LU88544A1 - Anticarcinogenic treatment for cigarette filters or the like - Google Patents

Description

ANTICARCINOGENIC TREATMENT FOR FILTERS OF * CIGARETTES OR THE LIKE

The present invention relates to the treatment of filters for tobacco smoke, in particular to cigarette filters, in order to limit the carcinogenic effect of the smoke which reaches the consumer through them.

Tobacco smoke, particularly that from cigarettes, is well known to contain various components that are either carcinogenic or pro-carcinogenic. A particular class of compounds that fall into this category includes polycyclic aromatic hydrocarbons (PAHs) which, in the liver or the lungs, are transformed by the cytochrome P 450 enzyme system into oxygen derivatives which have been shown to be carcinogenic. There is now a considerable amount of literature in this area, for example: Pryor et a 1. Science 220: 425 - 427; Pryor et al. Cancer and Free-Radical s in Antimutagenesis and Anticarcinogenesis Mechanisms; Ed. D. Shankel et al .; Plenum Press, New York N.Y., pages 45-59; Janoff et al. 1987 Am. Rev. Resp. Say 136: 1058-1064 and many others. The effect of free radicals in smoke has been widely discussed, for example by Church and Pryor Environ. Health. Perspect. 64: 111-126 (1985).

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In situations where free radicals are known to cause harm, for example in the skin, the use of free radical inhibitors is well known. For example, EP-B-0 345 362 describes the use of a particular type of free radical inhibitor in cosmetic products for the skin. The inhibitor in question is chosen from a group of identical furfuryl derivatives of sorbitol, in particular 2,4-monofurfurylidene sorbitol and its tetra-O-alkylated derivative. 2,4-monofurfurylidene sorbitol has been described in USA 3,383,279 as the product obtained by gradual addition of furfurol to acidified sorbitol, thus forming the 2,4-0-furfurylidene derivative.

We have now studied the effect of these sorbitol derivatives in other areas. Surprisingly, we have now found that free radical inhibitors, such as the furfurylidene sorbitol derivatives of EP-B-0 345 362, in combination with certain other components can be used to impregnate tobacco smoke filters to arrive to a smoke which has dramatically reduced toxicity and mutagenicity, as results from measurements by the Ames test and which must therefore more than likely have a similar reduced carcinogenicity. The mechanism of this action is unknown and unexpected: according to the model of the previous uses of free radical inhibitors, it could be expected that the inhibitor should be present at the site of its absorption by the body and not at a remote location. The compounds appear to eliminate the mutagenic or carcinogenic components of smoke, but other explanations are possible.

According to the present invention, the latter thus provides a filter for tobacco smoke, which comprises means forming a passage for the smoke, characterized in that on a surface of the passage arranged so as to be in contact with the smoke, it is a provision of a free radical inhibitor, in particular of the product known as 2,4-mono-furfurylidene sorbitol, namely the product which can be obtained by slow addition of furfurol to acidified sorbitol or an O derivative -alkylated thereof with an antioxidant or a chelating agent. The O-alkylated derivative is advantageously a C1-C6 alkylated derivative, eg the methylated derivative and the tetra-O-alkylated derivative is preferred.

The filter according to the invention is, in particular, represented by a cigarette filter which can be of any conventional construction arranged so as to provide a very large surface area in contact with the smoke passing through it, for example heaps of filaments, open cell foams, etc.

It appears that filters with a dose of protective agent retain the mutagenic and carcinogenic compounds better in the filter than if the protective agent is not present. This is surprising in that free radical inhibitors have not previously been considered as filter additives in the form of a solution.

The free radical inhibitor can be incorporated into the filter at any effective level, but typically a level of 2.5-20 mg per filter is used, especially around 5-10 mg, especially when tetra-O-methyl 2,4-monofurfurylidene sorbitol is used.

The filter also contains an antioxidant or chelating agent and it is desirable that the weight ratio of the free radical / inhibitor to the second component be about 1.51 to 3: 1, especially about 2: 1. As a particularly preferred antioxidant, there are, inter alia, tert-butylhydroxyanisole (BHA) or tert-butylhydroxytoluene (BHT). The preferred chelating agent is a dialkyldithiocarbamate salt, eg a diethyldithiocarbamate, especially the sodium salt.

It appears that there is a synergy between the sorbitol derivative and the second component and that all of the two components are necessary for maximum activity.

The active components can be added to the cigarette filter by any practical method, for example by dosing it with a solution of the components and allowing the solvent to evaporate. Alternatively, the packing material for the filter can be previously impregnated with the active component before the construction of the filter.

The following examples illustrate the invention in a complementary manner: EXAMPLE 1 PREPARATION PROCESS FOR 2,4-MONOFURFURYLIDENE-SORBITOL ^

Starting materials: sorbitol 70 1000 ml distilled furfurol 400 ml concentrated hydrochloric acid 10 ml active carbon 30 g sodium bicarbonate 14 g

With stirring, the hydrochloric acid is poured into sorbitol and then furfurol is added slowly. The reaction mixture is stirred for three hours and then left to stand overnight.

The reaction mixture is neutralized with sodium bicarbonate and gradually adding 3 liters of distilled water. The reactive mixture is heated to 85-90 ° C, the active carbon is added and the mixture is filtered while it is still hot and an initial precipitate is instantly obtained which is separated by filtration. he

The mother liquors are concentrated - up to approximately 1 h of the initial volume. After cooling, the second crop is filtered. By further concentration, a third harvest is obtained. The total yield is 900 g, p. fus. 190-191 "C.

Table 1 TOXICITY DL: o

Oral mouse 1226 mg / kg iv. 670 mg / kg

Rat per os 1940 mg / kg iv. 692 mg / kg EXAMPLE 2

SALMONELLA MUTAGENICITY TEST

Cigarettes with metered filters as described above were artificially smoked and the smoke collected in an ethanol trap. The contents of the traps were collected, added to the culture plate and evaporated. The test strain was then plated out and the development of colonies was monitored. Two sets of tests were performed, one with a liver enzyme activator (S9) to mimic the enzyme effect in the lungs or liver and the other without an activator.

The tests were Ames' essential tests, well recognized in the art, as performed by Microbiological Associates Inc. of Rockville, Md. E.U.A.

For the test strain TA 98 in the absence of activation by S9, a mutagenic response was observed at a dose level of 10 μΐ / plate as was demonstrated by an increase of 21.5 times in the counting of the colonies. reverberating by comparison with vehicle control (472 against 22). The 33 μΐ / plate doses were toxic to bacterial cultures, as evidenced by the absence of revertant colonies and a moderately to extremely reduced background bacterial mat. With the addition of protective agent to the cigarette filter before smoking cigarettes, there was a substantial reduction in the count of revertants to 10 μΐ / plate (34 revertants / plate, essentially in basal condition). The response to 33 μΐ / plate was also indicative of a substantial reduction in the toxicity of cigarette smoke with the addition of the protective agent.

For the test strain TA 98 in the presence of activation by S9, a mutagenic response was observed at all the dose levels tested, with one exception for the erratic response at 33 μΐ / plate. With the addition of protective agent to the cigarette filter before smoking cigarettes, there was a substantial reduction in the count of revertants at 3.3 and 10 μΐ / plate.

The test strain TA 98 responds to chemical compounds that cause offset weft mutations. Consequently, the observed response is indicative not only of the presence of polycyclic aromatic hydrocarbons (PAH which requires activation by S9) but also of the presence of other types of chemicals (requiring or not requiring activation by S9 ).

Table 2

Experimental Plan: 2 groups of 6 smoked cigarettes at a rate of 6 min / group. The smoke was collected in 2.5 ml of 50% ethanol

Table 3 -

Experimental Plan: 2 groups of 6 cigarettes smoked at a rate of 6 min / group. Each cigarette filter contained 500 µl of a 33 mg / ml solution of protective agent in 50% ethanol (added to the filter and then dried for 3 hours before smoking the cigarette). The smoke was collected in 2.5 ml of 50% ethanol

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All background bacterial mats were normal except as indicated with the following code (on display): 1 = Normal 2 = Slightly reduced 3 = Moderately reduced 4 = Extremely reduced 5 = Absent 6 = Obscured by a precipitate 0.0 = aliquot of spreading in plate of 50 / il of vehicle

Pos = Positive Control: without S9, 2-nitrofluorene at 1 / ig / plate for TA98; with S9, 2-aminoanthracene at 1 µg / plate for TA98.

EXAMPLE 3

Experiments were carried out to determine the synergistic effect of the association of two components in tests for mutagenicity of Salmonella similar to that of Example 2.

Table 4

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group. The smoke was collected in 2.5 ml of 50% ethanol.

The conditions are as for Table 3.

Table 5

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group. Each cigarette filter was dosed with 0.5 ml of a mixture containing 11.1 mg / ml of F $ 3 and 5.55 mg / ml of DDC in 50% ethanol. *). The smoke was collected in 50% ethanol.

*) The mixture was prepared by mixing equal volumes of FS3 (22.2 mg / ml in 50% ethanol) and DDC (11.1 mg / ml in 100% ethanol), the final ethanol concentration being 50% in the mixture. The other conditions are as for Table 3. FS3 = the tetra-0-methyl derivative of 2,4-monofurfurylidene sorbitol.

Table 6

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group. Each cigarette filter was dosed with 0.5 ml of a 22.2 mg / ml solution of FS3 in 50% ethanol. The smoke was collected in 2.5 ml of 50% ethanol.

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The conditions are as for Table 3.

Table 7

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group. Each cigarette filter was dosed with 0.5 ml of a 22.2 mg / ml solution of FS2 in 50% ethanol. The smoke was collected in 2.5 ml of 50% ethanol.

The conditions are as for Table 3.

FS2 = 2,4-monofurfurylidene sorbitol

Table 8

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min / group. The smoke was collected in 2.5 ml of 50% ethanol.

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The conditions are as for Table 3.

Table 9

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group. Each cigarette filter was dosed with 0.5 ml of an 11.1 mg / ml solution of DDC in 50% ethanol. The smoke was collected in 2.5 ml of 50% ethanol.

The conditions are as for Table 3.

Table 10

Experimental Plan: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group. Each cigarette filter was dosed with 0.5 ml of an 11.1 mg / ml solution of BHA in 50% ethanol. The smoke was collected in 2.5 ml of 50% ethanol

The conditions are as for Table 3.

Table 11

Experimental design: 2 groups of 6 research cigarettes smoked at a rate of 6 min./group, each cigarette filter was dosed with 0.5 ml of a mixture containing 22.2 mg / ml of FS2 and 11.1 mg / ml of DDC in 50% ethanol. The smoke was collected in 2.5 ml of 50% ethanol.

The conditions are as for Table 3.

EXAMPLE 4

PREPARATION OF A FILTRF

The filters can be prepared by passing the composition of the description through the material used to make the filter, by immersion or by spraying and by allowing it to evaporate or else by passing it directly through the cigarette filter itself. even. i

In the latter case, 250 mg of furfurylidene-sorbitol and 125 mg of BHA (tert-butylhydroxyanisole) are dissolved in 80 ml of ethyl ether (or hexane) and 16 μλ of such a solution are injected into each cigarette filter and the solvent is then evaporated to dryness. The ether evaporates while the active compounds which exhibit the favorable effects mentioned above remain in the filter.

Similar applications can be envisaged in other smoke filters, for example filter cartridges in tobacco pipes. A person skilled in the art will be able to see several modifications and variants which will be considered to be all within the scope of the present description.

Claims (13)

1. Filter for tobacco smoke comprising means forming a passage for the smoke, characterized in that on a surface of the passage arranged to be in contact with the smoke, there is an arrangement of a free radical inhibitor with a antioxidant or chelating agent. 2. Filter according to claim 1, wherein the free radical inhibitor comprises the product known as 2,4-monofurfurylidene sorbitol, namely the product which can be obtained by slow addition of furfurol to acidified sorbitol or one of its sorbitol 0-alkylated derivatives. 3. Filter according to Claim 2, in which the 0-alkylated derivative comprises 2,4-monofurfurylidene-1,3,5,6-tetra-0-methyl sorbitol. 4. Filter according to any one of Claims 1 to 3 in the form of a cigarette filter. 5. Filter according to Claim 4 containing 2.5 to 20 mg of the free radical inhibitor. 6. Filter according to Claim 5 containing about 5 to 10 mg of free radical inhibitor. 7. Filter according to any one of Claims 1 to 6, in which the antioxidant comprises tert-butylhydroxyanisole (BHA) tert-butylhydroxytoluene (BHT). 8. Filter according to any one of Claims 1 to 6, in which the chelating agent is a dialkyldithiocarbamate salt. 9. The filter of claim 7 or claim 8, wherein the weight ratio of the free radical inhibitor to the antioxidant or the chelating agent is 1.5: 1 to 3: 1. 10. The filter of claim 9, wherein the ratio is approximately 2: 1. 11. Use of a radical inhibitor'1 ibres in combination with an antioxidant or a chelating agent to treat a filter for tobacco smoke. 12. Use according to Claim 11, wherein the chelating agent is DDC. 13. Use according to Claim 11 or Claim 12, wherein the free radical inhibitor comprises 2,4-monofurfurylidenesorbitol, ie the product which can be obtained by slow addition of furfurol to acidified sorbitol or one of its sorbitol 0-alkylated derivatives.