個別成分之溶劑。根據本發明技術解決方案，水於組成物中之比例為50%至99%，更佳者為65%至90%，最佳者為75%至95%。
可用酸類或氫氧化物為調整酸度之成分，如以胺或胺基酸與尼古丁產生不完全鹽類或更佳者為緩衝系統醋酸鹽、檸檬酸、三乙醇胺、氨丁三醇、碳酸鹽等等。可將二羧基胺基酸單獨或組合使用，如穀胺酸或天冬胺酸，或鹼性胺基酸，如離胺酸或蛋白胺酸。為提高尼古丁穩定性及生物利用度，宜將溶液pH值範圍調整為6.0至9.5，更佳者為7.0至9.0，最佳之pH值為8.5。
其他可用於本發明組成物之成分尚包括防腐添加劑。適用者為山梨酸或安息香酸脂酸及鹽。其他適用於本發明之抗菌物質可包括對羥苯甲酸酯或安息香酸酚酯，尤以甲基安息香酸酚酯為佳。本發明組成物中亦可添加各種精油，如丁香油、百里香油、野百里香油、桉葉油或此等植物之半極性溶劑萃取物。丙烯乙二醇或乙醇亦可提供抗菌效果，其亦可用為植物原料之萃取劑。適用之防腐劑如金絲桃、冰島苔、苦楝、鼠尾草、柳皮等植物之酒精或丙烯乙二醇液體萃取物。
調整味覺感知之物質主要為增甜劑。最通用者為各種醣類及肌醇，如甘油、丙烯乙二醇、蔗糖、葡萄糖、左旋糖、山梨醇、甘露醇、木糖醇、蜂蜜等等。適用於此目的之另一類物質為人造非營養增甜劑，如甜味劑鹽、醋磺內酯鹽、阿斯巴甜、新橙皮苷二氫查爾酮、蔗糖素、甘草萃取物、甜菊萃取物等等。可利用精油調整嗅覺感知，如薄荷油、綠薄荷油、大茴香油、茴香油、尤加利油、芫荽油、小茴香油、肉桂油、丁香油、百里香油、野百里香油、水芹油、杜松油、墨角蘭油、薑油等等。
根據本發明之組成物亦可進一步包含其他用以正向調整其物理參數之成分。添加乙醇或丙烯乙二醇可降低物質水溶液之黏度及表面張力，亦可使用介面活性劑。對於黏膜和牙齒等口腔表面條件造成正面影響之物質可包含多種維生素及礦物質，如維生素B群及其鹽、維生素C及其鹽、酯和配糖、維生素H、輔酶Q10，以及鋅、銅、硒、鈣和錳等物質其鹽等等之複合物。可用抗炎劑為萃取自金絲桃、金盞花及甘菊等之沒藥醇和尿囊素。
本發明之組成物係透過噴灑方式施用於口腔，亦即組成物在氣體中以非均質或膠狀分散之方式接觸口腔黏膜、牙齦黏膜、硬顎及舌頭表面。空氣散佈產生器可為幫浦，或者亦可以具推進器之壓力容器將組成物以氣流型態噴出。推進氣體可為氮或其他化學惰性氣體，或丁烷、異丁烷或丙烷等烷烴之混合物。噴出氣霧之中之顆粒大小可為20 nm至100 μm，較佳者為500 nm至5 μm。為控制劑量，空氣散佈產生器係配備有分劑裝置。單次施用之液體劑量可為50微升至2000微升，較佳者為150微升至500微升。所列參數僅為說明之用，而非本案技術解決方案之主體。
較佳實施例範例
製備程序：將個別成分逐步添加溶解於水。視需要過濾溶液並將之裝入設有分配閥之壓力容器，或裝入設有分配閥且由手動幫浦驅動之封閉容器。
產業利用性：本發明之組成物可由藥業製造。製劑適用於以戒菸為目的之尼古丁透黏膜吸收。
Claims (8)
- 一種使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，目的為戒菸或為免除吸菸之尼古丁替代，其特徵在於該組成物包含有一尼古丁溶液、一具有化痰效果之物質、一具抗氧化效果植物複合物以及一緩衝液或酸性調整物質；該尼古丁溶液為濃度0.01至8.00%重量比，其型態為鹼及/或鹼與有機酸產生之鹽；該具化痰效果之物質係為3.0至30.0%重量比之乙醯化胱胺酸及/或濃度為0.50至15.00%重量比之具化痰效果植物複合物，該具化痰效果之植物複合物係萃取自至少一植物，該植物係選自以下群組：黃花九輪草(Primula veris)、高報春花(Primula elatior)、常春藤(Hedera helix)、尤加利(Eucalyptus globulus)或甘草(Liquiritia glabra)之其中一種；該具抗氧化效果植物複合物為0.05至1.50%重量比，該具抗氧化效果植物複合物係選自以下群組：黃酮(flavones)、類黃酮(flavonols)、黃烷酮(flavanones)、黃酮醇(flavanonols)、異黃酮(isoflavones)、新黄酮(neoflavonoids)、花青素(anthocyanidins)、原花青素(proanthocyanidins)及其寡聚物之其中一種以及至少一萃取自綠茶(Camellia sinensis)、薑黃(Curcuma longa)、迷迭香(Rosmarinus officinalis)、水飛薊(Sylibium marianum)、葡萄(Vitis vinifera)、銀杏(Ginkgo biloba)、巴西莓(Euterpe oleracea)、山桑子(Vaccinium myrtillus)、檄樹(Morinda citrifolia)及西印度櫻桃(Malpighia glabra)之其中一種之聚合物；且該緩衝液或酸性調整物質，以將該組成物之pH值範圍調整為7.0至9.0。
- 如申請專利範圍第1項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物包含一溶劑，該溶劑係濃度為50至99%重量比之水，或水與濃度為2至50%重量比之多元醇的混合物，其中所述多元醇為甘油、丙烯乙二醇及/或至少一醣類，該醣類係選自以下群組：甘露醇(mannitol)、木糖醇(xylitol)、葡萄糖(glucose)、左旋糖(fructose)及蔗糖(saccharose)之其中一種。
- 如申請專利範圍第1項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物包含以下群組中之至少一者：調整味覺感知之物質、調整嗅覺感知之物質、抗菌劑、隔離劑、 抗氧化劑、助溶劑及可濕性提升劑、改善施用組成物物理參數之物質，以及改善口腔表面條件之物質，其中該物理參數包含組成物之黏度及表面張力，且該口腔表面條件包含黏膜或牙齒之條件。
- 如申請專利範圍第2項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物包含以下群組中之至少一者：調整味覺感知之物質、調整嗅覺感知之物質、抗菌劑、隔離劑、抗氧化劑、助溶劑及可濕性提升劑、改善施用組成物物理參數之物質，以及改善口腔表面條件之物質，其中該物理參數包含組成物之黏度及表面張力，且該口腔表面條件包含黏膜或牙齒之條件。
- 如申請專利範圍第1項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物之單次使用劑量包含之尼古丁為0.05毫克至3.00毫克。
- 如申請專利範圍第2項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物之單次使用劑量包含之尼古丁為0.05毫克至3.00毫克。
- 如申請專利範圍第3項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物之單次使用劑量包含之尼古丁為0.05毫克至3.00毫克。
- 如申請專利範圍第4項所述之使尼古丁經口腔吸收而進入系統循環並分布於中央神經系統之組成物，其中該組成物之單次使用劑量包含之尼古丁為0.05毫克至3.00毫克。
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