HU189485B - Preparation for making people give up smoking - Google Patents

Abstract

The present invention relates to the discovery that the use of milk or ethyl macrol at the appropriate dosage and rate can significantly reduce the consumption of tobacco by fixed smokers. In a preferred embodiment of the present invention, a fine particle size ethyl maltol chewing gum base is dispersed, from which ethyl maltol is gradually released into the oral cavity at chewing. Adding more than one day in sufficient quantities will result in a gradual reduction in the number and suction time of the cigarettes that have been extracted. The decrease seems spontaneous and is not accompanied by the typical symptoms of nicotine withdrawal. -1-

Description

This invention relates to a smoking cessation composition.

Cigarette smoking has been recognized as an important public health problem for more than a decade. Despite this fact being passed on to the public, the proportion of smokers has only slightly decreased over the last 10-15 years. The US Department of Public Health, Public Education, and Public Welfare has released a survey showing that 39.3% of adult males and 28.9% of females continue to smoke and smoke an average of 23 and 19 cigarettes a day, respectively (Aduit Use Tobacco-1975, United States Public Health Service, 1976). The extreme persistence in smoking addiction is further highlighted by the fact that smokers are highly aware of the life-threatening effects of smoking. % Of screened smokers are concerned about the potential effects of smoking on their own health.

Despite the high awareness of the danger to life, smoking passion is extremely stubborn and difficult to break. According to the review quoted above, 61% of regular smokers have made at least one serious attempt to stop smoking. At least 90% of regular smokers have either tried to stop smoking or would probably have tried it if it were a simple method.

Smoking is difficult to quit and relapses are common. Yet there is a long-standing need and need for a convenient and relatively easy method to help smokers reduce or quit cigarette use.

The habit of smoking is maintained and enhanced by a combination of social, psychological and physiological influences, the nature, relative importance and interactions of which are little known. In smokers, the extent of smoking generally fluctuates depending on concerns, tensions, and anxieties. In addition, physiological adaptation to the pharmacological effects of nicotine causes a feeling of discomfort and / or discomfort when a smoker attempts to stop smoking. Although little is known about the dynamics of the pharmacological, physiological and psychological factors involved in smoking habits, we are well aware that it is difficult to give up the habit. Previous methods used to stop or reduce smoking include training of willpower, various psychological conditioning methods, and the use of various substances to counteract or replace the supposed cognitive effects of nicotine.

A comprehensive review of methods for reducing smoking addiction is provided by Larson PS and Silvette H. (Tobacco Experimental and Clinical Studies, Suppl. 2, The Williams and Wilkins Company, Baltimore, 1971). Exercising willpower or simply quitting smoking without any help, supplement or other means is at least as effective as any other method. A related procedure is withdrawal, including the gradual reduction in the number of cigarettes smoked over time. The method is less reliable because many smoking behaviors are unconscious and success requires accurate checking of the actual number of cigarettes smoked. A variety of industrial equ ⁵ spaces as different capacity filters are available to assist detoxication method.

A number of methods have been suggested, including those that trigger some type of aversion (such as disgust). One approach, a material ¹⁰ to provide the smoker, which brings up a bad taste in the mouth or interacts with the cigarettafüsttél unpleasant mouthfeel.

For example, silver nitrate, silver acetate and / or copper sulfate, alone or in combination with psychoactive agents or psychotherapy, have long been recommended. Similarly, bitter herbs such as tulip bark, quassia and ginseng root were said to make smoking unpleasant. However, the effectiveness of these methods is considered vi ²⁰ slidably. The main disadvantage of self-medication to induce this kind of reluctance is the easy interruption of continuing treatment. There has been some success with in-patient psychotherapy combined with other forms of aversion therapy other than electroshock. However, these methods are costly and time-consuming, and if the patient regains his or her passion, he or she is unlikely to undergo therapy again.

Other treatments are based on the supposed effects of nicotine on ³⁰ flags. One approach was to separate the mechanical and nervous sides of the tobacco addiction from the pharmacological effects of nicotine, such that the maintenance of the nicotine maintenance dose was eliminated or the use of cigarettes was eliminated. Nicotine-containing chewing gum has been produced and tested with apparent success [Brantmark B. et al., Psychopharmacología Béri. 31, 191 (1973); O. Femo et al., 1973, 31, 201]. The difficulty of the method is that the physiological dependence on nicotine is maintained and, as long as this dependence is overcome, there are many good times to restart smoking at the original pre-treatment dose level. In addition, the procedure does not solve the long-term health problems caused by the use of nicotine.

Significant amounts of research and commercial activity are associated with the use of lobelin. The pharmacological effect of lobeline is described as a weak nicotine-type effect 50, but which is free of nicotine and apparently interrupted pleasant érzeteitől El- ^v avoids cancellation syndrome. Therefore, the utility of Iobelin for smoking cessation is based on a plausible substitution hypothesis. In addition, the taste of lobelin is extremely bitter and, when used in combination with nicotine, causes very unpleasant symptoms. Therefore, the aversion element also plays a role in lobelin therapy.

Lobelin can be administered in the form of intramuscular or subcutaneous injections or in the form of tablets, chewing gums, lozenges and the like.

However, when compared to placebo in a controlled, double-blind study, lobelin was ineffective, ie not more effective than placebo.

189,485 to Merry J. and Preston G., The Practitioner (May 1983) 629-631. side].

The results obtained with lobelin point to the two methodological difficulties encountered in experimental design of any testing methods or products to reduce smoking. First, all studies show a high placebo effect, whatever substance is used. The dynamics of this placebo effect are unknown. However, the placebo effect alone can cause a 50% reduction in the amount and frequency of smoked cigarettes. Second, the physiological status of patients undergoing smoking cessation therapy or experimental testing should be considered. For example, a smoker who gives up the desire to quit but knows he / she is unable to do so, either unknowingly chooses to continue smoking or is satisfied with a 50% reduction. Therefore, the circumstances of the selected subjects should be carefully considered.

It is known that 3-hydroxy-2-methyl-4-pyrone (maltol) and 3-hydroxy-2-ethyl-4-pyrone (ethylmaltol) can enhance the flavor of certain foods when optimally present in small amounts. U.S. Patent 3,156,569 describes the use of milk as a flavor enhancer in combination with glutamate salts. U.S. Patent No. 3,271,167 discloses artificial beef broth and broth formulations containing alpha-glutarate, inosinate, glutamate and malt. U.S. Patent No. 3,293,045 discloses its use to enhance aromas of methyl salicylate, anethole and cinnamon aldehyde. U.S. Patent No. 3,296,079 discloses the use thereof to mask the aftertaste of artificial sweeteners. Up to 400 ppm may be used in the final sweetened product, since larger quantities will also have their own taste. Preferably, milk is offered at a lower concentration. The maximum amount may be used when bitter additives such as stannous difluoride are to be masked with a sweetener. U.S. Patent No. 3,338,718 discloses that animals gain weight by adding up to 200 g / tonne of milk to their diet. According to U.S. Patent Nos. 3,376,317 and 3,446,629, ethylmaltol is about six times more potent as a flavor enhancer. Ethyl maltol is used as a flavor enhancer in a concentration of 1-100 ppm in the final food product. At higher concentrations, ethyl maltol has its own aroma. Ethyl maltol is said to have a characteristic flavor, which is not further defined, except that it produces a velvety mouthfeel when used in sweet foods.

The milk was identified by Saguma H. et al., Agric. Biol. Chem. 42, 359 (1978)] as a component of a mixture formed during the pyrolysis of cellulose. This compound is said to cause a pleasant caramel or burnt sugar flavor. Shigematsu H. [Agric. Biol. Chem. 35, 1751 (1971)] and Schumacher

J.N. et al., J. Med. Agric. Food Chem., 1977, 310) showed maltol in the water soluble portion of the cigarette fly.

Maltol and ethyl maltol have been used as additives in tobacco products and tobacco substitutes. U.S. Patent No. 3,903,900 to Wolt et al. Discloses the addition of up to 600 ppm of mole to a composition for enhancing the taste and aroma of tobacco. British Patent No. 1,364,103 discloses an artificial tobacco composition for tobacco replacement. Such formulations may contain maltol or ethyl maltol up to 1.5% by weight as a flavoring and flavoring component.

Concerning the present invention, the concentration of maltol or ethyl maltol in the consumed product is very low, 1-400 ppm. The obvious exception to the Belgian patent specification 840 306 is Grieske et al., Who describe maltol as a chelating agent suitable for the removal of dyes from teeth by topical application in the form of toothpaste, mouthwash or chewing gum up to 5% (50,000 ppm). Used for 1 minute. Twice daily applications are described. The formulations used thus provide up to 150 mg of maltol per application, assuming a 3 g chewing gum containing 5% maltol. Such an application does not provide the lowest effective maltose dose that has been found to be effective according to the invention, as described in detail below. In fact, topical application in the mouth and short duration means that much less than the calculated maximum maltose dose is used.

The value of milk and ethyl maltol when used as a food additive is enhanced by the fact that they have low toxicity. Today, it is on the list of the "Flavoring Extract Company" among the compounds that are considered harmless when used as a food additive. Both compounds proved to be harmless on average at daily doses of t mg / kg and 2 mg / kg, for macaques and ethyl maltol (see Opdyke DLJ, Food Cosmet. Toxicol. 1975, 13, Suppl. 805 and 841). From today onwards, up to 1.5 g / day seems completely harmless. Pharmacological studies were not thorough. Both maltol and ethylmaltol are rapidly absorbed after oral administration and are rapidly excreted, primarily in the form of glucuronide and ether-sulfuric conjugates. In mice, 75 mg / kg of milk reduces spontaneous locomotor activity by about 50%. Ethyl maltol also inhibits, but is slightly less effective. Both compounds inhibit seizures induced by pentylene tetrazole or strychnine, while potentiating hexobarbital-induced sleep [Aoyagi N., Chem. Pharm. Bull. 221008 (1974)]. In these experiments, 300 to 500 mg / kg doses were used which were extremely high in view 820 and 910 mg / kg acute LD _S0 values obtained for mice maltol or ethyl maltol. In vitro oxygen uptake by rat or cerebral cortex was not affected by milk or ethyl maltol. These observations make it clear that the pharmacologic efficacy of maltol and ethyl maltol.

FIELD OF THE INVENTION The present invention relates to a smoking cessation composition comprising 20-300 mg of gamma-pyrone - milk or ethyl maltol - per dosage unit, together with an inhalable physiologically tolerated carrier, preferably chewing gum base, so that the dosage is kept at least 10 mg per smoker's mouth. release into the oral cavity for one minute.

It is an object of the present invention to provide that, when administered at an appropriate dosage level and at a rate, milk or ethyl maltol reduces tobacco consumption by an established smoker. In a preferred embodiment, the finely divided ethyl maltol is incorporated into a chewing gum base material from which ethyl maltol is gradually released into the oral cavity when chewing gum. When applied in appropriate amounts over a period of several days, the composition results in a gradual reduction in the number of cigarettes smoked and the smoking time. The decrease appears to be spontaneous and does not appear to be accompanied by typical symptoms of nicotine withdrawal. A decrease in the frequency and amount of smoking was observed in subjects who were unaware that their smoking behavior was controlled. Objectively, subjects treated according to the dosage regimen described below, gradually reduce their cigarette intake gradually over a period of several days, starting from the second or third day of treatment, without complaining of aversion reactions (such as discomfort) or unpleasant side effects. Subjectively, subjects have a reduced desire to smoke, tend not to light cigarettes, and tend to leave the cigarette in the ashtray after a few sniffs. The effect is quite unobtrusive, so that smokers are sometimes unaware of the decline in their tobacco consumption until the reduced rate of consumption becomes apparent. The effect of the treatment is most satisfying for smokers who sincerely wish to reduce or stop smoking. However, for smokers who are not psychologically committed to quitting smoking, the effects can be daunting. Of course, these effects of treatment can be countered by the conscious effort of these smokers to continue smoking at the pre-treatment level. Although this activity does not cause serious discomfort, the smoker will not find enough smoking pleasures to do so without significant conscious effort.

The actual dose to be used will depend on the individual as the effective dose will vary according to body weight and individual sensitivity. A typical daily dose for a 70 kg adult male is 1000 mg of ethyl maltol. The potency of maltol is the 'Λ-' 'of potency of ethyl maltol and the dose should be adjusted accordingly. The above dose corresponds to 14.28 mg ethyl maltol per kilogram body weight per day. Ethyl maltol appears to be effective for systemic administration. Due to the rapid metabolism and excretion of ethyl maltol, the most effective dosing strategy is considered to be the continuous administration of the product above the threshold efficacy. Preferably, today's or ethyl maltol is slowly released into the mouth through a slow release carrier such as chewing gum. The daily dose is divided into waking hours, for example, in about 7 portions. During the 10-day treatment, there was a gradual decrease in tobacco consumption, as measured by the number of cigarettes smoked and the smoking ratio. A reduction of about 50% occurs during the first 4-6 ni. However, placebo experiments would yield similar results, with an initial decrease followed by a gradual increase over days. Thus, after 7 to 10 days of treatment in the coal, tobacco consumption is further reduced, in most cases to 100%. Sometimes a reduction of 75% or more is observed. If greater than 50% is observed, a decrease in nicotine withdrawal occurs, as opposed to physiological reactions, suggesting that the long-term efficacy of the treatment, coupled with a downward adjustment of ethylmaltol, could be enhanced by gradual withdrawal.

Both maltol and ethyl maltol have a gamma-pyropoic ring structure. Gamma-pyrones having essentially similar flavoring and pharmacological properties to maltol and ethyl maltolho are included within the scope of the invention. Of the commercially available gamma-pyrones studied so far, ethyl maltol t is more potent and 4-6 ppm more potent than maltol per unit weight.

The smoking habit is complex and includes smoking cigarettes, pipes and cigars. In terms of both habit and health risks, smoking is considered to be the most serious. It is intended that the method of treatment described herein will effectively inhibit all forms of smoking habits associated with tobacco use. For simplicity, the following discussion focuses on smoking as a general example of smoking habits. Tobacco consumption depends on the number and size of cigarettes smoked. The decrease in consumption is determined by comparing the smoker's consumption before treatment. All data reported represents a percentage decrease, i.e., the difference between pre-treatment and current smoking rates is divided by pre-treatment consumption and the result multiplied by 100. When calculating smoking rates, we always consider the number and size of cigarettes smoked.

Gamma-pyrones, when administered orally, effectively inhibit tobacco consumption. Since milk and ethyl maltol are rapidly processed and excreted during metabolism, the mode of administration is advantageous when the daily dose is divided into waking hours! hours so that a dose series is used throughout the day. It has been found that dosing is much more effective if gamma-pyridine remains in the mouth for a while at each dose. The benefits of oral retention are observed when the doses are released over a period of at least 10, preferably 20 to 30 minutes. Such al-41

Application 189,485 is advantageously accomplished by the use of slow-dissolving lozenges, tablets or chewing gums in which gamma-pyrone is dispersed. Data to be completed raise the potential for systemic oral administration. In this case, other forms of systemic administration, such as subcutaneous injection, could be employed, particularly in combination with a slow release formulation.

The effective dose will vary depending upon the individual's sensitivity to the treatment. Higher doses are used in the initial stages of treatment than in later stages. Initially, a dose of 500 to 1500 mg, preferably 800 to 1200 mg, of ethyl maltol may be used. Individual susceptibility to gamma-pyrones varies widely; women and younger individuals appear to be more sensitive and thus require lower daily doses.

For a daily dose to be optimally effective, it should be divided into a series of doses, preferably 7-8 doses per day. In a preferred embodiment, each dose is administered from a slow release carrier such as a slow dissolving tablet or chewing gum. Chewing gum has been found to be the most effective carrier. It is advantageous for the user to control the dosage by chewing a rubber rod of the desired length for a sufficient period of time, at least 10 minutes, preferably 20-30 minutes. For example, a gum containing 156 mg of ethyl maltol per rod can be used for 7-8 individual doses. The release rate of ethylmaltol from the lozenge, tablet or chewing gum may be 2-16 mg / min, preferably 4-8 mg / min. It should be noted that 156 mg gamma-pyrone in a 1.75 g rubber rod has a concentration of about 90,000 ppm, which is several orders of magnitude higher than the amounts previously described for flavor enhancement purposes. The number of individual doses should be determined to provide at least 20 to 70 mg of ethyl maltol per dose, depending on the individual factors mentioned above. The minimum effective dose is 4-6 times higher than today. In the case of ethylmaltol, a 3 g rod contains only 0.60% ethylmaltol to deliver the minimum dose. The maximum amount would be about 30 mg, roughly 30% in a 1 g rod. The preferred concentration of ethyl maltol in chewing gum is between 5 and 15%. The presently preferred chewing gum composition containing 156 mg ethyl maltol per rod (1.75 g) (8.9%).

The treatment period is 10 days, preferably 20-30 days. As can be expected with a complex pattern of smoking where psychological and social factors play an important role in addition to individual changes in nicotine sensitivity and gamma-pyrone response, the extent of smoking reduction during treatment is extremely variable. Typically, a gradual reduction of about 50% over the first 4-6 days relative to the pre-treatment situation is observed. Often, for the first 2 days, the decrease is slight or non-existent, although in some cases a dramatic decrease occurs almost immediately. Over the next 7 to 10 days, a further decrease, typically 70 to 100%, was observed. Decreases of greater than 50% within the first 3 to 5 days are sometimes accompanied by physiological (but not psychological) symptoms of nicotine withdrawal such as dizziness, difficulty in eating, increased urine output, loss of vision and orientation. Such symptoms were never observed in non-smoking control subjects using the same doses of gamma-pyrone. In order to reduce the symptoms of nicotine withdrawal, it is preferable to reduce the gamma-pyrone dosage once the smoking level has been reduced to 50%, so that the further reduction occurs at a slightly slower rate. The overall course of the treatment is therefore slightly prolonged, preferably for a total of about 20-30 days. The fact that physiological nicotine withdrawal symptoms do not develop during the first 50% reduction in smoking is consistent with the observation of others that a reduction to 50% can be achieved with placebo without significant side effects [Merry J. and Preston G. , The Practitioner (May 1963) 629-631. side; Sutherland, A., et al., J. Consulting Clin. Psych. (August 1975) 443-447. side]. It seems that captive smokers generally consume as much tobacco as twice the daily dose required to prevent withdrawal symptoms. Therefore, only a decrease greater than 50% is considered clinically significant.

The objective perceptions are clear. In most cases, smoking gradually decreases, in terms of both the number of cigarettes lit and the percentage of cigarettes smoked, and the percentage reduction is ultimately significantly greater than 50%. The extent of the decrease varies significantly from individual to individual and is dose-dependent. It is noteworthy that the reduction in smoking occurs whether or not the individual knows the purpose of gamma-pyrone. In initial experiments, subjects were simply asked to apply the prescribed dose themselves and to communicate any observations. Some were unaware of the decline in their smoking for 1-2 days until it became inevitable, for example, if they smoked the same amount of cigarettes in two days.

The subjective effects of gamma-pyrone treatment are most interesting and informative. It is remarkable that the decline in cigarette consumption is not accompanied by any of the usual effects of smoking cessation, such as anxiety, nervousness or restlessness. If at all, after a decline of more than 70%, individuals appear to have reduced anxiety levels and often experience increased self-esteem and self-esteem. These subjective reactions can be observed even during the treatment phase, when minor physiological withdrawal symptoms of nicotine occur. Gamma-pyrone treatment seems to separate the physiological effects of the nicotine habit from the psychological effects and somehow abolish the latter.

The main side effects of the treatment are those that can be expected when a high concentration of flavor enhancer is present in the mouth for several days. The taste of gamma-pyrone, as ethyl maltol, is difficult to describe, in fact, depends to a great extent on what other flavors exist or have been in the past.

189,485, in the mouth. Similarly, the taste of other substances is affected by the last time gamma-pyrone was used. Certain substances and flavor combinations cause an unpleasant and bitter sensation in the presence of large amounts of gamma-pyrone used in the treatment. Therefore, chewing gum or tablet formulations should be free from bitter substances such as amino acids and tannins, as well as trace amounts of highly aromatic flavoring agents such as cinnamon or gaul oil. When properly formulated, with the exception of mild fruit flavors, such as apples, without flavorings, gamma-pyrone chewing gum or pastilles will have a pleasant taste. Initially, some people have a pungent taste and their saliva secretion increases. Like other substances, the taste of tobacco products depends on the time elapsed since the last dose of gamma-pyrone. After chewing on an ethyl maltol chewing gum, some people find the initial taste of the cigarette enjoyable. At most other times, the taste of a cigarette can be unpleasant.

Perhaps the most profound effect felt by those under treatment is the refinement of the sense of taste and smell. Every taste and smell seems more intense. Individuals will be susceptible and sensitive to the bad taste of food and drink. They tend to avoid foods containing such bad taste elements. Individuals have a clear preference for better quality coffee, tea and spirits. Bitter flavors like beer are badly tolerated. One person - an avid beer drinker - interrupted the treatment program because it inhibited his usual after-hours brewing.

The above effects are felt by smokers and non-smokers alike. If treatment is discontinued, the taste enhancing effects will disappear. To date, no psychological effects attributable to Gamma-Piron have been observed.

Example 1

The formulation of a slow dissolving tablet is described. Other known formulations are readily conceivable for the following purposes: the tablet should dissolve slowly in the mouth, preferably for about 15 minutes, while maintaining physical integrity; the taste should be mild, preferably fruity; and the tablet, if any, should only be slightly sweetened.

The primary ingredient (greater than 90% by weight) of the tablet is a high molecular weight polysaccharide, such as a non-hygroscopic, solid cereal hydrolyzate having a dextrose equivalent of less than 15 (e.g., Mor-Rex, code 1918, Trademark CPC International, Inc., Englewood Cliffs , New Jersey). The dissolution time is controlled by mixing up to 1% hydrophobic starch as modified waxy corn starch (Dry-Flo, National Starch Company). Waxy corn starches are also known as amyloid starches and consist almost exclusively of highly branched amylopectin. The effect of a small amount of waxy corn starch on the dissolution time of a 1.2 g tablet is shown in the following table:

Waxy Mouth-Dissolving Corn Starch, Time (minutes) by weight

6

Vi 8 y ₄ io

Addition of more than 1% waxy corn starch renders the composition too _{g 1 g} and difficult to handle.

The tablets are prepared by essentially conventional sugar-making techniques. The polysaccharide and starch are first mixed uniformly dry. About 3-4% by weight of water is added to the dry powder to form a thick paste. By heating the pulp, a uniform viscous melt is obtained. To the melt is added milk or ethyl maltol in the form of a saturated solution of hot water. The water solubility of gamma-pyrones is somewhat limited. For example, 1 g of ethyl maltol to ²⁵ necessary to complete dissolution in 6 ml of 100 'C water. Since the water content of the mixture should be kept low, the amount of ethyl maltol that can be mixed is 3-4% by weight, preferably 1%, by weight of the tablet. Since ethyl maltol is volatile, especially at elevated sékleteken thermometers ^30, it is essential that the mass after addition of the gamma-pyrone kept as short as possible at high temperature. The entire process can also be performed in a suitable extruder. Alternatively, ethyl maltol and other gamma-pyrones ³⁵ may be added to the mixture in an alcoholic solution, which is slightly more soluble, so that the final concentration of gamma-pyrone in the final product may be higher.

If desired, flavoring agents can be used in ⁴⁰ pounds. Small amounts of mild fruit flavors are preferred, and spicy flavors should be avoided.

The uniform distribution of the components is facilitated by stirring, and the molten mass is treated essentially as a mass of caramel candy, 45 which means that its stretches produce a uniform fine microstructure and water content. Like caramel candy, the mass is rolled or pressed into flexible, rope-like bars or strips, and is gelled at about 71 ° C, cut into tablets of desired length and re-granulated before coating to protect from moisture loss. Conventional equipment can be used to handle, cast or crush tablets of the desired size and shape.

The resulting tablet is a hard, hard product consisting predominantly of polysaccharides containing 1-5% by weight of ethyl maltol, depending on the formulation described. Each tablet is sized to deliver appropriate doses of ethylmaltol in the mouth and to dissolve gradually over a tablet life of about 15 minutes.

. 189,485.

Example 2

The composition of a chewing gum containing gamma-pyrone is described below. Crystalline ethylmaltol was ground and sieved to a mesh size of 0.044 mm. The ground particles are electrostatically charged and float upwards. In practice, it is only possible to sift through the particles above by collecting only those particles that pass through a 0.044 mm mesh screen.

The ground particles are ductile at 45 'C. mix with gum base until evenly distributed. Chewing gum base is used free of amino acids, tannins and other flavoring elements, as these substances can produce a bitter, unpleasant taste when interacting with gamma-pyrone. The release rate of gamma-pyrone in the oral cavity depends on the extent to which gamma-pyrone dissolves when chewing gum. The degree of dissolution can be controlled by the size of the gamma-pyrone particles dispersed in the rubber. In the case of ethylmaltol, if particles of an optimum size of 0.044 mm are dispersed in the above material, the particles dissolve in the mouth in about 30 minutes. Gamma-pyrone must be dispersed in particulate form in the rubber to achieve the desired sustained release effect; Particles smaller than 0.044 mm dissolve more slowly, so that individual doses are delivered more slowly into the mouth. Larger particles dissolve faster than desired, so that the dose is released in an undesirable short time. Larger particles also tend to crystallize into even larger aggregates during storage.

A 100 g portion of a refined, pleasant chewing gum base (Adam Sour Apple Gum, Warner-Lambert, Inc., Morris Plains, New Jersey) is heated to 45 ° C. 6.66 g of ethyl maltol 0.044 mm mesh is added to the chewing gum base with vigorous stirring to distribute the particles evenly throughout the mass. The mass was then rolled into 3 g rods each and allowed to cool. Alternatively, roll the mass into a single thin rectangular sheet, allow to cool, and cut into 3 g rods. Each rod is then covered with plastic or impregnated paper to prevent storage loss of ethyl maltol due to sublimation at room temperature. Each 3 g rod contains 200 mg ethyl maltol.

Ethyl maltol is added simply by chewing a suitable amount of rubber for at least 10 minutes, preferably for 15 minutes. For many people, chewing half a rubber rod is a good dose. Taste is described as pleasant, sometimes spicy, depending on the individual's taste in the past.

Example 3

Single dose effect

The effect of a single dose of ethyl maltol, 100-200 mg, was investigated in 30 volunteers who volunteered. Controllingly, a further 10 smokers were administered an inert placebo in the form of a similar gum made with ascorbic acid or citric acid. There is no change in smoking among subjects treated with a single dose of placebo. Individuals who received more than 300 mg of ethyl maltol immediately notice an obvious negative reaction to the cigarette. The efficacy threshold varies with the individual's age, sex, weight, smoking history and passion. The threshold dose depends on the route of administration; slightly lower if released from chewing gum in 10 to 15 minutes than when taken in tablet form. However, as a general rule, a single dose of less than 300 mg has no definitive effect. In contrast, substantially everyone desires to smoke at doses greater than 500 mg. The end result is a substantial reduction in smoking levels, which lasts from a few hours to 2 days. In some, physiological symptoms of nicotine withdrawal may be observed. Increased efficacy can be observed at higher doses up to 1200 mg, but no further benefit is obtained at 1200 mg. These tests indicate the existence of a critical threshold level below which the anti-smoking effect of ethyl maltol is not present. In subsequent studies, where gamma-pyrone is administered in a series of doses over several days, doses less than 30 mg / day are similarly ineffective.

Example 4

Extensive studies are conducted on individuals of different ages and genders with different smoking history over several days of treatment. Not all smokers tested in the experiment initially know the purpose of the study or the expected effect. Individuals volunteer for the test after they learn that the substance is harmless and ready to report any observed effects, according to FDA Food Supplement Standards. As far as can be ascertained, no person will infer the true purpose of the study until the effects become apparent due to a significant, unintentional decrease in their smoking activity. Before starting treatment, individuals are informed about their general health. Orientation is continued during and after treatment, at least every three days, to become aware of the physiological or psychological effects observed. No side effects occur during or after the treatment process.

In a controlled manner, five non-smoking volunteers were screened using the same regimen to receive varying amounts of ethyl maltol in excess of 500 mg daily for several days. Observations and inquiries do not indicate any psychological or physiological effect.

The original test series will be undertaken by several individuals on a voluntary basis. In each case, a treatment-free period of 3 weeks to 3 months is included in the studies.

The results of the tests are shown in Table 1. Individuals are identified by a number. The original so-called naïve test, which does not know the purpose of the study7

189,485 are marked with the letter "a" after the number of the subject. Other test sequences are indicated by the letters "b" and "c", respectively.

With the exception of individuals 10 and 11, ethyl maltol is all obtained in chewing gum, with the instruction that it be chewed for at least 10 minutes, preferably 15 minutes. Individuals 10 and 11 receive ethyl maltol in tablet form, not in slow release form in the mouth. The results suggest that systemic administration of gamma-pyrone is partially effective. Yet _g tek experiments do not exclude the possibility that the results attributed to retardation of a part of the dose in the mouth, such as by chewing or sucking the tablets.

Table 1

1 2 3 4 5 6 7 The investigated Tobacco- Unit dose Estimated person No past dose consumed Dosage course (days) number (years) per day (Mg) la 50 Man 35 4 bars 800 16 2a 54 Man 40 4.5 bars 900 12 2b 54 Man 40 4 bars 800 20 2c 54 Man 40 3.5 bars 700 30 3a 58 Man 40 7.5 bars 1500 25 3b 58 Man 40 3.5 bars 700 8 4a 45 Man 30 6 bars 1200 8 4b 45 Man 30 5 bars 1000 4 5a 40 Man 25 3.5 bars 700 14 6a 23 Woman 6 3 bars 600 1 7a 39 Woman 13 5 bars 1000 7 7b 39 Woman 13 4 bars 800 20 7c 39 Woman 13 3.5 bars 700 40 8a 28 Woman 9 4 bars 800 1 8b 28 Woman 9 3 bars 600 1 9a 40 Woman 25 4 bars 800 5 10a 36 Man 19 6 tablets 1200 . 10 I la 32 Man 14 5 tablets 1000 15 12a 43 Man 20 5 bars 1000 8 No 13a 44 Man confirmed smoker 5 bars 1000 2 Table 1 (continued) 1 8 9 10 11

Person Daily Cigarette Consumption Daily Cigarette Consumption “stL-a. Smoking method change per number at the start of the end 'cigarette

la 50 15 70% Decrease in ignition 2a 50 0 100% 2b 35 10-15 70-80% About% 2c 35 5 90% About% 3a 70 0 100% - 3b 50 15-20 60-70% Changed 4a 40 0 100% - 4b 30 5 or less 80% + '/ Á 5a 50 7-10 90% + less than% 6a 20 'Reduces to 6 packages for the next 2 weeks 7a 30 7-10 65-70% '/ Á 7b 17-20 7-10 41-68% '/ Á 7c 15 7-8 41-53% Decrease to 2-3 sniffs 8a 20 5 75% less than% 8b 20 7 40-50% Less than 54 9a 50 10-12 75-80% Less than 34 10a 40 10-12 70-75% Decrease to 3-4 sniffs Sat. 30 17-18 40-43% less than% 12a 30 3-4 87-90% Decrease to 3-4 sniffs 13a Not fixed It is unable to stop smoking during treatment smoker

, 189,485

Example J.

Daily reduction of smoking

Participants are already aware of the effects of the treatment. We ask them to try a new dosage form and tell them that the trial does not necessarily require a "cure". The dose is divided into 8 slow-dissolving pastilles with 1000 mg / day ethylene; the pastilles are prepared essentially as described above. Individuals use their own dose without control. Trials are designed and reviewed by the inventor but mediated by the mediator to maximize the opportunity for objective judgment of symptoms and to minimize the possibility of research prejudice affecting the results. (True double blinds are not possible because the taste of gamma-pyrone is peculiar and impossible to mask.) All individuals are in good general health and are selected to represent different ages, occupational stress states, and individual lifestyles.

The results of the tests are given in Annex II. Table. In determining the level of tobacco consumption, the number of cigarettes smoked and the proportion of each cigarette smoked are considered. Results are expressed as a percentage of the pre-treatment smoking level.

II. spreadsheet

Table notes showing a decrease in smoking levels (%)

Days number 1 2 3 4 5. 6 7 8 9 10 Person No First Man - 5 10 40 30 60 50 70 80 85 Second Man - 15 20 50 80 95 40 55 70 90 Third Man - 5 5 10 10 20 20 40 70 85 4th Man - 10 40 65 85 95 90 75 80 90 5th Man - 5 10 5 10 15 20 15 20 30 (serious alcohol consumption) 6th Woman 10 30 60 75 60 50 65 70 65 70 7th Woman - 10 30 70 90 70 85 90 95 90 8th Woman - 5 15 30 50 25 30 55 90 80 9th Woman - 10 15 10 35 20 45 50 65 70 10th Woman - 20 45 70 95 He stopped ("Beer tastes weird")

The numbers in the cubes represent the percentage reduction in smoking, taking into account the number of cigarettes smoked.

Placebo experiments

During the study described in Example 5, two groups of smokers were given a placebo consisting of the same sugar lozenge base but not containing gamma-pyrone and acrid as a result of the addition of ascorbic acid or citric acid.

1 placebo group of volunteers recruited coffee break holder, whose essence eben added to the same information, as in Example 5 ⁰ test of active participants. The study is directed by a mediator who does not know that the dose is only a placebo. The results are shown in Table III. Table.

III. Table I. Placebo group

Number of days 1 2 3 4 5 6 7 8 9 10 Person No First Man - 0 0 0 0 He stopped Second Man - 5 10 10 20 40 He stopped Third Woman - 0 0 0 0 He stopped 4th - Woman - 5 5 15 45 40 45 45 40 30 5th Woman - 15 35 55 65 70 60 55 55 55

The numbers in the cubes represent the percentage reduction in smoking, taking into account the length of the cigarettes smoked.

Placebo Group 2 consists of college students; the college professor himself has been involved in previous efficacy trials (subject # 2 in Example 3) and is in charge of Group 2 experiments but is unaware that a placebo dose is being used. Group 2 volunteers are provided with the same pre-treatment information 60 as Group 1 and the active trial of Example 5, although it is possible that the professor's enthusiasm for treatment may have influenced the results of IV. See the results in Table.

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Table ZK 2. Placebo group

Number of days 1 2 3 4 5 6 7 8 9 10 Person No 1. Man 15 20 60 95 90 60 60 ⁴⁵ 45 2. Man 25 60 85 90 100 60 50 40 40 3. Man 20 30 55 65 60 55 40 50 55 4. 'Woman 10 10 5 - 5 10 - 5 0 5. Woman 16 20 35 45 30 40 45 30 40 The numbers in the cubes are a show a percentage reduction in smoking, taking into account the length of cigarettes smoked.

We concluded that the smoking cessation trials were subject to a significant placebo effect. The magnitude of this effect will vary considerably depending on the individuals and the design of the experiment. The placebo effect is high and can account for up to 50% of the reduction in smoking.

Example 5 and comparisons of placebo groups support the conclusion that gamma-pyrone treatment results in a substantial reduction in smoking levels beyond the placebo effect over a 10-day treatment period. This conclusion can be further confirmed by standard deviation calculations. For this analysis, we omitted tests that were incomplete or showed unusual conditions. The results of placebo groups 1 and 2 were pooled. Figure 1 shows the mean percent reduction in smoking in the treated and placebo groups. 7-10. The analysis of the daily variance, where the curve of the placebo-treated group begins to divide, shows that the treated group is indeed significantly different from the placebo group.

Although the invention has been described in connection with a specific embodiment thereof, it will be understood that further modifications will be made and it is intended that the present disclosure cover any variation, use or application of the invention which generally follows the principles of the invention and includes departures therefrom they are within the scope of the appended claims and are known in the art, are compatible with the essential characteristics set forth above, and are within the scope of the appended claims.

Claims (7)

15 Patent claims CLAIMS 1. A smoking cessation composition comprising 20-300 mg of gamma-pyrone - maltose or ethyl20 maltol - per dosage unit, together with an inert, physiologically tolerable carrier, preferably chewing gum base. 2. A composition according to claim 1, characterized in that 90 parts of a high molecular weight polysaccharide with a physiologically tolerable carrier ₂₅ material - contains 1 part by weight waxy maize starch, molded mass of 3-5 g lozenges - having a dextrose equivalent of less than 15. 3. A composition according to claim 1, wherein 95% by weight of the sweet chewing gum rods contain 5-15% ethyl maltol. Composition according to claim 1, characterized in that it contains 8.9% ethyl maltol. 5. cessation of tobacco composition according to claim 1 to ₃₅ zásról, wherein said chewing gum comprises from 100 to 300 mg rudanként etilmaltolt granular chewing gum base. 6. A composition according to claim 5, characterized in that it contains ethyl maltol having a particle size of 50-38 µm. 7. A composition according to claim 6, characterized in that it contains from 150 to 200 mg of ethyl maltol per bar of 1.5 to 2 g.