CN1338902A - 含有抗氧化剂的吸烟制品 - Google Patents
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Abstract
一种用于加入大量无烟烟草中的组合物。该抗氧化剂组合物能减少由食用无烟烟草产生的自由基对使用者口咽腔的损伤。该组合物包括L-谷胱甘肽和硒源。
Description
发明领域
本发明涉及多种协同性抗氧化剂、酶促辅因子如含硒的化合物和氨基酸在合适的输送载体中的组合,它可用于通常所称的“无烟烟草”中作为预防或缓解由这些制品损伤所引起的口咽腔的征兆和症状和并发症的手段。
发明背景
烟草是含有成瘾性药物尼古丁的植物红叶烟草(Nicotiana tabacum)的干枝叶构成的物质。该植物原产于北美,但现在在全世界种植。滥用烟草被确认为是最可以预防的导致疾病、病态和死亡的原因。烟草含有并产生许多有毒的化学物质和自由基。吸食烟草有3种主要方式:1)吸烟;2)咀嚼和浸取,以及3)用鼻吸。50,000,000美国人吸烟,另有不计其数的人受到烟草烟的影响,即所谓二次或被动吸烟者。烟民的孩子也吸进二手烟,且比非吸烟者的孩子有更多的呼吸问题。吸烟者的不吸烟的配偶或同事患心脏病的频率高于真正不吸烟的对照。
有多达14,000,000人使用无烟烟草,无烟烟草对口腔有害,而且还因颊粘膜吸收尼古丁和其它有害化学物质而有全身性影响。使用无烟烟草的青少年正在增多。咀嚼松散的烟草叶和“浸渍”湿润的经研磨的鼻吸烟草是常见的不产生烟的烟草用法。在本国,很少有人使用“鼻吸”(即将烟草干粉“吸入”鼻通道)。无烟烟草对健康的危险性仍然非常显著,它并不是吸烟的替代物。国立癌症研究院已经开展了大量的教育活动,对10-12岁使用无烟烟草的吸烟者的增长提出了警告。
由于口咽接触环境,如皮肤接触氧气和紫外辐射一样,口腔结构会被吸入的、摄食的或咀嚼的有毒物质以及气体和颗粒破坏,而且会因体内过程(如发炎反应和药物(异生素))而受损。有反应性的氧化性物质(如吸入的和咀嚼的烟草诱导产生的、臭氧和氮氧化物)是产生自由基并诱导炎性反应的重要因素。
粘膜白斑病是在吸烟者中发现的由烟草诱导在颊粘膜上产生的白斑,它是一种因直接接触抽吸的烟草或无烟烟草所引起的局部刺激症状,它与吸烟的频率和年数直接相关。虽然粘膜白斑病是一种良性口腔损伤,但它有变成恶性的可能,需要通过损伤活检来排除癌症可能。当中断使用烟草制品后,粘膜白斑病会减退或完全消失。基层医师和牙医经常检查口腔对于减少吸烟诱导的口齿疾病是非常重要的。
每年诊断新增30,000例口腔癌,其占所有新发现癌病例的2%至4%。口腔癌每年造成8,000人死亡,每年确诊病例中5年存活率仅为半数。这些患者中大多数是烟草制品使用者。其他危险的因素包括滥用酒精,营养不良和口腔卫生不良。
另外,烟草还造成其他口腔症状或口腔、牙龈和牙齿疾病。烟草会造成口臭,造成味蕾麻木,干扰食物的香味和口味。它使牙齿发黄,造成龋齿。吸烟者的牙石多于非吸烟者。烟草还与牙龈炎、严重的牙周病和掉牙有关。急性坏死性溃疡性牙龈炎(“战壕口炎”)是一种破坏性,有痛感的炎症,主要发生于吸烟者。
除了粘膜白斑病,另一种在颊粘膜上的弥散性白色代表着口粘膜下纤维变性。该疾病主要发生于印度,它是一种慢性渐行性恶变前的状况。其病因是长期咀嚼烟草或槟榔或两者。纤维变性(瘢痕形成)导致口张开受限制,并牵连上颚、扁桃体窦、颊粘膜及下面的肌肉。口咽癌也与该状况有关,该疾病的印度的发病率很高,70%的病例与咀嚼烟草有关。使用无烟烟草和槟榔在巴基斯坦人、孟加拉国人和爪哇人以及移民到美国和英国的这些国家的人和印度人中也是常见的。
滥用烟草的有害作用是众所周知的,管理机构和公众经常对这些科学的和流行病学证据有所反应。由于显著的发病率和死亡率,烟草实际上是对全球公众健康的危害。
受到因摄食无烟烟草而引起的氧化应激的细胞会严重影响细胞功能,并对细胞膜的脂质、蛋白、细胞骨架结构和DNA造成伤害。已经测定了自由基对DNA的损害,如形成单链断裂,双链断裂和染色体畸变。还已经证明,经受离子辐射和香烟烟雾的细胞具有增加的细胞内DNA损伤,因此,吸烟者口咽癌、食管癌和肺癌的发病率增高。
现已研究了无烟烟草对发炎以及前列腺素E2和白介素的牙龈下隙水平的影响。将大量的无烟烟草置于颊粘膜上会使这些分子的水平增加,结果有显著的发炎。发现牙槽粘膜中的反应比牙龈中的更严重,其程度为红斑到溃疡,这证实了无烟烟草对牙周组织有不利影响的结论。
研究表明,Maras粉末(土耳其使用的一种无烟烟草)影响惯用者中颊粘膜细胞的微核。这提供了无烟烟草具有遗传毒性作用的证据及其与口腔癌的关系。另外,已经表明无烟烟草萃取物在利用正常人血清的体外测试中激活了补体系统。研究了松散的咀嚼烟草叶以及干的和湿的鼻烟。研究表明,这三种烟草激活补体途径,因此提出了这些制品提供了口粘膜中炎症引发的推定机理。炎症反应进而产生了无数的自由基,这些自由基进一步破坏了牙龈组织和口粘膜细胞DNA。更近一段时间,已经证实尼古丁对人原代牙周韧带和牙龈成纤维细胞培养物有细胞毒性。因此,得出结论,尼古丁无疑是牙周病发展中的一个危险的因素。有趣的是,在瑞典进行的流行病学研究有力地暗示食用啤酒和烈性酒为口鼻烟诱生口腔癌提供了非常危险的因素。
普遍存在的非酶促硫醇三肽—谷胱甘肽(GSH)—在维持对反应性氧自由基敏感的细胞组分的完整性中起重要作用。这种作用是通过其以还原型(GSH)作为抗氧化剂和作为辅因子的直接作用来实现的。已检测到支气管肺泡灌洗液中存在GSH。在细胞中,GSH在此过程中被氧化成GSSG,但抗氧化剂活性的细胞浓度通过谷胱甘肽还原酶消耗NADPH作为还原性等价物的来源来维持。在GSH耗尽状态下,包括营养不良和严重的氧化应激,例如吸烟和/或咀嚼烟草,细胞会受损和死亡。
发明概述
本发明包括将抗氧化剂防御系统掺入无烟烟草。本发明利用具有协同作用的抗氧化剂,在使用无烟烟草时,它们被输送到使用者的口咽,以预防和缓解这些制品诱导产生的自由基损伤。最广义的说,本发明包含还原型谷胱甘肽和用于再生并与还原型谷胱甘肽协同作用的辅助成分,后一成分包含硒,较佳的是硒代氨基酸,例如硒代甲硫氨酸或硒代半胱氨酸。作为其它任选成分,组合物可考虑包含抗坏血酸和/或其衍生物之一,含硫氨基酸例如L-半胱氨酸、L-牛磺酸和/或L-甲硫氨酸,α-生育酚和维生素A。还可包括其它抗氧化剂来发挥它们的抗氧化剂性质,如工业上已知的来自绿茶和葡萄籽萃取物的那些。
发明详述
不局限于任何具体理论,我们发现,还原型谷胱甘肽通过氧化自身来保护细胞不受氧化应激。所以,L-谷胱甘肽必须与其它酶系统组合来发挥作用,以便被还原而恢复行使其作为自由基清除者的作用。GSH还与需以硒为辅因子的谷胱甘肽过氧化物酶协同,发挥其生物抗氧化剂的功能。已知硒化合物能够通过谷胱甘肽过氧化物酶的作用与还原型谷胱甘肽一起清除体内以氧为中心的自由基。据信,硒-GSH过氧化物酶在还原型谷胱甘肽存在下催化有毒性的氢过氧化物酶。该反应减少谷胱甘肽,生成氧化型谷胱甘肽GSSG。然后,GSSG又被谷胱甘肽还原酶还原成GSH,从而保持了充足的细胞GSH来重新清除自由基。
此外,谷胱甘肽和硒还具有体内协同作用,因为它们都是同一酶系统的成员。GSH起着特异性供体底物的作用,通过饮食或口内和局部应用的硒制剂提供的硒或硒代氨基酸则提供GSH过氧化物酶的辅基。硒通过酶诱导增强了谷胱甘肽过氧化物酶的水平。谷胱甘肽与硒的抗氧化剂功能内在地相互关联,因为,通过保持过氧化物酶发挥作用,GSH与硒参与氧自由基歧化产物即过氧化氢的去除。广义的说,GSH与硒调节由氢过氧化物引发或维持的自由基链。在本发明中,利用了硒的抗氧化剂作用,以及其抗致癌和抗诱变特性。
考虑将具有协同作用抗氧化剂复合物分散到大量的无烟烟草(如咀嚼烟草和鼻烟)中。抗氧化剂复合物可以水性乳液形式进行分散,或可包囊在微囊化脂质体中,在使用无烟烟草制品时释放。还可通过将活性组分掺入糖球(glycosphere)和纳球(nanosphere)中使之被保护。用于口服和皮肤病用途的这些赋形剂是化妆品及药物工业上熟知的。脂质体是卵磷脂球,它在本发明活性组分组合物周围形成了油保护膜。脂质体所包裹的活性成分穿过烟草制品,传递到口腔,在此发挥其预防与治疗双重功能,中和各种反应性氧和其它自由基。此外,抗氧化剂还可以象通常那样由颊黏膜吸收而全身性使用,以进一步中和烟草制品产生的自由基。
松散的咀嚼烟草叶基本上是空气熟化过的烟草,它通常用甘草和糖来处理。本发明的抗氧化剂复合物可在加工烟草时加入,此时可加入调味剂。代替可消化的糖,增甜剂宜为多元醇木糖醇,以帮助发挥口服的优点。糖会发酵,因此引起龋齿,并有助于口腔内微生物数目增加。木糖醇减少口腔内变异链球菌的数目。因此,木糖醇有助于减少牙洞,在由推定的侵入细菌引起的牙龈炎和牙周炎中有作用。烟草块从植物顶部没有茎干的较重级别的叶子制得。这时将其浸在甘草和糖的混合物中并压成块。在生产的这一阶段可加入本发明的抗氧化剂复合物。糖将被多元醇增甜剂木糖醇替代。然后用外包叶包覆该烟草块,重新成形,这种块就可由无烟烟草使用者放在脸颊和齿龈之间。烟草块通常被咀嚼,从而使抗氧化剂复合物的治疗和预防效果能清除和中和无烟烟草块产生的自由基。
烟草股或卷从熟化的白肋烟(细纤维烟草)以及经空气熟化并经烟熏的叶子制得。给其加味并搓成绳状。在烟熏处理并使烟草冷却易于调味后,在烟草股或卷中加入本发明的抗氧化剂。
在美国消费量增加的经口鼻烟是从Kentucky和Tennessee的经烟熏处理的烟草制得的,该过程需要数周,多个阶段,而且与其它无烟类型不同,该过程经历发酵。然后将干的鼻烟加工成粉,其中可加入本专利申请的抗氧化剂复合物以及调味剂和芳香添加剂(包括香料)。经口食用的美国干鼻烟与欧洲的经鼻鼻烟非常相似,在后者中也可加入该抗氧化剂复合物来发挥其保护性优点。
注意到Unger及其同事在1996年12月3日的美国专利5,580,573(纳入本文作为参考)中说明了包含充气脂质体的治疗性药物输送系统,脂质体内包囊有活性制剂。此前,Chakrabarti及其同事公开了用脂质体作为输送载体的包含脂类和改性肽的制剂。参见1995年1月10日的美国专利5,380,531,该专利纳入本文作为参考。Knight及其同事在1991年9月17日的美国专利5,049,388(纳入本文作为参考)中公开了包含脂质体的小颗粒水性气雾液滴。该专利权人指出,将会相互作用的药物包含在脂质体膜内,这样,当后者破裂时,活性组分不会从脂质体内流失。该发明人还说明了各种制备含活性颗粒的脂质体的方法。相互作用的脂质体-药物组合颗粒被用于小颗粒治疗。
本发明的活性组分如下:
1. L-谷胱甘肽,量为0.01-2.0%,最佳为0.1-1.0%。
2.硒源,如L-硒代甲硫氨酸或L-硒代半胱氨酸,其浓度为0.001-1.0%,最佳为0.01-0.10%。
任选的组分
3. L-半胱氨酸和/或其酯,N-乙酰-L-半胱氨酸,范围是0.01-3.0%,最佳为0.1-1.0%。
4.抗坏血酸或抗坏血酸棕榈酸酯或其它抗坏血酸酯形式的维生素C,单独存在或包囊在诸如脂质体等微囊中,0.05-5.0%,较佳的0.1-3.0%,最佳的0.5-1.5%。
5.分散系的粉末形式的维生素E,如乙酸生育酚酯或琥珀酸生育酚酯或其它酯,用量为0.05-5.0%,较佳的为0.1-3.0%,最佳的为0.5-1.5%。维生素E也可以大致相同的剂量用于脂质体。
6.维生素A,如β-胡萝卜素或棕榈酸视黄酯或其它维生素A稳定化的酯,量在0.05-5.0%之间,较佳的为0.1-3.0%,最佳的为0.5-1.5%。维生素A组合物也可通过加入微囊如脂质体中来给予。
7.至于其它任选的组分,上述的氨基酸甲硫氨酸和/或牛磺酸可以各自以至少约0.01-3.0%、较佳的0.05-2.0%、最佳的0.1-1.0%的浓度加入。
在本发明的最佳实施方案中,相同组分可以水溶液加入烟草(可咀嚼烟草或鼻烟)中,其组成如下:
1. L-谷胱甘肽,至少0.01-2.0重量%,最佳为0.1-1.0重量%。
2. L-硒代甲硫氨酸,至少0.001-1.0%,最佳为0.01-0.10%。
3. L-半胱氨酸和/或其酯,N-乙酰-L-半胱氨酸,至少为0.01-3.0%,最佳为0.1-1.0%。
4.抗坏血酸或其酯,0.05-5.0%,较佳的为0.1-3.0%,最佳为0.5-1.5%。
5.维生素E或其酯之一,0.05-5.0%,较佳的为0.1-3.0%,最佳为0.5-1.5%。
6.维生素A或其酯之一,0.05-5.0%,较佳的为0.1-3.0%,最佳为0.5-1.5%。
7.氨基酸,牛磺酸和/或甲硫氨酸,0.01-3.0%,较佳的为0.05-2.0%,最佳为0.1-1.0%。
在本发明的一个实施方案中,可将任选的组分,尤其是外源抗氧化剂加入协同性复合物中,例如:
日本绿茶(儿茶酸类) 约0.5%
proauthouganidins 约0.2%
辅酶Q 约1.0%
N-乙酰-L-肉毒碱 约0.5%
在鼻烟中,可将活性组分,即本专利申请的抗氧化剂,以干粉形式(或作为抗氧化剂混合物,或作为在保护性脂质体、纳球或其它可接受的输送载体中的复合物)加入。该粉末可在生产咀嚼烟草和鼻烟的最后过程中加入,也可含有本行业中常用的合适的调味剂或芳香剂。
Claims (11)
1.一种组合物,用于掺入大量的诸如咀嚼烟草或鼻烟的无烟烟草中以减少自由基诱导的对使用者口咽腔的损伤,所述组合物包含L-谷胱甘肽和硒源。
2.根据权利要求1所述的组合物,其中所述硒源选自硒代氨基酸、硒代甲硫氨酸和硒代半胱氨酸。
3.根据权利要求1所述的组合物,该组合物还包含维生素C,其形式选自棕榈酸抗坏血酸酯和抗坏血酸酯。
4.根据权利要求1所述的组合物,该组合物还包含选自L-半胱氨酸和N-乙酰-L-半胱氨酸的一个成员。
5.根据权利要求1所述的组合物,该组合物还包含维生素E,其形式选自乙酸生育酚酯和琥珀酸生育酚酯。
6.根据权利要求1所述的组合物,该组合物还包含维生素A。
7.根据权利要求1所述的组合物,该组合物还包含选自甲硫氨酸和牛磺酸的氨基酸。
8.根据权利要求1所述的组合物,其中所述无烟烟草是咀嚼烟草。
9.根据权利要求1所述的组合物,其中所述无烟烟草是鼻烟。
10.根据权利要求1所述的组合物,该组合物还包含增甜剂。
11.根据权利要求10所述的组合物,其中所述增甜剂是木糖醇。
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US5766873A (en) * | 1994-01-31 | 1998-06-16 | Lugwig Institute For Cancer Research | Intracellular glutathione raising agents for therapeutic treatments |
FR2721208B1 (fr) * | 1994-06-16 | 1996-08-02 | Oreal | Composition à usage topique contenant un antioxidant et un extrait bactérien, et utilisation de cette composition. |
US5667791A (en) * | 1996-05-31 | 1997-09-16 | Thione International, Inc. | X-ray induced skin damage protective composition |
US5780489A (en) * | 1996-08-21 | 1998-07-14 | Brooks; Benjamin Rix | Method for treating amyotrophic lateral sclerosis |
US5906811A (en) * | 1997-06-27 | 1999-05-25 | Thione International, Inc. | Intra-oral antioxidant preparations |
US5829449A (en) * | 1997-09-19 | 1998-11-03 | Thione International, Inc. | Smoking products containing antioxidants |
US5922346A (en) * | 1997-12-01 | 1999-07-13 | Thione International, Inc. | Antioxidant preparation |
US6011067A (en) * | 1999-06-11 | 2000-01-04 | Thione International, Inc. | Antioxidant composition for the treatment of psoriasis and related diseases |
-
1998
- 1998-11-03 US US09/185,172 patent/US6138683A/en not_active Expired - Fee Related
-
1999
- 1999-10-29 CN CN99814275A patent/CN1338902A/zh active Pending
- 1999-10-29 CA CA002349241A patent/CA2349241A1/en not_active Abandoned
- 1999-10-29 JP JP2000579075A patent/JP2002528107A/ja active Pending
- 1999-10-29 AU AU13335/00A patent/AU768297B2/en not_active Ceased
- 1999-10-29 EP EP99956804A patent/EP1135036A4/en not_active Withdrawn
- 1999-10-29 WO PCT/US1999/025548 patent/WO2000025612A1/en not_active Application Discontinuation
- 1999-10-29 IL IL14293099A patent/IL142930A/xx not_active IP Right Cessation
-
2002
- 2002-03-25 HK HK02102256.3A patent/HK1042632A1/zh unknown
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CN103347409A (zh) * | 2010-08-11 | 2013-10-09 | R.J.雷诺兹烟草公司 | 可熔化的无烟烟草组合物 |
CN102475354A (zh) * | 2010-11-19 | 2012-05-30 | 红塔烟草(集团)有限责任公司 | 维生素b3维生素e酯在烟草制品中的应用以及烟草制品 |
CN102423125A (zh) * | 2011-08-17 | 2012-04-25 | 红塔烟草(集团)有限责任公司 | 一种含维生素c类化合物的烟草制品及其应用 |
CN103601711B (zh) * | 2013-11-04 | 2016-09-07 | 广东中烟工业有限责任公司 | 一种香豆素衍生物及其制备方法和应用 |
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CN104939075A (zh) * | 2015-05-26 | 2015-09-30 | 南昌大学 | 一种以l-硒甲基硒代半胱氨酸为主要原料的抗氧化保健品 |
CN106579541A (zh) * | 2016-12-30 | 2017-04-26 | 中国烟草总公司广东省公司 | 一种茉莉香型无烟烟草制品及其制备方法 |
CN106723299A (zh) * | 2016-12-30 | 2017-05-31 | 中国烟草总公司广东省公司 | 一种玫瑰香型抹香烟及其制备方法 |
CN108185507A (zh) * | 2018-01-04 | 2018-06-22 | 中国烟草总公司广东省公司 | 一种富含硒的烟草咀嚼片 |
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Also Published As
Publication number | Publication date |
---|---|
WO2000025612A1 (en) | 2000-05-11 |
HK1042632A1 (zh) | 2002-08-23 |
IL142930A0 (en) | 2002-04-21 |
JP2002528107A (ja) | 2002-09-03 |
US6138683A (en) | 2000-10-31 |
CA2349241A1 (en) | 2000-05-11 |
EP1135036A4 (en) | 2003-08-13 |
AU768297B2 (en) | 2003-12-04 |
IL142930A (en) | 2003-05-29 |
AU1333500A (en) | 2000-05-22 |
EP1135036A1 (en) | 2001-09-26 |
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