PT86814B - PROCESS FOR THE MANUFACTURE OF CIGARETTES - Google Patents

Abstract

Redried cut rag tobacco is directly sprayed with one or more pre-selected alcohols. These are capable, when the vapours are inhaled by the smoker, of inhibiting or blocking the selective localisation of at least one nitrosamine and/or a metabolite thereof in the smoker's tissues such as those of the epithelial lining of his lungs. An example of such an alcohol is cyclohexanol in an ethyl alcohol solution. After the alcohol solution has been sprayed on the tobacco, pref. as it tumbles in the cooler cylinder of the mechanised cigarette making line, and allowed to dry, the tobacco is made or machined in a conventional manner into the final cigarette, either filtered or unfiltered. The blocking alcohol is then efficiently heat released into the tobacco smoke stream as the cigarette is smoked, resulting in the desired blocking effect in the smoker, without noticeably altering the customary smoking experience and satisfaction.

Description

The present invention relates to articles for tobacco smokers and their construction, as well as methods to reduce the health risks of smokers. The invention also relates to processes for the manufacture of cigarettes and to cigarettes manufactured by said processes.

It is well known that tobacco and, more particularly, tobacco smoke contains numerous potential carcinogens and potential co-carcinogens. Accoungts of Chem, Res., S. Hedt et al, 12: 92-98 (1979). Cancer Research, D. McCoy et al., 41 2849-2854 (1981) (these and each of the other articles, patents and other documents and publications mentioned throughout this invention are incorporated herein in their entirety by reference). Some of these potential carcinogens and co-carcinogens are specific to tobacco; that is, they are associated with tobacco and are introduced only through the use of tobacco. In fact, almost all of the N-nitrosamines in tobacco products are carcinogenic. See the International Agency for Research or Cancer (1978) N-Nitrosoproline and. N-nitrosohydroxyproiine in; IARC Monografhs on i

- the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Nol. 17, Some N-Nitrosominas, Lyon, pp. 303-311; US Department of Health and Human Services (1982) The Health Consequences of Smoking: Cancer (DHHS (PHS) 82-50179) Washingt on DC, US Governmentally Printing Office; Hecht, S.S., Castonguay,

A., Rivenson, A., Mu, B. & Hoffman, D. (1983) Tobaco - Speciflc nitrosomines: carcinogenlty, metabolism and possible role in human cancer, J. Environ. Know. Health. Cl. 1-54. It is also known that N'-Nitrosonoronicotine (NNN) is one of the largest specific carcinogens in tobacco that occurs in tobacco and also in the particular stage of tobacco smoke. N-11-Ntro Compounds in the Environment; IARC Scientific Publlca | tlon. NS. 9, pp. 159-165, D. Hoffmann et al (1975). See also ^. | Mind, Studies on the Reduction of Nitrosamines in Tocabo, W.

J. Chamberlain et al, Tocabo Science 81 (1981). N-nitrous derivatives of tobacco alkaloids, such as N'-nitrosonicotine (NNN) and 4- (N-methyl-N-nitrosomino) -1- (3-pyridyl) -l-butane (NNK), are known ), are powerful environmental carcinogens. See also S. S. Hecht et al, Tobaco-Specific Nitrosamines: Formation from Nicotlne In Vitro and during Tobaco Cu; ring and carcinogenicity in Strain a mice, J. Natl. Cancer Inst., Vol. 60, N2. 4, April 1978, pp. 819-824.

Other related intramamines, such as N (-nitrosopyrroh-dine (NPIR), can be found in smoked bacon or other processed meats, as well as in tobacco or tobacco smoke. IARC Science Publication, D. Harvery et al., 17: 313 (1978) In this way, nitrosamines can reach the environment from various sources.

Recent experiments with N'nitrosonicotine (NNN) have left little doubt about the fact that this compound is a potent carcinogen or pre-carcinogen in mammals. Upon the administration of N * nitrosonicotine (NNN) in the drinking water, tremors were caused in the esophagus of rats F-344. Carclnogenesis, S. Hecht et al., 3: 453-456 (1982).

• In addition, it is also known that the administration of N'-nitrosonicotine (NNN) causes carcinogenesis in the olfactory epithelium, lung, and in the salivary glands of rodents. Vidé Cancer Research, W. Waddell et al, 40: 3518-3523 (1980). In addition, the presence of a Ν'-nitrosonicotin (NNN) metabolite at the sites of tumor formation has been confirmed by experiments with radioisotope labeling. An autoradiography study of the entire body of an adult male C 57 B1 / 6J rat, using _J / ~ ' ¹ ' ^ C_7 N'-nitrosonicotine to assess the specific distribution of Ν'-nitrosonicotine and its metabolites in all tissues of the organism, revealed an amazing correlation between the retention of radioactivity and the previously disclosed tumor formation sites. Cancer Research, W. Waddell et al., 40: 3518-3523 (1980).

It has been discovered with great interest that Ν’-nitrosonicotine has an extraordinary degree of selectivity in provoking tumors. More particularly, Ν'-nitrosonicotine (NNN) originates the formation of tumors in five locations, namely in the nasal cavity, salivary ducts, esophagus, bronchial epithelium and in the liver. Cancer Research, supra. While the precise method of carcinogenesis of N'-nitrosonic acid (NNN) is not clear, there is evidence that the nearby carcinogen is formed following α-hydroxylation of Ν'-nitrosonicotin in vivo Cancer Research, C. Chen et al, 38: 3639-3645 (1978). Cancer Research, W. Waddell et al, 40: 3518-3523 (1980). The experiments indicated, for example, that the esophagus of the F-344 rats, in contrast to the other tissues, preferentially catalyzes the α-carbon hydroxylation of Ν'-nitrosonicotine adjacent to the pyridine ring. Carcinogenesis, S. Hedt et al, 3: 453-456 (1982). Thus, the selective retention of Ν'-nitrosonicotine and its metabolites in places where tumor formations are preferentially originated allows for an excellent correlation of molecular accumulation with carcinogenic activity. However, and despite the bonds

. Since the incidence of the tumor is strongest, reactive nitrosamines such as N'-nitrosonicotin continue to be present in the environment, especially in the tobacco smoke stream.

They have been put forward in a series of proposals to reduce the amount of undesirable substances inhaled by the smoker in the tobacco smoke stream. Generally, these proposals fall into three categories: The first category relates to methods for reducing the irritating material itself, usually by introducing changes in tobacco mixtures, by growing, '' special processing or extraction, by total or partial replacement of tobacco by tobacco substitutes, or by varying the combustion temperatures of tobacco. The second category concerns the dilution of tobacco smoke before it enters the smoker's mouth, for example through the use of a highly permeable paper or cigarette filter or by perforating the cigarette filter to allow air to be drawn directly into the smoke stream. The third category of proposals concerns the manufacture of the filter itself to achieve high filtration or selective removal of particulate matter.

While many of these proposals, individually or jointly, have been successfully marketed, any of the solutions for reducing tar and nicotine production and for reducing irritating substances is accompanied by a correspondingly reduced level of resulting satisfaction for the smoker. Even the recently introduced smokeless cigarettes have disappointed many analysts and smokers as it changes the smoker's normal pleasures and routines. Furthermore, although many substances have been isolated because they are carcinogenic, a large reduction in tar and nicotine production and a large reduction in irritable substances does not reduce selecti6

the carcinogen isolated because these proposals do not selectively or effectively isolate these carcinogens. Recent sales figures indicate that, although several products presuppose unique methods for maintaining taste satisfaction at low tar and nicotine levels, sales of products low in tar, nicotine and irritable products, particularly those that are marketed with the classification of low tar and nicotine content has been decreasing. Also according to these facts, the practical deficiency of the products that indicate the selection or the sub-substantial removal of an isolated carcinogenic material, is evidenced by the recent data that indicate that the incidences! long-term cancer rates have not been reduced, as would be expected by the adoption of such products, and have steadily increased. While reducing health problems for smokers is vitally important, many cigarette smokers with low tar and nicotine content turn back and reuse cigarettes with higher tar and nicotine content, thereby invalidating their intentions to benefit. the health. Likewise, some low-tar and nicotine cigarette smokers compensate by smoking more cigarettes or inhaling the smoke of those cigarettes more deeply.

In addition, no known cigarette or cigarette filter design will preferably reduce or filter any chemical compound or, in particular, any carcinogens. Cigarettes and cigarette filters that are known also do not discriminate whether they are for particulate matter or carcinogen.

According to another known procedure, to reduce the production of undesirable smoke components, the tobacco is homogenized and reconstituted in an appropriate paper form after extraction or treatment. Since flavors are not

are completely reconstituted by such a procedure, this transformation process results in a marked reduction in the acceptance of these cigarettes.

It thus becomes very clear that the practice of reducing both the tar, nicotine and irritable substances content and reducing the content of specifically carcinogenic substances is severely limited in terms of its effectiveness in reducing the irritable elements that a smoker is exposed or to reduce the continued exposure of the smoker to the risks to his health associated with the carcinogenic matter I found in the tobacco smoke stream. Tal J

I becomes evident by the smoker's dissatisfaction with smoking cigarettes of very low tar and nicotine levels due to an unacceptably low taste satisfaction. It is also accepted that the mere high reductions in the constituents of the smoke stream fail, at least, with regard to the reduction of carcinogens below a concentration in the smoke stream of the cigarette that would be non-toxic and, in the case of elimination of carcinogens isolated, constitutes a deficient course of action.

2 ^ Ú®RÍÍY2§_®_Snçário_da_Invenção

It is a main objective of the present invention to present a new cigarette manufacture that will not adversely affect or decrease the satisfaction of the act of smoking but that selectively reduces some risks and concerns for the smoker's health that are specifically associated with it.

Another objective of the present invention is to present a new tobacco product to be smoked that does not require the smoker to vary his normal smoking regime and that does not

compromises the structure of the tobacco product to be smoked during the normal course of its manufacture, distribution, storage and handling.

Another objective of the present invention is to present a tobacco product or article to be smoked that represses, in a non-toxic way, the selective location of nitrosamines and their metabolites in the smoker's respiratory tissues.

Another objective is to add a substance to a tobacco product to be smoked that reduces the smoker's health risks in relation to his exposure to tobacco smoke, but that does not require any different handling of the product when he is being smoked. .

Another objective is to present a new construction for the cigarette that will block the location of N'-nitrosonicotine (NNN) in people who inhale cigarette smoke and that can be manufactured according to normal pace; high-speed production, ie around 1000 8 000 cigarettes per minute.

Another objective is to provide a new method to prevent the selective localization of nitrosoamines and their metabolites from tobacco smoke in the tissues of the smoker's body (or those around it), and more particularly to avoid the selective localization of N '. -nitrosonicotine (NNN) and its metabolites. Yet another objective

I of the present invention is to provide a new tobacco article to be smoked that does not reduce the presence of any substance in the tobacco smoke stream and that does not require a reduction in the tar and nicotine levels and irritable elements, but that reduces the health risks associated with smokers.

Another objective is to present a cigarette containing a single cigarette additive, which is invisible to the eyes

and that it does not change the size, shape and feel of the cigarette, thus increasing the chances that such cigarette will become meadow and smoked.

Another objective of the present invention is to provide a process for the formation of cigarettes that offer the smoker a new and significant reduction in the risks that his health runs and that completely maintains the satisfaction in smoking that the current cigarettes offer.

Yet another objective is to present a cigarette with an improved construction that obtains complete approval from the smoker and that is in line with current manufacturing science.

Another objective is to provide a new and improved method for administering vitamins, and in particular vitamin A, in the mouth and respiratory area of cigarette smokers.

Another objective is to present a process for the manufacture of cigarettes that imposes reduced risks to the health of smokers, and that do not suffer from a significant loss of validity, stability, appearance and pleasure in being smoked.

Another objective is to provide an improved cigarette construction that can take place with little, if any, changes in the manufacturing lines of the existing cigarette factories.

Another objective is to present an improved cigarette construction that does not add harmful vapors to the cigarette smoke stream.

Another objective is to provide an improved cigarette construction that reduces the health risks associated with them without altering the normal taste of cigarettes, the smoker's mouthfeel, their characteristics of ma10

nusation and burning that smokers are used to expect.

This invention proposes a new application for a blocking agent that has the effect of neutralizing tobacco specific nitrosamines, without presenting the problem of flavor unacceptability, associated with previous efforts to specifically isolate and remove carcinogenic compounds, as described above. This invention discloses a means of selectively blocking the biological activity of this carcinogen in identified organs of the smoker's body. More than reducing any element in the smoke stream of the cigarette, the introduction of a blocking agent in the smoke stream is termed for that same purpose. Notoriously, this blocking agent appears to be active only when it comes into contact with specific receptor cells that are found on or within the identified organs of the smoker's body. Since there is no need for a reduction in the tar and nicotine content of the smoked cigarette brand, there is no associated reduction in the taste satisfaction that the smoker is expecting. Although many processes for incorporating blocking alcohols into cigarettes, for example, are possible and are presented in detail here, a preferred process is to spray the alcohol (s) on the cut and dried tobacco during the manufacturing process of cigarettes.

Other objectives and advantages of the present invention will become apparent to persons who are experts in this field, and to whom this invention is addressed, from the description that follows in conjunction with the attached drawings;

Brief Description of Drawings

Figure 1 is a bar graph showing the test results of the present invention.

Figure 2 is a perspective view of a first embodiment of the cigarette manufacturing process of the present invention.

Figure 3 is a perspective view of a second embodiment of the process disclosed by the present invention.

Figure 4 is a perspective view of a third embodiment of the process disclosed by the present invention.

Figure 5 is an elevation plan of the third embodiment of the cigarette making process of the present invention.

Figure 6 is a perspective view of a fourth embodiment of the cigarette manufacturing process of the present invention.

Figure 7 is a perspective view of a fifth embodiment of the process of the present invention.

Figure 8 is a perspective view of a key part for a sixth embodiment of the process of the present invention, illustrated in isolation.

Figure 9 is a perspective view of a key part for a seventh embodiment of the process of the present invention, illustrated in isolation.

Figure 10 is a perspective view of a cigarette illustrating alternative locations for the sixth and seventh embodiments of Figures 8 and 9 of the present invention.

Presentation_General_of_Invention

According to the present invention, a tobacco product or article has been found to be smoked through which the selective localization of nitrosamines, such as N'-nitrosonicotine (NNN) and its metabolites, in at least three of the body's tissues of mammals in which these compounds are known to accumulate, it is inhibited by additives present in the tobacco smoke stream. These tissues are the epithelial lining of the bronchi, the lining (epithelial of salivary ducts and the liver, and without coincidence, these are the same tissues of the mammalian organism in which nitrosamines, such as N'-nitrosonicotine and its metabolites , work as carcinogens.

N'-nitrosonicotine (NNN) is one of the most abundant carcinogens found in cigarette smoke and cancerous tumors are formed where the accumulation of N'-nitrosonicotine is recorded, such as in the lungs. While the actual biochemical process involved here has not yet been precisely determined, it is thought that the N'-nitrosonicotin blocking alcohols of the present invention may perform their function in one of the following ways: or the blocking molecules adhere to cells surface receptors of ^v · tissue cells in the places where N'-nitrosonicotin is located, such as in the lung, liver and salivary ducts, thus preventing the adhesion of N'-nitrosonicotine and its carcinogenic metabolites; or, alternatively, the blocking molecules adhere to the cell receptors found within the tissue cells in these local media, either by blocking or altering the process by which N'-nitrosonicotin is metabolized in the cell, thus preventing the formation of metabolites carcinogens of N'-nltrosonicotin. In other words, the blocking molecules have the effect of ~ blocking the lock (the cell's receptor) and preventing cha13

ve N'-nitrosonicotine (the molecule) to be introduced, or to change the N'-nitrosonicotine key so that it no longer serves in the lock. Unable to enter or enter tissues, N'-nitrosonicotin then passes out of the lung without causing damage.

The present invention is therefore characterized by the fact that it is directed towards methods to prevent the selective localization of nitrosamines and their metabolites in the tissues of the mammalian organism, and not for the treatment of tumors. In other words, the subject of the invention is not directed towards the treatment of tumors or cancers but refers to the relocation of nitrosamines and their metabolites, that is, chemicals, which tend to be selectively located in the tissues of the mammalian organism. In fact, the tobacco products to be smoked of the present invention can be effective when there are no tumors.

Surprisingly, it was found that alcohol alcohols inhibit this selective localization of nitrosamines, such as Ν'-nitrosonicotine and its metabolites. In accordance with the present invention, alcohols that are functional in this regard include alcohols that have one or more carbon atoms. However, it is preferable to use alcohols that have alkyl groups having at least three or more carbon atoms. The alkyl groups can have a single chain or a branched structure. In addition, alkyl groups can have a cyclic or acyclic structure. Some of the alcohols that can be used are part of the group consisting of ethanol, n-propanol, isopropanol, n-butanol, secondary butanol, isobutanol, t-butanol, 2-methyl-1-butanol alcohol or active amyl alcohol, n-alcohol -amyl, secondary amyl alcohol, t-amyl alcohol, n-hexyl alcohol and cyclohexanol. There are other chemical compounds that have been discovered as compounds capable of relocating nitrosamines and which are dimethyl sulfoxide (DMSO), imidazole, pyrazole, diethyl-dithiocarbamate and benzyl-iso-thiocyan14

to. These and other alcohols and compounds of the present invention are listed in Table 1. Cyclohexanol is one of the preferred alcohols in that list when they are in the tobacco smoke stream, since they add very little flavor to the smoke and have a pleasant aroma. It has been specifically noted that alcohol menthol does not inhibit the location of nitrosamines as do the compounds disclosed by this invention.

Table 1

The present invention covers all monofunctional and polyfunctional alcohols and compounds with a resonant hydroxyl species of about two to forty carbon atoms including, but not limited to, the following:

Monofunctional alcohols: Polyfunctional alcohols: Ethyl alcohol Ethylene glycol N-propyl alcohol 1,2-propanediol Isopropyl Alcohol Glycol 1,3-propanediol (tri-methylene) Allyl alcohol 1,3-butanediol Crothyl alcohol 1,4-butanediol N-Butyl alcohol 2,3-butanediol Isobutyl alcohol 1,5-pentanediol Secondary butyl alcohol 1,6-hexanediol T-butyl alcohol 1.10-decanediol 2-pentanol Pinacol

3-pentanol

N-amyl alcohol

Isoamyl alcohol

T-amyl alcohol

2-methyl-1-butanol

HYDROXY SPECIES:

3- methyl-2-batanol Neopentyl alcohol Cyclopentanol N-hexyl alcohol

2- hexanol

3- hexanol

2- methyl-1-amyl

3- me til-1-amyl Cyclohexanol N-octyl alcohol Caprylic alcohol N-decyl alcohol Laaryl alcohol Myristyl alcohol Cetyl alcohol Stearyl alcohol Benzyl alcohol Benzhydrol

Clnamyl alcohol

Tri-phenylcarbinol.

Glycerol

1,2,4-butanotriol

1,2,6-hexanotriol

COMPOUND WITH RESONANT dimethyl-su.lfoxide (DMSO)

The amount of alcohol to be used can be any amount that is greater than the limit amount necessary to effect the relocation of nitrosamines in the affected tissues of the mammalian organism, but that is less than the amount that would cause any toxic effects on said mammal. In oral administration of the alcohols of the present invention, about 1 µl of an alcohol is used per gram of the total body weight of the mammal. The amounts of alcohols to be administered by inhalation are slightly lower than the amounts that will cause efa. toxic substances. Also, the higher alcohols have a low toxicity; its toxic effect is restricted to the sedative effect of the central nervous system. Table II summarizes the toxicological properties of some typical alcohols. Kink-Othmer: Encyclopedia of Chemical Technology, Vol. 1, in 727 (1978) and The Registry of Toxic Effects of Chemical Substances, U.S. Department of Health, Education and Welfare, Vol. 2 (1977).

Table II

Xlcool

Acute oral dosages of LD50

-g / Xg

N-propyl ethanol

5.4

Isopropyl

5.84 n-butyl

0.79 isobutyl

2.46 t-butyl

3.5 n-amyl secondary amyl

3.03

1.47

Table II

Iso-amyl alcohol t-amyl hexyl - active cyclohexyl amyl (such as 2-methyl-1-butanol) retinol menthol (continued)

Acute oral dosages of DD5O a & Ag

1.30

1.0

3.7

2.06

4.9

2.0

3.18

2.6

3.2-7.1

1.5

4.7-9.8

4-me til- 2-pentanol

2-ethylhexanol isoctyl ^ decyl - dodecanol, 98 $ (derived from coconut) hexadecanol octadecanol ^a ) The dose that caused the death of 50% of the animals tested expressed in terms of gram of material administered per kg of total body weight

Mixed isomers

The values for an acute oral toxicity can be compared to a DD50 by an administration of 3.75 g / kg equal.

be sodium chloride in rats. A substance with an LD _C ^ or greater than fifteen g / kg is generally found to be non-toxic.

same ! you are

By comparison, the oral dose of nicotine predicted to be fatal in tobacco is, for an adult, 1 mg / kg of total body weight. Principies of Internai Medicine, Harrison ΐ 11 p Edit. Section 18 (1975). In this way, as the alcohols of the present invention are used in dilute aqueous solutions, a person skilled in this field can easily achieve the desired effect of the intramolamines location while avoiding the toxic side effects inherent in an overdose.

In addition to the fact that smoking, the introduction of carcinogens in the body, smoking has also been linked to the depletion of certain B vitamins in the smoker's body. In addition, vitamins C and E 'have been shown to prevent the formation of nitrosamines in epithelial membranes; additionally vitamin A and retinoids inhibit the development of tumors. Selenium and other agents also inhibit the development of tumors. Inhibitio: i of Tumor Induction and Development; NS Zedeck, M. Lipkin, Prenum Press, NY 1981. Accordingly, it is within the scope of the present invention to combine alcohols with various vitamins and other agents known to be reduced by smoking, to inhibit the formation of nitrosamine and to inhibit the development of tumors. In addition, the amounts of such vitamins or other agents to be used, such as selenium, for the purpose of this disclosure are within the knowledge and capabilities of those skilled in the field. Inhibition of Tumor Induction and Development, supra.

Examples of the present invention will now be provided for further clarification. However, it is clear that these examples are not intended to limit the scope of the present invention.

Example 1

Adult male C57 B1 / 6J rats were intravenously injected with an amount between 0.12 and 0.19 uci / g of body weight, corresponding to a dose of 0.4 to 1.9 mg / kg of female ^ c7 N'-nitrosonicotine (NNN) (New England Nuclear; Spec. Act. 18.4 or 51.7 mCi / mmole). An hour later the rats were lightly anesthetized with ether and frozen by immersion in dry ice / hexane. Twenty sagittal sections of the entire body ₍ as a thickness u, of the frozen rats were placed on tape and then processed for autoradiography of the entire body by known methods. Vidé W. Waddel et al., Druk Fate and Metabolism; Methods and Tehcniques, É. R. Garrett and JL Hirtz, Eds (Maree DeKKer, New York, 1977, p. 1-25). The photometric density in the areas of the developed autoradiographies was measured with a photometer from ADG Instruments and with a photocell with an aperture of 3 neem placed on an easel of a photographic magnifier. The X-ray film was placed in the magnifier in order to obtain a 35 times greater magnification.

Aqueous solutions of ethanol, n-butanol and t-butanol were administered to some of the rats by oral intubation twenty minutes before receiving N'-nitrosonicotine. Ethanol solutions (1 g / kg and 5 g / kg) and n-butanol and t-butanol (0.2 g / kg and 1 g / kg) so that each rat received 0.02 ml / g of total body weight, (twenty minutes is the average time that oral intubation in rats it takes to reach the peak of blood level). The autoradiographies revealed that the location of radioactivity in the salivary ducts and in the bronchial epithelial lining and in both the periportal and central areas of the liver was reduced by the application of ethanol (a chemical-preventive agent of this invention) and by applying it on a larger scale. of n-butanol. By administering a higher dosage, t-butanol almost completely abolished the localization of N'-nitrosonicotine / ~ ^ Ç7 in the epithelial lining of the bronchi. In addition, the reduction in photometric density was related to dosage. Fig. 1 shows the absorbances of the areas measured with the densitometer. Control experiments were carried out as a comparative term.

More particularly, Fig. 1 shows the means of absorbances from the photometric densitometer for the four areas in which inhibition in the location of radioactivity was seen. The number inscribed within each bar of the graph in Fig. 1 represents the dose in g / kg of that alcohol that was administered orally twenty minutes before N'-nitrosonicotine was administered intravenously.

The rats were frozen one hour after receiving the Ν'-ηίtrostrosonicotina] _ ^^ C7 · The averages for each rat are between fifteen 'measurements in disordered areas of that location (five absorbances in each of the three autoradiographies) after having blood in each of the rats was set to zero. The control value is the average of six rats; n-butanol at a dose of 1 g / kg is from two rats; the other averages come from a single mouse. The coefficient of variation of each average was less than 10%. All measurements were made on one occasion only by the same observer, who did not know the treatment of each autoradiography chosen at random.

Further details and explanations of Example 1 are found in the article by William J. Waddel, M. D. and Carolyn Marlowe, entitled Inhibition by Alcohols of the Localization of Radioactive Nitrosonornicotine in Sites of Tumòr Formation, Science, Vol. 221, pp. 51-53, 1 July, 1983. A recent article on fígado'-nitrosonicotine (NNN) metabolism in the liver is by MF Hughes et al., Characterization of covalent binding of N-nitrosonicotine in rat liver microsomes ”, Carcinogenesis, Vol. 7 (1986).

Example 2

An adult C57 B1 / 6J rat was placed in a tall glass with a high bottom that had two ml of cyclohexanol under the bottom of the glass, covering the top of the tall glass with a sheet of metal. The rat was kept in the closed tall glass for about five minutes while maintaining the bottom of the glass in a water bath at a temperature of 5O ⁵ C. With reference to standard tables, it was calculated that under a temperature 50 0 0 the vapor pressure of cyclohexanol gives a concentration of alcohol in the air contained in the glass of 0.01%. Handbook of Chemistry and Physics (1979) on D-203 through D-217.

After spending five minutes in the tall glass, the rat was injected intravenously with an amount between 0.12 to 0.19 ucu / g of the total body weight, corresponding to a dose between 0.4 and 1.9 mg / g kg / 2 ^1-14 Ç7 N'-nitrosonicotine (NNN) (New England Nuclear, Spec. Act. 18.4 or 51.7 mCi / mmole). One hour later the rat was lightly anesthetized with ether and frozen by immersion in dry ice / hexane. Twenty sagittal sections of toto were removed from the body, with a thickness u, of the frozen rat, which were processed by autoradiography as in Example 1. No radioactivity was detected in any part of the epithelial lining of the bronchi. Control experiments were performed for comparative purposes and in those controls, radioactivity was detected in the respiratory epithelial lining.

Example 3

The procedures of Example 2 were followed, only here the rat was kept in the closed high glass for five minutes while the bottom of the glass was kept in a water bath at

temperature of 26 ² C. With reference to standard tables, it was calculated that under a temperature of 26 ² C the vapor pressure of chlorhexanol resulted in a concentration of alcohol in the air contained in the tall glass of 0.001%. After being injected as in Example 2, the rat was processed in the same manner as described in Example 2. No radioactivity was detected in any area of the bronchial epithelial lining contrary to what happened in the control experiments.

Example 4

A C57 B1 / 6J adult male rat was injected intraperitoneally with 0.02 ml / g of the total body weight of a solution of imidazole in water. The concentration of the imidazole solution was such that 0.05 g of imidazole was obtained per kg of body weight. Twenty minutes after injection, the rat was injected intravenously with an amount between 0.12 and 0.19 uCl / g by body weight, corresponding to a dose between 0.4 and 1.9 mg / kg / 2 ' -14Ç7 N'-nitrosonicotine (NNN) (New England Nuclear; Spec. Act. 18.4 or

51.7 mCi / mmole). After an hour, the rat was lightly anesthetized with ether and frozen by immersion in dry ice / hexane. Twenty sagittal sections of the entire frozen rat body with a thickness u were removed onto an adhesive tape, which were then processed, by known methods, by a full body autoradiography. See Example 1. A significant displacement of nitrosamine was found in the rat injected with the imidazole solution compared to that found in the control rat.

'Example 5

The procedures adopted in Example 4 were repeated, but now the rat was injected intraperitoneally with 0.02 ml / g of the body weight of a solution of imidazole in water, where the concentration of the solution was such that 0, 25 g of imidazole for every kg of body weight. After conducting the rest of the experiment as in Example 3, a significant displacement of nitrosamine was found in the injected rat with the imidazole solution compared to that found in the control rat.

Upon the analysis of Figure 1, the greatest inhibition was observed with t-butanol in the epithelial lining of the bronchi. The reductions were similar in both areas of the liver for all three alcohols in dosages administered. There were no significant differences between the control groups and the treated groups with regard to the obstructions in the nasal epithelial lining and in the epithelial lining of the esophagus. The results strongly suggest that the use of an alcohol of this invention as a chemo-preventive agent, inhibits the localization of the carcinogen in the epithelial lining of the salivary ducts and in the bronchial ducts as well as in the liver, but does not inhibit in the nasal and esophageal lining in male C57 B1 / 6J rats. In a molar dose, t-butanol has approximately fifty times the potency of ethanol to inhibit localization in the bronchial epithelial lining.

The specificity of inhibition in some locations suggests that some of the following mechanisms may be involved. One of these mechanisms is a competitive inhibition mechanism involving either a secondary alcohol dehydrogenase or a P-4 5 0- ^ 3 a cytochrome. With any of these systems, it is thought that the alcohols of the present invention can compete

successfully with the N-nitrosonicotin a-hydroxy substrate, to prevent the formation of the nearby carcinogen. Although it is possible that a simple solvent effect may be present, the specificity of the site and the potential differences of alcohols strongly favor metabolic inhibition.

Another possible explanation for this invention is disclosed as follows. It is generally accepted that the covalent modification of DNA by chemical carcinogens or their metabolites is the key step in initiating the carcinogenic process (SS Hecht, Chemical Carcinogenesis; An Overview, Drug Mechanisms, 8th Annual Meeting, NACB, Washington DC, 1984, Clin. Physiol, Biochem. 3: 89-87, 1985). The DNA bases have many nucleophilic sites that readily react with electron or electrophilic difficult carcinogenic metabolites (Hecht; EJ Lavoie, SS Hecht, Chemical Carcinogens; In Vitro Metabolism and Activation; in Azard Assessment of Chemicals, Current Developments, Vol. 1, pp. 155-169, Academic Press, New York, 1981). Conversion to an electrophilic metabolite that reacts with DNA is, accordingly, the unified property among structurally diverse chemical carcinogens (Hecht).

metabolic pathway of N'-nitrosonicotin TSNA and NNK has been studied in rats and hamsters (US Pepartment of Health, The Health Consequences of Smoking, A Report of the Surgeon General, 1982) and in the marmoset monkey (A. Castonguay, H. Tjalawe , N. Trushin, R. d'Argy and G. Sperber, Metabolism and Tissue Distribution of Tobaco Specific N-Nitrocomines in The Marmoset Monkey Carcinogenesis, Vol. 6, N ^5. 11, pp. 1543-1550, 1985). Metabolic activation of N'-nitrosonicotine (NNN) and NNK in rats, hamsters or monkeys most often starts with carbon hydroxylation a (US Dept. of Health; Castonguay). Initial hydroxylation is mediated by the cytochrome P-450 oxidase system (Μ. P. Hughes, WJ Brocl ·

L. J. Marion and M. Vore, Characterization of Covalent Binding

- of N-nitrosornicotine in Rat Liver Microsomes, Carcinogenesis 7 (1): pp. 3-8, 1986; Hecht). The electrophilic diazohydroxide intermediates of N'-nitrosonicotine (NNN) and NNK are identical (US Dept. of Health) · These electrophilic intermediates, or the resulting carbonium ions, are probably the last carcinogenic form of TSNA (US Dept. of Health) ). The electrophilic intermediates or carbonium ions then react with the DNA to form the TSNA-DNA binding adductor.

Autoradiographic and biochemical reports from • have shown that N'-nitrosonicotin (NNN) and (mNNK) metobolites clump into macromolecules of the tracheobronchial mucosa

Nasal and kidney, liver, sublingual and submaxillary glands, esophagus and ocular melanin (U.S. Dept. of Health). This specific organ binding can arise by mediating the interaction of a second enzyme. This secondary mechanism is, however, poorly understood. So far, there has been no study that characterized the microsomal enzyme of the liver - TSNA-mediated binding to nucleophilic tissues (Hughes). There have been no studies on specific enzymes to other organs and their TSNA-mediated linkages to tissue nucleophiles.

However, it is believed that the blocking compound or alcohol of this invention will disrupt the current metabolism of TSNA. In any event, it is not necessary to restrict the present invention based on any particular theory.

In order to inhibit the selective localization of nitrosamines, such as N'-nitrosonicotine and its metabolites, the alcohols of the present invention can be administered by several different techniques. However, the means for its application must be able to achieve four objectives, namely (1) to deliver alcohol in high concentration only, or first, to the desired action sites, such as respiratory epithelial lining, (2) to the en26

delivery only during the time period of maximum exposure to tobacco smoke, (3) deliver only, or first to the smoker and (4) the existence of a minimum exposure of other organs of the smoker's body to the inhibiting substance. The present invention is directed in particular to constructions in tobacco to be smoked to deliver alcohol in the tobacco smoke stream to the smoker and which fulfill the aforementioned requirements. It is more particularly aimed at cigarettes that fulfill these objectives and the processes for their manufacture.

Preferred Search

There are a variety of techniques by which the objectives listed above can be achieved while achieving the relocation of nitrosamines. By way of example and generally speaking, alcohols can be encapsulated in rupturable capsules filled with one or more alcohols of the present invention and mixed with tobacco before being smoked, as in a pipe, and the rupturable capsules can also be placed directly in the tobacco or filter of a cigarette or cigarette during its manufacture. Alternatively, the rupturable capsules can be placed inside a removable filter that can be placed in a cigar or cigarette, or a removable smoke filter having a cylindrical plastic or paper body which contains rupturable capsules containing one or more alcohols of the present invention. The use of any combination of the alcohol placement or attachment mechanism mentioned herein or suggested within an article or tobacco product to be smoked, such as a cigarette, is further included within the scope of the present invention.

One of the preferred constructions for making entre27

of these alcohols in the tobacco smoke stream is to micro-encapsulate the alcohol and then place the microcapsules inside the article. It is noted that the encupulation initially isolates the alcohol and provides a controlled release so that it can then act with the environment created by the tobacco smoke stream. The construction of microencapsulation by means of shell-like walls must be sufficiently compatible with the alcohol contained therein so that the alcohol is retained there until the moment when the heat from tobacco smoke forces the shell to open. In other words, the microcapsule is stable inside the cigarette, being actionable by the action of heat, releasing the alcohol contained therein in a controlled manner. The melting encapsulation, as opposed to volatilization, prevents the introduction of vapors into the tobacco smoke stream, which are normally a bi-product of the volatilization of the shell-like wall. The alcohols are thus automatically released for the smoker's convenience so that he no longer has to manipulate the product to be smoked, and in order to ensure a more consistent release.

As shown in Fig. 2, these micro-encapsulated alcohols (20) can be placed inside the cigarette, generally illustrated in (22), the gauze plug (23), in the acetate filter (24), in the cigarette tobacco (26), even mixed in the cut and dried tobacco (28) and / or the filter (24). The dosage will be determined by the average heavy time (for a normal 8-hour working day and a 40-hour working week) of alcohol in the human body so that enough alcohols are delivered to block cell receptors with a small loss or small excess delivery. The dosage can also vary according to the variety of mixtures, such as mixtures with low tar, very low tar, total flavor mixtures, mixtures with menthol and mixtures of the various brands of cigarettes.

You can use a construction of the type of a

shell, as referred to by the M-CAP Process of Insulation Technologies Corporation of Pennsylvania. The general specification of the M-CAP shell construction is capsules as small as three microns with melting temperatures between 64 and 650 ° Fahrenheit. The rate of controlled release should generally be constant but may vary. More particularly, capsules with varying melting temperatures can be included in a single cigarette to ensure constant release of the alcohols they contain as the coal burns down the tobacco roll and the higher temperatures force the filter section. Whenever the control speed varies, the shell-like material, the thickness is / 01. The size of the capsules may also vary. The M-CAP construction is usable for uniform capsule sizes or for capsules smaller than 50 microns.

>

shell construction material can be ELVAX (ethylene acetate / vinyl copolymers) or a similar material having the desired characteristics of a programmed shell release temperature of about 64 to 650 ° Fahrenheit. ELVAX is one. vinyl ethylene acetate resin, as described in Material Sapety Data Sheet - VAX001, dated 10/20/86, by E. I. Dupont de Nemours & Co. (Inc.) of V / ilmington, Delaware. A second viable material for shell-like construction is EUDRAGITE, which is a cationic copolymer synthesized from dimethyl-amino ethyl methacrylate and a neutral methacrylic acid ester, which can form a rapidly disintegrating coating film. Other candidate products to be used as a shell-like coating include BERMOCOLL, which is an ethylene-ethyl cellulose manufactured by Berol Remi AB of Stenimgsund, Sweden, and also Gelatin K & K, which is a gelatin produced by Kind & Knox, which is a division Knox Gelatine, Inc. of Saddle Brouuk, N.

. Y.

J s. · »· _} ·., I

N-LOK, which is an emulsion stabilizer product (55-129), is an alternative encapsulation product. In the publication Product Data: Bulletin N ² . 447 of the National Starch and Chemical Corporation, Products Division in Bridgewater, New Gersey, there is a description of said N-LOK.

Another construction of the present invention is to encapsulate the blocking alcohol, such as cyclohexanol, in a modified starch material from its inversion in a suspension. An example of this type of appropriate material is CAPSUL, which is described in the publication Product Data: Bulletin n ² . 409 of the National Starch and Chemical Corporation, Food Products Division, in Bridgewater, New Jersey. CAPSUL is made of wax corn, it is especially suitable for encapsulation and has demonstrated ease of dispersibility of the encapsulated fluid (especially for aromatic oils) and excellent stability during storage.

shell-like coating should comprise between 20 and 50 / c of the capsule volume for stability purposes in order to resist breakage during its manufacture and packaging and during the handling of the cigarette by the consumer. The capsules should be between three and ten microns in circumference when placed inside the cigarette paper or when mixed in the tobacco in order to avoid an undesirable swelling in the cigarette paper and in order to remain invisible if placed in the tobacco. Larger circumferences of up to 50 microns are acceptable if the capsules are placed inside the cigarette filter. The capsules can be further hardened with a plasticizer in order to control their melting temperatures. In addition, the capsules can be dyed with appropriate food inks to match the color of cigarette tobacco. It is also included in the scope of the present invention the fact of ensuring greater stability through

• the double encapsulation of the capsules, as for example by the M-CAP or coencapsulation processes.

One of the ways of attaching the capsules to the cigarette paper according to one of the constructions of this invention, is that disclosed in US Patent No. ⁵ . 4 236 532. Microencapsulated alcohols can be attached, in addition to the cigarette paper, to the gauze plug or be contained in the cigarette filter either distributed evenly or distributed within the center of gravity of a construction in which the filter is tripartite, as it is generally shown in (30) in Figure 3. The construction of the tripartite filter can have a plasticized container system in order to minimize leakage from the ruptured capsules.

Alternatively, the capsules can be attached to cigarette paper or gauze plugs via a standard gelatin or starch paste coating. The capsules can be mixed within the adhesion agent, and the paper can be coated by immersion in a suspension, a process similar to the method of fixation using carbonless paper. Preferably, the capsules are positioned in the filter section and not on the tobacco roll to thereby mask any noise or crack that may be associated with the release of alcohol.

Another construction mechanism of the present invention is a twin filter plug, as shown in Figures 4 and 5 · The twin filter plug section (40) of a cigarette generically illustrated in (42) is typically between 20 and 30 in length mm, 25 mm being the most common length. The twin filter plug (40) is used, in which a filter with a 10 mm section and a filter with a 15 mm section are placed, one after the other, within the cigarette section. Each tampon is wrapped in a separate gauze plug and the twin tampons are then re-wrapped by the gauze plug

and then by the outer covering paper. The filter with the 10 mm section (44) is placed so that it touches the tobacco roll (48), the filter with the 15 mm section being placed behind the filter with the 10 mm section. The 10 mm section (44) contains the encapsulated alcohols dispersed uniformly along its longitudinal axis. The capsules may have a thick circumference and shell-like coating as described above. The release temperatures of the shell shell of the capsules are preferably programmed, as described above, so that said temperatures are between 65 and 650 degrees Fahrenheit, to ensure continuous release from the first lower temperature of cigarette aspiration until your last aspiration, which is usually the hottest aspiration. Elements to enhance the taste can be added to the filter with the 10 mm section (44), as part of the encapsulated material. As the tobacco smoke stream is sucked through the filter (44), the walls of the shell-like coating have melted freeing the encapsulated alcohols, which are then transported by the smoke stream to the filter (46), which has a conventional cellulose acetate construction for its current filtration, before letting cigarette smoke (42) out into the smoker's respiratory system.

The filter section (44) can contain the encapsulated alcohols with the programmed shell-coated capsules, flavor reconstituters and vitamin A or other additives mentioned above. An example of the inclusion of vitamins is found in U.S. Patent 3,339,555. Other elements can be added to enhance the flavor, if necessary, in order to reconstitute the desired characteristics of the taste of the smoke after the smoke has absorbed the blocking compounds. The teachings included in U.S. Patent 3,144,024, which illustrates the construction of a filter to be used for tobacco in

smoked and impregnated with a flavor enhancing composition, can be used to obtain a device that makes the present invention feasible. This filter must have all of these materials aligned along its longitudinal axis and then radially dispersed.

It is also within the scope of the present invention to add esters and alcohols without encapsulation, or to process the alcohols with an ester.

It is also feasible through the process of this invention to impregnate the cut tobacco, wrapping paper of roll or filter tobacco with the alcohols of the present invention, and in this way the vapor of the alcohol is released and inhaled when the article is being smoked. The paper wrapper can be dipped in the alcohol by wrapping it around the cigarette before the outer wrapping paper and foil of each pack is placed. After a few weeks of storage, the alcohol will diffuse into the cigarettes. This method is similar to a method used to add menthol to cigarettes and is a very simple, relatively effective and inexpensive technique of this invention. It may even be that this form of impregnation will reduce smoker's health concerns and risks associated with passive smokers.

An alternative method for incorporating alcohol into the cigarette, so that it is easily released into the tobacco smoke stream and without adversely meeting the stability of the cigarette and the resultant smoker's satisfaction, is to print it on the side inside the cigarette paper. More specifically, one can use the engraving printing process to place the microcapsules, containing one or more alcohols of the present invention, inside the inside of the cigarette paper. This process creates an ink that consists of a suspension containing the microcapsules. The ink is fed to a standard printing machine and the printer applies it or places it on the cigarette paper.

As shown in Fig. 6, microencapsulated alcohols can be coated or implanted in the cigarette (50) on the cigarette paper (52) in bands (54) or in a disorderly manner, and / or on the outer coating paper (56) also in bands (58) or disorderly, and / or on the paper roll also in bands or disorderly. Alternatively or in combination, as shown in Figure 2, mi | Croencapsules can be positioned either in a disorderly way! or according to a predetermined pattern, in the filter and / or in the cut tabajco. Another method is to spray the alcohol (s)! through a spray, on the filter before smoking the cigarette.

Yet another mechanism for getting the alcohols to be delivered into the smoke stream of a cigarette (60) is to provide a double filter as shown in (62) of Figure 7. It can be seen that the central cavity (64) of the filter (66) contains microencapsulated alcohols, and / or crystallized alcohols, or coals impregnated with alcohol (68) such that the vapors of alcohol are released when the cigarette (60) is smoked. The cavity (62) can also be delineated with a sufficient membrane to prevent any flow or deterioration of the mixture.

The microencapsulated alcohols can also be positioned in the cigarette (70) in a suspension device, as is generally shown in (72) of Figure 8. The suspension device (72) can comprise plastic spokes (76) attached to a rigid plastic hole. (78) which is in alignment of the outer circumference of the cigarette roll. The microencapsulated alcohols (82) are suspended on the spokes (76) and in the central hole (78) and are released into the smoke stream (84) when the cigarette is smoked. By way of further explanation, a typical cigarette (90) includes

of a tobacco roll (92), and a soft filter (94) and being surrounded by an overlapping paper (96) is shown in Figure 10. The suspension device (74) can be positioned in any of the locations (98 , 100, or 102) marked there.

A double suction release cavity (15), shown separately in (110) of Fig. 9, can also be inserted in any of the positions (98, 100 or 102) of Fig. 10. The double cavity (110) comprises a first cavity (112), a second cavity (114) and a flushed membrane (116) that divides them. The first cavity (112) contains micro-encapsulated alcohols and / or crystalline alcohols, and is sealed by the membrane (116) on its side of the filter. When the membrane (116) breaks due to suction, it releases the alcohol pack contained in the second cavity (114). The second cavity comprises a plastic cell containing the released alcohols and gives a maximum exposure surface of the alcohols to the stream of cigarette smoke (118) also preventing them from flowing from the cigarette.

It is also foreseen by this invention the fact that the elements containing alcohol are placed anywhere inside the filter, including the placement of a large capsule inside the filter that can be manually or automatically broken by means other than thermal means, that is, by spraying, perforation or compression. See, for example, U.S. patents 3,547,130 and 3,339,558.

The alcohols can also be contained in a cigarette holder. The construction of a mouthpiece (not illustrated) can generally be up to 3/4 the normal length of a cigarette, which is 84 mm for a filter cigarette, and is plastic. The final end of the cigarette is fitted to an open end of the mouthpiece by pressing or tightening the cigarette in order to enter the open end. The other end of the mouthpiece is flattened so that it is inserted

in the smoker's mouth. With any cigarette that fits the mouthpiece, the blocking alcohols are controllably released from the mouthpiece into the stream of smoke as the cigarette is smoked. Reference is made here to the U.S. patent.

713 451 which shows a capsule containing a small filling of aromatic tobacco held in a mouthpiece that is placed adjacent to the filter and behind the filter. The hot smoke releases volatile aromas, which are inside the capsule, into the stream of smoke as the cigarette is smoked.

The alcohols of this invention can also be administered in a pipe-type construction (not shown) or in a special formulation for pipe tobacco as will be apparent to those skilled in the art through the present invention.

The present invention is also an extension of the technology disclosed in International Application PCT / US87 01978 of C.A. Blockers Inc. in Louisville Kentucky, entitled Tobacco Smoking Article. A preferred method of delivering one or more of the blocking alcohols or blocking compounds of this invention, as it is in that international application, into the smoke stream of a tobacco article to be smoked, such as a cigarette, is the method of spraying the alcohol (s) on the cut and dried tobacco leaf during the manufacture of the article to be smoked (cigarette), so that the finished cigarette contains the alcohol, in its tobacco section or roll. The alcohol should preferably remain stable inside the cigarette until it is smoked, at which point the alcohol is released by the action of heat into the smoke stream to be inhaled by the smoker. To avoid excessive evaporation, the alcohol is sprayed on the cut tobacco during the cigarette manufacturing process and after it has been dried, and the alcohol will then soak the cut tobacco. Also, and to be more effective, the amount

- the amount of alcohol to be sprayed on tobacco must be in sufficient quantity to ensure a transfer of the alcohol molecules to the volume of the smoke to be inhaled by the smoker equal to the number of nitrosamine molecules (or at least the N molecules) '-nitrosonicotin or molecules of

4- (N-methyl-N-nitrosomino) -1- (3-pyridyl) -1-butane (NNK), present in the same volume of smoke.

On the other hand, the amount of alcohol transferred and inhaled by the smoker must be present in an amount sufficient and below the maximum value of the volumetric concentrations allowed for each alcohol by any applicable government regulation, as in the case of the United States, the regulations of the US Occupational Safety and Health Administration (OSHA) Time Weighted Average (TWA). ! Other useful regulations are published by the Flavoring Extract Manufacturer's Association (generally regarded as a security ilist) and the Hunter Committee of Great Britain. If a substance has not yet been literarily evaluated, the toxicity of that substance (alcohol) must be evaluated before it is used. The compounds or alcohols referred to herein are individually analyzed and it is assumed that the toxicity of a mixture of compounds is the toxicity of the most toxic individual substance of the compound. It is expected that 1-1,000 micrograms (and, more particularly, approximately 800 micrograms) of the blocking alcohols should be present in the cut tobacco to constitute a cigarette containing 400 - 1,200 milligrams (and more particularly approximately 800 milligrams) of tobacco. Another way to define the amount of alcohol is its concentration in air, which should be between about 1% to 0.001% (see Example 3, supra).

While the cigarette industry is highly regulated on its own with regard to the inclusion of additives and materials in cigarettes, manufacturers strive to determine which new additives are safe for the consumer.

human organism. There are a number of resources that guide manufacturers. For example, OSHA has been testing the maximum exposure limits (TWA) of many common substances since 1972 in order to determine the extent to which exposure to a substance becomes toxic to humans and the extent to which exposure is non-toxic. . This list is extended by studies from Gras and Hunter Commission as well as studies from other countries. Accordingly, and considering the solvent additive that must be placed in the cigarette, the toxicological data of those compounds that are intended to be reviewed are reviewed. The compounds that have specific exposure limits TWA) and already disclosed are immediately applicable to human exposure, as long as that exposure is at the same level or below the indicated limits. Since the present invention includes many alcohols with no stated limits, the additional alcohols should only be available to be included in a commercially used cigarette after further toxicological studies have been completed on them.

In addition, the alcohols selected and sprayed on the tobacco must have physical properties such that it allows the cigarette to be produced at normal cigarette production rates and yet remains stable inside the cigarette until it is smoked. For example, the preferred blocking alcohol should have a sufficiently low vapor pressure to prevent excessive evaporation over the course of its storage time, should not cause the formation of moisture stains or wetting of the tobacco at sufficient loads to transfer and block in the lung, and should not cause chemical changes during tobacco pyrolysis.

Important is the fact that the TLV for alcohol must be sufficient to effect the desired blocking action. Fortunately, much is now understood about the metabolic pathway of this family of carcinogens and literary studies

provide clear guidelines on the potential effectiveness of compounds. For example, it is known that chemical compounds must first be metabolized in a DNA-binding intermediate. This metabolism is mediated by enzymatic action. While there may be any number of enzymes, there is a finite number of TSNA molecules available for metabolism. Accordingly, based on a molar theory of equality, an effective compound should be measurable in the smoke stream inhaled with a 1: 1 molecular base. The discussion that may take place here on the molar theory of equality should not, however, limit the horizon of this invention since it is possible but until now it is not known, that a fraction of the solvent can completely block nitrosamines.

Sample Calculations cyclohexanol appears to meet these criteria. OSHA considers 8 continuous hours safe in an atmosphere containing 200 milligrams of cyclohexanol per cubic meter of air. Approximately 10%, on a scale of 5 to 20%, of the initial charge on tobacco is transferred to the volume of smoke inhaled by the smoker in the course of smoking a cigarette.

Surprisingly, under a consistent molar theory of equality, this level of cyclohexanol is often higher than the minimum amount of blocking agent required to match the total molar concentration of inhaled nitrosamines as follows:

The concentration of tobacco-specific nitrosamines delivered by a cigarette with a fully smoked filter is given by the interval between 140 nanograms and 830 nanograms, the specific levels of that concentration are shown in Table III (Hoffman, D.Lavoie, EJ, and Hecht, SS Cancer Letters, 26 (1985) 67-75).

Table III

Nitrosamines delivered by cigarette smoke from filter cigarettes

Concentration level

Average Molecular Weight (Nanograms per Cigarette)

NNN 177 50 - 310 NNK 207 30 - 150 NATB + 190 60 - 370

f

k.

NABS *

NNN = N-nitrosonicotine

NNK = 4- (methyl-nitrosomino) -1- (3-pyridyl) -1-butanone

NATB = N-nitrosoanatabina

NABS = N-nitrosoanabasine

For the highest levels of nitrosamine concentrations given in Table III, the amount of blocking agent required to match the molecular concentrations in these upper limits are reported in Table IV.

It can be seen that when the highest level of all nitrosamines is to be blocked by cyclohexanol, the concentration of the blocking agent, in the TWA value of OSHA, provides 142 times more material than necessary to match the molecular concentrations of cyclohexanol with all nitrosamine molecules present.

Table IV

Blocking Nitrosamines in cigarette smoke (Nanograms of cyclohexanol per cigarette)

Nitrosamine f

Blocking agent required

Blocking agent delivered * to agent

lock required NNN 175 ng 360: 1 NNK 73 ng 863: 1 NATB + NABS 195 ng 323: 1 NNN + NNK 248 ng 254: 1 NNN + NNK + NATB + NABS 443 ng 142: 1 - Concentration in cycle -hexanol in cigarette smoke second the TWA limit of OSHA, this is, 200 mg / nr or 63 microgra- but / cigarette.

* *

- Assuming a molar condition of equality.

blockade known to

Although menthol does not have an effect of nitrosamines like the alcohols of this invention, the method of applying menthol to tobacco is relevant due to the established transfer efficiency and stability during the storage of menthol in the cigarette. Accordingly, the melting point, the boiling point, the vapor pressure and the molecular weight of menthol are relevant criteria for the selection

. of the preferred alcohols to be used. In this way, the preferred alcohols with no toxicity or low toxicity, can be applied directly under the tobacco and then be released by the action of heat as the tobacco is burned and are comparable to menthol in its molecular characteristics, in order to remain stable inside the tobacco roll and are effectively transferred to the smoke and are comparable, in molecular weight, to N-nitrosonicotine so that the amount to be applied to the tobacco does not wet it excessively, preferably has a taste and smell pleasant, and evidently has the desired blocking effect.

Although any of the alcohols mentioned in the present invention can be used by means of this method (direct spraying, the preferred alcohols are the following:! Monofunctional alcohols, n-octyl alcohol and caprylic alcohol, polyfunctional alcohols: 1,3-butanediol, pinacol and 1,2,4-butanotriol; compounds with resonant hydroxyl species: n-decyl alcohol, lauryl alcohol, cetyl alcohol, stearyl alcohol and cinnamyl alcohol; and alternative alcohols: 2-ethyl butyl alcohol, ethyl hexanol, n-nonyl alcohol and methyl cyclohexanol. Cetyl and stearyl alcohols are included here because, although they have a relatively high molecular dimension, they are non-toxic. The properties and characteristics of these alcohols are listed in Table V.

Table V

Alcohol

Formulas

1. n-octyl alcohol

2. caprylic alcohol

3. 1,3- Butanediol

4. Pinacol

15. 1,2,4-Butanotriol

6. n-decyl alcohol

7. lauryl alcohol

8. cetyl alcohol

9. stearyl alcohol

10. cinnamyl alcohol

11. 2-ethyl butyl alcohol

12. ethyl hexanol

13. n-nonyl alcohol

14. methyl cyclohexanol

15. cyclohexanol

16. monomethyl-dipropylene glycol ch ₃ (ch ₂ ) ₅ ch (oh) ch ₅ ch ₃ (ch ₂ ) ₅ chohch ₃

CH ₃ CHOHCH ₂ CH ₂ OH (CH ₃ ) ₂ COHCOH (CH ₃ ) ₂

H0CH ₂ CH0HCH ₂ CH ₂ 0H

CH ₃ CH ₂ CH ₂ CHOH (CH ₂ ) ₅ CH ₃ ch ₃ (ch ₂ ) ₁₁ oh ch ₃ (ch ₂ ) ₁₅ oh

CH ₃ (CH ₂ ) _1? OH

C ₆ H ₅ CH: CHGH ₂ 0H

C ₂ H ₅ CH (C ₂ H ₅ ) CH ₂ OH

CH ₃ (CH ₂ ) ₃ CH (C ₂ H ₃ ) CH ₂ OH

CH ₃ (CH ₂ ) ₇ CH ₂ OH ^CH 3 ^C 6 ^H 1O ^{OH C} 6 ^H 12 °

CH ₃ OC ₃ H ₆ OC ₃ HgOH

17. Menthol ^C 10 ^H 20 °

Table V

Alcohol Toxicity Weight Density g / cm ³ Melting point (° c) Score boiling (° c) Molecular 1. Aromatic agent 130 0.82 -15 86 2. Low toxicity aromatic 130 0.83 -30 178 3. non toxic 90 1.01 <-50 207 , ⁴ · Low toxicity 118 1.05 43 174 5. non toxic 106 1.02 AT 172 6. Low toxicity 158 0.83 -12 210 7. Low toxicity 186 0.83 26 255 8. non toxic 243 0.82 50 344 9. non toxic 271 0.81 59 210 10. 134 1.04 34 257.5 11. Low toxicity 102 0.83 <-15 149 12. Low toxicity 130 0.83 <-76 185 13. Low toxicity 144 0.83 215 14. -> 50ppm (235 mg / m ^J ) * 114 0.92 173 15. 50ppm (200 mg / nr 100 0.96 25 161 16. 100ppm (600 mg / 132 0.95 -80 189 17. Aromatic agent 156 0.90 44 216

w

TWA OSHA: Average time weighing for a normal period of 8 hours of work and for a week of 40 hours

working hours, unless otherwise indicated (adopted by OSHA)

Table V (continued)

Solubility *

Alcohol Vapor pressure (mm Hg) Water Alcohol Ethyl Ether 1. 1 (54 ° C) <1 s s 2. 1 (32.8 ° C) 9 & U 3. .06 (20 ° C) s s i 4. 1 (44 ° C) Q V V 5. AT U u 6. 1 (69.5 ° C) i s s 7. 1 (91 ° C i s s 8. 1 (122.7 ° C) i q V 9. l (50 ° C) i s s 10. 1 (72.6 ° C) q V V 11. 0.9 (20 ° C) q // 12. 1 (54 ° C) i u u 13. 1 (59.5 ° C) 1 14. 1.5 (30 ° C) q 15. 1 (21 ° C) s s s 16. .3 (20 ° C) 17. 1 (56 ° C) q V V

Key: 1 = insoluble q = slightly soluble s = soluble v = very soluble // = soluble at all levels.

Nowadays the manufacture of cigarettes involves a process with 18 phases, which are as follows: 1) purchase of tobacco leaf; 2) wrapping the tobacco leaves before they are cut; 3) cutting tobacco leaves; 4) dryness; 5) evaluation; 6) dating; 7) disposition; 8) batch mixing; 9) disposition; 10) coverage; 11) cutting 12) drying; 13) cooling; 14) leaf flavoring; 15) agglomeration; 16) manufacture; 17) packaging; and 18) storage of finished products. A known variant for this process reverses phase 14) and phase 15) so that the agglomeration of the leaves takes place before they are flavored. In the work of Max Samfield, Research and Manufacturing in the U.S.Cigarette Industry (1980), various methods are discussed in detail for the manufacture of cigarettes and cigarette constructions, formation of cigarette smoke and comparison to be smoked. In phase 16) (manufacture) the cut tobacco is transformed by machine tools into a final cigarette. In modern cigarette manufacturing facilities, a rapid transport system is used to continuously feed cut tobacco to the highly mechanized manufacturing line. After the tobacco has been packaged, cut, evaluated, cured, coated and agglomerated, the manufacturer forms the cigarette, adds the filter and brings the finished product into the packaging machinery.

alcohol or blocking compound of the present invention is preferably added to the cut tobacco after

the final drying stage (stage 12), and when it is already in the cooling stage (13). Coolers are typically of the rotary type and have a stationary injector inside their cylinders. The compounds added to tobacco during the cooling process (13) are called aromatization. In the work The casing and Plagoring of Cigarettes, Max Sambield, Tobaco Journal International, 5/1984, October, there are discussions about aromatic materials, processes for their application and their effects. The compost is sprayed onto the cut tobacco as it is rolled in the refrigerator cylinder. The aromatic elements, such as the alcohols or compounds of this invention, are added or sprayed after the final drying in order to minimize their losses, being immediately applied preferably before entering the manufacturing machines. Tobacco is preferably dried before aromatization is applied, since aromatizations do not age well and evaporate easily. Consequently, this is the normal practice of the cigarette manufacturing industry, and the process of this invention, of adding the blocking compound to the cut tobacco, can be done using current production machinery, with only minor modifications of minor importance. introduced, with a production rate of 3,200 to 8,000 cigarettes per minute. The blocking alcohol can either be sprayed by the same injector as the aromatic elements or via a different injector, and sprayed on the cut tobacco either simultaneously or after the other flavorings.

A carrier solution for the blocking alcohol may be necessary to ensure a sufficient load of alcohol on the tobacco dough. In other words, the amount of alcohol chosen, such as cyclohexanol, to be applied to a given amount of tobacco, may not provide a sufficient solution even to wet the tabai.

co, needing to use a vehicle solution for alcohol. Most of the blocking alcohols mentioned here are soluble in ethyl alcohol, which is a preferred solvent for cyclohexanol (and for methyl cyclohexanol) since it easily dissolves cyclohexanol and evaporates quickly from tobacco in the phase end of the charging phase. Ethyl alcohol is a solvent for alcohols that have been specifically mentioned here, and is also widely used as the solvent for flavoring elements. The minimum concentration of cyclohexanol in an ethyl solution is that which is necessary to solubilize cyclohexanol, and the maximum concentration is that which is necessary to distribute the cyclohexanol evenly in the refrigeration drum. This upper limit varies according to the size and / or speed of the refrigeration unit, and the amount of tobacco found in the refrigerator. Water is an alternative solvent, but its usefulness is limited as it raises the moisture content in the tobacco, and the moisture content of a cigarette should generally be between 10 and 50% underweight. In addition, the solubility of alcohols in water is, in most cases, limited.

As previously mentioned, one or more vitamins can also be added to the alcoholic solution, such as vitamins A, B, C and E. It is believed that vitamin A, in particular, is a cancer inhibitor. Some disclosures for the use of vitamin A in cigarettes are US patent N ² . 3 339 558 and Japanese No. ² . 55-79 319 (Shaman, June 14, 1980).

Example 6

Cigarettes were manually filled with cyclohexanol, that is, the alcohol was equally injected into the roll of a cigarette manufactured using a mechanically controlled syringe. To detect initial transfers, 8750 micrograms of cyclohexanol were injected into the butt of a single cigarette. 60 cigarettes were smoked in a standardized smoking machine, using Cambridge filter pads to collect the particulate phase where most of the material is transported. With this test, a transfer efficiency of 10% was established. This resulted in a smoked concentration of 2778 milligrams of cyclohexanol per cubic meter or 1389% TLV. The GC was then calibrated and cigarette production started. The charge was 620 micrograms per cigarette and the transfer efficiency was 10%. The smoked concentration was 197 milligrams per m \ which is 99% TLV cyclohexanol, thus being considered safe. This new manufactured cigarette delivered a safe concentration of cyclohexanol and the delivery exceeded, by a factor 132, the total TSNA concentrations in the cigarette.

In addition, the cigarettes of this invention on which a blocking alcohol (cyclohexanol) was sprayed were produced very successfully at a production speed of 3,200 cigarettes per minute and without making any changes to the manufacturing equipment or have verified any extraordinary damage to the resulting cigarettes.

This cigarette has characteristics of duration before being smoked that are not distinguished from the characteristics of ordinary cigarettes, and does not show any increased tendency to cause stains or to deform. Furthermore, this cigarette selectively reduces the smoker's exposure to the most abundant carcinogenic effects in smoking

of the cigarette located in the smoker's lung, this organ being the critical organ associated with the smoker's disease.

This cigarette concentration thus provides an effective passive release of the blocking alcohol into the cigarette smoke stream and then into the smoker's respiratory system. While the blocking alcohol, thus manufactured inside the cigarette, when inhaled through the tobacco smoke stream strengthens the smoker's lung resistance to the effects of a well-known family of carcinogens, it will not clash with the taste, mixture, sensation in the mouth, inspiration or way of burning the cigarette. However, it can give a slight aroma to the cigarette package. It also appears that the blocking alcohol will not collide with any type of mixture from a particular cigarette.

In addition, there is no need to limit the present invention to alcohols that exist in a liquid state at room temperature. Alcohols that exist in the solid state at room temperature are also covered by the processes of the present invention. While it is not important that the alcohols are administered either as solids or as liquids, it is also important that the alcohols are administered in such a way as to satisfy the 4 objectives stated above.

Another embodiment of the present invention is to incorporate the alcohols in a face mask (not shown) so that its vapors are released and inhaled by the mask user. This mask can be used in polluted industrial environments or in environments where nitrosamines are in the air.

A device can be used to spray the mouth to administer alcohols by inhalation before being exposed to any nitrosamines in the environment, and particularly those in the smoke stream of the environment.

- putt. In this way, there is another embodiment which contemplates a mouth spray or mixed device (not illustrated), having a cylindrical plastic or metal body and containing one or more alcohols of the present invention. A non-toxic carrier gas or propellant gas, such as compressed gas or nitrogen, can also be used. An aerosol is thus defined for the smoke stream of the tacabo containing the alcohol (s). When the alcohols of the present invention are administered by inhalation, a concentration of alcohol) in the air of only about 0.001% is sufficient to displace the nitro (samines in the epithelial lining of the bronchi. See also US patents 4 016 279, 4 232 002 and 4 243 543.

From the detailed description that has been provided, it will become evident that there are possibilities for introducing a number of changes, adaptations and modifications by the persons skilled in this field. However, it is intended that all such variations that do not escape the spirit of this invention are considered to be within its scope, being only limited to the claims listed in the annex.

Claims (15)

13. - Process for the manufacture of cigarettes, characterized by the fact that it comprises the operations that consist of spraying cut and dried tobacco with at least one alcohol that has two or more carbon atoms and that is capable of, when its vapor is inhaled by the smoker, inhibit the selective localization of at least one nitrosamine or its metabolite in the tissues of the smoker's body and in an amount sufficient to inhibit this selective localization but not cause any toxic effects on the smoker and transform the cut tobacco, after pulverized and dried, into cigarettes. 2 ^â . Process according to claim 1, characterized in that said spraying operation includes spraying said alcohol in solution. 3 · ³ - Process according to claim 1, characterized in that the said solution comprises ethyl alcohol. 4 ^â . Process according to claim 3, characterized in that said alcohol includes at least cyclohexanol. 5 ³ . Process according to claim 2, characterized in that said solution includes water. 6 ^. Process according to claim 1, characterized in that said alcohol has a sufficiently low vapor pressure to avoid its excessive evaporation during the time until the cigarettes are consumed. 7 · ³ - Process according to claim 1, wherein said alcohol is monometil52 -dipropylene glycol in an ether solution. 8 &. Process according to claim 1, characterized in that said alcohol has a sufficient molecular weight so as not to cause the formation of moisture stains or the wetting of the tobacco. 93. The method of claim 1, wherein said alcohol remains chemically unchanged during pyrolysis of cut tobacco. 10 ^â . Process according to claim 1, characterized in that said alcohol comprises at least a monofunctional alcohol. 113. The method of claim 10, wherein said monofunctional alcohol is n-octyl alcohol (octanol-1) or caprylic alcohol. 123. The method of claim 1, wherein said alcohol is an alcohol comprising at least one polyfunctional alcohol. 133. The method of claim 12, wherein said polyfunctional alcohol is 1,3-butanediol, 2,3-dimethyl-2,3-butanediol (pinacol) or 1,2,4-butanotriol. 14 ^s . Process according to claim 1, characterized in that said alcohol comprises I at least one compound with the resonant hydroxyl group 15 ^A · - Process according to claim 14, wherein said compound is selected from the group formed by alcohol n-decyl alcohol (1-decanol), lauryl alcohol (1-dodecanol), cetyl alcohol (1-hexadecanol) , stearyl alcohol (1-octadecanol) and cinnamyl alcohol (3-phenyl-2-propen-1-ol). 16th. Process according to claim 1, characterized in that said alcohol is chosen from the group consisting of 2-ethyl-butyl alcohol (2-ethyl-2-butanol), ethyl-hexanol, n-nonyl alcohol (1- nonanol) and methyl cyclohexanol. 17 ^â . Process according to claim 1, characterized in that said alcohol is present in an amount sufficient to guarantee a braid; difference of alcohol molecules for the volume of smoke inhaled by the smoker equal to the number of nitrosamine molecules present in the same volume of smoke. 18th. Process according to claim 1, characterized in that said alcohol is present in an amount sufficient to guarantee a transfer of the respective molecules to the volume of smoke inhaled by the smoker, generally at least in a number equal to the number of molecules of nitrosamines present in the same volume of smoke. 19 ^. Process according to claim 1, characterized in that said alcohol is present in an amount sufficient to guarantee a transfer of the respective molecules to the volume of smoke inhaled by the smoker, generally at least in a number equal to that of the molecules of N-nitrosonicotine (NNN) present in the same volume of smoke. 202. The method of claim 1, characterized in that the said spraying operation includes the spraying of at least one alcohol in the form of a solution and the said solution decreases the moisture content of the cigarette to a value less than twelve and a half percent by weight. 212. The method of claim 1, wherein at least one of the aforementioned alcohols on the cut tobacco is rolled into a container. 222. The method of claim 1 wherein said tobacco rolling operation is carried out in a rotary drum cooler. 232. Process according to claim 1, characterized in that odorizing agents are also added to the cut tobacco. 242. The method of claim 23, wherein said adding operation takes place during said spraying operation. 25 ^â . Process according to claim 23, i characterized in that the aforementioned addition operation is carried out before said spraying operation. 26a. - method according to claim 23, characterized in that the said addition operation takes place after the said spraying operation. 273. The method of claim 1, wherein said processing of the cut and pulverized tobacco machine includes the adaptation of a filter to each cigarette. « 283. The method of claim 1, characterized in that said sprayed alcohol is allowed to dry before the aforementioned machine operation begins. 293. The process of claim 1, wherein said alcohol is chosen from the group consisting of 1-octanol (n-octyl alcohol), 1-octanol (caprylic alcohol), 1,3-butanediol, 2 , 3-dimethyl-2,3-butanediol (pinacol), 1,2,4-butanotriol, 1-decanol (n-decyl alcohol), 1-dodecanol (lauryl alcohol), 1-hexadecanol (cetyl alcohol), 1- octadecanol (stearyl alcohol), 3-phenyl-2-propene-l-ol (cinnamyl alcohol), 2-ethylbutanol-l (2-ethylbutyl alcohol), ethylhexanol, 1-nonanol (n-nonyl alcohol), methyl- cyclohexanol and cyclohexanol. 303. The process of claim 1, wherein said alcohol is in the form of a solution that includes at least one vitamin chosen from the group consisting of Vitamins A, B, C and E. 31st. - Process characterized by the fact that the three carbon atoms. according to claim 1, said alcohol has at least 32 ^. - Process characterized by the fact that the four carbon atoms. according to claim 1, said alcohol has at least 33 ^a . Process according to claim 1, characterized in that said acid has less than thirty-three carbon atoms. í f 34 ^a . Process according to claim 1, characterized in that said alcohol has less than forty-one carbon atoms. 35 ^a . Process according to claim 1, characterized in that said alcohol is released into the tobacco smoke stream when the cigarette is smoked by the user. 36â. Process according to claim 1, characterized in that said released alcohol protects the tissues of the bronchial epithelium, the salivary ducts or the tissues of the smoker's liver. 37 ^a . Process according to claim 1, characterized in that one of the aforementioned nitrosamines is N-nitroso-nicotinamide (NNN), N-nitrosopyrrolidine (NPIR) or 4- (N-methyl-N-nitrosamino) -l- (3 -pyridyl) -l-butane (NNK) or its metabolites. 383. The method of claim 1, wherein the amount of said alcohol present is not greater than two hundred milligrams of cyclohexanol per cubic meter of cigarette smoke. · 39 - Process according to claim 1, characterized in that each cigarette comprises between 750 and 1100 milligrams of said cut tobacco and from 1 to 1000 micrograms of said alcohol. 40 ^â . Process according to Claim 39, characterized in that the amount of said alcohol constitutes approximately 800 micrograms of alcohol. ' 41 ^§ . Process according to claim 39, characterized in that said cut tobacco comprises approximately 800 milligrams of tobacco. 423. The process of claim 41, wherein said alcohol constitutes approximately 800 micrograms of alcohol. · 43 - Process according to claim 1, characterized in that said alcohol is methyl cyclohexanol. 44-. Process according to claim 1, characterized in that said alcohol is sprayed in an amount sufficient for at least one of its molecules to be inhaled by the smoker for each molecule of the inhaled nitrosamines. ³ · 45 - Process according to claim 1, characterized in that the said alcohol having a concentration in air of between 0.1 and 0.001 $ 0>. 46â. Cigarettes characterized in that they are manufactured using the tobacco blend according to claim 1. 47 ³ · - Process for the manufacture of cigarettes, characterized by the fact that it comprises the operations that consist of preparing an ink comprising a suspension of microcapsules of an alcohol that has two or more carbon atoms, the aforementioned alcohol being able, when released microcapsules and their vapors inhaled by the smoker, inhibit the selective localized accumulation of at least one nitrosamine or its metabolite in the tissues of the smoker's body, the said alcohol being present in an amount sufficient to inhibit the aforementioned localized accumulation selective but does not cause any toxic effects to the smoker and the cigarette paper is printed with the aforementioned ink. 483. The process of claim 47, wherein said alcohol is cyclohexane.