Formulation studies for eliminating saliva carcinogenic acetaldehyde with L-cysteine containing chewing gum (2012)

Tobacco smoke is a major risk factor for the development of cancers in the upper parts of gastrointestinal tract. It has been estimated that the risk of oral cancer among smokers is 7 10 times higher than for never-smokers. \n\nAcetaldehyde is formed during the tobacco smoking burning process and may be one of the most toxic compounds in tobacco smoke. According to the International Agency for Research on Cancer (IARC), in 2004 acetaldehyde was classified as a possible carcinogen in humans (Group 2B). In 2009, acetaldehyde was classified in Group 1, as a carcinogen to humans. A non-essential-amino acid such as L-cysteine, is able to bind acetaldehyde and form 2-methylthiziolidine-4-carboxylic acid (MTCA). \n\nThe general aim of this study was to through formulation studies to explore the ability of L-cysteine to eliminate carcinogenic acetaldehyde present in saliva. In addition, the aim was to develop user-friendly L-cysteine containing chewing gum to reduce acetaldehyde formed during tobacco smoking. The main variables were the chemical form of L-cysteine used (L-cysteine or L-cysteine hydrochloride) and the chewing gum preparation method (traditional and novel direct compression method). Furthermore, the aim was to obtain more information on the optimal formulation properties, using approaches such as stability studies and possible interactions between cysteine and used excipients. Caco-2 cell lines were used to access the ability of L-cysteine and MTCA to absorb from the gastrointestinal tract. A computational model was developed to analyse the effects of different physiological factors and effect of formulation parameters on tobacco smoke acetaldehyde. \n\nThe combined results of these studies suggested that tobacco smoke carcinogenic acetaldehyde can be successfully eliminated with prepared L-cysteine chewing gums. Compared to the traditional manufacturing process the directly compressed gum formulation can offer an alternative method to traditional chewing gum production. Due to the slower dissolution rate, better compatibility with excipients, and better stability under higher temperature and humidity, L-cysteine as a free base is a better candidate for chewing gum formulation than cysteine hydrochloride. \n\nThe Caco-2 permeability studies indicate no significant risk of the locally administered L-cysteine being absorbed before binding to acetaldehyde. Permeability results also indicated that MTCA is not absorbed locally from the gastrointestinal tract, which reduces the risk of systemic effects. An MTT assay, a widely used cytotoxicity test, demonstrated that neither L-cysteine nor MTCA was toxic to the Caco-2 cells. \n\nA computational model that was developed was able to show how sensitive acetaldehyde is to changes in the amount of L-cysteine as well as in saliva excretion rates. The model can be used as a tool for the prediction of drug amount and the local effect in the mouth of water-soluble compounds, such as L-cysteine. \n\nIn conclusion, elimination of acetaldehyde, not only carcinogen, but also agent which possibly increases the addictive potential of tobacco, might help in the fight against smoking and make smoking cessation programs more efficient. L-cysteine, a non-essential amino acid, is able to prevent the harmful effects of acetaldehyde by binding acetaldehyde and forming MTCA. It should be kept in mind that acetaldehyde elimination does not make smoking completely harmless and tobacco smoke contains other carcinogens and addictives. The best way to protect from tobacco induced diseases is to refrain from smoking. However, besides the fact that most smokers want to quit but most attempts fail and since tobacco smoke contains many carcinogenic compounds, in the future, developed computational models can offer a new view in eliminating or reducing not only one toxic compound from tobacco smoke but also many other compounds using only one formulation containing various active compounds.