RU2745039C1 - Nicotine edible paper - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: invention relates to an edible biodegradable product for oral consumption of nicotine. The product is an edible paper in the form of a strip impregnated with a solution of nicotine, its pharmaceutically acceptable salt or its analogue - an agonist from the group: cytisine, anabazine, lobelin, at a certain ratio of the solution components and a certain amount of solution applied to the paper.EFFECT: invention provides ease of obtaining an edible biodegradable product for oral consumption of nicotine by applying on edible paper a predetermined amount of ingredients of a composition with nicotine or its salt (an analogue), and also provides an optimization of the nicotine dosage, in which the consumer can regulate its intake by choosing a certain amount of edible paper to quit smoking completely or as a safer substitute for smoking.2 cl, 1 tbl, 6 ex

Description

The invention relates to medicine, treatment of nicotine addiction or nicotine substitution, pharmaceuticals, concerns the creation of new medicinal compositions.

Tobacco smoking is a highly addictive process associated with a sense of pleasure from the use of nicotine, and enhanced by the habits and rituals of smokers. The combination of these properties makes it difficult to quit smoking, despite the many proven adverse health effects of carbon monoxide, tar and other tobacco combustion products. The byproducts of tobacco smoke are hazardous to health, not nicotine itself. However, it is also an active substance that has a pronounced effect on the respiratory and cardiovascular systems of the body.

Unfortunately, not everyone succeeds in fighting nicotine addiction on their own, although even heavy smokers have no doubts that quitting smoking is beneficial both for health and for the family budget. According to a 2011 US government report, almost 70% of American smokers want to quit, about half of them have tried to quit at least once in their lives, but no more than 6% were able to completely overcome addiction.

Such a low result is associated with the peculiarities of the physiological action of nicotine. First, by acting on nicotinic acetylcholine receptors, nicotine increases the concentration of the stimulating hormone adrenaline in the body, the release of which leads to an increase in blood glucose, an accelerated heart rate, an increase in blood pressure and increased respiration. All this allows a person to temporarily feel an increase in concentration of attention and feel a temporary surge of strength after a smoked cigarette (when this effect stops, an inveterate smoker, in order to concentrate on work or just to cheer up, most often automatically takes another cigarette out of the pack). Secondly, nicotine increases the concentration of the pleasure hormone dopamine in the brain, as a result of which a causal relationship is formed not only between the fact of smoking a cigarette and an increase in performance, but also between a cigarette and the pleasure associated with smoking.

Psychological addiction to smoking, in which a person with a cigarette feels more confident or uses an extra smoke break to give himself an additional work break, turns into physical addiction, when it is impossible to go without a cigarette for a long time.

For the treatment of nicotine addiction in medicine, substitution therapy is used, the purpose of which is to make a person get sensations similar to those obtained from smoking, but without the smoking process itself. This is necessary in order to destroy the cause-and-effect relationship between the smoked cigarette and the sensation of the effect on the body of nicotine in the quit smoking (L. Biener et al., 2006. Impact of Smoking Cessation Aids and Mass Media Among Recent Quitters ). During such therapy, the patient, gradually lowering the dose of nicotine, takes it from other sources (nicotine patches, chewing gums and tablets), not as dangerous as a cigarette, the main harm from which is still caused not by nicotine itself, but by the combustion products of tobacco. Nicotine replacement therapy, or, in other words, the administration of nicotine by a route other than smoking - for example, when taking oral nicotine-containing products, can also be used as a replacement for smoking. That is, even if a person does not dare to quit smoking, his transition from traditional smoking to taking an oral nicotine-containing product, at least, will reduce the number of negative effects of smoking, as such, in particular, from inhaling tar and other combustion products when smoking a cigarette.

Another option for nicotine replacement therapy is taking medications that bind to the same receptors as nicotine itself. But even the most effective drug to date, varenicline, which appeared on the market in 2006, although it can reduce the urge to smoke and reduce the effect of getting pleasure from smoking, when used for six months or more, it turns out to be only three times more effective than placebo (M McDonough, 2015. Update on medicines for smoking cessation. However, it has unpleasant side effects (withdrawal symptoms) such as nausea, headache, and confused anxious dreams.

There are currently a significant number of smoking cessation aids on the market, such as nicotine patches, nicotine chewable tablets and gum, lozenges, nicotine cartridges and nicotine inhalers. These funds are designed to increase blood levels of nicotine without the associated dangerous by-products, however, they are not directed towards overcoming the habit of smoking cigarettes. Detailed analysis of the efficacy of such anti-smoking agents revealed wide differences in their effects in terms of delivery rate, concentration, retention of effect and bioavailability (Hukkanen et al., Pharmacol. Rev., 2005, 57, 79). Since these agents do not provide a pharmacokinetic profile similar to the nicotine profile achieved by smoking a conventional cigarette to which the consumer is accustomed, their use as nicotine replacement therapy (NRT) or as an alternative to “recreational smoking” of conventional cigarettes is severely limited.

A number of inhaled nicotine-containing compositions have been described (for example, RU 2662550 C2, 26.07.2018, KIND CONSUMER LIMITED, GB). However, they do not provide a conscious refusal of the smoker from important attributes associated specifically with the smoking process, which psychologically postpones the time of final refusal. In addition, inhalation of nicotine vapors directly into the lungs, their rapid entry into the respiratory tract, can cause side effects associated with impaired function.

WO 2011/095781 describes a smoking simulator comprising a filter box containing a nicotine composition and a reusable inhaler in the form of a cigarette. GB 1528391 describes a composition comprising nicotine or nicotine salt, a solvent for dissolving them, a flavoring agent and a propellant.

WO 2006/004646 describes an inhalable nicotinic composition comprising a free nicotinic base with an organic acid, a hydrofluoroalkane (HFA) and, if required, another solvent. However, none of these compositions provide the user with a pharmacokinetic profile similar to that of a conventional cigarette.

US 2009/005423 describes the use of a nicotine composition aimed at mimicking the plasma nicotine concentration generated by smoking a conventional cigarette, namely a rapid, pronounced peak in concentration after application of the composition in the oral mucosa. However, the peak provided by this composition appears in a shorter time, and the product also degrades faster than the peak typically seen with traditional cigarette smoking.

To reduce the toxicity from smoking when inhaling tobacco smoke in replacement products, its agonists are also used instead of nicotine - the alkaloids anabazine and cytisine (RU 95226 U1, 06/27/2010, Komissarov Yu.V.).

Known analogs (agonists) of nicotine can be used as means for smoking cessation (http://www.xumuk.ru/farmacevt/322.html).

Cytisine (Cytisinum) is also an alkaloid contained in the seeds of the broom plant (Cytisus laburnum L.) and lanceolate thermopsis (Thermopsis lanceolata, R. Br.), Both fam. legumes (Leguminosae). Refers to substances with a stimulating effect on respiration, is considered as a respiratory analeptic. For this purpose, it is produced in the form of a ready-made 0.15% aqueous solution under the name Cytitonum. In recent years, cytisine has been used as a smoking cessation aid. Cititon is a clear, colorless liquid; pH 7.0 - 7.5. Sterilized at + 100 ° C for 30 minutes. Cytisine has an exciting effect on the ganglia of the autonomic nervous system and related formations: adrenal chromaffin tissue and carotid glomeruli. A characteristic of the action of cytisine (as well as lobelin) is the excitation of respiration associated with reflex stimulation of the respiratory center by intensified impulses coming from the carotid glomeruli. Simultaneous stimulation of the sympathetic nodes and the adrenal glands leads to an increase in blood pressure. The effect of cytiton (cytisine solution) on respiration is short-term, however, in some cases, especially with reflex cessation of respiration, the use of cytiton can lead to a stable restoration of respiration and blood circulation. Previously, cytiton was widely used for poisoning (morphine, barbiturates, carbon monoxide, etc.). Due to the emergence of specific opiate antagonists (naloxone, etc.) and barbiturates (bemegrid) and the short duration of action, cytiton and lobelin are currently of limited use. Cytiton is injected into a vein or intramuscularly: for adults, 0.5-1 ml, for children - lower doses. Intravenous administration is most effective. If indicated, the injection of cititon can be repeated after 15-30 minutes. Higher doses for adults intravenously and intramuscularly: single 1 ml, daily 3 ml. Cytiton is contraindicated (because of its ability to increase blood pressure) with severe atherosclerosis and hypertension, bleeding from large vessels, pulmonary edema. Release form: 1 ml ampoules. Cytisine (0.0015 g = 1.5 mg) is included in tablets (Tabex, Bulgaria) used to ease smoking cessation. Prescribe 1 tablet per reception first 5 times a day with a further dose reduction to 1-2 tablets per day. People who take these pills experience discomfort when smoking. The course of treatment lasts 20-25 days. The mechanism of action of the drug is similar to that of lobeline and anabasine. The use of tablets should be done as directed and under the supervision of a physician. In case of an overdose, nausea, vomiting, dilated pupils, and increased heart rate are possible, which requires discontinuation of the drug. Films with cytisine (Membranulae cum Cytisino) are also available. Oval-shaped polymer plates with blunt edges, white or with a yellowish tinge (9 X 4.5 X 0.5 mm), each contain 0.0015 g of cytisine. The film is glued to the gum or the mucous membrane of the cheek region 4-8 times daily for the first 3-5 days. With a positive effect, treatment is continued according to the following scheme: from the 5th to the 8th day, 1 film 3 times a day, from the 9th to the 12th day, 1 film 2 times a day, from the 13th to 15th day. day 1 film 1 time per day. From the first day of treatment, you should stop smoking or sharply reduce the frequency of smoking. In the first days of using the film with cytisine, unpleasant taste sensations, nausea, mild headache, dizziness, and a slight increase in blood pressure are possible. In these cases, you should stop taking the drug. The use of films with cytisine is contraindicated in bleeding, severe hypertension, advanced stages of atherosclerosis.

Anabazine (α-piperidyl-β-pyridine) is an alkaloid found in the leafless barnyard (Anabasis aphylla L.) and in tobacco (Nicotiana tabacum) along with its nicotine isomer. Colorless viscous liquid, yellowing in air and light; boiling point 276 ° C. Easily soluble in water and organic solvents. Forms salts such as dipicrate. In reaction with HNO2, it gives N-nitrosamine, with benzoyl chloride - N-benzoylanabazine, with alkylating agents - N-alkylanabazines. In industry, anabazine is isolated from the leafless barnyard. Anabazine is a ganglionic poison, similar to nicotine in its effect on the body; LD50 = 10.2 mg / kg (mice, intraperitoneal). In small doses, it stimulates the central nervous system, enhances respiration, and increases blood pressure. Readily absorbed through the skin and may cause toxicity. Anabazine hydrochloride is a drug that facilitates smoking cessation.

Lobelin (Lobelinum) - alkaloid contained in the plant Lobelia inflata, fam. campanula (Campanulaceae). Optically active. Lobeline racemate is produced synthetically. Lobelin hydrochloride (Lobelini hydrochloridum) is used in medical practice. Synonyms: Antisol, Atmulatin, Bantron, Lobatox, Lobelinum hydrochloricum, Lobeton, Lobidan, etc. White crystalline powder of bitter taste, odorless. Let's hardly dissolve in water (1: 100), we will dissolve in alcohol (1:10). Aqueous solutions (with the addition of a solution of hydrochloric acid to pH 2.8 - 3.2) are tindalized at + 60 ° C 3 times every 3 hours for 1 hour. Lobelin is a substance that has a specific stimulating effect on the ganglia of the vegetative part of the nervous system and carotid glomeruli (see also Ganglion blocking drugs). This action of lobelin is accompanied by excitation of the respiratory and other centers of the medulla oblongata. In connection with the excitement of respiration, lobelin was proposed as an analeptic agent for use in reflex respiratory arrest (mainly when inhaling irritating substances, poisoning with carbon monoxide, etc.). Due to the simultaneous excitation of the vagus nerve, lobelin causes a slowdown in heartbeats and a decrease in blood pressure. Later, blood pressure may rise slightly, which depends on vasoconstriction caused by the excitatory effect of lobelin on the sympathetic ganglia and adrenal glands. In large doses, lobeline stimulates the vomiting center, causes deep respiratory depression, tonic-clonic seizures, and cardiac arrest. Recently, lobeline has been used extremely rarely as a respiratory stimulant. In case of weakening or stopping of breathing, developing as a result of progressive depletion of the respiratory center, the introduction of lobelin is not indicated. Into a vein and into muscles, injections are injected into adults at 0.003 - 0.005 g (0.3 - 0.5 ml of 1% solution), children, depending on age, at 0.001 - 0.003 g (0.1 - 0.3 ml of 1% solution) ... Intravenous administration is more effective, administered slowly (1 ml for 1 - 2 minutes). With a rapid introduction, sometimes temporary respiratory arrest (apnea) occurs and side effects from the cardiovascular system develop (bradycardia, conduction disturbances). Higher doses for adults in a vein: single 0.005 g, daily 0.01 g; in muscles: single 0.01 g, daily 0.02 g. Lobelin is contraindicated in severe organic diseases of the cardiovascular system. Release form: 1% solution in ampoules and syringe tubes of 1 ml. Lobelin and other substances similar to it in action (cytisine, anabasine) have been used in recent years as aids for smoking cessation. Lobelin tablets are marketed for this purpose under the name Tabulettae "Lobesilum". Each such tablet contains 0.002 g (2 mg) of lobeline hydrochloride. The tablets are coated with a coating (acetylphthalylcellulose), which ensures the passage of the drug unchanged through the stomach and its rapid release in the intestine. The use of tablets, as well as tablets of other drugs containing cytisine and anabazine hydrochloride, reduces the urge to smoke and alleviates the symptoms, painful for smokers, associated with smoking cessation. The mechanism of action of these agents is apparently associated with a competitive relationship in the area of the same receptors and biochemical substrates with which nicotine interacts in the body. Cessation of smoking requires not only the use of pills, but at the same time a firm decision of the smoker to stop smoking. After smoking cessation, take 1 tablet 4-5 times a day for 7-10 days. Subsequently, if necessary, you can continue taking the pills for 2-4 weeks with a gradual decrease in the frequency of taking. In case of relapses, the course of treatment can be repeated. The use of tablets with lobeline, cytisine and anabasine is contraindicated in exacerbation of gastric ulcer and duodenal ulcer, organic changes in the cardiovascular system. Treatment should be carried out under the supervision of a physician. In case of an overdose, side effects are possible: weakness, irritability, dizziness, nausea, vomiting.

Manufacturers are trying to solve the problem associated with withdrawal from the attributes of smoking, its inhalation effect, by creating the aforementioned transdermal or buccal agents, for which, however, it is difficult to calculate the pharmacokinetic and pharmacodynamic profile of nicotine or its analogs in the body.

US 2015328202 A1 (11/19/2015, IDEA LOGIC LLC, US) solves the problem of efficient absorption of nicotine in the body (when taken by mouth) to maintain the smoker during the period of abstinence from smoking. For this, various edible seeds are infused with a nicotine solution and various flavors are added. Reception can be carried out by chewing, sucking, swallowing seeds infused with nicotine. However, dosage accuracy is also difficult in this case.

An oral product is known (RU 2617262 C2, 04.24.2017, ALTRIA CLAINT SERVICES ELELSIE, US), which provides a satisfactory tactile and / or gustatory sensation, similar to that of tobacco, and a suitable tactile sensation. The product, in addition to nicotine, may include additives such as flavors, sweeteners, vitamins, minerals, other therapeutic agents, nutraceuticals, energizers, sedatives, colorants, amino acids, chemistetics (i.e., substances that affect the overall chemical sensation), antioxidants, food emulsifiers, pH modifiers, herbal remedies, teeth whitening agents. Combinations of additives (eg, sweeteners, flavors and nicotine) can be used. The product is a physical body (substance) that is completely placed in the oral cavity. The substance contains polymers soluble in the oral cavity, cellulose fibers and nicotine. In other words, the substance is a polymer matrix soluble in the oral cavity, cellulose fibers and nicotine or its derivative included in it, dispersed in this soluble polymer matrix. This oral product is adapted for the release of nicotine or its derivative from the specified substance when it is placed in the oral cavity and under the influence of saliva.

The oral product can be wrapped or covered with an edible or dissolving film that can easily break down when the product is placed in the mouth. Examples of coating materials include beeswax, gelatin, acetylated monoglyceride, starch (eg, native potato starch, high amylose starch, hydroxypropylated potato starch), zein, shellac, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose, and combinations thereof. The coating may include a combination of gelatin and methylcellulose, a colorant, a flavoring agent, and / or one or more of the additives discussed above. The coating can include nicotine to provide the consumer with an initial boost of nicotine. Oral product additives can be alkaloids (eg, nicotine or caffeine, or derivatives thereof), sweeteners, flavoring agents, or combinations thereof. With certain combinations of nicotine, sweeteners and flavors, an oral product can provide a flavor profile and tactile sensation similar to certain tobacco products.

The nicotine in the oral product can be tobacco derived nicotine, synthetic nicotine, or a combination thereof. In certain embodiments, the oral product comprises 0.1 mg to 6.0 mg nicotine.

In the known invention, the production of nicotine from tobacco can occur by mixing the dried and fermented tobacco with water or another solvent (eg ethanol) and then removing the insoluble tobacco material. The tobacco extract can be further concentrated or purified.

A known oral product can be prepared by extruding an orally soluble polymer (e.g., starch) with fibers (e.g., cellulose fiber) and / or an additive (e.g., nicotine) to form an orally soluble polymer matrix containing fibers and / or additives. The rod is cut into individual oral products. Extruded and cut, they can be injected into a mold to finalize the oral product. The oral product can also be obtained by injection molding and compression molding. Blocks of polymer, fibers and / or additives can also be formed and machined to the desired shape.

Such an oral product can be a coated stick and can be prepared by making a slurry of an orally soluble polymer, cellulose fibers, nicotine and one or more other additives, applying the slurry to the stick and drying the coating. A slurry is obtained by mixing materials with one or more solvents (water, ethanol). The suspension is applied to the stick by dipping it into the suspension manually or mechanically. The dipping procedure can include several dipping steps with partial drying stages in between. One or more coats can be applied to obtain a 0.1-2 mm thick coating on the stick. The coated stick is then dried in an oven to the desired degree of dryness.

However, such a stick product is not completely edible, and its presence in the oral cavity is more similar to the sensations of smoking a regular cigarette, while in order to finally quit the bad habit, it is necessary to get rid of the addiction to these pleasant sensations.

Known methods and means of treating nicotine addiction using a delivery system and controlled rapid release (WO 2009073190 A1, 11.06.2009, SWEDISH MATCH NORTH AMERICA, INC., US, et al.). In this case, nicotine in a solution with a sweetener is applied to a rapidly dissolving (biodegradable) polymer film in the mouth. Various polysaccharides, pullulans, alginates, cellulose derivatives are used as film-forming agents, and propylene glycol, etc., are used as emulsifiers, plasticizers. The film may also contain glycerin and is edible. Additionally, it may contain flavoring agents (aromas), sweeteners and other agents. The active substance of the biodegradable film is nicotine.

However, the use of the substance in the form of a film attached in the oral cavity is also not convenient for the consumer. In addition, it is difficult to achieve a certain, required concentration of nicotine in the body - control of its dosage with this form of administration becomes more difficult.

Known edible product (US2002025300 A1, 28.02.2002, WOLFSON PHILIP, JACOB PEYTON; SHULGIN ALEXANDER T; PHYTOS, INC, US) in the form of chewing gum, tablet or lozenge, to facilitate cravings for nicotine, containing its agonist - anabazine together with flavorings , sweeteners and the like. However, the difficulty in accurately dosing the agonist is hampered by both the choice of the dose itself and the time of its release in the oral cavity.

Also known edible paper (Edible paper: rice, waffle, sugar. Printing on edible paper, https://fb.ru/article/221989/syedobnaya-bumaga-risovaya-vafelnaya-saharnaya-pechat-na-syedobnoy-bumage ). Traditionally, the basis for the preparation of this product is rice flour, water and salt. Tapioca is often used - a starchy product that is obtained from the roots of edible cassava - a valuable tropical plant. Waffle paper is made from potato or rice starch, vegetable oil, and water.

Sugar edible paper contains ingredients such as sugar or other sweeteners, edible molasses, sorbitol syrup, water, potassium sorbate, palm oil, food additives, emulsifiers and stabilizers, modified cellulose. Thus, sugar or wafer paper can be a substrate for applying a certain amount of an active substance to it for oral delivery into the body.

Known edible film, (RU 2256442 C2 (20.07.2010, VARNER-LAMBERT COMPANY, US), the composition of which is similar to the above-mentioned edible paper. Edible water-soluble film is intended for the delivery of pharmaceutically active substances through the oral cavity, and along with the active substance, which can be, in particular, nicotine, the film contains a sweetener, a flavoring agent, propylene glycol. The method of its production involves obtaining an aqueous solution of active ingredients, mixing with a film-forming polymer, drying to obtain a water-soluble film. Consumable solid film contains at least one water-soluble polymer, for example, such as pullulan, a pharmaceutically active agent and an ion exchange resin as a taste masking agent containing polystyrene crosslinked with divinylbenzene. The method of making a film includes the steps of dissolving water-soluble ingredients in water, mixing a water-soluble film-former and one stabilizer to obtain a film forming mixture, combining this mixture and an aqueous solution, followed by stirring and obtaining a gel, mixing the oils to obtain an oil mixture and adding the oil mixture with the gel and obtaining a uniform gel and casting it on a substrate and drying to obtain a film. The film masks the taste of the agent well and has a good appearance. However, in this case, the problem of accurate dosage and time of release of the active agent in the oral cavity as required by the smoker has not been solved.

A solution to the problem of poorly soluble substances and accurate dosing of small doses in nicotine replacement therapy is presented in WO 214188079 A1, 11/27/2014 (ÅBO AKADEMI UNIVERSITY, FI), the publication of which can be considered as a prototype of the invention . This known patent publication proposes an oral dosage form, in particular nicotine, and a method for its production using printer technology. The method includes sequential production on a printer of a base material (substrate, carrier) of a dosage form, production of a solution, in particular, nicotine, as ink for the printer. Next, the solution is applied to the substrate using a printer, optionally a protective layer is added and the final dosage form is printed. In this case, nicotine is dissolved in the above solution with the help of a solvent, which can be propylene glycol, glycerin. Cellulosic materials and other biodegradable materials such as starch and rice based materials can be used as a base. The backing material can be sugar-based decorative paper or rice paper and be edible. The support material can also be a chitosan or hydroxypropyl methylcellulose film, suitable for oral or buccal administration. The substrate can also contain aromatic compounds that are applied to the material by printing or other means. However, in this case, the problem of dosing optimization has not been solved.

The problem to be solved by the present invention is to optimize the dosage of nicotine, in which the smoker himself can regulate its intake by choosing a certain amount of edible paper - the carrier of nicotine to satisfy the need for it. At the same time, there are no other attributes of smoking. The consumed product has a sweet taste and does not contain agents that additionally stimulate salivation, which is also comfortable for the consumer, while the compliance is optimal. When such an oral product is consumed as nicotine replacement therapy, there is no negative effect on the body of by-substances formed during the combustion of a cigarette, in particular tar. Accordingly, this product can be used not only for smoking cessation, but also as a safer substitute for smoking if the consumer does not want to quit it altogether.

The above aspects constitute the technical result achieved by the claimed product.

This product facilitates complete smoking cessation in a short time, within a month, with the use of no more than 10 doses of the drug per day. At the same time, such a nicotine-containing product (or with nicotine substitutes) does not prohibit the use of such a nicotine product in public places.

The technical result, which is also provided by the method of obtaining this product, is its simplicity and acceleration of its production due to the simplicity of applying on edible paper a given amount of ingredients of the composition with nicotine or its salt, analogue (by spraying or dipping into a solution). For simplicity, we will further call the active ingredient nicotine, meaning both nicotine itself and its pharmaceutically acceptable salt in an amount converted to nicotine, or its analogue in an appropriate amount (that is, in the amount that is after administration can cause the same effects as the corresponding amount of nicotine introduced into the body).

Edible paper (waffle, rice, sugar) is taken as the basis of the proposed edible product. A solution containing nicotine, or its pharmaceutically acceptable salt, or its analogue from the group: cytisine, anabasine, lobelin, as well as propylene glycol (glycerin), a flavoring agent and a sweetener, is applied to the paper. The active ingredients are used in the form of commercially available chemically pure substances.

Ingredients:

1.Edible paper (waffle, rice, sugar)

2.Fragrance

3.Propylene glycol

4 sweetener

5.Acidity regulator

6. Nicotine, its salts or analogs: cytisine, anabasine, lobeline.

7 water

A flavoring agent is used to give the product the appropriate taste and smell, water to dissolve the acidity regulator and make the paper strips flexible, the acidity regulator is needed to create an optimal pH level in order to shift the balance towards the formation of free nicotine, which penetrates much better through the oral mucosa to achieve faster absorption of the active substance. Nicotine, its pharmaceutically acceptable salt or analogue is the main active ingredient.

The resulting solution is sprayed on paper from a spray bottle, or the paper is immersed in a solution of the following composition:

Component Mass fraction% Flavoring 1.0-8.0 Purified water 5.0-30.0 Sweetener 0.1-1 Acidity regulator 0.1-7 Nicotine, its salt or its equivalent 0.1-20 Propylene glycol Up to 100

To prepare the sprayed solution, a sweetener and an acidity regulator are added to the purified water, heated to 37 ° C or left at room temperature until complete dissolution. It is possible to apply the acidity regulator in dry form at the end of the process to paper.

Separately prepare a solution by mixing sequentially propylene glycol, flavor and the corresponding active substance. Then the above-mentioned aqueous solution is added thereto.

The general solution obtained by mixing both solutions is filled into a spray bottle and edible A4 paper (or any other) is sprayed on one or both sides, covering its entire surface (or a sheet of paper is immersed in this solution). Allow the paper to be saturated with the solution as much as possible. Excess liquid is removed from the paper (it can be reused). The sheets of paper are left to dry on the grates, then they are placed in sealed boxes and insisted for 3 days at a temperature not exceeding 18˚С, so that the solution is evenly distributed over the paper, and its structure becomes more flexible. Thus, maximum absorption of the solution into the paper is achieved, and the paper becomes a carrier of nicotine or its analogue.

Cut the paper into strips for use, for example, under the lip, in the mouth.

Moreover, each strip intended for medicinal purposes to combat smoking contains from 5 to 30 mg of nicotine or, in the case of taking nicotine as a substitute for smoking, from 30 to 160 mg of nicotine. When spraying, the final concentration of the solution should be 1.8-10.7 mg of solution per cm2 of impregnated paper. The consumption of such a product roughly corresponds to the nicotine content of one cigarette, depending on the brand consumed (https://meduniver.com/Medical/toksikologia/otralenie_nikotinom.html).

Absorbability of paper strips: 1 g of paper absorbs 0.9-1.2 g of solution as much as possible. To control the amount of nicotine, it is necessary that the paper is saturated with the solution as much as possible.

The size of a strip of paper is also chosen as maximum possible, taking into account the convenience of use by the consumer. For example, for use under the lip, it could be the size of a gum (pad or strip), or it could be the size of a lollipop, on average 1 x 2 cm2 to 2 x 3 cm2.

The product is biodegradable, does not contain harmful, toxic impurities, in particular, lime, it does not cause excessive salivation and completely dissolves in the mouth. Nicotine or its analogue is used: cytisine, anabasine, lobeline of the highest degree of purification. Such chemically pure substances obtained by an industrial method are commercially available.

In the production of edible paper, which can be formed into a wafer or cookie strip, each unit (strip) contains a certain amount of a solution composition containing nicotine in a dose of 5 to 160 mg. The product, when consumed, practically melts in the oral cavity, in connection with this, the active ingredient of the composition is released and absorbed from the oral cavity into the blood. The residence time of the product in the oral cavity allows absorption of the entire amount of the active ingredient in the product in a soluble form. At the same time, the client consumes such an amount of waffles or cookies that can satisfy his current need for nicotine.

The paper dissolves, facilitating the release of the active agent, within about 1-3 minutes after being placed in the mouth.

As a flavoring agent, any commercially available additives of suitable taste and smell can be used - orange, strawberry, lemon, raspberry, currant, vanilla, apple, lime, etc. They can also include extracts, for example, licorice, hydrangea, magnolia leaf, chamomile , fenugreek, cloves, menthol, Japanese mint, aniseed, cinnamon, herbs, wintergreen, cherry, berries, peach, apple, Drambuey liqueur, bourbon, Scotch whiskey, American whiskey, curly mint, peppermint, lavender, cardamom, celery, cascarilla, nutmeg, sandalwood, bergamot, geranium, honey essence, rose oil, vanilla, lemon oil, orange oil, cassia, cumin, cognac, jasmine, ylang ylang, sage, fennel, pepper, clove, ginger , coriander, coffee or peppermint oil from any species of the genus Mentha.

As an acidity regulator, suitable substances from the group of glycerol buffers, citrate or borate buffers, phosphate buffers and buffers based on citric acid and phosphate can be used.

As a sweetener, both glucose and sucrose, fructose, and stevia can be used.

As the edible paper, the aforementioned commercially available edible paper — wafer, rice or sugar paper — is used.

Pharmaceutically acceptable nicotine salts for use in a product may include, but are not limited to: mono- and bitartrate, hydrochloride, dihydrochloride, sulfate, salicylate, and others.

An example of receiving a product.

The amount of active substance (nicotine, or its pharmaceutically acceptable salt, or its analogue, selected from cytisine, anabasine or lobelin) is taken such that in the composition at the outlet it is from 0.1 to 20 wt%. A highly purified substance (98-99%) obtained by an industrial method and commercially available is used.

First, an aqueous solution is prepared by adding a sweetener and an acidity regulator to purified water, followed by leaving at room temperature until complete dissolution.

Separately, a solution is prepared by mixing sequentially propylene glycol, flavor and an appropriate highly purified commercially available active ingredient. Then the resulting aqueous solution is added to it and mixed.

The general solution obtained by mixing these two solutions is filled into a spray bottle and edible paper is sprayed on both sides, covering its entire surface. Allow the solution to be saturated as much as possible. Excess liquid is removed from the paper. The sheets of paper are left to dry on the grates, then they are placed in sealed boxes and insisted for 3 days at a temperature not exceeding 18˚С, until the solution is evenly distributed over the paper.

The resulting paper, impregnated with said solution, is cut into strips for use in the oral cavity. The size of the strips is from 1x2 to 2x3 cm2. It is possible to divide into larger strips, however, as will be shown below, this can complicate the dosage of the administered nicotine. At the same time, in some embodiments of the invention, taking into account the needs of the smoker for nicotine, the principal possibility of dividing into larger strips is quite acceptable.

Each strip contains from 5 to 160 mg of nicotine, depending on the purpose of its use: products with 5 to 30 mg of nicotine are used for smoking cessation, products with nicotine content above 30 to 160 mg are used for the consumption of nicotine as a substitute (alternative) to smoking.

Do not use any preservatives in the solution.

Prepared edible paper is cut into product units in the form of wafers or biscuits, or strips, measuring 1x2-2x3 cm2 (or more). Each unit of the product is packed separately, for example, in a C / PP package, using a thermoforming bowl, with the date of packaging and expiration date stamped. The nicotine-containing paper processed in this way can be stored while maintaining the stability of the pharmaceutical composition with nicotine / analog and without losing the active properties of the active ingredient for at least 10 months.

Individual units of products for sale can be specially packaged in a common package in the amount of several pieces - 5, 10, 15, 20, 30, 40, 50 and 60 pieces each, based on the use of waffles or cookies or strips from 1 to 10 units.

The thickness of edible paper is usually 0.1 to 6 mm. Its thickness and, accordingly, the release and absorption profile of the active ingredient can be modified at the request of the manufacturer.

The edible paper can be cut to form a desired wafer or cookie or strip shape, for example, it can be round, elliptical, square, rectangular, irregular, and the like. The surface area of one unit of the product is about 2x3 cm ² (but it can be larger), which is due to the creation of convenience for the user and in order to avoid the use of a large single dose of nicotine or its analogs when placing a unit of product in the form of a wafer or cookie, or a strip in the oral cavity ...

To ensure medical control, the product can also be produced in the form of packaging units, in the form of undivided sheet or tape material, which can be divided into dose units for the purpose of application. This facilitates mass application and gives medical administrators the ability to subdivide the same material into different dose units depending on the dose requirement of a particular patient.

An example of the use of the product.

When using edible paper, formed in the form of a wafer or thin cookie, for each product unit, after uniform spraying, there is a certain amount of a composition containing nicotine, its pharmaceutically acceptable salt, or its analogue in the specified amount, in wt%.

In order to avoid toxic effects from the use of high doses of active ingredients contained in the solution and, accordingly, on edible paper, the daily dosage of used wafers or cookies or paper should not exceed 10 pieces (with a dose unit size of 2x3 cm2 or so).

The resulting product practically melts in the oral cavity, and therefore, the active ingredient of the composition is released and quickly - within 1-3 minutes is absorbed from the oral cavity directly into the blood.

Moreover, its concentration is provided by the amount of active ingredient that is dissolved and applied to edible paper. Accordingly, if the patient lacks the use of one unit of the product, he directly at his own request can continue to use it (another waffle or another cookie, another strip, etc.), or for a while refrain from using it with so that after a break and in the case when there is a desire to smoke, again use one or more units of the product (no more than 10 per day at a dose unit size of 2x3 cm2 or so).

The short residence time of the product in the oral cavity (during the process of chewing and dissolving) allows the entire amount of the active ingredient that is in the product in dissolved form to be absorbed quite quickly. At the same time, the client consumes such an amount (product units) of waffles or cookies, or strips, which subjectively can satisfy his current need for nicotine.

The wafer or cookie edible paper substrate and the fast dissolving active ingredient provide effective action when used in combination such that the product dissolves in the mouth, facilitating release of the active agent within about 1-3 minutes after the product is placed in the mouth. a cavity, which is useful for the delivery of many active agents in cases where an almost immediate onset of pharmacological action is desired.

Examples demonstrating the need to comply with the quantitative ranges of the ingredients proposed in this product, in order to achieve aspects of the technical result of the invention.

It has been experimentally established that when the amount of solution per unit area is reduced, edible paper cannot be completely saturated with the solution with the active component. In the case of an increase in the amount of solution sprayed on paper - more than 10.7 mg / cm2 - there is a danger of toxic effects of nicotine and its analogs when using even a small number of dose units (product units).

So, experimentally on 39 laboratory outbred rabbits, age 5 months with a formed dependence on nicotine by systematic use with drinking of its subtoxic doses during the previous 2 months, where the animals were randomly distributed by sex into 3 groups of 13 individuals each, it was found following.

1. In the case of applying the solution to paper in an amount of 0.01-1.75 mg / cm2 when the animals of the first group eat from 1 to 10 waffles or cookies, cut, randomly formed into flat pieces with a thickness of 1 to 5 mm and dimensions of 2x3 cm2, 1x1 cm2, 3x3 cm2 for 1 hour - the pharmacokinetic profile of nicotine and its analogs was unsatisfactory - the absorbed amounts of the active ingredient did not reach levels that could cover the need for nicotine or eliminate the existing addiction.

Accordingly, toxic effects were also absent.

2. In the case of applying the solution to paper in the amount of 1.8-10.7 mg / cm2 when part of the animals of the second group in the amount of 7 individuals from 1 to 5 wafers or cookies, cut, randomly formed into flat pieces with a thickness of 1 to 5 mm and dimensions 2x3 cm2, 1x1 cm2, 3x3 cm2, within 1 hour - the pharmacokinetic profile of nicotine and its analogs was satisfactory only in those animals that consumed 1-5 units of the product measuring 2x3 cm2, as suggested in the claimed product. The dependence on nicotine in animals was eliminated within 2-3 weeks (for humans, it was assumed that the guaranteed dependence could be eliminated within 1 month of consuming the product).

In the remaining 6 individuals of the second group, who consumed up to 5 waffles or biscuits of about 1 x 1 cm2 in 1 hour, the absorbed amounts of the active ingredient did not reach levels that could cover their nicotine requirement.

When these six other rabbits of the second group consumed from 6 to 10 units of the product measuring 3X3 cm2 in 1 hour, toxic effects of nicotine or, accordingly, its analogs, on the part of the respiratory and cardiovascular systems arose.

3. In the case of applying the solution to paper in an amount of 10.8-11.6 mg / cm2 when the animals of the third group eat from 1 to 5 wafers or cookies, cut, randomly formed into flat pieces with a thickness of 1 to 5 mm and dimensions of 2x3 cm2, 1x1 cm2, 3x3 cm2, within 1 hour - the pharmacokinetic profile of nicotine and its analogs showed a rapid achievement of the peak concentration in the blood with the rapid development of toxic effects from the respiratory and cardiovascular systems of animals.

Experiments on rabbits were carried out using various doses of nicotine in the range of 5 to 160 mg, the results were statistically comparable. At the same time, it was found that lower doses (up to 30 mg) led to the gradual withdrawal of nicotine. Higher doses (30 to 160 mg) - contributed to current addiction, however, without any of the side effects associated with inhaling fumes.

Thus, it was concluded that it is the claimed amounts and concentrations, as well as the sizes of the product units for consumption, that can provide a safe and effective profile of the release and pharmacokinetics of nicotine and its analogs in the blood of a living mammal.

It should be noted that the rabbits used in the experiment are much smaller in size than the average person, however, the absorption of the active ingredient of the product directly from the oral cavity into the blood suggests that the comparison of the pharmacokinetics of the drug in this case will be quite adequate. Accordingly, this provides a certain margin for the subtoxic dose range of the active ingredients, since those doses that were toxic to a small animal must be significantly higher for humans in order to be truly toxic and cause adverse effects. Accordingly, the consumer can quite widely choose the dose of the active substance (nicotine) required by his body by independently regulating the number of consumed product units, focusing on the content of the active ingredient in them.

In addition, the rate at which the paper dissolves to release the active agent is a function of several factors, which include the oral mucosal microenvironment, paper thickness and composition, temperature, size and chemical nature of the active agent and additives. In the context of the present invention, a wafer or cookie unit typically dissolves within 1-3 minutes after being placed in the mouth.

An example demonstrating the stability of the preservation of the properties of the composition and the product under the storage conditions in vacuum food packaging from C / PP for at least 10 months (at room temperature, relative humidity not more than 75%).

By repeating the experiment with rabbits after 10.5 months of storage of the product prepared according to the method described above to obtain the claimed product, in individual vacuum packages C / PP for a unit of the product, it was found that the effects of the product on reducing nicotine addiction in animals or nicotine replacement therapy are preserved in the same form and volume. Thus, the stability of the composition of such a composition and under such storage conditions is preserved.

It should be noted that the practice of the present invention employs, unless otherwise indicated, conventional techniques of chemistry, formulation, and drug delivery systems that are known to those skilled in the art. Such techniques are described in sufficient detail in the literature.

It should also be understood that while the present invention has been described in relation to preferred specific embodiments, the above description, as well as the examples presented, are intended for illustration only and do not limit the scope of the present invention in any way. Other aspects, advantages and modifications are known to those skilled in the art to which the present invention pertains.

Claims (4)

1. Edible biodegradable product for oral consumption of nicotine, which is a polymer substrate coated with a solution of nicotine, its pharmaceutically acceptable salt or its analogue, characterized in that the product is an edible paper in the form of a strip soaked in a solution of nicotine, its pharmaceutically acceptable salt or its analogue - an agonist from the group: cytisine, anabasine, lobelin, with the following ratio of solution components, wt%: nicotine, its pharmaceutically acceptable salt or its analogue, chemically pure 0.1-20 flavoring 1.0-8.0 purified water 5.0-30.0 sweetener 0.1-1.0 acidity regulator 0.1-7.0 propylene glycol up to 100 and where the amount of solution applied to the paper is 1.8-10.7 mg / cm ² . 2. The edible biodegradable product for oral consumption of nicotine according to claim 1, wherein the edible paper is wafer, sugar or rice paper.