Nikotinsoderzhaschie tablet and method of treatment area
(57) Abstract:The invention relates to medicine, namely to addiction. Tablet contains nicotine in the amount of 0.5 - 5.0 mg, adsorbing filler, non-nutrient sweetener and targeted supplements. The tablet is administered buccal and control the content of nicotine in the blood at the level of 5 - 50 ng/ml Method can improve the effectiveness of the treatment. 2 C. and 21 C.p. f-crystals, 2 tab., 2 Il. The invention relates to compositions and therapeutic methods for reducing nicotine cravings and stop Smoking. In particular, the object of the present invention are improved compositions nikotinsoderzhaschie tablets and therapeutic methods of providing periodic doses of nicotine persons who are trying to quit Smoking.Art
Replacement therapy nicotine as a means of quitting Smoking is becoming more popular. Nikotinsoderzhaschie chewing gum (nicotine polacrilex) and transdermal nicotine are two of the most popular forms of nicotine replacement available on the market. Was, however, clear that a simple replacement of cigarettes another source of nicotine may be insufficient to ensure success is we, associated with Smoking cessation.Of the many symptoms of abstinence from Smoking craving for cigarettes is one of the most difficult to facilitate. As described in Steuer, J. and D. Wewers, M. E. in Oncology nursing Forum, 1989, 16, 193-198, craving for cigarettes is one of the most persistent, the most severe and the first of the syndromes of withdrawal symptoms experienced by those who are trying to stop Smoking. Some of the reports is that the peaks thrust falls on the period from the first 24 to 72 hours of abstinence, and then they decline, although it was reported on the cases craving for cigarettes after five years of abstinence.The research is focused on those factors that reduce cravings, in an attempt to better understand and take action in relation to the problem of relapse. Some researchers believe that some smokers are much more influenced by the feeling symptoms of craving for Smoking, in particular when trying to quit Smoking. On the basis of literature data and own research Harrington (Br. J. Soc. Clin. Psychol. 1978, 17, 363-371) reported that smokers can be divided according to its condition on having cravings and not having cravings, and that these categories have different reactions to therapy for Smoking cessation. (In his study treatment was razlichnykh at the end of treatment were largely associated with the lack of traction to Smoking.Most of the substances sold for nicotine replacement in the treatment of Smoking is not aimed specifically at satisfying nicotine cravings. Instead, as mentioned above, they generally focus on achieving a minimum level of nicotine in the blood. There is evidence that persistent low levels of nicotine in the blood (which can be achieved with transdermal nicotine or, to a lesser extent, with nikotinsoderzhaschie chewing gum) alleviate some of the symptoms of abstinence from nicotine, but the symptoms thrust were not (see Russell, M. A. H. in Nicotine Replacement: a Critical Evaluation; Pomerleau, O. F. and Pomerleau,C. S., Eds.; Alan R. Liss, Inc.: New York, 1988; pp 63-94). This may be due to the fact that Smoking cigarettes gives immediately a sharp increase in the content of nicotine in the blood that is missing in these types of nicotine replacement therapies. Peak of the content of nicotine in the blood caused by cigarettes, while higher (in the range from 30 to 40 ng/ml) and sharper (this peak is reached within 10 minutes), than more moderate levels received from chewing gum or transdermal system. Russell argues that the optimal sustainable level for nicotine replacement ranges from 10 to 15 ng/ml, however, the effect of rapid growth, appears to be necessary for the, the increase in the concentration of nicotine in the blood is at least 10 ng/ml for 10 minutes is necessary to obtain the postsynaptic effects on cholinergic nicotine receptors in the Central nervous system and autonomic ganglia. These postsynaptic effects may be responsible for such drug "high feeling", such as lightness in the head or dizziness experienced by cigarette smokers.As stated above, nikotinsoderzhaschie chewing gum (polacrilex nicotine) is one of the commercially available sources for nicotine replacement therapy. Nikotinsoderzhaschie chewing gum is actually is an ion-exchange resin, which slowly releases nicotine in chewing and nicotine present in the mouth, is secreted directly into the systemic circulation by absorption through the mouth. However, much of the nicotine remains in chewing gum due to incomplete suviana or largely wasted due to ingestion, resulting in somatic bioavailability of nicotine from chewing gum and low average of only 30-40%. In addition, in comparison with Smoking cigarettes, nikotinsoderzhaschie ransdermal system nicotine is a different kind of therapy, which became commercially available. These nikotinsoderzhaschie patches provide a low, steady level of nicotine in the blood among consumers and bypass the impact of the first passage through the gut and the liver. System with transdermal nicotine may be intended to create a higher steady state levels of nicotine in the blood, but not able to create peaks or provide a quick increase in the level of nicotine in the blood. Thus, nikotinsoderzhaschie chewing gum and transdermal nicotine compete with one another as the products that generate the steady state levels of nicotine in the blood, but do not meet the symptom of craving for a cigarette some smokers.Other existing or proposed in the literature nicotinamidase matter of no great interest in the treatment of Smoking cessation because of the problems associated with their use, and also because of the limited ability to satisfy cravings for a cigarette. A pair of nicotine are introduced to patients in the form of an aerosol, like technology inhalations used for administering drugs in bronchial asthma, and "smokeless cigarettes", such as manufactured by advanced, Tobacco products under the trade considerable levels of nicotine in the blood in patients. In addition, inhalation of these products with pairs of nicotine may be too irritating to the mucous membrane, so that it could endure patients.Other smokeless way of getting nicotine to the mucous membrane of the mouth is chewing tobacco, inhalation of snuff by mouth or tobacco sachets. Tobacco sachets which are especially popular in Scandinavia and in the USA, contain powdered tobacco bags that suck or keep it in your mouth. However, as shown in Fig. 1 (levels cigarettes, nikotinsoderzhaschie chewing gum and a bag of tobacco from Russell, M. A. H., Jarvis, M. J., et al. Lancet 1985, 2 1370), the use of tobacco sachets leads to such levels of nicotine in the blood, which is more comparable to the levels obtained from the chewing gum than Smoking cigarettes; i.e., they require about 30 minutes to achieve a maximum level of about 12 ng/ml, less than half of the peak value from Smoking one cigarette. One possible reason for this slow absorption of nicotine from tobacco bags is slow, the selection of nicotine in the mouth, as when nikotinsoderzhaschie chewing gum: another may be that a significant part of nicoti these oral forms of introduction can be useful for creating low levels of nicotine in the blood in a stable condition, however, they do not provide the maximum levels required to meet the strong thrust.The literature describes other capsules, tablets and pellets for oral administration of nicotine. For example, in the application WO 88/03803 described chewable capsule, liquid filled, containing 0.1 - 10.0 mg nicotine, together with additives to improve taste and dispersion. Capsules have different pH values, which allows the patient to choose the rate of absorption of nicotine, and they are specially designed as an aid in Smoking cessation.Another part nikotinsoderzhaschie capsules described by the authors M. E. Jarvik et al. (Clin. Pharm. Ther. 1970, 11, 574-576) for oral administration as an aid for Smoking cessation. These capsules, however, apparently were swallowed by the patients as a whole in accordance with theory that the absorption of nicotine in the gut can create significant levels in the blood. In this study, shows a small but noticeable decrease in the number of cigarettes smoked by patients, but there was obtained a quantitative measurement of the levels of nicotine in the blood.The literature also describes the different formulations of tablets for the selection of nicotine in the mouth and what I described tablet, containing from 0.1 to 5 mg of nicotine in the form of a base or a water-soluble acid salt.Wesnes and Warburton (in Psychopharmacology 1984, 82, 147-150; and Psychopharmacology 1986, 89, 55-59) discuss the use of nicotine tablets in experiments on the study of the effects of nicotine on learning and information processing. During the first experience of nicotine was added to the dextrose tablets with a drop of hot spices to disguise the taste of nicotine. In the second experiment nicotine was added to the tablets of magnesium hydroxide, believing that an alkaline environment in the mouth should strengthen intra-oral absorption. And again for taste masking of nicotine spicy seasoning was added to both the active and in control pill. Patients were instructed to hold the tablet in your mouth for 5 minutes prior to ingestion, in order to ensure maximum contact with the mucous membrane.The show (for example, in patents in the UK 2142822 and USA 4.806.356) describes nikotinsoderzhaschie tablet prepared by cold pressing of a mixture of an inert filler, a binder, and either pure nicotine or nikotinsoderzhaschie substances. Tablets are designed for holding in the mouth, because they dissolve slowly and gradually produce nicotine in the oral cavity.In SAI cyclodextrines connection. This patent also discusses the use of different medical environments and direct extrusion for the manufacture of this product.In recent years, the UK market has several nikotinsoderzhaschie tablets. Tablet Resolution, produced by Phoenix of Pharmaceuticals and are being marketed by the firm Ernest Jackson, contain 0.5 mg of nicotine together with vitamins a, C and E antioxidants. Tablets Stoppers, which are being marketed by the firm Carvell of Pharmaceuticals contain 0.5 mg of nicotine and flavors of chocolate, orange or peppermint.Because nicotine has a sharp, burning taste, these nikotinsoderzhaschie tablets is usually made with sugar as a main component. However, weight gain after Smoking cessation was noted as a major factor contributing to the return to Smoking. In a recent survey of smokers who had tried to quit Smoking were asked to evaluate the importance of some of the possible reasons for their return to Smoking. Twenty-seven percent reported that "the real weight gain" was "very important" or "quite important" reason why they resumed Smoking; twenty-two percent said that "the possibility of weight gain" Biebrza, the compositions of the tablets on the basis of sugar can be unacceptable for a program of Smoking cessation for people concerned about weight gain.So far, it was difficult to introduce nicotine with such parameters, simulating achieved by constant Smoking nicotine levels in the blood to meet the acute craving for nicotine in people who are trying to quit Smoking, and thus provide more reliable protection from return to Smoking than at other types of nicotine replacement therapies for people trying to quit Smoking. It is therefore desirable to create an improved formulations of tablets and the ways in which eliminated the disadvantages of the known means and methods input nicotine, while providing effective means for its introduction.The essence of the invention.The present invention provides the use of nikotinsoderzhaschie tablets containing non-nutrient sweetener, as a method of mitigating acute nicotine cravings and therapy Smoking cessation. In particular, the present invention introduces a new method of obtaining temporary levels of nicotine in the blood, simulating the effect of Smoking cigarettes, which includes periodic application Niko is lactitol, and more preferably a combination of non-nutrient sweeteners, to ensure the rapid introduction of nicotine in the oral mucosa. Nikotinsoderzhaschie tablets are designed for holding in the mouth and sucking, as well as for the selection of nicotine in the oral cavity. In a preferred embodiment, the nicotine eagerly, reaching maximum levels of nicotine in the blood in 2 to 30 minutes after taking the pills.The pills contain a fairly low dose, preferably below 5 mg and more preferably from 0.5 to 2.0 mg of nicotine. In particularly preferred embodiments, the implementation of nicotine is dispersed in the mannitol or - cyclodextrin, and the tablet is a containing buffer solution composition, preferably from pH 6 to 11 and more preferably from pH 7-9. In the most preferred composition of the tablet contains non-nutrient sweetener xylitol, known for its nearisogenic properties, in combination with the sweetener ammonium glycyrrhizinate.List of drawings and other materials.Fig.1 chart average levels of nicotine in plasma (nanograms (ng)/milliliter (ml)), the result of the use of cigarettes, tobacco pattikonda/dissolution (dissolution in weight %) of three different formulations of tablets, each of which contains 1 mg of nicotine as a function of time.Information confirming the possibility of carrying out the invention.1. Terminology
Unless otherwise stated, the terms used hereinafter in the description and in the claims, have the following meanings:
"Buccal reception" refers to any system or means for intraoral patient medications that keep the mouth and used for the introduction of drugs through the oral mucosa into the body of the patient. The term includes, without being limited to this, tortillas, capsules and tablets."Essential oil" means natural oil with a characteristic odor secreted by glands of some aromatic plants containing terpenes as a main component. Examples of essential oils include, but are not limited to, citrus oils, flower oils (such as roses and Jasmine and clove oil."Nicotine" refers to the nicotine free base, i.e. the compound having the formula:
< / BR>"Nicotine salt" refers to any mono - or bis - pharmaceutically acceptable salt accession acid or metal salt and nicotine."Nicotinate the nicotine."Non-nutrient sweetener" means a synthetic or natural substance, the sweetness of which is higher or comparable with the sweetness of sucrose and which may have properties such as reduced chargesagainst useful properties for diabetics or reduced caloric value compared to sugars."Pharmaceutically acceptable salt accession acid" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically undesirable or otherwise, and formed with inorganic acids such as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric and the like, and organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, almond, methansulfonate, econsultancy, R-toluensulfonate, salicylic, and the like. For a description of pharmaceutically acceptable salts accession acid, see Bundgaard, H., ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam."Pharmaceutically acceptable metal salt" refers to salts that retain the biological effektivnosti and over the areas of alkali metals, such as sodium or potassium; alkaline earth metal ions such as calcium and magnesium; and ions of other metals such as zinc.2. Tablet
According to the present invention provides tablets used for introducing nicotine to the patient in order to reduce the strong nicotine cravings and for the treatment of Smoking, and ways to apply nikotinsoderzhaschie tablets for this purpose, including, but not being that limited options for implementation and the methods described below. Nikotinsoderzhaschie tablets of the present invention include any composition of pellets, tablets or capsules, that release the nicotine in the oral cavity, including nicotine, dispersed in an absorbent filler, and non-nutrient sweetener.A. Nicotine
Nicotine is a heterocyclic compound, which exists in the form of a free base and salt. The free base is highly volatile and readily absorbed through mucous membranes and intact skin. Most of the problems reported in relation to products on the basis of free-base nicotine, stem from the volatility of nicotine, its sharp, burning taste, irritating sensation in the mucous membrane of the nicotine in the form of a salt, i.e., in the form of salt accession acid or metal salt.Unexpectedly, these tablets can be manufactured in either free base or its pharmaceutically acceptable salt accession acid, or any combination thereof. In the example embodiment, used nicotine, i.e., the nicotine in the free base form.Regardless of the composition of the tablet contains a fairly low dose of nicotine, preferably from 0.5 to 5 mg, and most preferably from 0.5 to 2.0 mg, in order to avoid accidental overdose if swallowed pills in intact condition. High doses are not required, as the purpose nikotinsoderzhaschie tablets is to create a temporary peak of nicotine content in the blood.B. an Absorbent filler
As described here, the compositions and methods of nicotine is dispersed in an absorbent filler. Absorbent fillers are pharmaceutically acceptable substances that can: 1) reduce the volatility of nicotine, for example, by absorption or incorporation of nicotine as, for example, in the form of an inclusion complex, and 2) to be pressed into the form of pellet sludge is tea, - and - cyclodextrin, and derivatives of cyclodextrins, such as trimethyl - cyclodextrin, dimethyl-cyclodextrin, hydroxyethyl-cyclodextrin and hydroxypropyl-cyclodextrin; preparations of silicon oxide, such as synthetic silica, available on the market under the trade name Syloid company U. R. grace limited from North Dale house, North Sekula road, London (W. P. Grace Limited of North Dale House, North Circular Road, London); cellulosic materials, such as microcellulose Avicel, our firm FMS Corporation (FMC Corporation); and other conventional binders and fillers, used in the food industry, such as powdered acacia, gelatin, gum Arabic and sorbitol.According to some variants of the implementation of the absorbent filler will perform more than one function in the composition of the tablets. For example, mannitol can act simultaneously as non-nutrient sweetener and as an absorbent filler. Similarly, the absorbent filler can serve as a flavouring agent, buffering agents, lubricants or other component of the tablet.The absorbent filler is typically present in an amount of 5 to 25 weight. %, preferably in quantities of from 5 to 20 wt.%, and the more preferred is Omnitel contains mannitol or cyclodextrin.C. non-nutrient sweetener
The tablet should also contain non-nutrient sweetener. Because nicotine has a sharp, burning taste, the choice of sweetener for nikotinsoderzhaschie tablets can be critical, since many patients do not find pleasant the taste of nicotine in the form of tablets. Usually described in the tablets will be used non-nutrient sweetener or combination of sweeteners.Non-nutrient sweetener is a synthetic or natural sweetener, the sweetness of which is higher or comparable to sucrose. Table 1 provides examples of non-nutrient sweeteners and their relative values sweets.Thus, non-nutrient sweetener should be compared with sucrose relative magnitude of sweets approximately in the range from 0.4 to 2500, more typically in the range of about from 0.4 to 500, preferably in the range from 0.4 to 200 and more preferably in the range from 0.4 to 2. Cm. Makinen (1988) Oral Health 78:57-66, included in the present description by reference.In a preferred embodiment, non-nutrient sweetener is also nearisogenic. Chargesagainst substances mi. Researchers dentists have long recognized that formatiruem sweeteners such as sucrose, glucose, starch and corn syrup are cariogenic or causing caries. Polyol as one non-nutrient sweeteners, such as xylitol, sorbitol, fructose, invert sugar, palatinose, mannitol, ▫ maltitol, palatinit and ammonium glycyrrhizinate, however, in General does not get fermented in significant degree and less carinogenic than sucrose. Cm. Olinger, presented at the Conference/Exhibition Interfax-USA (Interphex-USA), new York, may 8-11, 1990More specifically, the ability of xylitol to inhibit the development of new caries has been demonstrated in numerous in vivo and in vitro. For example, field trials of products taken orally, contains xylitol, showed that the replacement of sucrose with xylitol in such products as chewing gum can help prevent tooth decay (see Soderling, E., and Scheinin, A., Proc. Finn. Dent. Soc. 1991, 87(2), 217-229). Research has also found that when using xylitol-containing sweets as part of a normal food along with the accepted practice of hygiene, the occurrence of new cases of caries is reduced by about 50% and 80%. Cm. above Olinger to be useful as a sugar substitute for weight management (see U.S. patent No 3.717.711), which clearly represents a serious concern of people who quit Smoking. In addition, as has been shown, xylitol prolongs gastric emptying and reduces digestion in humans. Cm. Shafer et al. (1987) Am. J. Clin. Nutr. 45:744-47. Similarly, due to the fact that xylitol is not metabolized as sugar, it has value for people who must restrict their intake of sugar, such as diabetes (see Maukinen, K., Oral Health 1988, 78(9), page 60).Xylitol also has a cooling effect when it dissolves in the mouth, because of its negative heat of dissolution. The heat of dissolution of xylitol is -36,6 cal/g compared with -28,9 cal/g for mannitol, -26,6 cal/g for sorbitol and -4,3 cal/g for sucrose (see Olinger, P. M., presented at the Conference/Exhibition Interfax-USA, new York, may 8-11, 1990). Therefore, xylitol is a great choice of sweetener and filler for tablets, which should be kept in the mouth for a long period of time and which must often be taken every day for maximum therapeutic effect.It is often necessary to use a combination of non-nutrient sweeteners. According to one embodiment p is I fade 13 seconds for example, some polyol as one sweeteners, saccharin, cyclamate and aspartame), will be combined with the sweetener, the sweetness of which has been slower or lasts longer. For example, the ammonium glycyrrhizinate, representing non-nutrient sweetener with a slight taste of licorice, has the appearance or occurrence of taste about 16 seconds for ammonium glycyrrhizinate and time preserving the taste or the decay time of 69 seconds.(Dubois and Lee (1983) Chem. Sens. 7:237-248). Other examples of non-nutrient sweeteners with temporary feelings, other than sucrose, include, but are not limited to, neohesperidoside (origin time of 9 seconds and a decay time of 40 seconds) and stevioside (the origin time of 4 seconds and a decay time of 22 seconds).Thus, in the preferred composition of the tablet will contain non-nutrient sweetener, such as xylitol, sorbitol, fructose, invert sugar, palatinose, mannitol, malicite palatinit, in pure form or in combination with other non-nutrient value of sweeteners. More preferably, will be used xylitol, without additives or in combination with non-nutrient sweetener having a decay time longer than shave example embodiment, non-nutrient sweetener will include xylitol and ammonium glycyrrhizinate.Non-nutrient sweetener is typically present in an amount of from 50 to 90 weight. %, preferably in an amount of from 70 to 90 wt.%, and more preferably in an amount of from 80 to 90 wt.%.G Other ingredients
The tablet preferably is a composition with a buffer in order to help in the absorption of nicotine in the oral cavity. The preferred composition has a pH of about 6 to 11 and preferably a pH of about 7-9. Preferred compositions of the buffer include sodium carbonate, sodium bicarbonate, nutrifaster, calcium carbonate, magnesium hydroxide, potassium hydroxide, magnesium carbonate, aluminum hydroxide, and other substances known in the art, and combinations of the aforementioned substances. In the most preferred composition as buffer substances tablet will contain carbonate and sodium bicarbonate.Buffer substances (buffering agent) must be present in sufficient quantity for pH adjustment to a value between 6 and 11, usually from 0.1 to 25 wt.%, preferably in quantities of from 0.1 to 10 wt.%, and more preferably in quantities of from 0.1 to 5 wt.%.In addition, the tablet may contain flavouring, for example, with a taste of chocolate, orange, Acai as anise, eucalyptus, 1-menthol, carvon, anethole, and the like, to mask the taste of nicotine. Cm. Hall et al. Food Technol. 14:488 (1960); 15:20 (1961); 19:151 (1965); 24:25 (1970); 26:35 (1972); 27:64 (1973): 27:56 (1973): 28:76 (1974); 29: 70 (1974); 31:65 (1977); 32:60 (1978) and 33:65 (1979), each of which is incorporated into this description by reference. It may also contain tobacco flavoring to play some part of the feeling of Smoking to the user. A small amount of colloidal silicon dioxide (less than 1 wt.%) usually add in tablets containing tobacco flavouring, to help in the manufacture.Magnesium stearate and/or hydrogenated vegetable oil can also be added to the composition as a lubricant. Typically, the lubricating substance is present in quantities of from 0.1 to 25 wt.%, preferably in quantities of from 0.1 to 10 wt.%, and more preferably in quantities of from 0.1 to 5 wt.%.These pills can also contain a number of other additives. For example, if necessary, can be added pharmacologically active ingredients such as monitoroff sodium, sodium fluoride, dextranase, Matanza, hinokitiol, allantoin, aminocaproic acid, tranexamic acid, azulene derivatives of vitamin E, chloride natily character, the above can greatly enhance the effectiveness of traditional forms of fluoride treatment. Thus, according to one embodiment, the fluoride and more specifically monitoroff sodium or sodium fluoride will be included in tablets containing xylitol as a non-nutrient sweeteners.In addition, the tablet may be coated with a conventional, pharmaceutically acceptable food dyes. Other additives that may be included in describe here the tablet include not wearing restrictive, preservatives, antimicrobial agents and antioxidants.That is, the Method of manufacturing
A method of manufacturing tablets may be any suitable, well known in this field, including but not being limited to this, add nikotinsoderzhaschie connection to a pre-manufactured tablets; pressing cold inert filler, a binder, and either pure nicotine or nikotinsoderzhaschie substances (as described in U.S. patent N 4806356 included in the present description by reference); and packaging in capsules nicotine or nikotinsoderzhaschie connection. Cm. U.S. patent N 5135753 included in the present description by reference of globsol. In a preferred embodiment, the tablets formed by direct compression. Cm. example 4 for description of method of manufacture, in which nicotine is dispersed in the mannitol.According to another variant implementation, the complex receive enable in situ of the nicotine and a-cyclodextrin, using the technology of mixing. In particular, a small amount of a solution of nicotine-water is added to the cyclodextrin and kneaded or mixed, see SzezetIi in Cyclodextrins and Their Inclusion Complexes, Akademia Kiado: Budapest, 1992; p. 109; included in the present description by reference. This method of formation of the complex include nicotine-cyclodextrin is preferred because it minimizes the use of solvents or diluents, and thus eliminates the purification steps in the manufacturing process. Cm. also Example 5 in the description of technology of mixing with nicotine-cyclodextrin.Another variant implementation of the present invention ensures inclusion complexes as nicotine, and flavoring. This option is used, for example, when the composition of the tablets use essential oil or other volatile flavoring, such as carvon or menthol. As in case the honor of flavor and enhances the stability of the composition. In addition, because the flavor slowly released from this complex while taking pills, it will "stay" longer, and thus will remove the sharp taste of nicotine for a longer period of time.According to this embodiment, the mixture of nicotine and flavoring, and optionally water, add to the cyclodextrin are added and mixed. Alternatively, the inclusion complex of nicotine and the complex include flavoring can be prepared separately and then mixed to prepare the composition of the tablets.According to another embodiment, some non-nutrient sweetener, preferably xylitol, used for hard coatings nikotinsoderzhaschie tablets. You can use the traditional technology of coating on the lateral surface. Usually weight gain of about 35% can be achieved in less than three hours (see above Olinger).Tablets can be Packed in such a way as to help maintain the stability of nicotine. Preferred packaging techniques include the generation of layered strips of material such as foil, such as Barex, or packing into balls, using a material such as Teflon, so it is. Reported short-term storage for nikotinsoderzhaschie tablets due to evaporation of nicotine, in particular, when the ambient temperature is above 15o(see Belcher et al. (1989) Brit. J. Med. 298:570. These tablets, however, is stable over long periods of time at elevated temperatures, as shown in table 2 (see Example 6 in the description of the test procedures used to determine stability.Described here tablets at the usual case will have a weight in the range from about 70 to 1000 mg and will contain quite a low dose of nicotine, preferably less than 5 mg, and most preferably from 0.5 to 2.0 mg.3. Method of application
The present invention also relates to a method of applying nikotinsoderzhaschie tablets to create periodic time of the peaks of the content of nicotine in the blood as a means of reducing the symptoms of acute nicotine cravings. Usually this tablet will be used at will by the patient to mitigate acute nicotine cravings as it is occurring. Thus, this method provides the patient with the tools for self-regulation of their requirements for admission.More specifically, acute craving ktula intensity of Smoking and the like. Thus, the desire to receive tablets or need them (comparable with the desire to smoke cigarettes) will typically change during any single day and from day to day, as well as from patient to patient. The described methods allow the patient to consume the tablets in such quantities and at such times, when he feels most strongly craving for nicotine. As a strong craving for nicotine is considered by some as the most stable and the most important factor preventing quit Smoking, the ability to self-regulate the amount and, thus, relieve the craving for nicotine will increase the effectiveness of Smoking cessation.To assess the degree of nicotine cravings, you can use a number of methods, including, but not limited to, the verification test nicotine cravings that are described in the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) (see (1991) J. Am. Med. Assoc. 266:3133); podskalo traction on Shiffman - Arvika (see O'connel and Martin (1987) J. Consult. Clin. Psychol. 55: 367-371 and Steur and Wewers (1989) ONF 16:193-198, also describing the parallel visual analogue test); West et al. (1984) Br. J. Addiction 79: 215-219: Hughes et al. (1984) Psychopharmacology 83:82-87, each of which is specifically included in the present description by reference.P the rate is asked to evaluate according to the degree of the seriousness of his nicotine cravings on a scale from 0 to 4, where 0 means no; 1 means weak; 2 means moderate; 3 means moderate and 4 indicates strong cravings. Using the described compositions and methods, the patient should reduce nicotine cravings at least one and preferably at least two units, as measured in the Protocol described in the DSM-III-R, 2 - 30 minutes after taking nikotinsoderzhaschie tablets. More preferably, the maximum reduction in nicotine cravings occurs approximately 2 to 10 minutes after taking nikotinsoderzhaschie tablets.Scale thrust of Shiffman-Arvika is restposition tool of forced choice and self-assessment, which measures cravings. Each position has seven possible responses, which correspond to the numbers in the range from 1 (no traction) to 7 (strong desire). The average result is obtained to determine the level of thrust of the Respondent to Smoking. A typical figure is measured 48 hours after the start of the program Smoking cessation, is in the range from 4 to 5; while the scale of the two-week tracking thrust usually gives a result of about 3 to 4. When using the compositions and methods described here, the patient should achieve snimak measured in the Protocol, made in the scale thrust of Shiffman-Arvika in 2 to 30 minutes after administration nikotinsoderzhaschie tablets. More preferably, when the maximum decrease nicotine cravings will occur after 2 to 10 minutes after taking nikotinsoderzhaschie tablets.In scale thrust "questionnaire traction control uses five questionnaire in which patients are asked to rate how much they lacked cigarettes before, to what extent they were aware of the fact that I do not smoke, as they were previously difficult to be without cigarettes, as they were previously concerned about, thinking about cigarettes and how strong it was before their craving for cigarettes. The patient responds to each question with a number from 1 to 3, where 1 means little, and 3 means a lot. Figures are summed to obtain a single indicator. According to this scale thrust combined ratio in the range of 9 to 12 is typical. Using the described compositions and methods patient should reduce nicotine cravings at least three units and preferably at least four units that is measured by the Protocol made for use with this questionnaire about the strength of the pull through 2 - 30 minutes after administration nikotinsoderzhaschie tablets. More preferably, when maximally.Of course, the tablet can also be used in accordance with the nature of the dosage prescribed by the doctor. The nature of the dosage will vary with conditions. For example, in addition to using, in the course of therapy cessation or reduction of Smoking, the above nikotinsoderzhaschie tablets can be used for the treatment of Alzheimer's disease, ulcerative colitis and related conditions and diseases associated with reduced Central cholinergic function, loss of cholinergic neurons, a significant reduction of binding of the receptor nicotine, neurodegenerative dementia or decrease in cognitive ability and memory (see Masterson (1991) US patent N 5069904; Wesnes and Warburton (1984) Psychopharmacology 82:147-150; and Warburton et al. (1986) Psychopharmacology 89:55-59.The tablet should be entered without the presence in the mouth of any other substances, such as food or drink. It is especially important to acidic substances or drinks, such as fruit, coffee, tea or fruit juices, was not used directly before nikotinsoderzhaschie tablet or at the same time in order to ensure the maintenance of the primary environment in the mouth.The tablet preferably held in the mouth for 2-10 minutes, after which it completely correctly for a long time to absorb nicotine through the mucous membrane.Example 7 describes the Protocol for measuring the levels of nicotine in the blood in patients using nikotinsoderzhaschie tablet according to the present invention. The tablets will result in a temporary peak level of nicotine in the blood in 2 to 30 minutes, and more preferably after 2 to 10 minutes after placing the tablet in the mouth.In Fig.2 presents profiles of disintegration/dissolution of setreg compositions described in Examples 1-3 (part 1 contains nicotine, mannitol, xylitol, peppermint flavouring and other fillers: composition 2 contains nicotine, mannitol, xylitol, flavoring substance, tobacco and other fillers, and part 3 contains nicotine, cyclodextrin, xylitol and peppermint flavor). As shown in Fig. 2, the tablet having the composition according to the present invention, will be dissolved at least 60% after 3 minutes of holding in the mouth, at least 80% dissolved after 5 minutes and about 100% dissolved after 10 minutes.Specific examples of the composition according to the present invention is shown below.For a more complete understanding of the described invention provides the following examples. You need to realize that these examples are given only for purposes of illustration is p 1
The composition nikotinsoderzhaschie tablets with xylitol, mannitol and mint flavoring
Nicotine - 1,0
Mannitol - 200,0
Xylitol - 1309,0
Mint flavor - 20,0
The ammonium glycyrrhizinate - 15,0
Sodium carbonate - 5,0
Sodium bicarbonate - 15,0
Hydrogenated vegetable oil - 25,0
Magnesium stearate - 10,0
A method of manufacturing
Nicotine was dispersible in mannitol. The powders were mixed. The mixture is extruded through a suitable alternating tablet press using square 16-millimeter punch and the dosage of 1600 mg/tablet.Packing
The tablets were Packed in strips of aluminum/Baracca.Example 2
The composition nikotinsoderzhaschie tablets with xylitol, mannitol and flavoring additive tobacco
Nicotine - 1,0
Mannitol - 200,0
Xylitol - 1316,5
Flavoring additive tobacco - 6,0
The colloidal silica - 1,5
The ammonium glycyrrhizinate - 15,0
Sodium carbonate - 5,0
Sodium bicarbonate - 15,0
Hydrogenated vegetable oil - 30,0
Magnesium stearate - 10,0
A method of manufacturing
Nicotine was dispersible in mannitol. Powders of smgo 16-millimeter punch and the dosage of 1600 mg/tablet.Packing
The tablets were Packed in strips of aluminum/Baracca.Example 3
The composition nikotinsoderzhaschie tablets with xylitol-cyclodextrin and mint flavoring
Nicotine - 1,0
-cyclodextrin - 109,0
Water - 10,0
Xylitol - 1400,0
Mint flavor - 20,0
The ammonium glycyrrhizinate - 15,0
Sodium carbonate - 5,0
Sodium bicarbonate - 15,0
Hydrogenated vegetable oil - 25,0
Magnesium stearate - 10,0
A method of manufacturing
Nicotine was dispersively b-cyclodextrin. The powders were mixed. The mixture is extruded through a suitable alternating tablet press using square 16-millimeter punch and the dosage of 1600 mg/tablet.Packing
The tablets were Packed in strips of aluminum/Baracca.Example 4
The composition of manufacturing nikotinsoderzhaschie tablets with xylitol, mannitol and mint flavoring
1) preparation of a mixture of nicotine-mannitol
One kg of mannitol sieved through a sieve of 50 mesh and placed in a mixer of Tonazzi. Then slowly added 10 g of nicotine under stirring for 10 minutes. The mixture was transferred into a 2-liter bottle glass amber color and displaced vedennogo of paragraph (1) and 654,5 g Xilitab 200 (xylitol) was sifted through a sieve of 20 mesh and then mixed with 50 g of mannitol, 5 g of magnesium stearate, 12.5 g Lubritab (hydrogenated vegetable oil), 10 g mint flavoring, 7.5 g of ammonium glycyrrhizinate, 7.5 g of sodium bicarbonate and 2.5 g of sodium carbonate and sieved through a sieve of 50 mesh. The mixture was transferred into a 2-liter bottle glass amber color and was stirred for 15 minutes in the mixer, Turbula.3) Preparation of tablets
The mixture of alloy preformed in alternating press Belloni using stamp on 16 mm2. The weight of the tablets was 1600 mg/tablet.4) Packing
The tablets were Packed in strips of paper/aluminum/Baracca.Example 5
A method of manufacturing nikotinsoderzhaschie tablets with xylitol-cyclodextrin and mint flavoring
1) preparation of the complex compounds nicotine--cyclodextrin
The original number in 56,76 g-cyclodextrin were placed in 400-ml beaker and stirring was added of 5.68 g H2O (equivalent to 10% of powder). Water was added in quantities at 1.9 grams per time, with stirring for 10 minutes at each stage. Powder before adding nicotine was similar to a wet granulate. Then, very slowly, with stirring, was added 6,37 g nicotine and at the end of this process, the granulate was mixed in t is or analysis of samples for nicotine content.2) Preparation of a dry granulate
The total number of the 5.25 g nicotine-cyclodextrine complex compounds, 50 g-cyclodextrin, 5 g of magnesium stearate, 12.5 g LubritabR (hydrogenated vegetable oil), 10 g mint flavoring, 7.5 g of ammonium glycyrrhizinate, 7.5 g of sodium bicarbonate and 2.5 g of sodium carbonate was sifted through a sieve of 80 mesh.Then through a sieve of 50 mesh sieved 700 g XilitabR 100 (xylitol). The mixture was mixed in a mixer, Turbula for 20 minutes.3) Preparation of tablets
A mixture of the above paragraph (2) alloy preformed using tabletiruemogo press Belloni, includes a square stamps. The weight of the tablets was 1600 mg/tablet.4) Packing
Tablets were placed in a ribbon of paper/aluminum/Baracca having the following composition: paper 50 g/m2the aluminum of a thickness of 12 μm, 32 g/m2Barex 35 g/m2.Example 6
Stability nikotinsoderzhaschie tablets
One nikotinsoderzhaschie tablet rastolkli and placed in 50-ml volumetric flask. Then the flask was added tetrahydrofuran (25 ml) and the flask was transferred to an ultrasonic bath, where he left for 20 minutes. Added a sufficient amount of ethyl acetate to trust what the flask was added a few milliliters of water and 0.25 ml of the internal standard, consisting of 50 mg of acetanilide, diluted to 100 ml with water. Organic solvents were removed using a weak duct gaseous nitrogen, which gave a cloudy solution. Then added enough water to this turbid solution to bring the solution volume to 25 ml of the Solution is then filtered through a 0.22 μm membrane.The amount of nicotine in the sample was determined using high performance liquid chromatography (temperature in the column 301oC; mobile phase, buffer water:methanol:acetate (0.1 M, pH = 4,0):acetonitrile 60:31:7:2, with bringing to pH = 6,82 by triethylamine, filtration and deaeration; the flow rate of the mobile phase (1.0 ml/min; solid phase Supelcosil LC1808 (5 μm) 25 centimeters (cm) x4,6 millimeters (mm), supplied by the company Supelco Inc.; and analytical wavelength 2541 nanometers (nm)). Under these conditions, nicotine and acetanilide had a retention time of approximately 7.7 and 9.3 min, respectively. The ratio of the components in the mobile phase can be changed to provide a suitable time for elution of nicotine and internal standard.Example 7
Measurement of in vivo selection of nicotine tablets
Clinical trials tablets described in example 1 was carried out in six turut the blood sample. Patients are asked to suck the tablet. Blood samples are taken through 2,5, 5, 7,5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120 and 240 minutes. In addition, immediately after the tablets have dissolved, he shall so inform the medical staff to check the time of dissolution.Blood samples of 5 ml are collected in tubes with litigaiton. Immediately after collecting the sample is cooled and centrifuged at 4oC at 1500 rpm for 15 minutes. Then the plasma was transferred to polypropylene tubes and kept at -30oC until analyzed for nicotine and cotinine. For the analysis of nicotine and cotinine using the method of capillary gas chromatography. The detection limit of 0.8 ng/ml for nicotine and 5.0 ng/ml for cotinine. The limit of quantification is 1.0 ng/ml for nicotine and 10 ng/ml for cotinine.Description in this application all articles and references, including patent documents is hereby incorporated into this description by reference.You must understand that the above description is for illustration and is not restrictive. For specialists in the art many options for implementation will be apparent upon review of the above description. Therefore, the scope of the appended claims, together with the whole scope of equivalents to which applies this invention. 1. Nikotinsoderzhaschie a pill that contains nicotine, an absorbent filler, sweetener and targeted supplements, in particular aromatic, characterized in that it contains nicotine in quantities of from 0.5 to 5 mg and the specified components in the following proportions based on the weight of the whole tablet, and Mac. %:
The absorbent filler - 5 - 15
Non-nutrient sweetener - 80 - 90
Targeted supplements - Rest
2. Nikotinsoderzhaschie tablet p. 1, characterized in that as the target additives it contains a lubricating substance.3. Nikotinsoderzhaschie tablet p. 2, characterized in that the lubricant is magnesium stearate.4. Nikotinsoderzhaschie tablet p. 2, characterized in that the lubricant is hydrogenated vegetable oil.5. Nikotinsoderzhaschie tablet PP.1 to 4, characterized in that as the target additives it contains a buffering agent.6. Nikotinsoderzhaschie tablet under item 5, wherein the buffer substance is sodium carbonate.7. Nikotinsoderzhaschie tablet p. 5, otlichayushchayasya fact, as flavouring substances it contains a complex of cyclodextrin and aromatic essential oils.9. Nikotinsoderzhaschie tablet PP.1 to 8, characterized in that as pharmaceutical additives it contains fluoride salts of sodium.10. Nikotinsoderzhaschie tablet p. 9, characterized in that it contains monitoroff sodium.11. Nikotinsoderzhaschie tablet p. 9, characterized in that it contains sodium fluoride.12. Nikotinsoderzhaschie tablet PP.1 - 11, characterized in that the absorbent filler is mannitol.13. Nikotinsoderzhaschie tablet PP.1 - 12, characterized in that the non-nutrient sweetener is xylitol.14. Nikotinsoderzhaschie tablet PP.1 - 12, characterized in that the non-nutrient sweetener is an ammonium glycyrrhizinate.15. Nikotinsoderzhaschie tablet PP.1 to 14, characterized in that the non-nutrient sweetener consists of a mixture of xylitol and ammonium glycyrrhizinate.16. Nikotinsoderzhaschie tablet PP.1 - 15, characterized in that the pH of the tablets is in the range between 6 and 11.17. The method of treatment area, including buccal centuries the ina is carried out using pills, containing nicotine in an amount of from 0.5 to 5 mg, absorbent filler, non-nutrient sweetener and targeted supplements, and control the dose of nicotine is implemented by assessing the degree of traction of the patient to nicotine using Protocol nicotine cravings.18. The method according to p. 17, characterized in that the control of the dose of nicotine is carried out by controlling the amount of nicotine in the blood of the patient at the level of from 5 to 50 ng/ml19. The method according to p. 17, characterized in that the buccal introduction nicotine is carried out at pH values ranging from 6 to 11, in addition allow the tablet to fully dissolve in the mouth.20. The method according to PP.17 to 19, characterized in that immediately before the buccal introduction nikotinsoderzhaschie tablets assessing thrust patient to nicotine and are Protocol nicotine cravings, and after buccal introduction nikotinsoderzhaschie tablets assess further thrust patient to nicotine by comparing the received data with the specified Protocol traction.21. The method according to PP.17 to 20, characterized in that for the Protocol nicotine cravings using a scale of DSM-III-R, the Statistical Handbook on the diagnosis psihicheskoe use the scale thrust of Shiffman-Arvika.23. The method according to PP.17 to 20, characterized in that for the Protocol nicotine cravings use pre-prepared questionnaire.
FIELD: pharmaceutical industry.
SUBSTANCE: invention is characterized by that system contains underlayer, therapeutical substance storage layer, and agent attaching the system on the person's skin and allowing access of nicotine to skin. System is transparent (opacity factor below 48.6%).
EFFECT: facilitated transcutaneous transport of nicotine.
8 cl, 1 tbl
SUBSTANCE: method involves recording arterial blood pressure, heart beat rate, respiration frequency, sublingual body temperature and rectal body temperature. The measurements are repeated 3, 5, 7, 9, 11, 13, 15, 20 min later after introducing xanthinol niacinate. Difference of maximum and minimum values of each factor is calculated, respectively. Parasympathetic patient responses predominance is determined from calculated values.
EFFECT: high accuracy in determining organism tolerance to reactive vasoconstriction.
2 cl, 4 tbl
FIELD: medicine, narcology, pharmacy.
SUBSTANCE: invention relates to nicotine-containing preparations possessing prolonged stimulating effect and used in loss the smoking habit. The preparation is prepared by a method involving preparing a gel-base by addition of 2.5-3.0% gel of hydroxypropylcellulose in ethanol to 10-13% ethanol solution of copolymer of N-vinylpyrrolidone with organic unsaturated acid ester in the mass ratio copolymer of N-vinylpyrrolidone with organic unsaturated acid ester : hydroxypropylcellulose in gel-base = (7.0-1):(7.5-1). Then cetyl alcohol, isopropyl myristate, propylene glycol, preliminary melted stearic acid, colloidal silicon dioxide and nicotine are added successively to the prepared gel-base at constant stirring and temperature 30-35°C. Invention provides enhancing the prolonged effect of the preparation.
EFFECT: improved preparing method, enhanced and valuable properties of preparation.
3 cl, 1 tbl, 2 ex
SUBSTANCE: method involves delivering nicotine to patient organism and administering medicament by smearing internal surface of superior and inferior nasal passage part. Treatment is carried out with cigarette consumption being retained. Smell receptor canal blocker like rapid sodium canal blocker lidocaine is used as the medicament. Its aerosol is introduced immediately before smoking action as single jet in each nasal passage. Medicament introduction is localized with epithelial smell receptor cells arrangement.
EFFECT: enhanced effectiveness of treatment.
2 cl, 2 tbl
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to the development of medicines used for enhancing resistance of humans and animals to hypothermia. Agent for enhancing resistance of humans and animals to hypothermia comprises nicotinic acid, glutamic acid, riboflavin, ascorbic acid, uniquinone, succinic acid, polyethylene oxide and water taken in the definite ratio. Also, invention proposes a method for enhancing resistance of humans and animals to hypothermia involving administration of the abovementioned agent 30 min before works associated with hypothermia and after its termination for activation of vital essential biochemical processes. Invention provides enhancing resistance to overcooling under extreme conditions and using in surgery practice in cooling organs (in operations in heart and brain).
EFFECT: enhanced effectiveness and valuable medicinal properties of agent.
2 cl, 2 tbl, 1 dwg, 2 ex
FIELD: medicine, vitamins.
SUBSTANCE: invention proposes a composition of vitamins riboflavin and nicotinic acid (niacin) or nicotinamide for treatment of primary headaches representing usual migraine, classic migraine, migraine combined with "histamine" headache. The composition comprises the combination of 0.5-750 mg of nicotinic acid (niacin or nicotinamide) and 0.1-250 mg of riboflavin. Also, the invention involves the corresponding method for treatment. Proposed treatment provides body with necessary NAD/NADP and FAD/FMN in order to modulate activity of mast cells when changes in their secretion results to migraine. Method provides disappearance of all migraine symptoms during the next 20 months of dispensary observation.
EFFECT: enhanced medicinal effectiveness of vitamins.
SUBSTANCE: invention proposes a liquid pharmaceutical composition containing nicotine in any form for administration into the mouth cavity and alkalinized with a buffer and/or by regulation of pH value. Administration is carried out preferably by spraying and the most preferably by sublingual spraying. Also, invention relates to a method for preparing the indicated composition. Use of indicated composition in therapy, such as therapy for treatment of addiction to tobacco.
EFFECT: valuable pharmaceutical properties of composition.
51 cl, 11 ex
SUBSTANCE: method involves acidifying and/or alkalinized by buffering and/or controlling pH to provide nicotine tmax in arterial subject blood in short time after introduction. Aerosol atomizing is preferentially done into oral cavity for following distribution in lungs. Method for preparing the composition, system for achieving smoking desire reduction and/or satisfaction feeling without smoking is also suggested.
EFFECT: enhanced effectiveness in introducing nicotine via lungs; avoided harmful actions caused by smoking.
FIELD: medicine, pharmaceuticals.
SUBSTANCE: invention relates to nicotine-containing pharmaceutical compositions comprising 0.5-10 mg of nicotine and 17-70 % cocoa powder as taste masking agent, filler/diluent and smoothing or corrective agent; to application of such composition in production of medicine preparation for nicotine replacement therapy (NRT), withdrawal from tobacco, application reducing and temporary cancellation of tobacco, in treatment of Alzheimer disease, Parkinson disease, ulcerative colitis and/or Tourette's syndrome, and/or in body weight loss therapy; as well as to methods for nicotine replacement therapy (NRT), withdrawal from tobacco, application reducing and temporary cancellation of tobacco, in treatment of tobacco dependence, treatment of Alzheimer disease, Parkinson disease, ulcerative colitis and/or Tourette's syndrome, and/or in body weight loss therapy by administration of such compositions.
EFFECT: new preparation for nicotine replacement therapy and for treatment of other diseases and conditions.
22 cl, 3 ex
SUBSTANCE: invention relates to a chew with cover used fir delivery of nicotine in a subject in any form. Proposed chew comprises at least one buffered or an unbuffered core, nicotine in the amount 0.05-10 mg as measured for a free nicotine base and/or nicotine-simulating agent, at least one cover layer wherein one cover layer comprises a buffer. Also, invention proposes a method for delivery of nicotine in any form, method for decreasing for smoking dependence or using tobacco, and using this chew for providing rapid assimilation of nicotine through mucosa in mouth cavity of a subject. Invention provides the more rapid assimilation of nicotine by mucosa in mouth cavity and reducing amount of swallowed nicotine and its accumulation in digestive tract.
EFFECT: improved and valuable properties of chew.
41 cl, 2 tbl, 5 ex
SUBSTANCE: means comprises amber acid and/or its salts, fructose, dry extraction of Saint John's wort, magnesium ion sources, potassium ion sources as active bases and auxiliary substances, carriers and/or fillers when needed.
EFFECT: enhanced effectiveness of treatment.
4 cl, 4 tbl
SUBSTANCE: the suggested preparation is being cytidine diphosphate choline (CDP-choline) known previously as the preparation to restore cerebral phospholipid structure and for treating mammalians, people among them, subjected to the action of stimulants. Moreover, it is necessary to note that CDP-choline decreases the duration of abstinence symptoms (tremor, convulsions, weakness, emotional instability, nervousness, social reserve) and causes either the decrease or stoppage of alcohol intake.
EFFECT: higher efficiency of therapy.
5 cl, 5 ex
SUBSTANCE: preparation is a crushed and UV-radiation activated β-(3-indolyl)-α-aminocapronic acid obtained by treating dry initial preparation (native aminocapronic acid) crushed to 1-5 mcm large particles with UV-radiation during 12-18 h to the moment the substance decomposition starts. Method involves crushing dry substance of β-(3-indolyl)-α-aminocapronic acid by means of vibration mill with 1500-3000 oscillations per min to 1-5 mcm large particles, activating the crushed product by exposing it to UV-radiation of 250-280 nm wavelength during 12-18 h to the moment the initial substance decomposition starts. The moment is determined by 3-5% large initial mass loss.
EFFECT: enhanced effectiveness of the preparation with no adverse side effects.
6 cl, 3 tbl