201247203 六、發明說明： 【發明所屬之技術領域】 本發明係關於-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，藉以提供非吸終之尼古丁替 代，以協助戒菸。 【先前技術】 由吸於者及非吸終者所進行之廣泛統計研究以證明吸終對於人體 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2〇至 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nl et al.，201247203 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a composition which provides oral absorption of nicotine, allows nicotine to enter the systemic circulation and is distributed to the central nervous system, thereby providing a non-absorbent nicotine replacement. To help stop smoking. [Prior Art] Extensive statistical studies conducted by both inhalers and non-suckers to demonstrate the effects of end-of-sucking on the human body. Smokers who smoke a pack of cigarettes a day consume between 2 and 30 milligrams of circulating nicotine per day (Benowitz NL et al) Clin. Pharmacol. Ther. 44 (1988) 23-28). Nicotine absorption is very rapid' Ten to twenty seconds after inhalation, you will reach the brain 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(H〇ffilian 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)。由於成瘾是對 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(Shiffinan 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 etal，Drug Alcohol Depend. 33 (1993)23-29)。尼古 丁之生物利用度主要 201247203 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），遠較吸终釋出速度為慢(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 6,280,76】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(Shiffinan 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25〇/O(ch〇i JH et al·，Nicotine Tob. Res. 5 (2003) 635-644)。另一種較為少見之型態為 舌下旋。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)。 鼻用喷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〇·5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專利之口腔喷劑是以有效物質之 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喷灑 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 201247203 體之口，喷劑亦為前案專利所保護（美國專利第5,939,ι⑻號）。 所5胃的電子_時下最卿且為廣受歡迎之尼古丁製劑產品型態 (1/州專利中4第161_號）。尼古τ攝人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 乂，、做為戒於_助手段(An〇n.，Marketers 0f eiectr〇njc cigatettes alt unproved therapy claims. World Health Organization » 2008 -09—19)。 ，呼出尼古T轉濃度於交通玉具之賴空間巾對於非吸於者的健 康影響時為令人憂賴題，尤其孩童對於尼古了祕毒能力遠不如 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δ危險劑量門檻更低。目前對此物質尚未發現有效的解毒劑。 包括尼古丁在内，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驗 型態與及其鹽以適當比例混合。在本發明則是利用菸鹼(尼古丁驗)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 201247203 可降低其黏度。許多目前常用之化痰劑分子中所包含的锍基可減少二 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 脱胺酸、蛋胺酸及其酯和醚之功效(Takatsuka S et al., Int. J. Pharm. 349 (2008) 94-100) » 尚有其他許多非酼基類之化痰劑，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氣化銨及氣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 用此專植物包含二結皂皆和紛酸配糖(Anon.: Assessment report onAnnu. Rev. Pharmacol. Toxicol. 36 (1996) 597-613). There is much evidence that nicotine affects dopamine receptors in the brain, leading to increased tolerance and addiction to nicotine in the brain (H〇ffilian D et al) Am. J. Health 73 (1983) 1050-1053). Abandoning nicotine addiction is a nicotine poisoning therapy. The smoking cessation process is often a long-term war of resistance (Cummings KM ' Hyland A, Ann. Rev. Pub. Health 26 (2005) 583-599). Nicotine preparations of various routes of administration are utilized. For the convenience of use and sufficient nicotine bioavailability, the most common absorption method is absorption through the oral mucosa. The concentration of nicotine in the blood that the smoker wants to achieve is 30 to liters per liter. 50 micrograms (Lawson GM et al., J. Clin. Pharmacol. 38 (1998) 510-516). Since addiction is a pharmacological response to the immediate peak of high nicotine in the blood, slow release of nicotine does not help (Henningfield) JE, Keenan RM, J. Consult. Clin. Psychol. 61 (1993) 743-750) « Bioavailability of chewing gum containing 2 mg or 4 mg of nicotine (Shiffinan S et al., Addiction 97 (2002) 505-516 ) 50% (Benowitz NL, Jacob P III, Savanapridi C, Clin. Pharmacol. Ther. 41 (1987) 467-473). In terms of stability, since the chewing gum makes nicotine slowly and continuously released into the cavity, it is in the blood. The situation in which the concentration of nicotine changes with time is different from that of smokers (Henningfield JE etal, Drug Alcohol Depend. 33 (1993) 23-29). The bioavailability of nicotine is mainly 201247203 depending on the pH in the mouth, before and after chewing gum It is not recommended to drink sour drinks for 15 minutes (Henningfield JE et al_, JAMA 264 (1990) 1560-1564) because its ionized salt reduces the absorption of the transmucosal membrane. This type of use can also cause damage to the mouth and throat. Unpleasant scalding (Henningfield JE et al., CA Cancer J. Clin. 55 (2005) 281-299). Nicotine release rates are difficult to control, and some manufacturers recommend avoiding excessive concentration of chewing to avoid excessive nicotine ( U.S. Patent No. 6,344,222). Chewing gum and other lozenge products slow the dissolution of nicotine into the mouth (U.S. Patent No. 4,967,773), which is much slower than the final release rate (Russel MAH et al., Lancet 2 (1985) 1370). The prior patent has disclosed a composition for the faster dissolution of nicotine (U.S. Patent No. 6,280,761). In order to achieve a higher bioavailability, the recommended pH is 7 to 9, and the composition can be sufficiently stabilized by controlling the pH of the carbonate buffer (U.S. Patent No. 6,280,76). Increasing the pH to 7.4 to 8.5 increases the release rate of the non-ionized form from 30% to 80%, and the bioavailability can be increased by 3.8 times (U.S. Patent No. 6,110,495). Tablets have lower doses of nicotine and are less efficient. Therefore, the US approved doses range from 1 mg to 2 mg and 4 mg (Shiffinan S et al., Arch. Intern. Med. 162 (2002) 1267-1276). Nicotine release is slow' bioavailability is higher than chewing gum 25〇/O (ch〇i JH et al., Nicotine Tob. Res. 5 (2003) 635-644). Another less common type is sublingual rotation. The medicinal body is small in size, soluble in water, and placed under the tongue when in use. The single dose of nicotine bioavailability is similar to that of chewing gum (Molander L, Lunell E, Eur. J. Clin. Pharmacol. 56 (2001) 813-819). Nasal sprays are another form of nicotine preparation. Such formulations are restricted to use by medical prescribes in the United States (Henningfield JE et al., CA Cancer J. Clin. 55 (2005) 281-299). At the time of use, 50 microliters of a solution containing a dose of 毫克·5 mg of nicotine was administered to each side of the nasal cavity. Nicotine is absorbed very quickly, and the advantage of the spray is that the nicotine dose can be set according to the degree of addiction of the patient (Schneider NG et al., Clin. Pharmacokinet 31 (1996) 65-80). This preparation often causes nasal mucosal allergy in the initial stage of use. The oral spray of WO/1997/038662 and EP 0 904 055 is composed of an effective substance of alcohol, water or a polyethylene glycol solution and a flavor additive, and the nicotine and its salts, pyridoxamine and steroid hormones are applied via a pump. ejection. Other patented techniques also include the use of a pump sprayer to apply a nicotine formulation to the oral cavity (U.S. Patent No. 5,186,925); a nicotine-containing microsphere 201247203 body, the spray is also protected by a prior patent (US Patent No. 5,939) , ι (8)). The electrophoresis of the 5 stomachs is the most popular and popular nicotine preparation product type (1/State Patent No. 4 No. 161_). Nigu τ is absorbed by the mouth and lungs after being taken. The World Health Organization has expressed its suspicion of the safety and efficacy of this product in an official statement, and claimed that it does not recommend 乂, as a means of 戒 助 (., eter . , Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark Mark ( Mark ( ( ( ( ( ( ( ( ( World Health Organization » 2008 -09-19). The exhalation of Niko T to the concentration of the traffic jade in the space towel for the health effects of non-absorbers is a worrying problem, especially children have a far less toxic ability than Nico, so they are more affected. . Nicotine is a highly efficient natural substance belonging to alkaloids. The effect is very rapid, affecting a variety of organs, especially the heart, blood vessels and brain. The lethal dose (LD 50) is 30 to 60 mg (Gosselin RE, Clinical toxicology of commercial products, VI. Ed., Williams & Wilkins, Baltimore 1988, pp - 311-313), but 4 to 8 mg can make non- Smokers develop severe toxic reactions, and the threshold for δ dangerous doses is lower for children. No effective antidote has been found for this substance. All alkaloids, including nicotine, are more susceptible to passage through the biological barrier when applied in a non-ionized form, i.e., the greater the pH than the pKa, the better. The pKa value is a parameter which is used to express the pH value when a substance is equal in ionization and non-ionization type. Physiological conditions must also be considered when administering biologically active substances. The trade-off between the physiologically optimal pH (heteroacid solution) and the pH of the most penetrating barrier is the so-called euacid solution. This suitably acidic pH ensures sufficient bioavailability at both pH values suitable for both the biological environment and the applied material. The bioavailability is a parameter that expresses the ratio of the total amount of applied material entering the systemic circulation or the target tissue or structure. In many materials, this appropriate acidic pH is achieved by mixing the acid or test form of a substance with its salt in an appropriate ratio. In the present invention, the nicotine salt formed by using nicotine (nicotine test) in combination with the addition of an appropriate amount of acid is a source of nicotine. In order to improve the bioavailability of substances, in addition to increasing the proportion of non-ionized forms, another method that is particularly suitable for oral administration is to reduce the barrier function of mucin. Mucin is a high molecular weight glycoprotein characterized by high aqueous solution viscosity. The quinone agent 201247203 can reduce its viscosity. Many of the sulfhydryl groups contained in the currently used chelating agents reduce the disulfide group, thereby reducing the cross-linking of mucin molecules. As a result of the reaction, the viscosity of the solution is greatly reduced, so that it can be used to solve the symptoms of lung diseases and respiratory diseases. This is the effect of amino acid deaminating acid, methionine and its esters and ethers (Takatsuka S et al., Int. J. Pharm. 349 (2008) 94-100) » There are many other non-purine based Peony agents, each with a different mechanism. A variety of enzymes have a depolymerization effect on mucin (Rubin B K, Respiratory Care, 52 (2007) 859-865). Treatment practices have traditionally used electrolyte solutions such as ammonium sulfate and sodium vaporated to cause partial dehydration of the macromolecular coating of mucin, thereby reducing the viscosity of the solution. The use of the treated seawater as an aerosol type tanning agent is the technique disclosed in the prior patent (U.S. Patent No. 7097852). In traditional and alternative medicine, pediatrics mainly use a combination of a high-temperature solution of a sugar (honey, fig, etc.) or a polyol (mannitol, sorbitol, xylitol, pentaerythritol) and an electrolyte. Many plant complexes derived from extracts of various parts of the plant are also widely used in therapeutic practice. The flowers or root extracts of plants such as the yellow-flowered primrose or the high-grade spring flower are used for a long time. This special plant contains two knots of soap and a sour sugar (Anon.: Assessment report on
Primula veris，Primula elatior (L.)，radix. EMEA(HPMC/144474/2006) 〇 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普亦有類似效果(KraftK 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(〗，8 cine〇1)及其他多種物質如萜、 倍伟及倍半W，各以不同_侧，其巾亦包含化舰果(職池 J，Med. J. AUst· 163 (1995) 177-_。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瘦效果(Gus丨andi M，Im』ain p_⑶I黯Primula veris, Primula elatior (L.), radix. EMEA (HPMC/144474/2006) 〇 Saponin has a significant effect on the surface activity mechanism in aqueous solution. The use of plant saponins and sapogenins to reduce human saliva viscosity for microbiological analysis is a patented technology (US Patent No. 4053363). Triterpenoids contained in ivy leaves have similar effects (Kraft K Zeitschr Phytotherap. 25 (2004) 179-181; Fazio S et al., Phytomedicine 16 (2009) 17-24). Eucalyptus essential oils mainly contain eucalyptus (8, cine〇1) and many other substances such as 萜, weiwei and half W, each with a different _ side, and its towel also contains a navy (Yuchi J, Med) J. AUst· 163 (1995) 177-_. Licorice root also provides a variety of surface active substances, which can exert slimming effect after removing glycyrrhizin (Gus丨andi M, Im』ain p_(3)I黯
Toxicd” 23⑽5) 398_402)。冰島笞和藥蜀葵内含物質與局部麻醉劑之 組合為WO···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4魏，亦_具有化痰效果"_】丨c A，Ande_ 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胁治療實務，如碎 201247203 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 ALJetal·，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』比咯烷基)-3·吡啶基及其他降 解產物(Mihranyan A，Andersson S-B, Ek R，Eur. J. Phami. 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。 發明内容 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，更佳者為〇 1〇至4 〇〇%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/或〇 5〇至15 〇〇%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-步包含0.05至[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 •細、黃_、異伽、新黄_、花㈣、原花青素及其寡聚物以I 萃取自綠茶、薑黃、迷迭香'水飛莉、葡萄、銀杏、巴西每、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 值範圍調整為6.0至9.5，更佳者為7·〇至9 〇，最佳者為8 5。、 該組成物包含-溶劑，該溶劑為5Q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、丙稀乙二 201247203 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(黏皮及表面張力)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喷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5〇微升至2〇〇〇微升， 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〇 〇5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。 【發明内容】 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，更佳者為〇.1〇至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〗5 〇〇%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、南報春化、常春藤、尤加利或甘草。 組成物可進一步包含0.05至〗.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、新黄酮、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？11 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、 201247203 : 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2〇〇〇微升， 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005至3 〇〇毫克，更佳 者為0.10毫克至2.00毫克，最佳者為0.25毫克至】.〇〇毫克。 【實施方式】 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，如乙醢化胱胺酸及/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 疋性，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% ’更佳者為〇 10%至4.00%，最佳者為02〇〇/0至 1.00%。單次施用之尼古丁劑量可為〇 〇5毫克至3 〇〇毫克，更佳者為 0.10毫克至2_00毫克，最佳者為〇 25毫克至〗〇〇毫克。 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 201247203 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，巯基可為電子施體。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 筅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(l，8_cine〇丨)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 /舌吐物質，在除去甘草素後具有化痰效果。另一適用於本發明組成物 之成分為冰岛笞和藥蜀葵所含物質之組合，以及款冬種及毛芯屬植物 内所含物質。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，其濃度係為〇 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2¾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、新黄酮、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黄烷醇類，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 201247203 酸及其鹽之主要麵。在本個組成物濃度巾，包含各種 T, ^ !,〇/〇 比至1.0。/幸I μ U。 至1·5%重量比’最佳者為0.50%重量 技術解決k 在本案組成物巾為侧成分之溶劑。根據本發明 -，最Utitr之比例為鄕至99%，更佳者為⑽至 丁產物為調整酸度之成分，如以胺或胺基酸與尼古 =生，全鹽類或更佳者為緩衝系統醋酸鹽、轉檬酸、三乙醇胺、 ϋ j、碳酸鹽等等。可將二縣胺基酸單獨或組合使用，如穀胺 丨或雜胺基酸，如離㈣或蛋自㈣。為提高尼古丁 ，疋性及生物利用度’宜將溶液PH值範圍調整為6 〇至9 5，更佳者 為7.0至9.0 ’最佳之pH值為8 5。 本發明組成物之成分尚包括防腐添加劑。適用者為山 酸及鹽。其他適用於本發明之抗菌物質可包括對經 = 息香酸義，尤以甲基安息香酸_為佳。本發明组成 =此等植物之半極性溶劑萃取物。⑽乙：醇或乙醇亦=供= 植物原料之萃取劑。適用之防腐劑如金絲桃、冰島苔、 古 尾草柳皮專植物之酒精或丙稀乙二醇液體萃取物。 醇，Γί味覺感知之物f t要為增_。最·者為各種_及肌 …、丙稀乙二醇、絲、葡萄糖、左旋糖、山梨醇、甘露醇、 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=劑鹽、醋續内㈣、阿斯巴甜、新燈皮苦二氫查_、薦糖素、 取物、甜菊萃取物等等。可利用精油調整嗅覺感知，如薄荷油、 何油、大®香油、菌香油、尤加利油m小μ香油、肉桂 油百里香油、野百里香油、水序油、杜松油、墨角蘭油、 畺油#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。添加乙醇或丙稀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 201247203 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Q〗〇，以及鋅、銅硒、鈣 和猛等物質其鹽等等之複合物。可用抗炎劑為萃取自金絲桃、金盖花 及甘菊等之沒藥醇和尿囊素。 本發明之組成物係透過喷灑方式施用於口腔，亦即組成物在氣體 中以非均質或勝狀分散之方式接觸σ腔減、牙轉膜硬韻及舌頭 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㈣噴^推進氣體可為氮或其他化學惰性氣避，或丁 坑、異丁院或峨魏烴之混合物。喷域霧之中之顆粒 ⑽至100 μιΏ，較佳者為5⑻細至5卿。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5〇微升至屬微 升’較佳者為150微升至500微升。所列參數 案技術解決方案之主體。 巧飞月之用而非本 較佳實施例範例 範例卜2、3 :Toxicd" 23(10)5) 398_402). The combination of Icelandic cockroach and hollyhock's content and local anesthetic is disclosed by WO···. The flowers of the winter cultivar and the genus Verbascum contain a variety of substances, especially flavonoids and 4 Wei, also _ Has a phlegm effect "_] 丨c A, Ande_ LA, Phillipson JD, Herbal Medicines, Pharmaceutical Press, London 1996). Many other plant complexes are also treated with the alleged phlegm effect, such as broken 201247203 snow grass Nicotine, anise, anise, thyme and clover, etc. Nicotine is a relatively stable substance that decomposes when exposed to air and is accelerated by light. The strong receptors of electrons catalyze reactions and capture substances. The reaction inhibits the reaction. The decomposition reaction mainly produces alkylpyrrolidine oxynitrides (Suffredini HB et al., Anal. Letters 38 (2005) 1587-1599) and similar amounts of pyrrolidone (Beckwith ALJetal·, Austral. J). Chem. 36 (1983) 719-739). Nicotine absorbed in various celluloses contains cotinine, ketone-(1-methyl „3』pyrrolidyl)-3·pyridyl and others Degradation product (Mi Hranyan A, Andersson S-B, Ek R, Eur. J. Phami. Sci. 22 (2004) 279-286). One method of stabilizing nicotine is to absorb nicotine from cellulose of algae, bacteria or fungi (WO/2005/023227). The main metabolic site of nicotine in the human body is the lungs, which are known to produce dozens of metabolites (Moyer TP et al., Clin. Chem. 48 (2002) 1460-1471). To stabilize nicotine, water soluble antioxidants must be added. SUMMARY OF THE INVENTION A composition in which nicotine is absorbed into the system by the oral cavity and distributed in the central nervous system for the purpose of quitting smoking or nicotine replacement for smoking exemption is characterized by comprising a concentration of 0.01 to 8.00% by weight, more preferably The ratio of 〇1〇 to 4〇〇% by weight, preferably 0.20 to 1.00% by weight of the nicotine solution, the form being a salt of a base and/or a base and an organic acid; further comprising a hydrazine-forming effect a substance having a pupation effect of 3.0 to 30.0% by weight of acetylated cystine and/or 〇5〇 to 15% by weight of a pupation-effect plant complex. The plant complex of the cockroach effect is extracted from the yellow flower, the high primrose, the ivy, the eucalyptus or the licorice. The composition may further comprise 0.05 to [50% by weight of an antioxidant compound plant complex, and the antioxidant effect plant complex is selected from the group consisting of flavonoids, flavonoid yellow, fine, yellow _, and different gamma , New Yellow _, Flower (4), Proanthocyanidins and their oligomers are extracted from the aggregation of green tea, turmeric, rosemary 'shuifeili, grape, ginkgo, Brazil, mulberry, eucalyptus, West Indian cherry, etc. Things. The composition may preferably further comprise a buffer or an acid adjusting substance to adjust the value range to 6.0 to 9.5, more preferably 7·〇 to 9 〇, and most preferably 8 5 . The composition comprises a solvent, which is a mixture of 5Q to 99% by weight of water, or a mixture of water and 2 to 50% by weight of a polyol, wherein the polyol is glycerin, propylene oxide 201247203 alcohol and / or saccharide ' and the saccharide is selected from the group consisting of mannitol, xylitol, glucose, levulose and sucrose. The composition also preferably comprises at least one of the following: a substance that adjusts taste perception, a substance that adjusts olfactory perception, an antibacterial agent, a release agent, an antioxidant, a co-solvent, and a wettability enhancer, and improves physical parameters of the applied composition ( Substances of the skin and surface tension, as well as substances that improve the condition of the oral surface (mucosa or teeth). The composition of the present invention is applied to the oral cavity in a colloidal form or a heterogeneous air dispersion generated by a spraying device, and the single-use dosage of the composition is 5 〇 microliter to 2 〇〇〇 microliter. The best is 150 microliters to 500 microliters. The single-use dose of the composition comprises nicotine of 5 to 3.00 mg, more preferably 0.10 mg to 2,000 mg, and most preferably 0.25 mg to 1.00 mg. SUMMARY OF THE INVENTION A composition that causes nicotine to be absorbed into the system and distributed in the central nervous system by the mouth is intended to quit smoking or to eliminate smoking. The nicotine replacement is characterized by a concentration of 0.01 to 8.00% by weight, and more The preferred one is 〇.1〇 to 4.00% by weight, and the most preferred is 0.20 to 1.00% by weight of the nicotine solution, the type of which is a salt of a base and/or a base and an organic acid; further comprising a hydrazine effect a substance having a pupation effect of 3# to 30.0% by weight of acetylated cystine and/or 0.50 to 5% by weight of a quinone-effect plant complex, The plant complex of the cockroach effect is extracted from the yellow flower, the vernal, the ivy, the eucalyptus, the eucalyptus or the licorice. The composition may further comprise 0.05 to 〖.50% by weight of an antioxidant compound plant complex, and the antioxidant effect plant complex is selected from the group consisting of flavonoids, flavonoids, flavanones, flavonols, isoflavones , new flavonoids, anthocyanins, proanthocyanidins and their oligomers, and polymers extracted from plants such as green tea, turmeric, rosemary, milk thistle, grape, ginkgo, acai, mulberry, eucalyptus, and West Indian cherry . The composition preferably further comprises a buffer or an acid adjusting substance to be used? The 11 value range is adjusted to 6.0 to 9.5, preferably 7.0 to 9.0, and the best is 8.5. The composition comprises a solvent which is 50 to 99% by weight of water, or a mixture of water and 2 to 50% by weight of a polyol, wherein the polyol is glycerol 'propylene glycol and/or sugar And the saccharide is selected from the group consisting of mannitol, xylitol, glucose, 201247203: levulose and sucrose. The composition also preferably comprises at least one of the following: a substance that adjusts taste perception, a substance that adjusts olfactory perception, an antibacterial agent, a release agent, an antioxidant, a co-solvent, and a wettability enhancer, and improves physical parameters of the applied composition ( Viscosity and surface tension) and substances that improve the condition of the oral surface (mucosa or teeth). The composition of the present invention is applied to the oral cavity in a gel form or a heterogeneous air dispersion generated by a spraying device, and the single use dose of the composition is 50 microliters to 2 microliters, preferably It is from 150 microliters to 500 microliters. The single-use dose of the composition comprises 005 to 3 mg of nicotine, more preferably 0.10 mg to 2.00 mg, and most preferably 0.25 mg to 〇〇. [Embodiment] The composition of the present invention contains, in addition to nicotine and a salt thereof, an antimony agent such as acetylated cysteine and/or a plant complex having a pupation effect, which has a pupation effect - The plant complex is extracted from plants to increase nicotine bioavailability. The composition of the present invention may further comprise an antioxidant derived from a natural plant to enhance the stability of nicotine and prevent oxidation thereof, and water is used as a solvent in the composition. The composition of the present invention may also contain various stabilizers such as antibacterial agents, release agents, and free radical quenchers; and sensory property adjusting substances may also be added. The composition of the present invention may also contain a substance which improves physical parameters such as viscosity and surface tension at the time of application of the composition, and a substance which improves oral surface conditions such as mucosa or teeth. Nicotine is an extremely potent alkaloid that dissolves easily in water-to-strong alkaline solutions. The oral mucosa is well tolerated, and it can be fully absorbed into the systemic circulation after absorption through the oral mucosa. The pH of the nicotine solution is preferably below 9.0 and above 7.0. The pH of the aqueous nicotine solution can be easily lowered by adding a salt such as citric acid, malic acid, tartaric acid, lactic acid, glycolic acid or phosphoric acid. The concentration of nicotine in the solution depends on the dose to be administered; it may be from 0.01% to 8.00%' more preferably from 10% to 4.00%, and most preferably from 02〇〇/0 to 1.00%. The dose of nicotine for a single administration may be from 5 mg to 3 mg, more preferably from 0.10 mg to 2 mg, and most preferably from 25 mg to 〇〇 mg. The quinone agent is a highly hydrophilic substance which lowers the viscosity of mucin, and the mucin contains a mucin substance. Decreasing the viscosity of mucins allows nicotine molecules to spread faster to the surface of the mucosal screen 201247203, thus accelerating and enhancing the absorption of nicotine. Acetylcysteine is a highly hydrophilic substance. The carboxyl group can interact with the basic nitrogen of the pyrrolidine ring of nicotine. It has an antioxidant effect and the sulfhydryl group can be an electron donor. It is an important bismuth agent that interacts with disulfide bonds to reduce the viscosity of aqueous mucoprotein solutions. Natural plant-derived elixirs capable of increasing the nicotine bioavailability of the compositions of the present invention are the same as those conventionally used to promote phlegm and phlegm, which are especially commonly used in pediatrics. Applicable to the extraction of a complex from a medicinal plant, such as a yellow flower or a high water or alcohol extract of the roots of the spring, which contains triterpenoid saponins and phenolic sugars. Triterpenoid saponins contained in ivy leaves have similar effects. The composition of the present invention may also comprise an essential oil derived from eucalyptus leaves, which particularly contains eucalyptus (l, 8_cine) and various other substances such as hydrazine, sesquiterpene and sesquiterpene alcohol. The plant complex extracted from the licorice root can provide a surface/tongue substance and has a phlegm effect after removing the glycyrrhizin. Another component suitable for use in the compositions of the present invention is a combination of the substances contained in Icelandic and medicinal hollyhocks, and the contents of the plants of the winter and the genus. There are many other plant complexes that provide the desired phlegm effects such as crushed grass, oregano, anise, 'thyme, clover and more. When the plant complex having the pupation effect is used as a component of the composition of the present invention, the concentration thereof is from 5% by weight to 15% by weight, more preferably from 0.5% by weight to 5% by weight, most preferably 1% by weight to 23⁄4 by weight. The antioxidants in the composition of the present invention are important for maintaining the stability of nicotine in the solution, preventing the oxidation reaction of nicotine, and the antioxidant also has a positive effect on the oral mucosa. The composition of the present invention may comprise a natural plant. a substance or a water-soluble mixture thereof, such as ascorbic acid and its salts, various flavonoids such as flavonoids, flavonoids, flavanones, flavonols, isoflavones, new flavonoids, anthocyanins, proanthocyanidins and oligomers thereof polymer. In many plant complexes extracted from plant materials containing known species, the catechin-containing green tea leaf extract is a flavanol, the milk thistle extract contains a milk thistle complex, and the turmeric extract contains turmeric. The complex, the rosemary extract comprises rosmarinic acid, the grape extract comprises proanthocyanidins and various other polyphenolic materials, the ginkgo leaves contain flavonoids, and both the mulberry fruit and the acai berry contain anthocyanins. In addition to epicatechins contained in green tea, quercetin of flavonols and resveratrol of polyphenols are most commonly used in foods. French Coast Pine Pycnogenol extract contains a mixture of many bioflavonoid catechins, oligomeric proanthocyanidins and phenolic acid with antioxidant capacity. Extraction of plants such as eucalyptus and West Indian cherry 201247203 Main surface of acid and its salt. In this composition concentration towel, it contains various T, ^ !, 〇 / 〇 ratios to 1.0. / Fortunately I μ U. To the weight ratio of 5% to 0.5% by weight, the technical solution is k. In the present case, the composition of the towel is a solvent for the side component. According to the invention - the ratio of the most Utitr is from 鄕 to 99%, more preferably from (10) to the butyl product as a component for adjusting the acidity, such as with an amine or an amino acid and a nicotine, a whole salt or better. Buffer system acetate, citric acid, triethanolamine, ϋ j, carbonate, etc. The two county amino acids may be used singly or in combination, such as glutamine or a heteroamino acid, such as from (iv) or from egg (tetra). In order to improve nicotine, sputum and bioavailability, the pH range of the solution should be adjusted to 6 〇 to 95, and more preferably 7.0 to 9.0 ‘the optimum pH is 85. The ingredients of the compositions of the present invention also include antiseptic additives. Applicable to sorbic acid and salt. Other antibacterial substances suitable for use in the present invention may include p-acetic acid, especially methyl benzoic acid. Composition of the invention = semi-polar solvent extract of such plants. (10) B: Alcohol or ethanol also = extractant for plant material. Suitable preservatives such as Hypericum, Icelandic Moss, Alcoholic Willow Skin Plant Alcohol or Ethylene Glycol Liquid Extract. Alcohol, Γί taste perception of the object f t to increase _. Most of them are various kinds of _ and muscle ..., propylene glycol, silk, glucose, levulose, sorbitol, mannitol, sugar alcohol honey and so on. Another class of substances suitable for this purpose are artificial non-nutritive sweeteners, such as = salt, vinegar continuation (four), aspartame, new lamp dermatitis dihydrogen check _, sucrose, extract, stevia extract and many more. Essential oils can be used to adjust olfactory perception, such as peppermint oil, pecan oil, large sesame oil, bactericidal oil, eucalyptus oil m small μ sesame oil, cinnamon oil thyme oil, wild thyme oil, water sequence oil, juniper oil, marjoram Oil, oyster sauce # and so on. The composition according to the present invention may further comprise other components for positively adjusting its physical parameters. The addition of ethanol or propylene glycol can reduce the viscosity and surface tension of the aqueous solution. It is also possible to use an surfactant. For substances such as mucous membranes and teeth that affect the positive 201247203, the substance may contain a variety of vitamins and minerals, such as vitamin B group and its salts, vitamin C and its salts, esters and glycosides, vitamin H, coenzyme Q, and A complex of zinc, copper selenium, calcium, and other substances, salts thereof, and the like. An anti-inflammatory agent can be used as the bisabolol and allantoin extracted from hypericum, golden ginseng and chamomile. The composition of the present invention is applied to the oral cavity by means of spraying, i.e., the composition is in contact with the sigma cavity reduction, the tooth transition film rhyme and the tongue surface in a gas dispersed manner in a heterogeneous or victorious manner. The air distribution generator can be a pump, or can also be a pressure vessel with a propeller to spray the composition in a gas stream (4). The gas can be nitrogen or other chemically inert gas, or Dingkeng, Yidingyuan or Weiwei hydrocarbon. mixture. Particles in the mist of the spray zone (10) to 100 μιη, preferably 5 (8) to 5 cm. To control the dose, the air dispersing generator is equipped with a dispensing device. The liquid dose for a single administration may range from 5 microliters to microliters, preferably from 150 microliters to 500 microliters. The main body of the listed technical solution. The use of the moon is not the case of the preferred embodiment. Examples 2, 3:
12 201247203 水 達 100.00 g 達 100.00 g 達 100.00 g 範例 4、5、6、7 : 成分 組成物（％重量比） 4號樣本 5號樣本 6號樣本 7號樣本 尼古丁 1.00 0.2 2 1 檸檬酸 0.95 1.55 1.55 2.10 黃花九輪草萃取物 2.00 - - - 常春藤萃取物 - 3.00 - - 甘草萃取物 - - 10.00 - 款冬萃取物 - - - 1.00 綠茶萃取物 1.00 - - - 迷迭香萃取物 - 0.50 - 問荊萃取物 - 0.30 - 銀杏萃取物 - - 1.00 - 葡萄萃取物 - - - 0.10 山梨酸鉀 0.10 0.10 0.1 0.10 苯曱酸鈉 0.10 0.10 0.1 0.10 蔗糖素 0.07 0.08 0.07 0.10 甘油 5.00 10.00 10 15.00 香料 0.10 0.20 0.3 0.35 氫化聚乙二醇化蓖麻油 0.12 0.12 0.12 0.12 氫氧化鈉 適量，pH 適量，pH 適量，pH 適量，pH 7.0-9.0 7.0-9.0 7.0-9.0 7.0-9.0 水 達 100.00 g 達 100.00 g 達 100.00 g 達 100.00 g 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。 13 201247203 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。 【圖式簡單說明】 無。 【主要元件符號說明】 無。12 201247203 Water up to 100.00 g up to 100.00 g up to 100.00 g Example 4, 5, 6, 7 : Composition (% by weight) No. 4 Sample No. 5 Sample No. 6 Sample No. 7 Sample Nicotine 1.00 0.2 2 1 Citric acid 0.95 1.55 1.55 2.10 Yellow Flower Herb Extract 2.00 - - - Ivy Extract - 3.00 - - Licorice Extract - - 10.00 - Coltsfoot Extract - - - 1.00 Green Tea Extract 1.00 - - - Rosemary Extract - 0.50 - Question Jing extract - 0.30 - Ginkgo biloba extract - - 1.00 - Grape extract - - - 0.10 Potassium sorbate 0.10 0.10 0.1 0.10 Sodium benzoate 0.10 0.10 0.1 0.10 Sucralose 0.07 0.08 0.07 0.10 Glycerin 5.00 10.00 10 15.00 Flavor 0.10 0.20 0.3 0.35 Hydrogenated PEGylated castor oil 0.12 0.12 0.12 0.12 Sodium hydroxide, proper pH, proper pH, proper pH, pH 7.0-9.0 7.0-9.0 7.0-9.0 7.0-9.0 Water up to 100.00 g up to 100.00 g up to 100.00 g 100.00 g Preparation procedure: Individual ingredients are added stepwise to dissolve in water. The solution is filtered as needed and loaded into a pressure vessel provided with a dispensing valve or a closed vessel provided with a dispensing valve and driven by a manual pump. 13 201247203 Industrial Applicability: The composition of the present invention can be manufactured by the pharmaceutical industry. The preparation is suitable for the absorption of nicotine transmucosal for the purpose of smoking cessation. [Simple description of the diagram] None. [Main component symbol description] None.
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