CA1134748A - Method for eliminating or reducing the desire for smoking - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to a method of preventing or reducing the desire for smoking tobacco in humans by administering thereto a sulfurized polyunsaturated oil.

Description

1~34~423 The invention relates to a method of preventing or reducing the desire for smoking tobacco in humans by the internal administration of a composition produced by heating certain allylically unsaturated compounds sufficient to substantially increase the peroxide titer. The incorporation of sulphur in the composition during the heating has been found to be particularly advantageous.
Sulfurized polyunsaturated oils, or sulfurized oils, are disclosed in a book entitled RESEARCH IN PHYSIOPATHOLOGY
AS BASIS OF GUIDED CHEMOTHERAPY by Emanuel Revici, M.D., published by D. Van Nostrand Company, Inc., 1961, pages 334 to 335. A method of preparing sulfurized polyunsaturated oils referred to in the book as hydropersulfides is set forth in Note 7, page 711 of the book. This book does not disclose the use of the sulfurized compounds for preventing or reducing the desire for smoking tobacco claimed herein.
The invention relates to a method of eliminating or reducing the desire for smoking tobacco in humans by administering thereto a sulfurized polyunsaturated oil. The sulfurized polyunsaturated oils (hydropersulfides) can be administered to the patient by the various known methods of injection or preferably orally in capsule form.
The invention relates to a method of eliminating or reducing the desire for smoking tobacco in humans by the internal administration of a composition produced by heating certain allylically unsaturated compounds in the presence of oxygen sufficient to substantially increase the peroxide titer. The incorporation of sulfur into the composition during or before the heating of the compositions has been found to be particularly advantageous and represents the most effective composition found to date. The compositions can be administered to the patient by the various accepted methods 113~748 such as by injection or preferably orally in capsule form.
It is desirable to have a method for treating or aiding in the treatment of the tobacco habit or addiction ina human by controlling the craving for tobacco and/or by con-trolling withdrawal symptoms.
This invention relates to such methods of treatment involving the internal administration to a human host of a composition produced by oxidizing a fatty acid or fatty ester, for example, by bubbling air through the reaction mixture, structurally characterized by allylic unsaturation alone.
The fatty acid or ester advantageously includes elemental sulfur and/or a conventional free radical initiator such as tertiary-butyl peroxide during the heating step.
The allylically unsaturated compound is preferably a naturally occurring fatty ester such as an animal, vegetable, or fish oil. Sesame oil i~ a vegetable oil consisting largely of triglycerides and is the most advantageous composition found to date in the practice of this invention.
The composition utilized preferably should contain a significant percentage of allylic moieties to render the compositions useful according to the invention indicated by the following partial structures:
-CH=CH-CH2-CH=CH-and/or -C~=CH-CH=CH-CH2 -as indicated, the unsaturation can be conjugated or noncon-jugated but the composition must contain allylic methylene hydrogen.
Such compositions, as the case may be, should be oxidized or heated in the presence of oxygen at a temperature in the range of between 110C. to about 150C.
The oxygen can be obtained by merely heating the composition open 1134'748 to the atmosphere but preferably and advantageously, the source of oxygen is a gas such as air injected into a heated oil such as sesame oil. The injected air also serves as a source of agitation.
Various polyunsaturated fatty acids or oils or tri-glycerides can be used to react or combine with sulfur to form sulfurized oil according to this invention. These poly-unsaturated fatty acids constitute a well known class of com-pounds and includes such fatty acids as conjugated linoleic acid, conjugated eleostearic acid, cottonseed oil, and mixtures of fatty acids obtained from such sources as cod liver oil, fish oil, etc. Sesame oil is preferred, however.
The sulfur used to form the sulfurized oils can be precipitation, biprecipitated or sublimed sulfur, sometimes referred to as flower of sulfur, that is, sulfur which is produced by sublimation or by the sublimation of elemental sulfur has been found to be most advantageous.
As previously stated it is most advantageous to add elemental sulfur such as sublimed, precipitated, or washed sulfur to the compositions so that the sulfur is present with oxygen during at least a portion of the heating period and the sulfur incorporated into the composition. Additionally, a previous batch of the oxidized oil with or without sulfur or tert.-butyl peroxide may advantageously be present during at least a portion of the heating period.
If sulfur is added to the selected composition, for example, sesame oil, the temperature should be maintained at an upper limit within the range of about 120C. to about 130C.
and preferably 125C. and 127C. These temperature limitations are based on a heating time of about one-half hour. The temperatures can be altered within limits depending on the time of heating. For example, the temperature can be 129-130C.

1~34748 if the time is shorter or even at 140~C. for very short period of time. High temperatures for a prolonged period of time tend to degrade the composition and should thus be avoided.
If sulfur is not present during the heating period, the temperature should be maintained in the range between about 110C. and about 150C.'and preferably in the range between about 120C. and about 140C.
The heat treatment is conducted for a period of from about 15 minutes to about two hours. If sulfur is present, optimal results are obtained if the heat treatment is con-ducted for a period of time between 30 minutes to about one hour. If a free radical initiator is present, or if a selected composition inherently contains a significant amount of initiator, the heat treatment period may be conducted for a relatively shorter period of time.
The precise nature of the composition which results from the above-described treatment or the identity of the effective component or components is not presently known to the Applicant. However, while Applicant does not wish his invention limited by the following theory or fact, or mixed theory and fact as the case may be, certain evidence is avail-able which indicates that an efficacious composition for the preventing or reducing the or the desire for tobacco in a human can be produced according to this invention.
In particular, it appears that a correlation exists between a composition useful for the subject purpose and its presumed peroxide or hydroperoxide content. By adhering to the process according to this invention, it has been found that efficacious compositions are produced which yield a significant peroxide titer when monitored by conventional iodometric analysis, the results being expressed, for example, in terms of micro-e~uivalents per gram. By significant peroxide titer is 1134~
meant a value obtained which is greater than that which inherently may be present in the initial untreated compound.
In the case of triglycerides which contain the allylic type unsaturation as described above, the resulting oxidized species is thought to be a hydroperoxide represented by the following partial structure -CH=CH-CH=CH-CH-OOH
as interpreted via W spectroscopic analysis, inter alia.

Whatever the nature of the oxidized species, it appears amenable to monitoring by conventional iodometric analysis with or without the addition of sulfur.
Although it appears that the activity of the composition is coincident with the presence of peroxides or hydroperoxides, the efficacious agent need not necessarily be directly derived from these classes. It may in fact be those species derived from radicals resulting from decomposition of compounds of, for example, triglyceride oils or sulfur including olefinic polymerization products and/or lower molecular weight decom-position products of the oils or addition products withsulfur such as sulfides, disulfides, hydropersulfides, etc.
With regard to a preferred em~odiment, it appears that the presence of elemental sulfur (approximately 1 percent by weight based on sesame seed oil) during the oxidation on sesame oil increase the amounts of oxidation products (conjugated hydroperoxides, diene, triene, unsaturated carbonyl) and that this increase appears optimal near 127~C. as evidenced by W spectroscopic analysis studies. In the absence of sulfur, it appears that the region near 127C. is optimal for the production of oxidation products.
As mentioned above, it appears that the most effective compositions are those which have a relatively high peroxide titer. Comparisons of a preferred composition, namely sesame seed oil oxidized or treated with air in the present of sulfur, with other triglycerides, or triglyceride containing oils, including corn oil, cottonseed oil, and triolein with regard to their respective peroxide titers indicates a trend in peroxide levels concordant with observed bioactivity in alcoholics. Such trend of bioactivity agrees in general with the results of a peroxide analysis involving the above-identified oils in their untreated state and wh~n oxidized in the presence of elemental sulfur under similar conditions as follows:

Oil Used A B B-A
(PeroxideOil SaturatedOil Treated*with Difference Analysis)with Sulfur Sulfur and Air in Peroxide Sesame Seed (10.2) 18.~ 35.7 16.9 Corn (6.8) 11.3 14.9 3.6 Cottonseed (7.3) 10.9 10.2 -0.7**

Olive (~.9) 12.4 13.8 1.4 Triolein (7.2) ~3.6 8.5 -0.1**
* Heated at ~7C. for 0.50 hrs. with 90 l/min.
Air addition and rapid mechanical stirring and containing 1.0 percent elemental sulfur by weight.
** Within experimental error.
It is thought that a lower bioactivity and a lower peroxide titer of cottonseed oil is due to the presence of natural antioxidants. The elimination of the antioxidants from oils such as corn and cottonseed oil or the use of the relatively pure allylically unsaturated compounds or mixtures thereof will produce in a substantially increased peroxide titer when treated according to this invention. Triolein contains only oleic acid moieties which are characterized by 11347~8 he allylically unsaturated group and hence is quite difficult to oxidize*, particularly when compared to the preferred sesame seed oil. A peroxide titer value of 35.7 meg/kg has been attained for the sesame seed oil-sulfur-oxygen treated composition while sesame seed oil oxidized alone at 137C. yields a value of 63.3 meg/kg. A
peroxide titer value of 35~7 meg/kg (35.7-1~3.8) = 16.9 has been attained for the sesame seed oil-sulfur-oxygen treated com-position while sesame seed oil without sulfur oxidized at137C. yields a value of 63.3 meg/kg (63.3-10.2) = 53.1).
Generally a substantial increase in the peroxide titer value can be defined as 3 to about 100 in cases where sulfur is incorporated into the composition and as from about 3 to about 400 when the oil is oxidized alone, or in the absence of sulfur.
The process used for determining the peroxide titer values discussed and reported herein are determined by placing

2 gr. sample of the composition in a flash purged with nitrogen, and adding thereto 2 ml. of concentrated acetic acid and 0.5 grams of KI. The mixture is capped to exclude air and allowed to remain in the dark for 30 minutes to complete the reaction.
The side walls are then wet down with a minimum of water and approximately 1-2 ml of a 2 per cent starch added thereto. The solution is then immediately titrated to the end point with 0.007 normal Na2S2O2 solution. The end point is white when small amounts of peroxides are present and slightly yellow when larger amounts are present.
The compositions as prepared according to the process of this invention should be used soon after preparation as there is indication that the peroxide titer values and effectiveness of the compositions decrease upon aging.
* J. Sci. Fd Agric. 1975, 26, 1353-1356.

1134~48 Preferred compositions according to this invention can be prepared by adding the sulfur to the oil, such as sesame oil, and heating the mixture with agitation at a temperature not to exceed about 130C. It is preferable or advantageous to heat the mixture between 120 and 127C. Heat-ing the mixture above about 130C. for a sufficient time causes a progressive color change in the mixture and otherwise appears to be detrimental. The temperatures given above relate to the use of sulfur with sesame oil. The ranges of temperatures which can be used to produce the compositions made according to this invention may vary with the particular oil being used, but generally a temperature of 120C.
preferably 125C. to 127C., will be sufficient for most oils when sulfur is added.
If the oil and surfur is heated below about 90C. it is difficult to incorporate the sulfur into the oil by heating and stirring alone. The best results have been obtained to date by maintaining the temperature used in forming the com-positions over a prolonged period of time from about 30 minutes to one hour. Stirring aids in the reaction, the experiments to date indicate that a fairly violent stirring is advantageous. The introduction of air into the mixture during the heating is also very advantageous, particularly when the mixture is not subjected to prolonged heating and is the preferred method. The stirring can be accomplished with the introduction of the air.
After the reaction has taken place, it is cooled.
Sulfur crystals remaining in the bottom of the reaction vessel can easily be removed by filtration. The remaining fluid is

3~ ready for use after appropriate sterilization for injection or incorporated into capsules, such as gelatin, for oral administration.

1134'748 The amount of sulfur incorporated into the oil is advantageously between about 0.1 percent to 2.5 percent by weight, based on the oil. If higher amounts of sulfur are used they generally precipitate out. There appears to be no advantage to using higher amounts of sulfur in any event since the ultimate dosage given to the patient is the criteria rather than the amount of sulfur content in the oil.
As can be observed from example 2 below, the incorporation of the sulfur into the oil seems to be limited to about 1 percent by the process presently being used to produce the sulfurized unsaturated oils.
The sulfur content can be much less than about 1 per cent if desired and smaller sulfur content is advantageous when administered by injection as discussed below. Varying the amount of sulfur below about 1 per cent in the sulfurized poly-unsaturated oils for oral administration only affects the number of capsules to be taken at a given time by a particular patient.
Experiments to date indicate that the optimum sulfur content for oral administrations is about 1 per cent and by injection about 0.1 per cent to 0.3 per cent by weight of the sulfur based on the weight of the oil.
The dosage prescribed to a patient will, of course, vary depending upon the particular patient and the num~er of cigarettes being smoked a day. In general, a daily dose of 3-5 capsules containing about 1 ml of the sulfurized oil for the first three days after which the dose is progressively reduced. For example, for a heavy smoker it is advantageous for the patient to take a~out 8 capsules containing 1 ml of the sulfu~ized oil containing about 1 per cent to 2 per cent sulfur for the first three days and take 3 or 4 capsules a day for the next four days. This is generally sufficient to eliminate or 113~748 reduce the desire or need for tobacco. The desire or need for tobacco generally disappears from the patient within 2-3 days.
This single treatment may last for months. However, the patient can be given an additional supply of the encapsulated sulfurized oil and directed to take additional capsules if he feels any desire or need for tobacco.
When the sulfurized oil is used by injection, such as intermuscularly or intraperiotoneally, it is advantageous to have the sulfur contained in the sulfurized oil below about 0.5 per cent by weight, preferably between about 0.1 per cent to 0.3 per cent by weight, and to inject from 1/2 to 3 ml of this solution into the patient. The treatment can be con-tinued by giving single injections for 2 to 5 days. Experi-ments to date indicate that the injection of sulfurized oil is somewhat painful when it contains above about 0.5 per cent sulfur. Administration by injection is, of course, not necessary, but it may act faster initially. Generally if a per-son is given the injection of the sulfurized oil, he can also be given a supply of the oral capsules and directed to take 3 to 4 capsules a day following the injection for one week.

A sulfurized oil was prepared by mixing 50 grams of sublimed sulfur, obtained from Fisher Scientific, with one liter of sesame oil. The mixture was heated under fairly rapid agitation by air to a temperature of about 127C. until all of the sulfur was incorporated into the sesame oil. The reaction mixture was then cooled to room temperature, producing at the bottom of the reaction vessel a small amount of sulfur crystals.
The crystals were then separated from the liquid by filtration and about half of the crystals replaced in the resulting liquid, wherein they slowly dissolved.

113~748 The resulting sulfurized oil was then incorporated into gelatin capsules in the amount of 1 ml per capsule.
Four patients reported that they had been smoking three to four packs of cigarettes a day. The patients were given 5 of the above capsules the first day and directed to take 5 capsules on the second and third days and 3 capsules for each of the four days remaining in the week. The patients reported no strong desire for tobacco after the third day and reduced their smoking habits to three to four cigarettes a day without nervousness or withdrawal symptoms.
Another patient who was smoking 60-80 cigarettes a day for the last 20 years was given 8 capsules of 1 ml of 1 per cent sulfur in oil for three days. She remained without discomfort during this period. The treatment lasted 10 days with progressive reduced doses. The patient has not smoked for four months without the need or desire for smoking tobacco.
A number of other persons who were cronic smokers of varying degrees were also given the same dosage. Over all, based on the total number of persons so treated about 80 per cent had an almost immediate loss of the desire to smoke while about 50 per cent of the remaining persons felt a considerable loss of the desire to smoke after some time had past while continuing the treatment. The remaining persons apparently did not lose their desire to smoke.

.

4 g. of sulfur were weighed out and p7aced in an Erlinmeyer flask. 200 ml. of sesame oil were added, the con-tents were heated to 125~C. with stirring until the sulfur dis-solved. The flask was removed from heat and allowed to cool to room temperature (5 hours). Sulfur crystals were filtered into a Buchner ~unnel, washed thoroughly with hexane to remove residual oil, and weighed.

113~7 ~8 The above example was repeated three times. The washed sulfur precipitate was weighed in each trial and the amount of sulfur in the sesame oil calculated by difference as follows:
Initial weight of sulfur: 4.00 g Weight of sulfur ppt.:
Trial 1 2.05 g Trial 2 2.00 g Trial 3 1.92 g % (w/v) sulfur in sesame oil:
Trial 1 1.02%
Trial 2 l.0~/o Trial 3 0.96%
Average 0.99%
From this it was concluded that the solutions con-tained approximately 1 per cent sulfur after filtration. This preparation can be used in the same manner as described in Example 1.
There were no toxic or side effects observed by using the compositions as set forth in the Examples in man or animals.
Colloidal sulfur has also been found to be effective in preventing or reducing the desire for smoking tobacco when administered in high doses of 5 to S0 mg. three to ten times a day for approximately three to five days with progressively increasing dosages in a few days thereafter.
The invention also includes the use of selenium in place of elemental sul~ur and for the same use. When using selenium it is combined with the allylic moiety in the same manner as sulfur but heated to a temperature in the range of 230 to 250C. preferably about 240C. from 15 minutes to an hour or more or until the peroxide titer value is substantially 1~34748 greater than that of the untreated allylic moiety in the same manner as disclosed herein with respect to the use of sulfur.
These compositions into which selenium is incorporated have to date not indicated as good an effect as those compositions into which sulfur is incorporated.

Claims (32)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of making a liquid composition for internal administration for eliminating or reducing the desire for tobacco in a human, comprising oxidizing a liquid com-position containing allylic unsaturation of the type -CH=CH-CH2-CH=CH-and/or -CH=CH-CH=CH-CH2-selected from fatty acids and fatty esters for a period of time sufficient to produce a peroxide titer substantially greater than that of the untreated liquid.

2. The method as described in claim 1, in which the oxidation is carried out by heating the composition while contacting the composition with air or oxygen.

3. A method as described in claim 1, wherein said composition is an animal, vegetable or fish oil.

4. A method as described in claim 3, wherein said oil is treated with oxygen in the presence of a free radical initiator.

5. A method as described in claim 3, wherein the oxidation is carried out by heating the composition in the presence of oxygen for a period of time within the range of from about 15 minutes to about two hours.

6. A method as described in claim 3, wherein said oil is heated with oxygen in the presence of sulfur.

7. A method as described in claim 6, wherein the heating time is in the range between about one half hour to about one hour, and said temperature is in the range of from 120°C. to about 130°C.

8. A method of making a liquid composition for internal administration for eliminating or reducing the desire for tobacco in a human, comprising oxidizing a liquid com-position containing allylic unsaturation of the type -CH=CH-CH2-CH=CH-and/or -CH=CH-CH=CH-CH2 -selected from fatty acids and fatty esters in the presence of sulfur for a period of time sufficient to produce a peroxide titer substantially greater than that of the untreated liquid.

9. The method as described in claim 8, in which the oxidation is carried out by heating the composition while contacting the composition with air or oxygen.

10. A method as described in claim 9, wherein said composition is an animal, vegetable or fish oil.

11. A method as described in claim 10, wherein said period of time is in the range between about one half hour to about one hour, and said temperature is in the range of from about 120°C. to about 130°C.

12. A composition for eliminating or reducing the desire for tobacco in a human which comprises an effective amount of a product produced by oxidizing a liquid composition contain-ing at least one type of allylic unsaturation selected from --CH=CH-CH2-CH=CH-and -CH=CH-CH=CH-CH2 -said liquid composition being selected from fatty acids and fatty esters, for a period of time sufficient to produce a peroxide titer substantially greater than that of the untreated liquid composition in association with a physio-logically compatible carrier.

13. A composition according to claim 12, wherein the liquid composition is an animal, vegetable or fish oil.

14. A composition according to claim 13, wherein said oxidizing is carried out in the presence of sulphur.

15. A composition according to claim 14, wherein said liquid composition is sesame oil.

16. A composition according to claim 14 or 15, wherein said sulphur is incorporated into said oil in an amount of about 0.1 to 2.5% by weight.

17. A composition according to claim 14 or 15, wherein the increase in the peroxide titer value is from about 3 to about 100.

18, A composition according to claim 12 or 13, in the form of a sterile injection liquid, wherein said carrier comprises a liquid injection medium.

19. A composition according to claim 14 or 15, in the form of a sterile injection liquid, wherein said carrier comprises a liquid injection medium and said oil contains 0.1 to 0.3% by weight of sulphur incorporated therein, based on the weight of oil.

20. A composition according to claim 12 or 13, in the form of an orally ingestible capsule.

21. A composition according to claim 12 or 13, in the form of an orally ingestible capsule, wherein said carrier comprises gelatin.

22. A composition according to claim 14 or 15, in the form of an orally ingestible capsule.

23. A composition according to claim 14 or 15, in the form of an orally ingestible capsule, wherein said carrier comprises gelatin.

24. A composition according to claim 14 or 15, in the form of an orally ingestible capsule, wherein said oil contains about 1% by weight of sulphur incorporated therein, based on the weight of oil.

25. A composition for eliminating or reducing the desire for tobacco in a host which comprises a sulfurized polyunsaturated oil in an amount sufficient to eliminate or reduce the craving for tobacco, in a physiologically com-patible carrier.

26 A composition according to claim 25, in the form of an orally ingestible capsule.

27. A composition according to claim 26, in which the oil contains at least about 0.1% of sulphur, based on the weight of oil.

28. A composition according to claim 26, in which the oil contains about 1% of sulphur, based on the weight of oil

29. A composition according to claim 26, 27 or 28, in which said oil is sesame oil and said carrier is gelatin.

30. The method as described in claim 1, wherein the liquid composition is produced by heating the liquid in the presence of air or oxygen at a temperature between 110°C
and 150°C.

31. The method as described in claim 30, wherein the liquid is oxidized in the presence of a free radical initiator.

32. The method as described in claim 31, wherein the heating is for 15 minutes to 2 hours.